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ACR Appropriateness Criteria®

Clinical Condition: Post Treatment Follow-up of Prostate Cancer

Variant 1: Status post radical prostatectomy. Rising PSA Level.

Note: Abbreviations used in the tables are listed at the end of the "Major Recommendations" field.

Variant 2: Status post radiation therapy. Rising PSA level.

Note: Abbreviations used in the tables are listed at the end of the "Major Recommendations" field.

Variant 3: Treatment of metastatic prostate cancer by androgen deprivation therapy (ADT). Rising PSA level.

Note: Abbreviations used in the tables are listed at the end of the "Major Recommendations" field.

Summary of Literature Review

In evaluating of patients with recurrent or metastatic prostate cancer, it is important to define the location, size and the extent of local and/or distant tumors. Prostate cancer is treated by four standard methods: radical prostatectomy, radiation therapy, cryosurgical ablation, or androgen deprivation therapy (ADT). The treatment choice is based on the stage of the tumor as well as the histology and grade and is influenced to a certain extent by the preference of the treating physician and the patient. After treatment, patients are followed at periodic intervals with measurement of serum prostate-specific antigen (PSA) levels and digital rectal examination (DRE). However, DRE is frequently unreliable in evaluating local recurrent disease after radical prostatectomy.

PSA is produced by the epithelial cells of the prostate gland and is therefore specific for prostatic tissue. A rise in PSA is detected in the serum when the prostate gland has been disrupted as with prostate cancer, benign prostatic hyperplasia (BPH), or acute prostatitis, or following prostate biopsy. PSA is now widely used as a tumor marker for prostate cancer, both for detection and for monitoring response to therapy. No imaging study is necessary after treatment for clinically localized prostate cancer unless the PSA is elevated, the DRE is abnormal, or the patient has bone pain.

Although PSA alone does not differentiate local from distant disease recurrence, the patterns of PSA rise after local therapy can help to differentiate local from distant failure. Patients with a late biochemical recurrence (>24 months after local treatment), low PSA velocity (change in PSA over time), and/or prolonged PSA doubling time (>6 months) most likely have recurrent local disease. Conversely, patients with a rapid PSA recurrence (<24 months after local treatment), high PSA velocity, or short PSA doubling time (<6 months) are more likely to have distant disease recurrence.

Bone x-rays are not sensitive for detecting metastasis compared with radionuclide bone scans, but they may be helpful in identifying degenerative changes as the cause for a positive bone scan. Chest x-ray is not necessary because lung metastases are only found in late-stage disease after other more common sites are involved by tumor.

Whole-body bone scans are frequently performed for detecting skeletal metastases in patients with rising PSA following treatment. If the bone scan is positive for metastatic disease, no other imaging is indicated. One study suggested that bone scans be done annually in patients without evidence of metastatic disease and in patients with clinical or biochemical indications of recurrent disease. However, since bone scans are rarely positive without symptoms or without abnormal PSA levels, the routine use of this study post treatment is considered unproductive by some investigators. Another study found three patients with bone metastases in a series of 59 patients without suspicious serum PSA levels. A bone scan may be inconclusive since it is a sensitive but not specific examination. Magnetic resonance imaging (MRI) may be helpful in the diagnosis of bone metastasis when other examinations are conflicting, and it can be used to determine response to hormonal treatment. A comparison of MRI and bone scans showed 818 abnormal vertebrae detected by MRI versus 499 by bone scan in the same group of patients.

Post Radical Prostatectomy

Following radical prostatectomy, PSA levels are expected to be undetectable to less than 0.15 ng/ml within several weeks of surgery. Waiting 6-8 weeks after treatment is advisable before assessing the serum PSA value since the half-life of serum PSA is relatively long. Since the PSA is specific for the prostate, detectable PSA levels mean that there is residual prostate tissue. If there is a rise in a previously undetectable or stable postoperative PSA level, a prompt search for persistent, recurrent, or metastatic disease should be pursued. The major objective of the diagnostic imaging studies is to assess patients for the presence of distant metastatic disease or local recurrent disease, each requiring different forms of systemic or local therapy.

