Pending Policies - Surgery


Pancreas and Related Organ Tissue Transplantation

Number:SUR703.013

Effective Date:12-01-2017

Coverage:

*CAREFULLY CHECK STATE REGULATIONS AND/OR THE MEMBER CONTRACT*

Pancreas Transplantation

The following individual pancreatic transplantation procedures may be considered medically necessary when following specific indications or criteria are met:

A combined (or simultaneous) pancreas-kidney transplant (CPK) for insulin dependent diabetic mellitus (IDDM) patients with uremia;

A pancreas transplant, after a prior kidney transplant (PAK) for patients with insulin dependent diabetes mellitus (IDDM); or

A pancreas transplant alone (PTA) for patients with severely disabling and potentially life-threatening complications due to hypoglycemia unawareness and labile diabetes that persists in spite of optimal medical management (refer to NOTE 1 below);

Pancreatic retransplantation (PR), after a failed primary pancreas transplant and continue to meet the criteria for a pancreas transplantation.

NOTE 1: Candidates for a pancreas transplant alone should meet ONE of the following severities of illness criteria:

Documentation of severe hypoglycemia unawareness as evidenced by chart notes or emergency room visits; or

Documentation of potentially life threatening labile diabetes mellitus as evidenced by chart notes or hospitalization for diabetic ketoacidosis.

NOTE 2: For kidney transplantation, see policy SUR703.007, Kidney Transplants.

NOTE 3: For small bowel/liver and multivisceral transplantation, which can include pancreas transplantation, see policy SUR703.009, Small Bowel/Liver and Multivisceral Transplant.

The following individual pancreatic transplantation procedures are considered experimental, investigational and unproven, including but not limited to:

Pancreatic retransplantation (PR) after two or more failed pancreas transplants;

Transplantation of a segment of a pancreas from a living related donor (i.e., head or tail sections).

Islet Cell Transplantation

Autologous pancreas islet cell transplantation may be considered medically necessary as an adjunct to a total or near total pancreatectomy in patients with chronic pancreatitis.

Allogeneic pancreas islet cell transplantation is considered experimental, investigational and unproven for patients with type 1 diabetes mellitus.

Islet cell transplantation is considered experimental, investigational and/or unproven in all other situations.

Description:

Pancreas Transplantation

Transplantation of a normal pancreas is a treatment method for patients with insulin-dependent diabetes mellitus (IDDM). Pancreas transplantation can restore glucose control and is intended to prevent, halt, or reverse the secondary complications from diabetes mellitus.

Background

Achievement of insulin independence with resultant decreased morbidity and increased quality of life is the primary health outcome of pancreas transplantation. While pancreas transplantation is generally not considered a life-saving treatment, in a small subset of patients who experience life-threatening complications from diabetes mellitus, pancreas transplantation could be considered life-saving. Pancreas transplant alone (PTA) has also been investigated in patients following total pancreatectomy for chronic pancreatitis. In addition to the immune rejection issues common to all allograft transplants, autoimmune destruction of beta cells has been observed in the transplanted pancreas, presumably from the same mechanism responsible for type 1 diabetes mellitus. (1)

Pancreas transplantation occurs in several different scenarios such as a:

1. Diabetic patient with renal failure who may receive a cadaveric combined/simultaneous pancreas/kidney (CPK/SPK) transplant;

2. Diabetic patient who may receive a cadaveric or living-related pancreas transplant after a kidney transplantation (pancreas after kidney [PAK]); or

3. Non-uremic diabetic patient with specific severely disabling and potentially life-threatening diabetic problems who may receive a PTA.

The total number of adult pancreas transplants (pancreas and pancreas/kidney) in the U.S. peaked at 1484 in 2004; the number has since declined. (2) In 2013, 214 PTAs and 651 SPKs were performed in the U.S.

According to International Registry data, the proportion of pancreas transplant recipients worldwide who have type 2 diabetes mellitus has increased over time, from 2% in 1995 to 7% in 2010. (3) In 2010, approximately 8% of SPK, 5% of PAK, and 1% of PTA were performed in patients with type 2 diabetes mellitus.

The approach to retransplantation varies according to the cause of failure. Surgical/technical

complications such as venous thrombosis are the leading cause of pancreatic graft loss among diabetic patients. Graft loss from chronic rejection may result in sensitization, increasing both the difficulty of finding a cross-matched donor and the risk of rejection of a subsequent transplant. Each center has its own guidelines based on experience; some transplant centers may wait to allow reconstitution of the immune system before initiating retransplant with an augmented immunosuppression protocol.

Potential contraindications subject to the judgment of the transplant center:

General

1. Known current malignancy, including metastatic cancer,

2. Recent malignancy with high risk of recurrence,

3. Untreated systemic infection making immunosuppression unsafe, including chronic infection,

4. Other irreversible end-stage disease not attributed to kidney disease,

5. History of cancer with a moderate risk of recurrence,

6. Systemic disease that could be exacerbated by immunosuppression,

7. Psychosocial conditions or chemical dependency affecting ability to adhere to therapy.

Pancreas Specific

In addition, the vast majority of pancreas transplant patients will have type 1 diabetes mellitus. Those transplant candidates with type 2 diabetes mellitus, in addition to being insulin-dependent, should also not be obese (body mass index [BMI] should be 32 or less). According to International Registry data, in 2010, 7% of pancreas transplant recipients had type 2 diabetes mellitus. (3)

Islet Cell Transplantation

Transplantation of pancreatic islet cells is defined as removing isolated islet cells from a donor pancreas to the recipient. In autologous transplantation, the donor and recipient is the same individual. For allogeneic transplantation, the donor and the recipient are not the same individual, but matched as closely as possible to promote islet cell engraftment. Autologous islet transplantation, performed in conjunction with pancreatectomy, is proposed to reduce the likelihood of IDDM. Moreover, allogeneic islet cell transplantation is being investigated as a treatment or cure for patients with type 1 diabetes mellitus.

