|MP 6.01.37||Radioimmunoscintigraphy Imaging (Monoclonal Antibody Imaging) with Indium-111 Capromab Pendetide (Prostascint®) for Prostate Cancer|
|Original Policy Date
|Last Review Status/Date
Reviewed with literature search/1:2015
|Return to Medical Policy Index|
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.
Radioimmunoscintigraphy is an imaging modality that uses radiolabeled monoclonal antibodies (MAbs) to target specific tissue types. MAbs that react with specific cellular antigens are conjugated with a radiolabeled isotope. The labeled antibody-isotope conjugate is then injected into the patient and allowed to localize to the target over a 2- to 7-day period. The patient then undergoes imaging with a nuclear medicine gamma camera, and radioisotope counts are analyzed. Imaging can be performed with planar techniques or by using single-photon emission computed tomography (SPECT).
Indium-111 capromab pendetide (ProstaScint®) (also referred to as CYT-356) targets an intracellular binding site on prostate-specific membrane antigen (PSMA) and has been approved by the U.S. Food and Drug Administration for use as a “diagnosing imaging agent in newly diagnosed patients with biopsy-proven prostate cancer, thought to be clinically localized after standard diagnostic evaluation, who are at risk for pelvic lymph node metastases and in postprostatectomy patients with a rising prostate-specific antigen (PSA) and a negative or equivocal standard metastatic evaluation in whom there is a high clinical suspicion of occult metastatic disease.” Other monoclonal antibodies, directed at extracellular PSMA binding sites, are also under development.
Radioimmunoscintigraphy using indium-111 capromab pendetide (Prostascint®) is considered investigational.
No applicable information
BlueCard/National Account Issues
State or federal mandates (e.g., FEP) may dictate that all devices approved by the U.S. Food and Drug Administration (FDA) may not be considered investigational. Therefore, FDA-approved devices may be assessed on the basis of their medical necessity.
This policy regarding the use of radioimmunoscintigraphy (RIS) in patients with prostate cancer was created in 2002 and was based on a 1998 TEC Assessment.(1) The policy was updated regularly with searches of the MEDLINE database. The most recent literature review was performed for the period of December 12, 2013 through December 18, 2014. RIS may be considered for use in a number of clinical indications. For the purposes of this policy, 2 main clinical situations will be considered:
This policy regarding the use of radioimmunoscintigraphy (RIS) in patients with prostate cancer was created in 2002 and was based on a 1998 TEC Assessment.(1) The policy was updated regularly with searches of the MEDLINE database. The most recent literature review was performed for the period of December 12, 2013 through December 18, 2014.
RIS may be considered for use in a number of clinical indications. For the purposes of this policy, 2 main clinical situations will be considered:
- As part of the pretreatment workup for staging of prostate cancer. In this situation, the value of RIS is in detecting distant metastases that are not evident on other imaging studies, since detection of occult metastases is likely to alter treatment recommendations.
- In patients who have received curative treatment, but present with biochemical failure, ie, a rising prostate-specific antigen (PSA) without definite disease on standard imaging studies. In this situation, differentiating between local and distant recurrence is important because local recurrence may be treated with salvage radiotherapy, while distant recurrence is usually treated with androgen deprivation therapy.
Pretreatment staging Before Ccurative Treatment
Based on the 1998 TEC Assessment of RIS,(1) sensitivity in detecting tumor in the pelvic lymph nodes ranged from 50% to 75% and specificity ranged from 72% to 92.6%. Pooled data from the studies reviewed in the TEC Assessment produced an estimated 61% positive predictive value (PPV). If positive RIS results were used to exclude a patient from receiving potentially curative therapy (ie, radical prostatectomy), then 38% of patients might be harmed by inappropriately withholding the potentially curative treatment. A pooled negative predictive value (NPP) of 73% suggests that if radioimmunoscintigraphy played a key role in determining that pelvic lymph nodes were clear of tumor prior to radical prostatectomy, then 26.7% of patients with a negative RIS scan and truly positive lymph nodes might receive potentially ineffective surgery. In addition, there is debate over a potential survival benefit with performing prostatectomy in the setting of positive lymph nodes.(2,3) Nevertheless, in terms of evaluating the pelvic nodes, the PPVs and NPVs are not sufficiently high enough to avoid pelvic lymph node dissection when necessary to determine patient management.
