BlueCross and BlueShield of Montana Medical Policy/Codes
Cellular Immunotherapy for Prostate Cancer (Sipuleucel-T [Provenge])
Chapter: Drugs - Medical Benefit
Current Effective Date: July 18, 2013
Original Effective Date: October 13, 2011
Publish Date: April 18, 2013
Revised Dates: November 6, 2012; April 17, 2013

Prostate cancer is the second leading cause of cancer-related deaths among American men with an estimated incidence of 218,890 cases and an estimated number of 27,050 deaths in 2007. The majority of cases is diagnosed at a localized stage and is treated with prostatectomy or radiation therapy. However, some patients are diagnosed with metastatic disease or recurrent disease after treatment of localized disease. Androgen ablation is the standard treatment for metastatic or recurrent disease. However, most patients who survive long enough eventually develop androgen-independent prostate cancer. At this stage of metastatic disease docetaxel, a chemotherapeutic agent has been demonstrated to confer a survival benefit of 1.9 to 2.4 months in randomized clinical trials. Chemotherapy with docetaxel causes adverse effects in large proportions of patients, including alopecia, fatigue, neutropenia, neuropathy, and other symptoms. The trials evaluating docetaxel included both asymptomatic and symptomatic patients, and results suggested a survival benefit for both symptomatic and asymptomatic patients. Because of the burden of treatment and its side effects, most patients therefore defer docetaxel treatment until the cancer recurrence is symptomatic.

Cancer immunotherapy has been investigated as a treatment which might be instituted at the point of detection of androgen-independent metastatic disease before significant symptomatic manifestations have occurred. The quantity of cancer cells in the patient during this time interval is thought to be relatively low, and it is thought that an effective immune response against the cancer during this period could effectively delay or prevent progression. Such a delay could allow effective chemotherapy such as docetaxel to be deferred or delayed until necessary, thus providing an overall survival benefit.

Sipuleucel-T (Provenge®, Dendreon Corp.) is a new class of therapeutic agent used in the treatment of asymptomatic or minimally symptomatic, androgen-independent (hormone-refractory), metastatic prostate cancer. It consists of specially treated dendritic cells obtained from the patient with leukapheresis. The cells are then exposed in vitro to proteins that contain prostate antigens and immunologic stimulating factors, and then reinfused back into the patient. The proposed mechanism of action is that the treatment stimulates the patient’s own immune system to resist spread of the cancer.

The cells are administered as three intravenous (IV) infusions, each infusion given approximately two weeks apart.

Regulatory Status

On April 29, 2010, the U.S. Food and Drug Administration (FDA) approved Provenge® (sipuleucel-T, Dendreon Corp.) via a Biologics Licensing Application (BLA) for "the treatment of asymptomatic or minimally symptomatic metastatic castrate resistant (hormone refractory) prostate cancer (for autologous use only). Approval was contingent on agreement of the manufacturer to conduct a postmarketing study, based on a registry design, to assess the risk of cerebrovascular events in 1,500 patients with prostate cancer who receive sipuleucel-T.


According to the FDA-approved labeling of Provenge, the recommended course of therapy for sipuleucel-T is three complete doses, given at approximately two-week intervals. In controlled clinical trials, the median dosing interval between infusions was two weeks (range 1 to 15 weeks); the maximum dosing interval has not been established.


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.


Sipuleucel-T therapy (Provenge) may be considered medically necessary for the treatment of patients who meet all the following criteria:

  • Histologically documented adenocarcinoma of the prostate; and 
  • Metastatic disease as evidenced by soft tissue and/or bony metastases; and 
  • Asymptomatic or minimally symptomatic – (without cancer-related bone pain or use of opioid analgesics for cancer pain); and
  • Current hormonal therapy consisting of castration by orchiectomy or Luteinizing hormone-releasing hormone (LHRH) agonists* documented by castrate level of testosterone (<50 ng/dl); and
  • Documented evidence of progressive disease** after surgical or chemical castration, (known as castrate-resistant, hormone-refractory, or androgen-independent prostate cancer); and
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 (defined below);
    • 0 - Fully active, able to carry on all pre-disease performance without restriction,
    • 1 - Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, (e.g., light house work, office work); and
  • No visceral (liver, lung, or brain) metastases; and
  • Life expectancy greater than six months.

Sipuleucel-T therapy (Provenge) is considered experimental, investigational and unproven for all other indications including but not limited to prevention of prostate cancer and treatment of localized prostate cancer.

*Note: LHRH agonists (analogs) include leuprolide (Lupron, Viadur, and Eligard), goserelin (Zoladex), triptorelin (Trelstar), and histrelin (Vantas). Degarelix (Firmagon) is an LHRH antagonist that is thought to work like LHRH agonists.