Radionuclide Bone Scintigraphy

Radionuclide bone scan is traditionally the first examination obtained. If the bone scan is positive for metastatic disease, no further imaging studies are necessary. If the bone scan is inconclusive, further imaging studies are performed, including conventional radiographs, MRI, or computed tomography (CT). However, the level of post-treatment PSA that should prompt a bone scan is uncertain. In a study of patients with biochemical failure following radical prostatectomy, the probability of a positive bone scan was less than 5% with PSA levels between 40 to 45 ng/mL. In another study, bone scan was limited until PSA rose above 30 to 40 ng/mL. Men with PSA doubling times less than 6 months after radical prostatectomy were at increased risk of a positive bone scan (26% vs. 3%) or positive CT (24% vs. 0%) compared to those with longer PSA doubling time.

Based on a survey by the American Urology Association (AUA) on current practice strategies for follow-up after radical prostatectomy, bone scans are recommended only if the patient had symptoms of bone pain, a rapid rise in PSA (PSA velocity), or a significantly elevated PSA value.

Transrectal Ultrasonography

The use of imaging in the evaluation of local tumor recurrence is controversial. Transrectal ultrasound (TRUS) with guided biopsy of the vesicourethral anastomosis (VUA) has been the standard imaging approach to document local recurrence. A palpable abnormality is not always a good guide to the location of recurrent or progressive tumor because postoperative fibrosis may mimic tumor. Negative results of ultrasound-guided transrectal biopsy of the VUA, regardless of a palpable mass or indurations, may be inconclusive because of sampling error. The use of biopsy has been questioned in the face of a rising PSA level, since the negative results are unreliable and elevated PSA levels usually precede clinical evidence of local recurrence by one or more years. Repeat TRUS with VUA needle biopsy may be necessary in one-third of cases. The yield for detecting local recurrent tumor with TRUS with needle biopsy rises significantly with serum PSA levels. Only about 25% of men with prostatectomy PSA levels of less than 1 ng/mL have histologic confirmation of local recurrence after biopsy of the prostatic fossa. None of the patients with PSA levels of 0.5 ng/mL or less who had negative DRE and TRUS have a biopsy-proved local recurrence.

A staging pelvic lymphadenectomy is sometimes done at the time of a radical retropubic prostatectomy; therefore, follow-up of the lymph nodes usually is not necessary in such cases. However, if the biopsy of the VUA is repeatedly negative in the face of a rising PSA level, then pelvic imaging looking for adenopathy with CT or MRI may be indicated.

Computed Tomography

CT is not effective for detecting recurrent tumor in the surgical bed. A CT scan can recognize only local recurrences that are greater than or equal to 2 grams. The mean PSA value associated with a positive CT scan after radical prostatectomy was 27.4 ng/mL.

In the evaluation of nodal disease, CT has replaced lymphography and relies on nodal size to detect nodal metastases. Using 1 cm as a cutoff, studies have reported sensitivity between 27% to 75% and specificity between 66% to 100%. By decreasing the size cutoff to 0.7 cm and by sampling suspicious nodes by fine-needle aspiration (FNA), one group of researchers were able to attain a sensitivity of 78% and specificity of 100%. However, this decreased size criteria with concomitant use of FNA has not been widely adopted. CT is useful in detecting bone and visceral metastases, although bone scan and MRI are superior in the diagnosis and follow-up of bone metastases.