Since the 1998 TEC Assessment, several reports have been published that address the role of RIS in evaluating pelvic lymph node staging.(4-9) However, several of the authors of these reports appear in multiple new and prior publications, and it seems possible that some of these populations overlap with previously reported results derived from multicenter studies. Moreover, the diagnostic accuracy of RIS for evaluating pelvic lymph nodes does not appear to be substantially improved in later reports.(9)
Several of these reports use predictive modeling or cross-sectional correlation analysis to explore the value of RIS results in predicting the extent of disease in comparison with other factors such as PSA level, Gleason score, and clinical stage of disease.(6,7,10)
In 2011, Reiter et al(11) published a retrospective review of 197 patients who had both RIS and histopathology available at 1 institution over a 4-month period. For the lymph nodes, the sensitivity of RIS was 60.0% (95% confidence interval [CI], 14.7% to 94.7%) and the specificity was 97.4% (95% CI, 92.3% to 100%). The area under the curve by receiver operating characteristic (ROC) analysis was 78.7%. Increasing Gleason score was predictive of a positive RIS scan, as was the setting of a pretreatment evaluation.
These analyses suggest that RIS provides additional and independent information that correlates with extent of disease; however, the conclusions of these studies are derived from relationships across populations and do not directly translate into how RIS results would actually be used to guide management in a manner that would improve net health outcome. Without an understanding of diagnostic accuracy and how results would influence management, it is not possible to model potential effects on health outcomes. Thus, none of the reports identified in the update support the clinical effectiveness of using RIS to evaluate pelvic lymph nodes.
Evaluating patients with biochemical failure following prostatectomy or radiotherapy
Patients who experience a rising PSA following curative treatment for prostate cancer are considered to have a recurrence; however, the location of the recurrence is sometimes not evident for a period of time after biochemical failure. Localized recurrence is typically treated with salvage radiotherapy, whereas distant recurrence, ie, metastatic disease, is usually treated with androgen deprivation therapy.
In terms of evaluating recurrent or residual disease, there are limited data showing that the use of RIS in this patient group can detect additional sites of disease and would result in different management decisions compared to decisions based on usual care.(6,8-10,12-17) Imaging evaluation may be useful in suspected recurrence due to rising PSA to localize recurrent tumor and to determine whether recurrent tumor is local to the prostate area, involves distant sites, or both. When residual or recurrent disease is only local, patients may undergo postoperative radiation therapy (RT), whereas, when the recurrence includes distant sites, hormonal therapy would be considered. Distant hematogenous metastasis from prostate cancer most frequently involves bone but can infrequently involve other soft tissue sites. Bone scan is generally considered to be more sensitive than RIS for detecting bone metastases.(9) Positive RIS findings have been reported anecdotally in abnormalities other than prostate cancer, so biopsy confirmation of unexpected distant findings may be necessary to ensure proper patient management.(18-20)
The available studies are generally retrospective, descriptive reports of patterns of RIS uptake in patients with suspected recurrence. These studies, however, do not provide consistent verification of disease status, and thus the rate of false positive and false negative RIS studies is not well-established. While some studies report what percent of cases had associated changes in management, it is frequently difficult to specifically determine how RIS results affected management and to determine whether these changes resulted in an improvement in net health outcome.
A retrospective study by Raj et al(16) included 252 patients with biochemical failure following radical prostatectomy (PSA ≤0.4 ng/mL) who had RIS performed to localize recurrence. In this study, 72% of subjects had a positive scan. A localized (prostatic fossa only) uptake pattern was seen in 30.6%, regional uptake pattern (regional lymph nodes plus or minus prostatic fossa and no distant disease) in 42.8%, and distant uptake noted in 29.4%. This study did not report the proportion of subjects in whom patient management was altered by RIS findings. Only a minority of patients (<20%) had also received a computed tomography (CT) scan or bone scan showing positive findings, making comparisons across technologies subject to potential bias. A uniform reference standard was not applied in this study, and detailed follow-up was available for only approximately half of the patients (132 of 255). The study reports sensitivity and specificity in a small subset of subjects (ie, 95 of 252 total or 38% of subjects) who had some degree of verification of disease status. Reported sensitivity was 73% and specificity was 53%. However, due to the selected nature of the small subset analysis, these estimates are subject to potential verification bias and may not be considered valid measures of expected performance.
