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MP 7.03.12 Islet Transplantation

Medical Policy    
Section
Surgery
 
Original Policy Date
8/15/01
Last Review Status/Date
Reviewed with literature search/6:2013
Issue
6:2013
  Return to Medical Policy Index

Disclaimer

Our medical policies are designed for informational purposes only and are not an authorization, or an explanation of benefits, or a contract.  Receipt of benefits is subject to satisfaction of all terms and conditions of the coverage.  Medical technology is constantly changing, and we reserve the right to review and update our policies periodically.

 


Description

 

Autologous islet transplantation, performed in conjunction with pancreatectomy, is proposed to reduce the likelihood of insulin-dependent diabetes. Moreover, allogeneic islet cell transplantation is being investigated as a treatment or cure for patients with type 1 diabetes.

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 (the 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

Allogeneic islet transplantation has been used for type 1 diabetes to restore normoglycemia and, ultimately, reduce or eliminate the long-term complications of diabetes 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.

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. While at least 35 IND applications have been submitted to the FDA, no center has submitted a biologics license application.


Policy

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

Allogeneic islet transplantation is considered investigational for the treatment of type 1 diabetes.

 


 

Policy Guidelines

CPT code 48160 explicitly describes autologous pancreas islet cell transplantation.

Effective October 1, 2004, there are 3 HCPCS codes specific to these procedures:

G0341 Percutaneous islet cell transplant, includes portal vein catheterization and infusion

G0342 Laparoscopy for islet cell transplant, includes portal vein catheterization and infusion

G0343 Laparotomy for islet cell transplant, includes portal vein catheterization and infusion

Between 2006 and 2012, there were 3 category III CPT codes specific to these procedures:

0141T Pancreatic islet cell transplantation through portal vein, percutaneous

0142T Pancreatic islet cell transplantation through portal vein, open

0143T Laparoscopy, surgical, pancreatic islet cell transplantation through portal vein

CPT now instructs the use of code 48999 (unlisted procedure, pancreas) for these procedures.


Benefit Application

BlueCard/National Account Issues

Islet transplantation is a specialized procedure that may require referral to an out of network facility.


Rationale

The policy was created in 2001 and was updated regularly with searches of the MEDLINE database. The most recent literature search was for period April 2012 through April 18, 2013. Following is a summary of the key literature to date on islet cell transplantation.

Chronic Pancreatitis

In 2012, Bramis and colleagues published a systematic review of studies on islet transplantation after total pancreatectomy in patients with chronic pancreatitis. (1) The investigators searched for studies reporting on patients who had been treated with total, subtotal or completion pancreatectomy followed by islet autotransplantation. Case series were included if they included more than 5 individuals and reported outcomes for consecutive patients. A total of 72 full-text articles were reviewed, and 5 studies were found to meet inclusion criteria. The postoperative insulin independence rate in the 5 studies ranged from 10% (mean follow-up=8 years) to 46% (mean follow-up=5 years). In the study with the longest follow-up, the insulin independence rate was 28% at 10 years. Two studies reported postoperative morphine use. In one study, patients reported a mean post-operative decrease in morphine use of 116 mg and in the other, a mean decrease of 55 mg of morphine was reported.

An earlier systematic review of studies on islet transplantation after pancreatectomy was published in 2011 by Dong and colleagues. (2) 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% confidence interval [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: 21-33%) and at 2 years (3 studies) was 21% (95% CI: 16-27%).

Representative studies included in the systematic reviews or published more recently are described below:

A large single center series was reported by Sutherland and colleagues in 2012. (3) The study included 409 patients with chronic pancreatitis who underwent total pancreatectomy and islet transplantation between February 1977 and September 2011. Fifty-three of the 409 patients (13%) were children between the ages of 5 and 18 years. Actuarial survival post-surgery 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.

In 2008, Webb and colleagues reported on 46 patients who had total pancreatectomy with immediate islet auto transplant. Twelve had periods of insulin independence for a median of 16.5 months (range, 2–63 months), and 5 remain insulin-independent. (4) Insulin requirements increased over the 10-year follow-up, as have HgA1c levels; however, all patients tested were C-peptide positive at their most recent assessment, and high fasting and stimulated C-peptide positive values recorded at 10 years after transplantation suggest significant graft function in the long term.