**Note:  Progressive measurable disease, worsening disease on bone scan, or an increasing prostate-specific antigen (PSA), is defined by the “Prostate Cancer Clinical Trials Working Group” as:

  • Progressive measurable disease, as evidenced by changes in size of lymph nodes or parenchymal masses on physical examination or radiographic studies; or
  • Bone scan progression, as evidenced by one or more new lesions or increase in size of lesions (not including "flare" that occurs at commencement of hormonal therapy or chemotherapy); or
  • PSA progression: An increase in PSA over a previous reference value, where the PSA value is a measurement at a minimum of one week from the reference value, and the PSA measurement is a minimum of 25 percent greater than the reference value, and an absolute-value increase in PSA of at least 5 ng/ml over the reference value, and this PSA increase is confirmed by a second value.


This policy was originally developed in 2011 and has been updated with searches of scientific literature through July 2013. This section of the current policy has been substantially revised. The following is a summary of the key literature to date.

Metastatic, androgen-independent prostate cancer

Sipuleucel-T has been studied most definitively in a series of double-blind, placebo-controlled randomized controlled trials (RCTs). (3) Results of 2 of these studies have been published by Small et al. (4) and Higano et al. (5) and extensively presented in a briefing document available from the U.S. Food and Drug Administration (FDA). (6) Results of the third and largest trial are not published but were presented at the American Urological Association meeting in April 2009 and summarized in an FDA press release in April 2010. (7) Patients enrolled in these trials all had androgen-independent metastatic prostate cancer, were asymptomatic or mildly symptomatic, in good physical health characterized by Eastern Cooperative Oncology Group (ECOG ) performance status 0 or 1, and had tumors with positive staining for prostatic acid phosphatase.

In the 2 early identically designed studies, (3-6) patients with asymptomatic metastatic prostate cancer were randomized to receive either sipuleucel-T or a control infusion of untreated dendritic cells. The principal outcome of these studies was time to disease progression, defined as the time from randomization to the first observation of disease progression. Disease progression could be defined as radiologic progression (based on several imaging criteria), clinical progression (based on prostate cancer-related clinical events such as pathologic fracture), or pain progression (based on onset of pain corresponding to anatomic location of disease).

The studies were not designed to establish efficacy based on overall survival. Upon progression of cancer, patients were allowed to have additional treatment as needed including chemotherapy. Patients originally assigned to placebo were allowed to cross over by receiving their own dendritic cells pulsed with PA2024, but prepared from frozen dendritic cells harvested from their initial leukapheresis procedures.

Results of study 9901A for the principal outcome of time to progression did not show a significant difference between vaccine and control. Median time to progression was 11.7 weeks for the vaccine group and 10.0 weeks for the control group.

A survival analysis of study 9901A was presented in the FDA briefing document, with the caveats that the study was not powered to show a survival effect and that a primary method of survival analysis was not prespecified in the protocol. The median survival times for vaccine-treated patients was 25.9 months and for placebo-treated patients was 21.4 months, which was statistically significant (p=0.011; log-rank test). At 36 months, the survival rate was 34% for vaccine-treated patients and 11% for placebo-treated patients.

The FDA briefing document (6) shows analyses of possible confounders regarding the survival analysis. After disease progression, patients in both groups received chemotherapy, but the rate of chemotherapy was slightly higher in the placebo-treated groups (48% versus 36%, respectively). Examination of the causes of death did not reveal any obvious spurious elevation of non-cancer causes of death in the placebo group. The published version of study 9901A by Small et al. (4) analyzed the survival data after adjusting for prognostic factors and found a significant association of sipuleucel-T treatment and survival (hazard ratio [HR]: 2.12; 95% confidence interval [CI]: 1.31–3.44).

Because study 9901A did not meet its principal outcome endpoint for efficacy, enrollment for its partner study 9902A was suspended. Its sample size was therefore smaller, and the study subsequently had lower statistical power. Results for study 9902A showed a median time to progression of 10.9 weeks in the vaccine group versus 9.9 weeks in the placebo group, which was not statistically significant. A survival analysis of study 9902A showed that vaccine-treated patients had a median survival of 19 months, and control patients had a median survival of 15.7 months, which was also not statistically significant.

The two studies’ survival data were pooled in the study by Higano et al. (5) The pooled analysis showed a 33% reduction in the risk of death (HR: 1.50; 95% CI: 1.10–2.05, p=0.011). The association was robust to adjustments in imbalances in baseline prognostic factors and post-progression chemotherapy use.