Sodee et al(10) performed a retrospective analysis on a large multicenter study including 2290 RIS scans in 2154 patients with prostate cancer, either before or after treatment. This study reports the rates of positive RIS scans in local, regional, and distant sites but does not provide detailed verification of results and thus, sensitivity and specificity cannot be determined. When analysis was stratified by whether primary treatment had been surgery, radiation, or hormonal therapy, RIS showed uptake limited to extrapelvic nodes in 8.5% to 15.1% of patients and uptake in both pelvic and extrapelvic nodes in 22.1% to 33.2% of patients. Relatively few patients had also undergone CT scanning (n=146). When CT was compared with RIS, CT did not detect pelvic or extrapelvic nodes that were detected by RIS in 73% of CT cases. In contrast, in a separate study of 45 subjects, RIS did not perform as well as CT in detecting metastatic disease.(17)
Kahn et al(13) reported results in 32 patients who received salvage pelvic radiation for suspected recurrence and had received RIS imaging. The authors reported that RIS had 50% sensitivity, 89% specificity, 78% PPV, and 70% NPV for detecting patients who would develop tumor recurrence after irradiation. Thomas et al reported on the results of RIS in a case series of 30 men with recurrent prostate cancer treated with RT.(21) This study found no correlation between the results of RIS and tumor control, as assessed by serial PSA levels. Further studies would be necessary to demonstrate that long-term outcomes after RT are improved when RIS is used to select patients.
Liauw et al reported on 82 patients with adenocarcinoma of the prostate treated with salvage RT for an elevated PSA level after prostatectomy.(22) The median pre-RT PSA level was 0.63 ng/mL. Of the 82 patients, 47 (57%) had a pre-RT RIS ProstaScint scan, which was used for both patient selection and target delineation. Patients with a pre-RT RIS scan had a lower preoperative PSA level (p=0.024) and shorter follow-up (p=0.022) than those without RIS. With a median follow-up of 44 months, the biochemical control rate was 56% at 3 years and 48% at 5 years. Margin status was the only factor associated with biochemical control on univariate (p=0.005) and multivariate (p=0.004) analysis. Patients who had prostate bed-only uptake on RIS (n=38) did not have improved outcomes, with biochemical control rates of 51% at 3 years and 40% at 5 years. These data support the conclusion that patients who were selected for treatment with RIS did not have better biochemical outcomes.
Nagda et al reported on a series of 58 patients who had ProstaScint scans as part of an assessment of rising PSA after prostatectomy who were then treated with prostate bed RT.(23) The 4-year biochemical relapse-free survival (BRFS) rates for patients with negative ProstaScint scans (53%), positive in the prostate bed alone (45%), or positive elsewhere (74%) scan findings did not differ significantly (p=0.51). The capromab pendetide scan status had no effect on BRFS. Those with a pre-RT PSA level of less than 1 ng/mL had improved BRFS (p=.003). The authors concluded that the capromab pendetide scan has a low PPV in patients with positive elsewhere uptake and the 4-year BRFS was similar to that for those who did not exhibit positive elsewhere uptake.
Proano et al(24) reported “early experience” on outcomes among a group of 44 patients with biochemical recurrence after radical prostatectomy who underwent a ProstaScint scan immediately before salvage radiotherapy. They noted an improved prognosis (mean follow-up, 22 months) in patients who had a negative preradiotherapy scan but also noted that this finding was not necessarily independent of preradiotherapy PSA level.
Two publications raise questions about the accuracy (including sensitivity and specificity) of immunoscintigraphy, coregistered with CT, in imaging localized prostate cancer within the prostate gland and in detecting seminal vesicle invasion.(25,26) In a prospective evaluation of 93 patients with recurrent prostate cancer, Schuster et al reported positron-emission tomography (PET)-CT with the radiotracer anti-1-amino-3-[(18)Fluorocyclobutane-1-carboxylic acid was significantly better in detecting prostatic and extraprostatic prostate cancer recurrence than RIS single-photon emission computed tomography (SPECT)-CT imaging.(27)
Use of RIS scanning to direct “image-guided” radiotherapy
One trial was identified that used the results of ProstaScint to change management. Wong et al(28) prospectively enrolled 71 patients with localized prostate cancer and performed capromab pendetide scans on all prior to initiating intensity-modulated radiation therapy (IMRT) treatment. Areas of increased uptake within the prostate gland on RIS scanning were given an additional “boost” of radiation in addition to the baseline dose given to the entire gland. Grade 2 urinary and gastrointestinal toxicity was common, affecting up to 50% of patients, but grade 3 or higher toxicity was less frequent, with 4% of patients exhibiting grade 2 urinary toxicity. At a median of 66 months’ follow-up, biochemical control was 94%. No attempt was made in this study to compare outcomes of “image-guided” IMRT with standard treatment.