Background

In autologous islet transplantation, during the pancreatectomy procedure, islet cells are isolated from the resected pancreas using enzymes, and a suspension of the cells is injected into the portal vein of the patient’s liver. Once implanted, the beta cells in these islets begin to make and release insulin. In the case of allogeneic islet cell transplantation, cells are harvested from the deceased donor’s pancreas, processed, and injected into the recipient’s portal vein. Up to 3 donor pancreas transplants may be required to achieve insulin independence. Allogeneic transplantation may be performed in the radiology department.

Chronic Pancreatitis

Primary risk factors for chronic pancreatitis include toxic-metabolic, idiopathic, genetic, autoimmune, recurrent and severe acute pancreatitis, or obstructive (TIGAR-O classification system). Patients with chronic pancreatitis may experience intractable pain that can only be relieved with a total or near total pancreatectomy. However, the pain relief must be balanced against the certainty that the patient will be rendered an insulin-dependent diabetic. Autologous islet transplantation has been investigated as a technique to prevent this serious morbidity.

Type 1 Diabetes Mellitus

Allogeneic islet transplantation has been used for type 1 diabetes mellitus to restore normoglycemia and, ultimately, to reduce or eliminate the long-term complications of diabetes mellitus such as retinopathy, neuropathy, nephropathy, and cardiovascular disease. Islet transplantation potentially offers an alternative to whole-organ pancreas transplantation. However, a limitation of islet transplantation is that 2 or more donor organs are usually required for successful transplantation, although experimentation with single-donor transplantation is occurring. A pancreas that is rejected for whole-organ transplant is typically used for islet transplantation. Therefore, islet transplantation has generally been reserved for patients with frequent and severe metabolic complications who have consistently failed to achieve control with insulin-based management.

In 2000, a modified immunosuppression regimen increased the success of allogeneic islet transplantation. This regimen was developed in Edmonton, AB, Canada, and is known as the “Edmonton protocol.”

Regulatory Status

Islet cells are subject to regulation by the U.S. Food and Drug Administration (FDA), which classifies allogeneic islet cell transplantation as somatic cell therapy, requiring premarket approval. Islet cells also meet the definition of a drug under the Federal Food, Drug, and Cosmetic Act. Clinical studies to determine safety and effectiveness outcomes of allogeneic islet transplantation must be conducted under FDA investigational new drug (IND) regulation. At least 35 IND applications have been submitted to FDA, no center has submitted a biologics license application.

Rationale:

The pancreatic transplantation portion of this policy was created in 1990 and updated regularly with searches of the MedLine database. Islet cell transplantation was added to this policy in 2002. The most recent search was performed for the period up through September 15, 2016. Much of the published literature consists of case series reported by single centers and registry data. The extant randomized controlled trials (RCTs) compare immunosuppression regimens and surgical techniques and therefore do not address the comparison of pancreas transplantation to insulin therapy, combined (or simultaneous) pancreas-kidney (CPK or SPK) transplant to insulin therapy and hemodialysis, or islet cell transplantation to insulin therapy.

Pancreas Transplantation

This policy is based in part on a 1998 Blue Cross Blue Shield Association (BCBSA) Technology Evaluation Center (TEC) Assessment, which focused on pancreas graft survival and health outcomes associated with both pancreas transplant alone (PTA) and pancreas after kidney transplant (PAK). (4) A 2001 BCBSA TEC Assessment focused on the issue of pancreas retransplant. (5)

The assessments and subsequent evidence offer the following observations and conclusions.

Pancreas After Kidney (PAK) Transplant

PAK transplantation allows the uremic patient the benefits of a living-related kidney graft, if available and the benefits of a subsequent pancreas transplant that is likely to result in improved quality of life compared with a kidney transplant alone. Uremic patients for whom a cadaveric kidney graft is available, but a pancreas graft is not simultaneously available benefit similarly from a later pancreas transplant. Based on International Pancreas Registry data reported in 2011, the patient survival rate after PAK was 83% at 5 years posttransplant. (3)

In 2009, Fridell et al. reported a retrospective review (N=203) of a single center’s experience with PAK and simultaneous pancreas-kidney (SPK) transplant since 2003, when current induction/tacrolimus immunosuppressive strategies became standard. (6) Of the cases studied, 61 (30%) were PAK and 142 (70%) were SPK. One-year patient survival rates were 98% and 95% (PAK and SPK, respectively; p=0.44). Pancreas graft survival rates at 1 year were 95% and 90%, respectively (p=0.28). The authors concluded that in the modern immunosuppressive era, PAK should be considered as an acceptable alternative to SPK in candidates with an available living kidney donor.

In 2012, Bazarbachi et al. reviewed a single center’s experience with PAK and SPK. (7) Between 2002 and 2010, 172 pancreas transplants were performed in diabetic patients; 123 SPK and 49 PAK. The median length of time between kidney and pancreas transplantation in the PAK group was 4.8 years. Graft and patient survival rates were similar in the 2 groups. Death-censored pancreas graft survival rates for SPK and PAK were 94% and 90% at 1 year, 92% and 90% at 3 years, and 85% and 85% at 5 years (all, p=0.93, respectively). Patient survival rates (calculated beginning at the time of pancreas transplantation) in the SPK versus PAK groups were, respectively, 98% and 100% after 1 year, 96% and 100% after 3 years, and 94% and 100% after 5 years (all p=0.09).