Type 1 Diabetes

In April 2004, TEC completed an evidence report on islet cell transplantation in type 1 diabetes in its capacity as an Evidence-based Practice Center for the Agency for Healthcare Research and Quality (AHRQ). (5) The evidence report found that published data on clinical outcomes of islet-alone transplantation were limited by small patient numbers, few transplant centers, short duration of follow-up, and lack of standardized methods of reporting clinical outcomes. Rare, serious adverse events have occurred in patients given islet transplants; recent procedure modifications reportedly minimize risks of these adverse events. No procedure-related deaths, cytomegalovirus (CMV) infection, or post-transplantation lymphoproliferative disease (PTL) 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, had 325 adult recipients in their registry as of April 2008. (6) Three years after first infusion, 23% of islet-alone recipients were insulin-independent (defined as insulin-independent 2 or more 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. The CITR published an updated report in 2012; the focus of the article was changes in outcomes over time. (7) The number of patients receiving islet transplants was 214 during 1999-2002, 255 between mid-2003-2006 and 208 from 2007-2010. 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 50-53% 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 and colleagues in Canada published findings from a prospective cross-over study of intensive medical therapy (pretransplant) versus islet cell transplantation in patients with type 1 diabetes. (8) The article reported on 45 patients; at the time of data analysis, 32 had received islet cell transplants. Median follow-up was 47 months pre-transplant and 66 months post-transplant. The overall mean HbA1c was 7.8% pretransplant and 6.7% post-transplant; this difference was statistically significant, p<0.001. In the 16 patients for whom sufficient data pre- and post-transplant were available on renal outcomes, the median decline in glomular filtration rate (GFR, mL/min/month) was -6.7 pretransplant and -1.3 post-transplant (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 post-transplant (p<0.01). (The numbers of patients in the retinopathy analyses was 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).

In 2012, Vantyghem and colleagues reported on 23 patients with type 1 diabetes who underwent islet transplantation; 14 had islet-only transplants and 9 had islet after kidney transplants. (9) Median HbA1c was 8.3% at baseline and 6.7% at 3 years. Ten of the 23 patients (43%) were insulin independent 3 years after islet transplantation. Findings were not reported separately for the islet-only transplant recipients.

Recent papers have highlighted research in the areas of islet cell regenerative therapy including stem-cell technology, encapsulating islets to protect them from the host immune system by a semipermeable capsule, and xenotransplantation. (10-13) In addition, novel immunosuppressive regimens using biologics have been discussed. (14)

Ongoing Clinical Trials

A comparison of strict glucose control with usual care at the time of islet cell transplantation (NCT01123122) (15): This is a single-center randomized controlled trial (RCT) comparing the impact of strict glucose control versus usual care prior to islet cell transplantation on outcomes in patients with type 1 diabetes. The primary study outcome is islet cell function 3 months post-transplantation. The estimated enrollment is 32 patients, and the estimated study completion date is September 2015.

A comparison of islet cell transplantation with medical therapy on the risk of progression of diabetic retinopathy and diabetic macular edema (NCT00853424) (16): This RCT is comparing islet cell transplantation to standard medical therapy in patients with diabetic eye disease. The primary outcome is progression of diabetic retinopathy or moderate visual loss. The estimated enrollment is 40 patients, and the estimated study completion date is June 2015.

Summary

Autologous islet transplantation is proposed in conjunction with pancreatectomy for patients with chronic pancreatitis. 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 as an adjunct to the pancreatectomy procedure. Thus, this may be considered medically necessary.

The techniques for allogeneic islet cell transplants are evolving, and the impact on the net health outcome 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 investigational for patients with diabetes type 1.

Practice Guidelines and Position Statements

Guidance from the National Institute for Clinical Excellence (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. (17) Evidence on safety shows that serious complications may occur, and the long-term immunosuppression required is also associated with risk of adverse events. The procedure is particularly indicated for patients with hypoglycemia unawareness or those already on immunosuppressive therapy because of renal transplantation. A 2008 update of guidance 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. (18)

Medicare National Coverage

Effective October 1, 2004, Medicare will cover pancreatic islet transplantation in patients with type 1 diabetes participating in the context of a clinical trial sponsored by the National Institutes of Health. (19) Partial pancreatic tissue transplantation or islet transplantation performed outside the context of a clinical trial will continue to not be covered.