Ongoing Clinical Trials
A search of online site ClinicalTrials.gov on December 18, 2014 identified no ongoing trials of ProstaScint or radioimmunoscintigraphy and prostate.
Summary of Evidence
Radioimmunoscintigraphy (RIS) imaging with Indium-111 (In-111) capromab pendetide (ProstaScint) is an alternative imaging modality for patients with prostate cancer that is intended to assist in determining the extent and location of disease. For determining whether disease is present in the lymph nodes, RIS has a modest sensitivity, estimated at 50% to 75% and a moderate to high specificity, estimated at 72% to 93%. Because other imaging modalities have a suboptimal sensitivity for disease in the lymph nodes, RIS has been proposed to be used for staging prior to curative treatment. However, no studies have demonstrated that use of RIS for this purpose changes management, and therefore the evidence is insufficient to determine whether RIS improves health outcomes when used to stage prostate cancer pretreatment.
For patients with biochemical failure following curative treatment, RIS has been proposed to help differentiate between local and distant recurrence. There are numerous small case series that evaluate RIS in this population, and describe rates of positivity for local and distant disease. However, none of these studies demonstrate a change in management as a result of RIS. As a result, it is not possible to determine whether use of RIS in this population improves outcomes. For the above reasons, RIS with In-111 capromab pendetide is considered investigational.
Practice Guidelines and Position Statements
Version 1:2014 of the National Comprehensive Cancer Network (NCCN) Guidelines for prostate cancer does not mention ProstaScint or radioimmunoscintigraphy.(29)
US Preventive Services Task Force Recommendations
The US Preventive Servies Task Force has not addressed ProstaScint or radioimmunoscintigraphy.
Medicare Coverage Determinations
No national guidelines or Medicare national coverage decisions (NCD) related to the use of indium-111 (In-111) capromab pendetide were identified. In the absence of an NCD, coverage decisions are left to the discretion of local Medicare carriers.
- Blue Cross and Blue Shield Association Technology Evaluation Center (TEC). Radioimmunoscintigraphy for Prostate Cancer – Update. TEC Assessments 1998; Volume 13, Tab 21. PMID
- Lange PH. PROSTASCINT scan for staging prostate cancer. Urology. Mar 2001;57(3):402-406. PMID 11248606
- Moul JW, Kane CJ, Malkowicz SB. The role of imaging studies and molecular markers for selecting candidates for radical prostatectomy. Urol Clin North Am. Aug 2001;28(3):459-472. PMID 11590806
- Lau HY, Kindrachuk G, Carter M, et al. Surgical confirmation of ProstaScint abnormalities in two patients with high risk prostate cancer. Can J Urol. Feb 2001;8(1):1199-1202. PMID 11268308
- Manyak MJ, Hinkle GH, Olsen JO, et al. Immunoscintigraphy with indium-111-capromab pendetide: evaluation before definitive therapy in patients with prostate cancer. Urology. Dec 1999;54(6):1058-1063. PMID 10604708
- Murphy GP, Snow PB, Brandt J, et al. Evaluation of prostate cancer patients receiving multiple staging tests, including ProstaScint scintiscans. Prostate. Feb 1 2000;42(2):145-149. PMID 10617872
- Polascik TJ, Manyak MJ, Haseman MK, et al. Comparison of clinical staging algorithms and 111indium-capromab pendetide immunoscintigraphy in the prediction of lymph node involvement in high risk prostate carcinoma patients. Cancer. Apr 1 1999;85(7):1586-1592. PMID 10193950
- Quintana JC, Blend MJ. The dual-isotope ProstaScint imaging procedure: clinical experience and staging results in 145 patients. Clin Nucl Med. Jan 2000;25(1):33-40. PMID 10634528
- Rosenthal SA, Haseman MK, Polascik TJ. Utility of capromab pendetide (ProstaScint) imaging in the management of prostate cancer. Tech Urol. Mar 2001;7(1):27-37. PMID 11272670
- Sodee DB, Malguria N, Faulhaber P, et al. Multicenter ProstaScint imaging findings in 2154 patients with prostate cancer. The ProstaScint Imaging Centers. Urology. Dec 20 2000;56(6):988-993. PMID 11113745
- Rieter WJ, Keane TE, Ahlman MA, et al. Diagnostic performance of In-111 capromab pendetide SPECT/CT in localized and metastatic prostate cancer. Clin Nucl Med. Oct 2011;36(10):872-878. PMID 21892036