Because these earlier studies did not meet criteria for success for their principal endpoints, the FDA did not approve sipuleucel-T in 2007. A larger Phase III trial of similar design called IMPACT enrolling 512 patients was designed with a principal endpoint of overall survival. Analyses reported at the American Urological Association in April 2009 and used to support FDA approval reported a 22% reduction in overall mortality in patients treated with sipuleucel-T. Treatment extended median survival by 4.1 months, compared to placebo (25.8 months versus 21.7 months, respectively) and improved 3-year survival by a relative 38%, compared to placebo (31.7% versus 23.0%, respectively). Results adjusted for subsequent docetaxel use and timing, as well as analyses examining prostate cancer-specific survival showed similar magnitude and statistical significance of the survival benefit. Of note, 14% of enrolled subjects in this trial had received prior docetaxel treatment.

Regarding the safety of sipuleucel-T, most adverse effects were grade 1 and 2 and resolved within 48 hours. The rate of serious adverse events was not statistically different between vaccine- and placebo-treated patients. However, one difficulty in assessing potential adverse effects by comparing sipuleucel-T to placebo is that the placebo consisted of infusion of untreated dendritic cells, which may cause adverse effects. Concern was expressed in the FDA review regarding a possible association with cerebrovascular events, as 8/147 vaccine-treated patients experienced cerebrovascular-related adverse events, compared to zero placebo-treated patients in the 2 early trials. (6) In the latest available report of adverse effects reported in the full prescribing information documents, (3) the stroke rate was 3.5% in the sipuleucel-T group and 2.6% in the control group, but these figures appear to include data from trials evaluating a different indication. In the FDA review summarizing cerebrovascular event rates from studies 9901A, 9902A, and interim data from IMPACT, the rate was 4.9% (17/345) in the sipuleucel-T- treated subjects and 1.7% (3/172) in placebo-treated subjects (p=0.092). The FDA review called the cerebrovascular event rate a “potential safety signal” and included as part of the approval, a postmarketing study, based on a registry design, to assess the risk of cerebrovascular events in 1,500 patients with prostate cancer who receive sipuleucel-T.


For patients with metastatic, androgen-independent prostate cancer, 3 RCTs have been completed and 2 of these have been published. The 3 RCTs are consistent in reporting an improvement in overall survival of approximately 4 months compared to placebo. Two trials also report that 36-month survival was significantly improved for patients receiving sipuleucel-T, with absolute improvements in survival of 9% and 23%. Time to progression was slightly longer in the sipuleucel-T groups, but this difference was not statistically significant. Serious adverse events were not increased in the sipuleucel-T group. There has been concern raised about a possible increase in stroke risk, but the available trials do not show a significantly increased rate of stroke.

Other indications

A Phase III trial of sipuleucel-T in the setting of androgen-dependent, nonmetastatic prostate cancer was published in 2011. (8) Patients with prostate cancer detectable by PSA following radical prostatectomy received 3 to 4 months of androgen suppression therapy and were then randomized (2:1) to receive sipuleucel-T (n=117) or control (n=59). The primary endpoint was time to biochemical failure. There was no difference in this endpoint between groups; median time to biochemical failure was 18.0 months for sipuleucel-T and 15.4 months for control (HR: 0.936, p=0.737). Sipuleucel-T patients had a 48% increase in PSA doubling time following testosterone recovery (155 vs. 105 days, p=0.038). Sixteen percent of patients developed distant failure. The treatment effect favored sipuleucel-T but was not statistically significant (HR: 0.728, p=0.421).


 A single RCT has been performed in patients with non-metastatic prostate cancer, and this trial did not show any benefit for sipuleucel-T compared to control. Therefore, the evidence on treatment of non-metastatic prostate cancer is not sufficient to determine that health outcomes are improved.

Ongoing trials

Other indications are currently being investigated in clinical trials in progress or recruiting patients. A trial to determine whether sipuleucel-T and androgen deprivation therapy augment each other in patients with recurrent but non-metastatic prostate cancer is currently in progress. Concurrent versus sequential sipuleucel-T plus a newly approved drug abiraterone is also being investigated. Finally, sipuleucel-T as neoadjuvant therapy for patients with localized prostate cancer undergoing prostatectomy is being investigated.

Practice Guidelines and Position Statements

The National Comprehensive Cancer Network (NCCN) Guidelines for Prostate Cancer Version 4/2013 list Sipuleucel-T as a category 1 treatment recommendation for patients with castration-recurrent prostate cancer. (9) A note was also added indicating that sipuleucel-T is appropriate for asymptomatic or minimally symptomatic patients with ECOG performance status 0-1; and it is not recommended for patients with visceral disease and a life expectancy less than 6 months. A 2012 update to the NCCN guidelines updated this recommendation to include patients who had failed chemotherapy who otherwise met criteria for treatment with sipuleucel-T. (10) Sipuleucel-T is considered second-line therapy in this setting, however. This was based on further analysis of the previously reviewed clinical trials which showed similar benefit in both those who had and had not received prior chemotherapy.