Kleinclauss et al. (2009) retrospectively examined data from diabetic kidney transplant recipients (N=307) from a single center and compared renal graft survival rates in those who subsequently received a pancreatic transplant with those who did not. (8) The comparative group was analyzed separately depending on whether patients were medically eligible for pancreas transplant, but chose not to proceed for financial or personal reasons, or were ineligible for medical reasons. The ineligible (n=57) group differed significantly at baseline from both the PAK group (n=175) and the eligible group (n=75) with respect to age, type of diabetes mellitus, and dialysis experience; kidney graft survival rates in this group were lower compared with both of the other groups, with 1-, 5-, and 10-year rates of 75%, 54%, and 22%, respectively (p<0.001) and 1-, 5-, and 10-year kidney graft survival rates in PAK patients with those in the eligible group: 98%, 82%, and 67% versus 100%, 84%, and 62%, respectively, and concluded that the subsequent transplant of a pancreas after a living donor kidney transplant does not adversely affect patient or kidney graft survival rates.

Simultaneous Pancreas/Kidney (SPK) Transplant

According to International Registry data through 2005, recent 5-year graft survival rates for SPK transplants were 72% for the pancreas and 80% for the kidney. (9) Ten-year graft survival rates reached almost 60% for SPK transplants. The U.S.-based Organ Procurement and Transplant Network (OPTN) reported a 5-year survival rate of 85.5% (95% confidence interval [CI], 84.3% to 86.7%) for SPK procedures performed between 1997 and 2000. (2)

Pancreas transplant has been found to improve mortality in patients with type 1 diabetes mellitus. In 2014, van Dellen et al. in the U.K. reported a retrospective analysis of data on 148 SPK patients and a wait-list control group of 120 patients. (10) All patients had uncomplicated type 1 (insulin dependent) diabetes mellitus. (The study also included 33 patients who had PAK and 11 PTA patients.) Overall mortality (mortality at any time point) was 30% (30/120 patients) on the waiting list and 9% (20/193 patients) in transplanted patients; the difference between groups was statistically significant (Fisher exact test; p<0.001). One-year mortality was 13% (n=16) on the waiting list and 4% (n=8) in the transplant group (Fisher exact test; p<0.001).

There are some data on outcomes in patients with type 2 compared with type 1 diabetes mellitus. In 2011, Sampaio et al. published an analysis of data from the United Network for Organ Sharing (UNOS) database. (11) The investigators compared outcomes in 6141 patients with type 1 diabetes mellitus and 582 patients with type 2 diabetes mellitus who underwent SPK between 2000 and 2007. In adjusted analyses, outcomes were similar between the 2 groups. After adjusting for other factors such as body weight; dialysis time; and cardiovascular comorbidities, type 2 diabetes mellitus was not associated with an increased risk of pancreas or kidney graft failure or mortality compared with type 1 diabetes mellitus.

Pancreas Transplant Alone (PTA)

PTA graft survival has improved in recent years. According to International Registry data 1-year graft function increased from 51.5% in 1987-1993 to 77.8% in 2006-2010 (p<0.001). (3) One-year immunologic graft loss remained higher (6%) after PTA than PAK (3.7%) or SPK (1.8%). In carefully selected patients with insulin dependent diabetes mellitus (IDDM) and severely disabling and potentially life-threatening complications due to hypoglycemia unawareness and persistent labile diabetes mellitus despite optimal medical management, benefits of PTA were judged to outweigh the risk of performing pancreas transplantation with subsequent immunosuppression.

Most patients undergoing PTA are those with either hypoglycemic unawareness or labile diabetes mellitus. However, other exceptional circumstances may exist where non-uremic IDDM patients have significant morbidity risks due to secondary complications of diabetes mellitus (e.g., peripheral neuropathy) that exceed those of the transplant surgery and subsequent chronic immunosuppression. Because virtually no published evidence regarding outcomes of medical management in this very small group of exceptional diabetic patients exists, it is not possible to generalize about which circumstances represent appropriate indications for PTA. Case-by-case consideration of each patient’s clinical situation may be the best option for determining the balance of risks and benefits.

Noting that nephrotoxic immunosuppression may exacerbate diabetic renal injury after PTA, Scalea et al. (2008) reported a single institutional review of 123 patients who received 131 PTA for development of renal failure. (12) Mean graft survival was 3.3 years (range, 0-11.3), and 21 patients were lost to follow-up. At mean follow-up of 3.7 years, mean estimated glomerular filtration rate was 88.9 mL/min/1.73 m2 pretransplantation versus 55.6 mL/min/1.73 m2 posttransplantation. All but 16 patients had a decrease in estimated glomerular filtration rate. Thirteen developed end-stage renal disease, which required kidney transplantation at a mean of 4.4 years. The authors suggested that patients should be made aware of the risk and only the most appropriate patients offered PTA. Future updates of this policy will continue to follow this clinical topic.

Pancreas Retransplantation

OPTN reported data on transplants performed between 1997 and 2004. (2) Patient survival rates after repeat transplants were similar to survival rates after primary transplants. For example, 1-year survival was 94% (95% CI [confidence interval], 93% to 95%) after a primary pancreas transplant and 96% (95% CI, 93% to 99%) after a repeat pancreas transplant. The numbers of patients transplanted were not reported, but OPTN data stated that 1217 patients were alive 1 year after primary transplant and 256 after repeat transplants. Three-year patient survival was 90% (95% CI, 88% to 91%) after primary transplants and 90% (95% CI, 86% to 94%) after repeat transplants. One-year graft survival was 78% (95% CI, 76% to 81%) after primary pancreas transplant and 70% (95% CI, 65% to 76%) after repeat transplant.

Data are similar for patients receiving SPK transplants, but follow-up data are only available on a small number of patients who had repeat kidney/pancreas transplants so estimates of survival rates in this group are imprecise. Three-year patient survival was 90% (95% CI, 89% to 91%) after primary combined transplant and 80% (95% CI, 64% to 96%) after a repeat combined transplant. The number of patients who were living 3 years after transplant was 2907 after a primary combined procedure and 26 after a repeat combined procedure.