- Elgamal AA, Troychak MJ, Murphy GP. ProstaScint scan may enhance identification of prostate cancer recurrences after prostatectomy, radiation, or hormone therapy: analysis of 136 scans of 100 patients. Prostate. Dec 1 1998;37(4):261-269. PMID 9831223
- Kahn D, Williams RD, Haseman MK, et al. Radioimmunoscintigraphy with In-111-labeled capromab pendetide predicts prostate cancer response to salvage radiotherapy after failed radical prostatectomy. J Clin Oncol. Jan 1998;16(1):284-289. PMID 9440754
- Murphy GP, Elgamal AA, Troychak MJ, et al. Follow-up ProstaScint scans verify detection of occult soft-tissue recurrence after failure of primary prostate cancer therapy. Prostate. Mar 1 2000;42(4):315-317. PMID 10679761
- Petronis JD, Regan F, Lin K. Indium-111 capromab pendetide (ProstaScint) imaging to detect recurrent and metastatic prostate cancer. Clin Nucl Med. Oct 1998;23(10):672-677. PMID 9790041
- Raj GV, Partin AW, Polascik TJ. Clinical utility of indium 111-capromab pendetide immunoscintigraphy in the detection of early, recurrent prostate carcinoma after radical prostatectomy. Cancer. Feb 15 2002;94(4):987-996. PMID 11920467
- Seltzer MA, Barbaric Z, Belldegrun A, et al. Comparison of helical computerized tomography, positron emission tomography and monoclonal antibody scans for evaluation of lymph node metastases in patients with prostate specific antigen relapse after treatment for localized prostate cancer. J Urol. Oct 1999;162(4):1322-1328. PMID 10492189
- Khan A, Caride VJ. Indium-111 capromab pendetide (ProstaScint) uptake in neurofibromatosis. Urology. Jul 1 2000;56(1):154. PMID 10869655
- Michaels EK, Blend M, Quintana JC. 111Indium-capromab pendetide unexpectedly localizes to renal cell carcinoma. J Urol. Feb 1999;161(2):597-598. PMID 9915456
- Scott DL, Halkar RK, Fischer A, et al. False-positive 111 indium capromab pendetide scan due to benign myelolipoma. J Urol. Mar 2001;165(3):910-911. PMID 11176508
- Thomas CT, Bradshaw PT, Pollock BH, et al. Indium-111-capromab pendetide radioimmunoscintigraphy and prognosis for durable biochemical response to salvage radiation therapy in men after failed prostatectomy. J Clin Oncol. May 1 2003;21(9):1715-1721. PMID 12721246
- Liauw SL, Weichselbaum RR, Zagaja GP, et al. Salvage radiotherapy after postprostatectomy biochemical failure: does pretreatment radioimmunoscintigraphy help select patients with locally confined disease? Int J Radiat Oncol Biol Phys. Aug 1 2008;71(5):1316-1321. PMID 18234446
- Nagda SN, Mohideen N, Lo SS, et al. Long-term follow-up of 111In-capromab pendetide (ProstaScint) scan as pretreatment assessment in patients who undergo salvage radiotherapy for rising prostate-specific antigen after radical prostatectomy for prostate cancer. Int J Radiat Oncol Biol Phys. Mar 1 2007;67(3):834-840. PMID 17293236
- Proano JM, Sodee DB, Resnick MI, et al. The impact of a negative (111)indium-capromab pendetide scan before salvage radiotherapy. J Urol. May 2006;175(5):1668-1672. PMID 16600726
- Mouraviev V, Madden JF, Broadwater G, et al. Use of 111in-capromab pendetide immunoscintigraphy to image localized prostate cancer foci within the prostate gland. J Urol. Sep 2009;182(3):938-947. PMID 19616259
- Tsivian M, Wright T, Price M, et al. 111-In-capromab pendetide imaging using hybrid-gamma camera-computer tomography technology is not reliable in detecting seminal vesicle invasion in patients with prostate cancer. Urol Oncol. Feb 27 2010. PMID 20189846
- Schuster DM, Nieh PT, Jani AB, et al. Anti-3-[18F]FACBC PET-CT and 111In-capromabpendetide SPECT-CT in Recurrent Prostate Carcinoma: Results of a Prospective Clinical Trial. J Urol. Oct 18 2013. PMID 24144687
- Wong WW, Schild SE, Vora SA, et al. Image-guided radiotherapy for prostate cancer: a prospective trial of concomitant boost using indium-111-capromab pendetide (ProstaScint) imaging. Int J Radiat Oncol Biol Phys. Nov 15 2011;81(4):e423-429. PMID 21477947
- National Comprehensive Cancer Network. Clincial Practice Guidelines in Oncology. Prostate Cancer. V.1.2015. http://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf. Accessed November 19, 2014.