Magnetic Resonance Imaging

The use of MRI is evolving and has potential to evaluate both local recurrence and distant bony and nodal metastases. MRI utilizing an endorectal coil is used to evaluate local recurrence. In a study by one group of researchers, MRI was positive in men with cancer recurrence only with a concomitant rise in PSA level. In the absence of PSA rise, despite suspicious findings on DRE, the MRI was negative. In another study of 16 patients with rising PSA after radical prostatectomy and negative transrectal ultrasound-guided biopsy, gadolinium-enhanced, dynamic endorectal coil MRI demonstrated nodular enhancing lesions in 13 of 16 patients (84%). In 8 of the 13 patients with positive MRI findings, PSA levels decreased after radiation therapy. Concurrent MRI-directed biopsy of suspicious sites is not available, making histologic correlation and assessment of its true utility difficult.

The accuracy of MRI for staging pelvic lymph nodes by size criteria is similar to that of CT. MRI can be more sensitive and specific in the diagnosis of bone metastases with better spatial and contrast resolution when compared to bone scan. MRI cannot cover the entire skeleton within a reasonable time at a reasonable cost. Therefore, it is only useful when other imaging modality findings are indeterminate. Response of bone metastases to treatment can be more accurately monitored by serial MRI scans.

Post Radiation Therapy

Prostate cancer treated with radiation therapy (RT) is monitored differently, since the prostate and the lymph nodes are left in place. Following radiation therapy, the serum PSA level decreases in the majority of the patients during the first year. Surveillance for tumor recurrence in patients post radiation therapy should include a DRE and serial serum PSA levels. The prostate gland becomes atrophic and fibrotic after radiation treatment, making distinction between local recurrent disease and benign irradiated prostatic gland difficult by DRE alone. The American Society of Therapeutic Radiology and Oncology (ASTRO) has defined recurrence following radiation therapy as three consecutive rises in serum PSA following a post-RT PSA nadir. An increasing serum PSA level will prompt radionuclide bone scan. If the bone scan is positive, no further evaluation is necessary. If the bone scan is inconclusive, MRI may be helpful. If the bone scan is negative or inconclusive, TRUS-directed biopsy of the prostate is indicated. MRI may be indicated to depict local recurrence after radiotherapy. In 22 patients with rising PSA after external beam radiation therapy, contrast-enhanced dynamic MRI demonstrated areas of recurrent intraprostatic tumor more accurately and with less interobserver variability than T2-weighted images did. Evaluation for lymph node enlargement is done by either CT or MRI. Both imaging tests are relatively accurate for detecting lymph node enlargement.

Post Cryosurgery

Serum PSA should fall to a low level 6 to 8 weeks following cryosurgery and should not rise on successive occasions. Follow-up after cryosurgery should be the same as that after radiotherapy, and it seems reasonable to use similar guidelines to define disease recurrence. It is often difficult to differentiate recurrent tumor from post-cryosurgery changes by means of DRE, TRUS, and MRI.

Post Androgen Deprivation Therapy

ADT—using bilateral orchiectomy, luteinizing hormone-releasing hormone analogue, diethylstilbestrol, bilateral orchiectomy and flutamide, and luteinizing hormone-releasing hormone analogue and flutamide—may control prostate cancer for long periods by decreasing the size of the tumor, thus relieving pain and other symptoms in patients with advanced disease. ADT may be added to definitive therapy (radical prostatectomy, radiation therapy, and cryosurgery) in patients with early-stage disease as adjuvant therapy (after definitive therapy) or neoadjuvant therapy (prior to definitive therapy). ADT may have a direct suppressive effect on serum PSA level that is independent of tumor activity. PSA production is under hormonal control, and ADT reduces the cell's ability to produce and secrete PSA. Therefore, serum PSA is not always a reliable marker of disease status in these patients.

In a study by one group of researchers, serial serum PSA measurements after ADT were able to predict response to the treatment. Patients whose serum PSA levels remained elevated for more than three months after treatment had a high risk of disease progression within two years. Serial PSA determinations in combination with radionuclide bone scanning are clinically warranted in these patients with advanced disease as follow-up. In patients with an increasing serum PSA level, the investigation can end if the bone scan is conclusive. CT is also useful in assessing nodal or visceral metastatic disease. If the bone scan and CT are negative or inconclusive, further investigation for metastasis may be pursued using MRI.