Several centers have published outcomes after pancreas retransplantation. In 2014, Seal et al. reported on 96 consecutive PTA patients treated at a single center in Canada; 78 were initial transplants, and 18 were retransplants. (13) Pancreas graft survival was similar for primary transplants and retransplants at 1 year (88% versus 100%, p=0.88) and 3 years (85% in both groups, p=0.99). Patient survival rates were also similar in the 2 groups at 1 year (96% and 100%, p=0.95) and 3 years (93% and 100%, p=0.93). In 2013, Buron et al. reported on their experience with pancreas retransplantation in France and Geneva. (14) Between 1976 and 2008, 568 pancreas transplants were performed at 2 centers, including 37 repeat transplants. Patient survival after a repeat pancreas transplant was 100% after 1 year and 89% after 5 years. Graft survival was 64% at 1 year and 46% at 5 years. Among the 17 patients who underwent a second transplant in a later time period, i.e., between 1995 and 2007, graft survival was 71% at 1 year and 59% at 5 years. In this more recently transplanted group, graft survival rates were similar to primary pancreas transplants, which was 79% at 1 year and 69% at 5 years.

Pancreas Transplant in HIV-Positive Transplant Recipients

Current OPTN policy on Identification of Transmissible Diseases states: “OPTN permits HIV test-positive individuals as organ candidates if permitted by the transplant hospital.” (15)

In 2006, the British HIV Association and the British Transplantation Society Standards Committee published guidelines for kidney transplantation in patients with HIV disease. (16) As described earlier, these criteria may be extrapolated to other organs. The guidelines recommend that any patient with end-stage organ disease and life expectancy of at least 5 years is considered appropriate for transplantation under the following conditions:

CD4 count greater than 200 cells/microliter for at least 6 months;

Undetectable HIV viremia (<50 HIV-1 RNA copies/mL) for at least 6 months;

Demonstrable adherence and a stable HAART [highly active antiretroviral therapy] regimen for at least 6 months;

Absence of AIDS-defining illness following successful immune reconstitution after HAART.

Age

Recipient age older than 50 years has in the past been considered a relative contraindication for pancreas transplant. In the past 5 to 10 years, several analyses of outcomes by patient age group have been published and there is now general agreement among experts that age should not be a contraindication; however, age-related comorbidities are important to consider when selecting patients for transplantation.

In the largest study of pancreas outcomes by recipient age, Siskind et al. (2014) used data from the UNOS database. (17) Investigators included all adult patients who received SPK or PTA between 1996 and 2012 (N=20,854). This included 3160 patients between the ages of 50 and 59 years, and 280 patients, 60 years or older. Overall, Kaplan-Meier survival analysis found statistically significant differences in patient survival (p<0.001) and graft survival (p<0.001) among age categories. Graft survival was lowest in the 18- to-29 age group at 1, 5, and 10 years, which the authors noted might be due to early immunologic graft rejection as a result of more robust immune responses. However, 10- and 15-year graft survival was lowest in the 60 and older age group. Patient survival rates decreased with increasing age, and the differential between survival in older and younger ages increased with longer follow-up intervals. Lower survival rates in patients 50 and older could be due in part to comorbidities at the time of transplantation. Also, as patients age, they are more likely to die from other causes. Still, patient survival at 5 and 10 years was relatively high, as shown in Table 1.

Table 1. Patient Survival by Age Group (17)

Age 18-29, %

Age 30-39, %

Age 40-49, %

Age 50-59, %

Age 60+, %

1-year

95.4

96.0

94.9

93.3

91.0

5-years

86.3

87.8

85.7

81.6

71.4

10-years

73.5

76.8

71.8

61.5

42.5

Among previous studies on pancreas outcomes in older patients, Shah et al. (2013) reviewed data on 405 patients who underwent PTA between 2003 and 2011. (18) One-year patient survival was 100% for patients younger than age 30 years, 98% for patients age 30 to 39 years, 94% for patients 40 to 49 years, 95% for patients 50 to 59 years, and 93% for patients age 60 or older. There was not a statistically significant difference in patient survival by age (p=0.38). Findings were similar for 1-year graft survival; there was not a statistically significant difference in outcomes by age of transplant recipients (p=0.10).

A 2011 study by Afaneh et al. reviewed data on 17 individuals at least 50 years old and 119 individuals younger than 50 years who had a pancreas transplant at a single institution in the U.S. (19) The 2 groups had similar rates of surgical complications, acute rejection, and nonsurgical infections. Overall patient survival was similar. Three- and 5-year survival rates were 93% and 90%, respectively, in the younger group, and 92% and 82%, respectively, in the older group. Schenker et al. (2011) in Germany compared outcomes in 69 individuals at least 50 years old and 329 individuals younger than 50 years who had received pancreas transplants. (20) Mean duration of follow-up was 7.7 years. One-, 5-, and 10-year patient and graft survival rates were similar in the 2 groups. For example, 5-year patient survival was 89% in both groups. Five-year pancreas graft survival was 76% in the older group and 72% in the younger group. The authors of both studies, as well as the authors of a commentary accompanying the Schenker article, (21) agreed that individuals age 50 years and older are suitable candidates for pancreas transplantation.

Ongoing and Unpublished Clinical Trials

An online search of site ClinicalTrials.gov through August 2016 identified no clinical trials that addressed pancreas transplantation.

Practice Guidelines and Position Statements

Organ Procurement and Transplantation Network (OPTN)

In 2014, the Board of Directors of the OPTN issued an updated comprehensive list of transplant related policies. (22)

Each candidate registered on the pancreas waiting list must meet one of the following requirements:

Be diagnosed with diabetes,

Have pancreatic exocrine insufficiency,

Require the procurement or transplantation of a pancreas as part of a multiple organ transplant for technical reasons.

The policy also delineated pancreas, kidney-pancreas, and islet allocation, classifications, and rankings.