|CPT||78800||Radiopharmaceutical localization of tumor or distribution of radiopharmaceutical agent(s); limited area|
|78801||Radiopharmaceutical localization of tumor or distribution of radiopharmaceutical agent(s); multiple areas|
|78802||Radiopharmaceutical localization of tumor or distribution of radiopharmaceutical agent(s); whole body, single day imaging|
|78803||Radiopharmaceutical localization of tumor or distribution of radiopharmaceutical agent(s); tomographic (SPECT)|
|78804||Radiopharmaceutical localization of tumor or distribution of radiopharmaceutical agent(s); whole body, requiring two or more days imaging|
|ICD-9 Procedure||92.16||Scan of lymphatic system|
|92.18||Total body scan, radioisotope|
|92.19||Scan, other sites|
|ICD-9 Diagnosis||185||Malignant neoplasm of prostate|
|V10.46||Personal history of prostate cancer|
|HCPCS||A9507||Supply of radiopharmaceutical diagnostic imaging agent, indium In-111 capromab pendetide, per dose|
|ICD-10-CM (effective 10/1/15)||Investigational for all relevant diagnoses|
|C61||Malignant neoplasm prostate|
|Z45.46||Personal history malignant neoplasm prostate|
|ICD-10-PCS (effective 10/1/15)||ICD-10-PCS codes are only used for inpatient services. There is no specific ICD-10-PCS code for this imaging.|
|C72YYZZ||Tomographic nuclear medicine imaging lymphatic and hematologic system other radionuclide|
|C75YYZZ||Nonimaging nuclear medicine probe lymphatic and hematologic system other radionuclide|
|CT6YYZZ||Planar nuclear medicine imaging male reproductive system other radionuclide|
|CW1ZYZZ||Planar nuclear medicine imaging anatomical regions, other, other radionuclide|
|Type of Service:||Radiology|
|Place of Service:||Outpatient|
Indium-111 Capromab Pendetide
|12/18/02||Add policy to Radiology section||New policy; ProstaScint originally addressed in global policy on monoclonal antibody imaging (policy No. 6.01.05). Policy statement regarding ProstaScint unchanged; still considered investigational. Policy updated with additional discussion and references|
|02/25/04||Replace policy||Policy updated with literature review; 1 reference added; no change in policy statement|
|08/17/05||Replace policy||Policy updated with literature review; no change in policy statement. References 25 to 27 added and coding updated.|
|02/15/07||Replace policy||Policy updated with literature search; no change in policy statement. Reference numbers 28 to 30 added|
|11/13/08||Replace policy||Policy updated with literature search, reference numbers 31 and 32 added. No change in policy statement|
|2/10/11||Replace policy||Policy update with literature review, reference numbers 33 to 35 added. No change in policy statement|
|02/09/12||Replace policy||Policy updated with literature review. Rationale section re-written, references revised/renumbered. No change to policy statement.|
|2/14/13||Replace policy||Policy updated with literature review. No new references added. No change to policy statement|
|1/09/14||Replace policy||Policy updated with literature review on December 12, 2013. Reference 27 added. Reference 29 updated. No change to policy statement.|
|1/15/15||Replace policy||Policy updated with literature review through December 18, 2014. Policy statement unchanged.|