Summary

All patients treated for prostate cancer are monitored with serial PSA measurements and DRE. A radionuclide bone scan has traditionally been obtained at one year after treatment regardless of PSA level. This tradition is now being challenged, but bone scans are still commonly obtained after ADT.

A rising PSA level usually prompts a bone scan. If it is positive, no other imaging is indicated. An equivocal bone scan may lead to more refined imaging such as MRI or CT. A negative bone scan requires further investigation such as TRUS-guided biopsy (post local therapy, including prostatectomy, radiation therapy, and cryosurgery) and lymph node evaluation with CT or MRI. Endorectal coil MRI is evolving and provides useful information regarding local recurrence as well as pelvic nodal and bone metastases. Chest x-ray is not necessary because prostatic lung metastasis is only found in late stage disease after other metastatic sites are well established. Bone x-rays are only used to help in identifying degenerative bone changes as a cause for abnormal foci on radionuclide bone scans.

New Techniques

ProstaScint Scan (111 Indium capromab pendetide)

ProstaScint is a murine monoclonal antibody that targets prostate-specific membrane antigen (PSMA). ProstaScint imaging in the detection of metastases and local recurrence has been reported to have a sensitivity of 49% to 94%, a specificity of 65% to 72%, and an overall accuracy of 63% to 80%. However, there are still questions remaining regarding its optimal use. Further, the scans are challenging to interpret and expensive to perform. It has been reported that the likelihood of a positive scan outcome is enhanced when patients with high PSA levels and high Gleason grade tumors are felt to have a recurrence. Fused SPECT/CT or MRI will improve the specificity of ProstaScint examination in detecting recurrent prostate cancer.

Positron Emission Tomography with 2-deoxy-2- [F-18] fluoro-D-glucose

Many foci of metastatic prostate cancer demonstrate increased FDG accumulation, though this uptake is generally low compared to the other cancers. FDG-PET is relatively insensitive in detecting osseous metastases compared to standard bone scintigraphy. Helical CT and FDG-PET scanning may be more helpful than ProstaScint imaging in detecting nodal disease in men with high PSA level after radical prostatectomy. PET/CT can provide information about anatomy and metabolism of the recurrent and metastatic disease.

Positron Emission Tomography with Newer Radiotracers including [11-C]-acetate, [11-C or 18-F]-choline, and [11-C]-methionine

PET with 11C acetate and PET with 11C and 18F choline have been reported to detect recurrent disease in patients with high PSA after local treatment. PET with 11C methionine has been reported to be more sensitive than FDG-PET in detecting bone metastases. The efficacy and clinical utility of PET with these new agents are under investigation.

Magnetic Resonance Spectroscopic Imaging

MR spectroscopic imaging (MRSI) provides metabolic information from 3-dimensional multiple contiguous volumes (voxels) within the prostate gland. Addition of the metabolic information provided by MRSI to the morphologic information provided by endorectal coil MRI can help discriminate regions of residual tumor from other prostatic tissues and necrosis following radiation therapy, cryosurgery, and hormone therapy. Time-dependent effects of hormone therapy on prostate metabolism are detected on MRSI. However, prostate metabolic profiles associated with prostate cancer can be identifiable on MRSI in patients with PSA levels exceeding 0.20 ng/mL and with 3 months or less of neoadjuvant hormone therapy for locally confined prostate cancer.

Newer Lymph Nodal Magnetic Resonance Contrast Agent

MRI following IV administration of lymphotropic superparamagnetic iron oxide nanoparticles has been reported to improve detection of positive lymph nodal metastases from prostate cancer when compared to unenhanced MRI. This MRI contrast agent is investigational and is not commercially available at this time.

Anticipated Exceptions

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