References:

  1. Bramis K, Gordon-Weeks AN, Friend PJ et al. Systematic review of total pancreatectomy and islet autotransplantation for chronic pancreatitis. Br J Surg 2012; 99(6):761-6.
  2. Dong M, Parsaik AK, Erwin PJ et al. Systematic review and meta-analysis: islet autotransplantation after pancreatectomy for minimizing diabetes. Clin Endocrinol (Oxf) 2011; 75(6):771-9.
  3. Sutherland DE, Radosevich DM, Bellin MD et al. Total pancreatectomy and islet autotransplantation for chronic pancreatitis. J Am Coll Surg 2012; 214(4):409-24.
  4. Webb MA, Illouz SC, Pollard CA et al. Islet auto transplantation following total pancreatectomy: a long-term assessment of graft function. Pancreas 2008; 37(3):282-7.
  5. Piper MA, Seidenfeld J, Aronson N. Islet transplantation in type 1 diabetes, Prepared for Agency for Healthcare Research and Qualtiy by the Blue Cross Blue Shield Association Technology Evaluation Center. Contract No. 290-02-0026. 2005. Available online at: http://archive.ahrq.gov/clinic/epcsums/isletsum.htm. Last accessed May, 2013.
  6. Alejandro R, Barton FB, Hering BJ et al. 2008 Update from the Collaborative Islet Transplant Registry. Transplantation 2008; 86(12):1783-8.
  7. Barton FB, Rickels MR, Alejandro R et al. Improvement in outcomes of clinical islet transplantation: 1999-2010. Diabetes Care 2012; 35(7):1436-45.
  8. Thompson DM, Meloche M, Ao Z et al. Reduced progression of diabetic microvascular complications with islet cell transplantation compared with intensive medical therapy. Transplantation 2011; 91(3):373-8.
  9. Vantyghem MC, Raverdy V, Balavoine AS et al. Continuous glucose monitoring after islet transplantation in type 1 diabetes: an excellent graft function (beta-score greater than 7) Is required to abrogate hyperglycemia, whereas a minimal function is necessary to suppress severe hypoglycemia (beta-score greater than 3). J Clin Endocrinol Metab 2012; 97(11):E2078-83.
  10. Ekser B, Cooper DK. Overcoming the barriers to xenotransplantation: prospects for the future. Expert Rev Clin Immunol 2010; 6(2):219-30.
  11. van der Windt DJ, Bottino R, Kumar G et al. Clinical islet xenotransplantation: how close are we? Diabetes 2012; 61(12):3046-55.
  12. Aguayo-Mazzucato C, Bonner-Weir S. Stem cell therapy for type 1 diabetes mellitus. Nat Rev Endocrinol 2010; 6(3):139-48.
  13. de Vos P, Spasojevic M, Faas MM. Treatment of diabetes with encapsulated islets. Adv Exp Med Biol 2010; 670:38-53.
  14. Posselt AM, Szot GL, Frassetto LA et al. Islet transplantation in type 1 diabetic patients using calcineurin inhibitor-free immunosuppressive protocols based on T-cell adhesion or costimulation blockade. Transplantation 2010; 90(12):1595-601.
  15. Sponsored by Vancouver Coastal Health. A comparison of strict glucose control with usual care at the time of islet cell transplantation (NCT01123122) Available online at: www.clinicaltrials.gov. Last accessed April, 2013.
  16. Sponsored by University of British Columbia. A Comparison of Islet Cell Transplantation With Medical Therapy on the Risk of Progression of Diabetic Retinopathy and Diabetic Macular Edema (NCT00853424) Available online at: www.clinicaltrials.gov. Last accessed April, 2013.
  17. National Institute for Health and Clinical Excellence. Allogenic pancreatic islet cell transplantation for type 1 diabetes mellitus. 2008. Available online at: http://www.nice.org.uk/Guidance/IPG257. Last accessed April, 2013.
  18. National Institute for Health and Clinical Excellence. Autologous pancreatic islet cell transplantation for improved glycemic control after pancreatectomy. 2008. Available online at: http://www.nice.org.uk/Guidance/IPG274. Last accessed April, 2013.
  19. Centers for Medicare and Medicaid. National Coverage Determination (NCD) for ISLET CELL Transplantation in the Context of a Clinical Trial (260.3.1). 2004. Available online at: http://www.cms.gov/medicare-coverage-database/details/ncd-details.aspx?NCDId=286&ncdver=1&CoverageSelection=Both&ArticleType=All&PolicyType=Final&s=All&KeyWord=islet+cell&KeyWordLookUp=Title&KeyWordSearchType=And&bc=gAAAABAAAAAA&. Last accessed April, 2013.