Summary of Evidence for Pancreas Transplantation

The literature, consisting primarily of case series and registry data, demonstrate graft survival rates comparable with other solid organ transplants, as well as attendant risks associated with the immunosuppressive therapy necessary to prevent allograft rejection. No RCTs have compared any form of pancreas transplant with insulin therapy. Pancreas transplant may be considered medically necessary in patients who are undergoing, or have undergone, kidney transplantation for renal failure. It may also be considered medically necessary as a stand-alone treatment in patients with hypoglycemia unawareness and labile diabetes mellitus, despite optimal medical therapy and in whom severe complications have developed.

Islet Cell Transplantation

Following is a summary of the key literature to date on islet cell transplantation.

Chronic Pancreatitis

There are several systematic reviews of the literature on chronic pancreatitis patients. In 2015, Wu et al. published a systematic review of studies on islet transplantation after total pancreatectomy for chronic pancreatitis. (24) Studies could use any type of design but needed to include at least 5 patients or have a median follow-up of at least 6 months. Twelve studies with a total of 677 patients met the review’s inclusion criteria. The mean age of the patients was 38 years and mean duration of pancreatitis was 6.6 years. A meta-analysis of the insulin independence rate at 1 year (5 studies, 362 patients) was 28.4% (95% confidence interval [CI], 15.7% to 46.0%). At 2 years, the pooled insulin independence rate (3 studies, 297 patients) was 19.7% (95% CI, 5.1% to 52.6%). The pooled 30-day mortality rate (11 studies) was 2.1% (95% CI, 1.2% to 3.8%). Long-term mortality data were not pooled.

In 2011, Dong et al. published a systematic review that included meta-analyses. (25) Studies were included regardless of design or sample size. After reviewing 84 studies, 15 observational studies were found to meet eligibility criteria. There were 11 studies of total pancreatectomy, 2 studies of partial pancreatectomy, and 2 studies that included both types of surgery. Sample sizes in individual studies ranged from 3 to 173 patients. Thirteen studies included patients with chronic pancreatitis, and 2 included patients with benign pancreatic tumors. The pooled 30-day mortality was 5% (95% CI, 2% to 10%), and the cumulative mortality at 1 year (reported by 10 studies) was 4.9% (95% CI, 2.6% to 7.3%) In a pooled analysis of data from 14 studies, the rate of insulin dependence at last follow-up was 4.6 per 100 person years (95% CI, 1.53 to 7.62). The pooled rate of insulin independence at 1 year (5 studies) was 27% (95% CI, 21% to 33%) and at 2 years (3 studies) was 21% (95% CI, 16% to 27%).

Representative studies are described next.

In 2014, Wilson et al. reported on 166 patients age 14 or older with chronic pancreatitis who underwent total pancreatectomy and islet transplantation at a single center. (26) Actuarial survival at 5 years was 94.6%. Five year or longer data were available for 112 patients (67%). At 1 year, 38% of patients were insulin dependent and that declined to 27% at the 5-year follow-up. Daily insulin requirement, however, remained stable over the 5 years. Fifty-five percent of patients were narcotic independent at 1 year, and this increased to 73% at 5 years.

A 2014 study by Chinnakotla et al. included 484 patients with chronic pancreatitis. (27) Patients underwent total pancreatectomy and immediate islet auto transplantation. Actuarial 10-year survival was 84%. Patient survival at 5 years was 90.3% in the 80 patients with hereditary/genetic pancreatitis and 89.7% in the 404 patients with nonhereditary pancreatitis; the difference between groups was not statistically significant. Pancreatitis pain decreased significantly after the procedures, and there was no statistically significant difference in the rate of pancreatitis pain between the groups with and without genetic/hereditary disease.

In 2012, Sutherland et al. reported on 409 patients with chronic pancreatitis who underwent total pancreatectomy and islet transplantation at a single center. (28) Fifty-three of the 409 patients (13%) were children between the ages of 5 and 18 years. Actuarial survival postsurgery was 96% in adults and 98% in children after 1 year and 89% in adults and 98% in children after 5 years. A total of 15.9% of patients experienced surgical complications requiring reoperation during the initial admission. The most common reason for reoperation was bleeding, occurring in 9.5% of patients. At 3 years, 30% of patients were insulin independent (25% of adults and 55% of children). A survey of quality-of-life outcomes was initiated in October 2008; responses were available for 102 patients. At baseline, all 102 patients reported using narcotics for pain. At 12 months, the proportion of patients on narcotics decreased to 56% (n=32), and at 24 months, 41% of respondents (n=21) reported using narcotics.

Type 1 Diabetes Mellitus

According to U.S. Food and Drug Administration (FDA) industry guidance on evaluating allogeneic pancreatic islet cell products, published in 2009, single-arm trials with historical controls may be acceptable alternatives to RCTs for evaluating the safety and efficacy of islet cell products in patients with metabolically unstable type 1 diabetes. (29) Attainment of normal range HbA level (i.e., ≤6.5%) and elimination of hypoglycemia are acceptable primary end points. To assess durability of the islet cell procedure, primary end points should be measured at least 12 months after the final infusion. Other key clinical outcomes include insulin independence, measures of glucose metabolic control such as fasting plasma glucose level and loss of hypoglycemia unawareness.

In April 2004, in its capacity as an Evidence-based Practice Center for the Agency for Healthcare Research and Quality (AHRQ), BCBSA TEC published a systematic review of evidence on islet cell transplantation in type 1 diabetes. (30) The report found that published data on clinical outcomes of islet-alone transplantation were limited by small sample sizes (i.e., ≤35 enrolled patients), few transplant centers, short duration of follow- up, lack of standardized methods of reporting clinical outcomes. In addition, rare, serious adverse events have occurred in patients given islet transplants, although recent procedure modifications reportedly minimize risks of these adverse events. No procedure-related deaths, cytomegalovirus infection, or post-transplantation lymphoproliferative disease have been reported for islet-alone transplantation.