For patients with metastatic, androgen-independent prostate cancer, 3 randomized, controlled trials of sipuleucel-T report an improvement in median survival of approximately 4 months. The 2 early studies of sipuleucel-T were not specifically designed to demonstrate a difference in overall mortality but did show a survival difference. The third study, which was designed to demonstrate a mortality difference, showed a similar improvement in overall survival. All 3 studies are also consistent in demonstrating that sipuleucel-T treatment does not delay time to measureable progression of disease. In all studies, many patients had further chemotherapy treatment at the discretion of their physician, thus, the survival benefit accrues in the context of additional treatment as needed for symptomatic recurrence. This evidence is sufficient to conclude that sipuleucel-T is medically necessary for patients with androgen-independent, asymptomatic or minimally symptomatic, metastatic prostate cancer.


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. 

Rationale for Benefit Administration
ICD-9 Codes

185, 198.5, 198.89, V45.77

ICD-10 Codes
C61, 6A550Z1, 6A551Z1, 30233Q0, 30243Q0
Procedural Codes: Q2043
  1. Berry DL, Moinpour CM, Jiang CS et al. Quality of life and pain in advanced stage prostate cancer: results of a Southwest Oncology Group randomized trial comparing docetaxel and estramustine to mitoxantrone and prednisone. J Clin Oncol 2006; 24(18):2828-35.
  2. Tannock IF, de WR, Berry WR et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 2004; 351(15):1502-12.
  3. Dendreon Corporation. Seattle W. Provenge® (sipuleucel-T) prescribing information. 2010. Available online at: . Last accessed June 2013.
  4. Small EJ, Schellhammer PF, Higano CS et al. Placebo-controlled phase III trial of immunologic therapy with sipuleucel-T (APC8015) in patients with metastatic, asymptomatic hormone refractory prostate cancer. J Clin Oncol 2006; 24(19):3089-94.
  5. Higano CS, Schellhammer PF, Small EJ et al. Integrated data from 2 randomized, double-blind, placebo-controlled, phase 3 trials of active cellular immunotherapy with sipuleucel-T in advanced prostate cancer. Cancer 2009; 115(16):3670-9.
  6. U.S. Food and Drug Administration. Cellular Tissue and Gene Therapies Advisory Committee Meeting. Clinical Briefing Document: Provenge (Sipuleucel T). March 29, 2007. Available online at: . Last accessed June 2013.
  7. U.S. Food and Drug Administration. Press release: FDA Approves a Cellular Immunotherapy for Men with Advanced Prostate Cancer. 2010. Available online at: . Last accessed June 2013.
  8. Beer TM, Bernstein GT, Corman JM et al. Randomized trial of autologous cellular immunotherapy with sipuleucel-T in androgen-dependent prostate cancer. Clin Cancer Res 2011; 17(13):4558-567.
  9. National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology Prostate Cancer. Version 4 2013. Available online at: . Last accessed July 2013.
  10. Mohler JL, Armstrong AJ, Bahnson RR et al. Prostate cancer, Version 3.2012: featured updates to the NCCN guidelines. J Natl Compr Canc Netw 2012; 10(9):1081-7.
  11. Cellular Immunotherapy for Prostate Cancer. Blue Cross Blue Shield Association Medical Policy Reference Manual (2013 July) 8.01.53.
July 2011 New policy, New HCPCS code Q2043
November 2012 Previously unpublished preliminary trial information updated with published information.  Medicare coverage decision granted 6/30/2011, section updated.  Policy updated with literature review.  References 8 and 10 added.  No change to policy statements.  Policy title changed from Provenge(sipuleucel-t) to Cellular Immunotherapy for Prostate Cancer.
April 2013 Policy title changed from "Cellular Immunotherapy for Prostate Cancer" to "Cellular Immunotherapy for Prostate Cancer (Sipuleucel-T [Provenge])".  More restrictive criteria added to the Medically Necessary statement.  Removed codes 36511, 96365, and C9273.  Language and formatting revised.
®Registered marks of the Blue Cross and Blue Shield Association, an association of independent Blue Cross and Blue Shield Plans. ®LIVE SMART. LIVE HEALTHY. is a registered mark of BCBSMT, an independent licensee of the Blue Cross and Blue Shield Association, serving the residents and businesses of Montana.
CPT codes, descriptions and material only are copyrighted by the American Medical Association. All Rights Reserved. No fee schedules, basic units, relative values or related listings are included in CPT. The AMA assumes no liability for the data contained herein. Applicable FARS/DFARS Restrictions Apply to Government Use. CPT only © American Medical Association.
Cellular Immunotherapy for Prostate Cancer (Sipuleucel-T [Provenge])