 

Codes

Number

Description

CPT  48160  Pancreatectomy, total or subtotal, with autologous transplantation of pancreas or pancreatic islet cells 
  0141T  Pancreatic islet cell transplantation through portal vein, percutaneous (code deleted 12/31/11)
  0142T  Pancreatic islet cell transplantation through portal vein, open (code deleted 12/31/11)
  0143T  Laparoscopy, surgical, pancreatic islet cell transplantation through portal vein (code deleted 12/31/11)
ICD-9 Procedure  52.84  Autotransplantation of cells of islets of Langerhans 
  52.85  Allotransplantation of cells of islets of Langerhans 
  52.86  Transplantation of cells of islets of Langerhans, not otherwise specified 
ICD-9 Diagnosis  577.1  Chronic pancreatitis 
  250.00 – 250.93  Diabetes mellitus coding range 
HCPCS  G0341  Percutaneous islet cell transplant, includes portal vein catheterization and infusion 
  G0342  Laparoscopy for islet cell transplant, includes portal vein catheterization and infusion 
  G0343  Laparotomy for islet cell transplant, includes portal vein catheterization and infusion 
  S2102  Transplant, islet cell tissue, allogeneic 
ICD-10-CM (effective 10/1/14) K86.1 Other chronic pancreatitis
ICD-10-PCS (effective 10/1/14) 3E033U0 Percutaneous administration, peripheral vein, pancreatic islet cells, autologous
  3E0J3U0 Percutaneous administration, biliary and pancreatic tract, pancreatic islet cells, autologous
   3E0J7U0 Administration via natural or artificial opening, biliary and pancreatic tract, pancreatic islet cells, autologous
   3E0J8U0 Endoscopic administration via natural or artificial opening, biliary and pancreatic tract, pancreatic islet cells, autologous
Type of Service  Surgery 
Place of Service  Inpatient 

 


Index

 

Allogeneic Transplantation, Islet
Autologous Transplantation, Islet Cell
Islet Cell Transplantation
Transplantation, Allogeneic Islet
Transplantation, Autologous Islet Cell
Transplantation, Pancreas, Autologous Islet Cell


Policy History

Date Action Reason
08/15/01 Add to Surgery section New policy
04/29/03 Replace policy Policy updated; no change to policy statement, reference added
11/9/04 Replace policy Literature review update for the period of January 2003 through September 2004. Added information on islet transplantation for type 1 diabetes and statement that this indication is considered investigational. Added Medicare coverage policy information on islet transplantation for type 1 diabetes; removed “autologous” from the policy title. HCPCS codes updated
08/17/05 Replace policy Literature review update for the period of September 2004 through June 2005; reference No. 5 added. Policy statement unchanged. Removed “cell” from title and policy when describing islet transplantation rather than “islet cell transplantation.” CPT Category III codes for 1/1/06 added
12/14/05 Replace policy – typographical error corrected Date corrected in Policy Guidelines section
10/10/06 Replace policy Literature review update for the period of June 2005 through September 2006; reference numbers 6 and 7 added. Policy statement unchanged. 
02/14/08 Replace policy  Policy updated with literature review; references 8-11 added; policy statements unchanged
03/12/09 Replace policy Policy updated with literature review; references 12-22 added; policy statements unchanged
6/10/10 Replace policy Policy updated with literature review; rationale section extensively edited; reference numbers 16-18 added; policy statements unchanged
6/9/11 Replace policy Policy updated with literature review. Reference numbers 13 and 17 added; other references renumbered or removed; policy statements unchanged.
06/14/12 Replace policy Policy updated with literature review. Reference numbers 1, 2, 3 and 14 added; other references renumbered or removed; policy statements unchanged.
6/13/13 Replace policy Policy updated with literature review through April 18, 2013. Reference numbers 7,9,11 and 16 added; other references renumbered or removed; policy statements unchanged.