The 2008 report from the Collaborative Islet Transplant Registry (CITR), which collects and monitors data on allogeneic islet transplantation in North America, Europe, and Australia, published a report with data on 325 adult recipients. (31) Three years after first infusion, 23% of islet-alone recipients were insulin independent (defined as insulin independent ≥ 2 weeks), 29% were insulin dependent with detectable C- peptide, 26% had lost function, and 22% had missing data. Seventy percent achieved insulin independence at least once, 71% of whom were still insulin independent 1 year later and 52% at 2 years. Factors that favored primary outcomes were higher number of islet infusions, greater number of total islet equivalents infused, lower pretransplant HbA1c levels, processing centers related to the transplant center, and larger islet size.

CITR published an updated report in 2012; the focus of the article was changes in outcomes over time. (32) The number of patients receiving islet transplants was 214 during 1999-2002, 255 between mid-2003 and 2006, and 208 from 2007 to 2010. A total of 575 of the 677 (85%) islet transplant recipients received islets only; the remainder underwent simultaneous kidney and islet transplants. In the 1999-2002 group, rates of insulin independence were 51% after 1 year, 36% after 2 years, and 27% after 3 years. Rates for the 2007-2010 group were 66%, 55% and 44%, respectively. The incidence of clinically reportable adverse events in the first year after infusion decreased from 50% to 53% in 1999-2006 to 38% in 2007- 2010. The rates of peritoneal hemorrhage or gallbladder infusion were 5.4% in 1999-2003 and 3.1% in 2007-2010. The authors did not report findings separately for the subset of patients who underwent islet- only transplants.

In 2011, Thompson et al. in Canada published findings from a prospective crossover study of intensive medical therapy (pretransplant) versus islet cell transplantation in patients with type 1 diabetes. (33) The article reported on 45 patients; at the time of data analysis, 32 had received islet cell transplants. Median follow-up was 47 months pretransplant and 66 months’ post-transplant. The overall mean HbA1c was 7.8% pretransplant and 6.7% posttransplant; this difference was statistically significant (p<0.001). In the 16 patients for whom sufficient data pre- and posttransplant were available on renal outcomes, the median decline in glomular filtration rate (in milliliters per minute per month) was -6.7 pretransplant and -1.3 posttransplant (p=0.01). Retinopathy was assessed using the International Scale, which categorizes nonproliferative diabetic retinopathy as mild, moderate, or severe. Retinopathy progressed in 10 of 82 (12%) eyes pretransplant versus 0 of 51 posttransplant (p<0.01). (The numbers of patients in the retinopathy analyses were not reported). The rate of change in nerve conduction velocity did not differ significantly between groups (exact numbers not reported). The authors noted that their finding of reduced microvascular complications after islet transplantation may be due, in part, to their choice of maintenance immunosuppression. The study used a combination of tacrolimus and mycophenolate mofetil (MMF).

Small case series continue to be published, and these tend to report some success and also adverse events. (34-36) For example, in 2013, O’Connell et al. reported on 17 patients with type 1 diabetes mellitus and severe hypoglycemia who underwent islet transplantation in Australia. (35) Fourteen patients (82%) attained the primary end point, which was an HbA1c less than 7% and no severe hypoglycemic events 2 months after the initial transplant. Nine (53%) patients attained insulin independence for a median of 26 months. Most adverse events related to immunosuppression. Seven of the 17 (41%) patients developed mild lymphopenia and 1 developed Clostridium difficile colitis; these all responded to treatment. Eight patients developed anemia shortly after transplant and 1 required a blood transfusion. Procedure-related complications included 1 partial portal vein thrombosis and 3 postoperative bleeds; 2 of the bleeds required transfusion.

Ongoing and Unpublished Clinical Trials

An online search of site ClinicalTrials.gov through August 2016 identified no clinical trials that addressed islet cell transplantation.

Practice Guidelines and Position Statements

National Institute for Clinical Excellence (NICE)

Guidance from the NICE, published in 2008, states that the evidence on allogeneic pancreatic islet cell transplantation for type 1 diabetes mellitus shows short-term efficacy with some evidence of long-term efficacy. (37) Evidence on safety shows that serious complications may occur, and the long-term immunosuppression required is also associated with risk of adverse events. A related NICE guidance document on autologous islet cell transplantation for improved glycemic control after pancreatectomy states that studies show some short-term efficacy, although most patients require insulin therapy in the long term. Complications mainly result from the major surgery involved in pancreatectomy rather than from the islet cell transplantation. (38)

Summary of Evidence for Islet Cell Transplantation

Although the published experience with autologous islet cell transplantation is limited, the procedure appears to significantly decrease the incidence of diabetes after total or near total pancreatectomy in patients with chronic pancreatitis. In addition, this procedure is not associated with serious complications itself and is performed in patients who are already undergoing a pancreatectomy procedure. Thus, this technology may be considered medically necessary as an adjunct to a total or near total pancreatectomy in patients with chronic pancreatitis.

The techniques for allogeneic islet cell transplants are evolving, and the impact on the net health outcome for patients with type 1 diabetes mellitus, not otherwise undergoing surgery, is still uncertain. Moreover, longer follow-up with larger numbers of patients is needed before conclusions can be drawn about the safety of allogeneic islet transplantation and its impact on diabetes mellitus and associated complications. Thus, this technology is considered experimental, investigational and/or unproven for patients with type 1 diabetes mellitus.

Contract:

Each benefit plan, summary plan description or contract defines which services are covered, which services are excluded, and which services are subject to dollar caps or other limitations, conditions or exclusions. Members and their providers have the responsibility for consulting the member's benefit plan, summary plan description or contract to determine if there are any exclusions or other benefit limitations applicable to this service or supply. If there is a discrepancy between a Medical Policy and a member's benefit plan, summary plan description or contract, the benefit plan, summary plan description or contract will govern.

Coding:

CODING:

Disclaimer for coding information on Medical Policies

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

The presence or absence of procedure, service, supply, device or diagnosis codes in a Medical Policy document has no relevance for determination of benefit coverage for members or reimbursement for providers. Only the written coverage position in a medical policy should be used for such determinations.

Benefit coverage determinations based on written Medical Policy coverage positions must include review of the member’s benefit contract or Summary Plan Description (SPD) for defined coverage vs. non-coverage, benefit exclusions, and benefit limitations such as dollar or duration caps.

CPT/HCPCS/ICD-9/ICD-10 Codes

The following codes may be applicable to this Medical policy and may not be all inclusive.

CPT Codes

48160, 48550, 48551, 48552, 48554, 48556, 50300, 50320, 50323, 50325, 50327, 50328, 50329, 50340, 50360, 50365, 50370, 50380

HCPCS Codes

G0341, G0342, G0343, S2054, S2055, S2065, S2102, S2152

ICD-9 Diagnosis Codes

Refer to the ICD-9-CM manual

ICD-9 Procedure Codes

Refer to the ICD-9-CM manual

ICD-10 Diagnosis Codes

Refer to the ICD-10-CM manual

ICD-10 Procedure Codes

Refer to the ICD-10-CM manual


Medicare Coverage:

The information contained in this section is for informational purposes only. HCSC makes no representation as to the accuracy of this information. It is not to be used for claims adjudication for HCSC Plans.

The Centers for Medicare and Medicaid Services (CMS) does have a national Medicare coverage position.

A national coverage position for Medicare may have been changed since this medical policy document was written. See Medicare's National Coverage at <http://www.cms.hhs.gov>.

References:

Pancreas Transplantation

1. Hirshberg B. The cardinal features of recurrent autoimmunity in simultaneous pancreas-kidney transplant recipients. Curr Diab Rep. Oct 2010; 10(5):321-2. PMID 20640940

2. Organ Procurement and Transplantation Network (OPTN). Available at <http://optn.transplant.hrsa.gov> (accessed 2016 September 15).

3. Gruessner AC. 2011 update on pancreas transplantation: Comprehensive trend analysis of 25,000 cases followed up over the course of twenty-four years at the International Pancreas Transplant Registry. Rev Diabet Stud. Spring 2011; 8(1):6-16. PMID 21720668

4. Pancreas Transplantation. Chicago, Illinois: Blue Cross Blue Shield Association Technology Evaluation Center Assessment Program (1998 May) 15 (7):1-31.

5. Pancreas Retransplantation. Chicago, Illinois: Blue Cross Blue Shield Association Technology Evaluation Center Assessment Program. (2002 April) 16 (25):1-31.

6. Fridell JA, Mangus RS, Hollinger EF, et al. The case for pancreas after kidney transplantation. Clin Transplant. Aug-Sep 2009; 23(4):447-53. PMID 19453642

7. Bazerbachi F, Selzner M, Marquez MA, et al. Pancreas-after-kidney versus synchronous pancreas-kidney transplantation: comparison of intermediate-term results. Transplantation. Feb 15 2013; 95(3):489-94. PMID 23183776

8. Kleinclauss F, Fauda M, Sutherland DE, et al. Pancreas after living donor kidney transplants in diabetic patients: impact on long-term kidney graft function. Clin Transplant. Aug-Sep 2009; 23(4):437-46. PMID 19496790

9. Gruessner AC, Sutherland DE, Gruessner RW. Long-term outcome after pancreas transplantation. Curr Opin Organ Transplant. Feb 2012; 17(1):100-5. PMID 22186094

10. van Dellen D, Worthington J, Mitu-Pretorian OM, et al. Mortality in diabetes: pancreas transplantation is associated with significant survival benefit. Nephrol Dial Transplant. May 2013; 28(5):1315-22. PMID 23512107

11. Sampaio MS, Kuo HT, Bunnapradist S. Outcomes of simultaneous pancreas-kidney transplantation in type 2 diabetic patients. Clin J Am Soc Nephrol. May 2011; 6(5):1198-206. PMID 21441123

12. Scalea JR, Butler CC, Munivenkatappa RB, et al. Pancreas transplant alone as an independent risk factor for the development of renal failure: a retrospective study. Transplantation. Dec 27 2008; 86(12):1789-94. PMID 19104423

13. Seal J, Selzner M, Laurence J, et al. Outcomes of pancreas retransplantation after simultaneous kidney-pancreas transplantation are comparable to pancreas after kidney transplantation alone. Transplantation. Mar 2015; 99(3):623-8. PMID 25148379

14. Buron F, Thaunat O, Demuylder-Mischler S, et al. Pancreas Retransplantation: A Second Chance for Diabetic Patients? Transplantation. Jan 27 2013; 95(2):347-52. PMID 23222920

15. Organ Procurement and Transplantation Network (OPTN). Identification of Transmissible Diseases in Organ Recipients. Available at <http://optn.transplant.hrsa.gov> (accessed 2016 September 15).

16. Bhagani S, Sweny P, Brook G. Guidelines for kidney transplantation in patients with HIV disease. HIV Med. Apr 2006; 7(3):133-9. PMID 16494626

17. Siskind E, Maloney C, Akerman M, et al. An analysis of pancreas transplantation outcomes based on age groupings--an update of the UNOS database. Clin Transplant. Sep 2014; 28(9):990-4. PMID 24954160

18. Shah AP, Mangus RS, Powelson JA, et al. Impact of recipient age on whole organ pancreas transplantation. Clin Transplant. Jan-Feb 2013; 27(1):E49-55. PMID 23228216

19. Afaneh C, Rich BS, Aull MJ, et al. Pancreas transplantation: does age increase morbidity? J Transplant 2011; epub 2011:596801. PMID 21766007

20. Schenker P, Vonend O, Kruger B, et al. Long-term results of pancreas transplantation in patients older than 50 years. Transplant Int. Feb 2011; 24(2):136-42. PMID 21039944

21. Gruessner AC, Sutherland DE. Access to pancreas transplantation should not be restricted because of age. Transplant Int. Feb 2011; 24(2):134-35. PMID 21208293

22. Organ Procurement and Transplantation Network (OPTN). Policies and Bylaws: Allocation of Deceased Kidneys. Available at <http://optn.transplant.hrsa.gov> (accessed 2016 September 15).

23. Allogeneic Pancreas Transplant. Chicago, Illinois: Blue Cross Blue Shield Association Medical Policy Reference Manual. (2015 February) Surgery: 7.03.02.

Islet Cell Transplantation

24. Wu Q, Zhang M, Qin Y, et al. Systematic review and meta-analysis of islet autotransplantation after total pancreatectomy in chronic pancreatitis patients [Review]. Endocr J. Mar 30 2015; 62(3):227-34. PMID 25735805

25. Dong M, Parsaik AK, Erwin PJ, et al. Systematic review and meta-analysis: islet autotransplantation after pancreatectomy for minimizing diabetes. Clin Endocrinol (Oxf). Dec 2011; 75(6):771-9. PMID 21605156

26. Wilson GC, Sutton JM, Abbott DE, et al. Long-term outcomes after total pancreatectomy and islet cell autotransplantation: is it a durable operation? Ann Surg. Oct 2014; 260(4):659-65; discussion 665-7. PMID 25203883

27. Chinnakotla S, Radosevich DM, Dunn TB, et al. Long-term outcomes of total pancreatectomy and islet auto transplantation for hereditary/genetic pancreatitis. J Am Coll Surg. Apr 2014; 218(4):530-43. PMID 24655839

28. Sutherland DE, Radosevich DM, Bellin MD, et al. Total pancreatectomy and islet autotransplantation for chronic pancreatitis. J Am Coll Surg. Apr 2012; 214(4):409-24. PMID 22397977

29. U.S. Department of Health and Human Services (HHS) Food and Drug Administration (FDA). Guidance for Industry: Considerations for Allogeneic Pancreatic Islet Cell Products (2009). Available at <http://www.fda.gov> (accessed 2016 September 15).

30. Piper MA, Seidenfeld J, Aronson N. Islet transplantation in type 1 diabetes (Contract No. 290-02-0026. 2005). Prepared for Agency for Healthcare Research and Quality by the Blue Cross Blue Shield Association Technology Evaluation Center, Chicago, Illinois. Available at <http://archive.ahrq.gov> (accessed 2013 May).

31. Alejandro R, Barton FB, Hering BJ, et al. 2008 Update from the Collaborative Islet Transplant Registry. Transplantation. Dec 27 2008; 86(12):1783-8. PMID 19104422

32. Barton FB, Rickels MR, Alejandro R, et al. Improvement in outcomes of clinical islet transplantation: 1999-2010. Diabetes Care. Jul 2012; 35(7):1436-45. PMID 22723582

33. Thompson DM, Meloche M, Ao Z, et al. Reduced progression of diabetic microvascular complications with islet cell transplantation compared with intensive medical therapy. Transplantation. Feb 15 2011; 91(3):373-8. PMID 21258272

34. Caiazzo R, Vantyghem MC, Raverdi V, et al. Impact of procedure-related complications on long-term islet transplantation outcome. Transplantation. May 15 2015; 99(5):979-84. PMID 25393157

35. O'Connell PJ, Holmes-Walker DJ, Goodman D, et al. Multicenter Australian trial of islet transplantation: improving accessibility and outcomes. Am J Transplant. Jul 2013; 13(7):1850-8. PMID 23668890

36. Rickels MR, Kong SM, Fuller C, et al. Improvement in insulin sensitivity after human islet transplantation for type 1 diabetes. J Clin Endocrinol Metab. Nov 2013; 98(11):E1780-5. PMID 24085506

37. National Institute for Health and Clinical Excellence. Allogenic pancreatic islet cell transplantation for type 1 diabetes mellitus (2008). Available at <http://www.nice.org.uk> (accessed 2013 April).

38. National Institute for Health and Clinical Excellence. Autologous pancreatic islet cell transplantation for improved glycemic control after pancreatectomy (2008). Available at <http://www.nice.org.uk> (accessed 2013 April).

39. ECRI Institute. Indications and contraindications for islet cell transplantation for treating type 1 diabetes. Plymouth Meeting (PA): ECRI Institute; 2012 Nov. 12 p. (Hotline Response).

40. Islet Transplantation. Chicago, Illinois: Blue Cross Blue Shield Association Medical Policy Reference Manual. (2015 May) Surgery: 7.03.12.

Policy History:

DateReason
12/1/2017 Reviewed. No changes.
2/15/2017 Document updated with literature review. For pancreas transplantation, the following was changed: 1) Coverage statement on pancreas retransplantation was modified that it applies to patients who meet criteria for pancreas transplantation; 2) Experimental, investigational and/or unproven statement on individual pancreatic transplantation was modified by adding, “including but not limited to.” For pancreatic transplantation, Description, Rationale, and References significantly reorganized. For islet cell transplantation, the following was changed: Experimental, investigational and/or unproven statement on allogeneic pancreas islet cell transplantation was modified by adding, “for patients with type I diabetes mellitus. For islet cell transplantation, the following was added: “Islet cell transplantation is considered experimental, investigational and/or unproven in all other situations.”
8/15/2015 Reviewed. No changes.
3/1/2014 Document updated with literature review. The following was added to the criteria for combined (or simultaneous) pancreas-kidney transplantation: for insulin dependent diabetes mellitus. The following was removed: pancreas transplantation coverage for HIV positive patients. Description and Rationale significantly revised. CPT/HCPCS code(s) updated.
1/1/2005 Document updated.
8/1/2002 Document updated.
2/1/2002 Codes Added/Deleted
11/1/1999 Document updated.
5/1/1998 Document updated.
5/1/1996 Document updated.
4/1/1996 Document updated.
7/1/1994 Document updated.
4/1/1993 Document updated.
1/1/1992 Document updated.
3/1/1991 Document updated.
5/1/1990 New medical document.

Archived Document(s):

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