Initial staging and evaluation of males with newly diagnosed prostate cancer

INTRODUCTION — Prostate cancer is the second most common cancer in males worldwide, according to data from the worldwide GLOBOCAN database. In the United States, it is the most common cancer diagnosed in males; there will be an estimated 268,490 cases and 34,500 deaths from prostate cancer in 2022 [1].

Once the diagnosis of prostate cancer is established, further evaluation that incorporates known risk factors is required to determine appropriate treatment options. The prostate cancer staging system and initial staging evaluation are reviewed here.

The initial clinical presentation, indications for prostate biopsy, utility of prostate magnetic resonance imaging (MRI), ramifications of risk stratification, and approach to treatment are discussed separately:

●(See "Clinical presentation and diagnosis of prostate cancer".)

●(See "Localized prostate cancer: Risk stratification and choice of initial treatment".)

●(See "The role of magnetic resonance imaging in prostate cancer".)

●(See "Initial approach to low- and very low-risk clinically localized prostate cancer".)

●(See "Initial management of regionally localized intermediate-, high-, and very high-risk prostate cancer and those with clinical lymph node involvement".)

STAGING SYSTEM — The staging system developed jointly by the American Joint Committee on Cancer (AJCC) and the Union for International Cancer Control (UICC) is used in males with newly diagnosed prostate cancer [2].

The eighth edition (2017) combines information about the extent of the primary tumor (T), lymph node (N) involvement, and presence or absence of distant metastasis (M), along with the serum prostate-specific antigen (PSA) level and the histologic grade group of the primary tumor, to classify males into prognostic stage groups according to their risk of recurrence (table 1 and table 2) [2].

Clinical versus pathologic TNM staging — Males with newly diagnosed prostate cancers are assigned a clinical prognostic stage group, which is based on information from the prostate biopsy, digital rectal examination (DRE), and in some cases, imaging studies.

Patients who subsequently undergo radical prostatectomy are assigned a pathologic prognostic stage group based on histologic examination of the surgical resection specimen. Males who do not undergo prostatectomy are not assigned a pathologic stage, and treatment decisions are based on the clinical stage.

Clinical staging can underestimate or overestimate the extent of disease when compared with results based on pathologic examination of a resection specimen. The limitations of clinical staging and its implications for risk stratification are discussed separately. (See "Localized prostate cancer: Risk stratification and choice of initial treatment", section on 'Risk stratification'.)

Tumor (T) stage

Clinical T stage — Clinical staging of the tumor provides the basis for initial decisions regarding the extent of evaluation and treatment options. (See 'Evaluating the extent of local disease' below.)

Clinical staging is based on the results of the DRE, transrectal ultrasound (TRUS)-guided biopsy findings, and in some cases, imaging studies (table 1):

●T1 lesions are not palpable. T1a and T1b lesions are those detected incidentally in pathology specimens of resected prostate tissue, including detection during transurethral resection performed for nononcologic reasons. T1c lesions are those diagnosed in a prostate biopsy performed because of an elevated PSA or prostatic symptoms in the absence of an abnormality on DRE.

●T2 lesions are palpable but appear to be confined to the prostate. Unilateral T2 lesions are subdivided into T2a and T2b lesions based on the extent of involvement; if there is bilateral involvement, lesions are classified as T2c.

●T3 lesions extend through the prostatic capsule (T3a). If there is involvement of the seminal vesicles, these are classified as T3b lesions.

●T4 tumors are fixed to or invade adjacent structures.

Although clinical staging is necessary to plan initial treatment, both DRE and imaging procedures can significantly underestimate the extent of disease.

Pathologic T stage — A more accurate assessment of the extent of disease is possible in patients who undergo radical prostatectomy, which permits pathologic staging (table 1):

●T2 lesions are confined to the prostate. These lesions are subdivided based on whether disease is unilateral or bilateral and the extent of involvement.

●T3 lesions have extraprostatic extension. Pathologic T3a lesions have extraprostatic extension to or microscopic invasion of the bladder neck. Seminal vesicle invasion categorizes a lesion as pathologic T3b.

●T4 lesions are fixed or have invasion of adjacent structures other than the seminal vesicles.

Node (N) stage — Both clinical and pathologic staging define regional lymph nodes as not assessed (NX), negative (N0), or positive (N1) (table 1).

Regional lymph nodes are the nodes of the true pelvis, which are below the bifurcation of the common iliac arteries; they include pelvic, not otherwise specified, hypogastric, obturator, iliac, and sacral nodes (figure 1). Lymph nodes that lie outside of the confines of the true pelvis (paraaortic lumbar, common iliac, superficial and deep inguinal, retroperitoneal, and anything more distant) are considered distant metastases.

Metastasis (M) — Patients are classified as either not having distant metastasis (M0) or distant metastasis present (M1). Patients with metastasis are subclassified based on the site(s) of disease (table 1). Patients with metastasis are subdivided into those with nonregional lymph node involvement (M1a), bone metastasis (M1b), or other metastatic sites with or without bone involvement (M1c). Prostate cancer metastasizes preferentially to bone, and early involvement of other distant sites is uncommon.

Serum prostate-specific antigen (PSA) — The serum PSA level at presentation provides important prognostic information that is useful for determining the extent of workup required after initial biopsy and for planning subsequent treatment. A higher baseline serum PSA is associated with an increased risk of identifying more advanced disease, as well as of subsequent disease progression. This information is incorporated into the prognostic stage groups (table 2). (See "Clinical presentation and diagnosis of prostate cancer", section on 'PSA testing' and "Measurement of prostate-specific antigen".)

Histologic grade group — The histologic grade group is based solely on the architectural features of the prostate cancer cells (table 3). (See "Interpretation of prostate biopsy", section on 'Gleason grading system'.)

A higher histologic grade group indicates a greater likelihood of having non-organ-confined disease, as well as a worse outcome after treatment of localized disease.

Notably, biopsy obtained from extraprostatic disease (bone marrow, lymph node) is not assigned a Gleason score. In addition, a Gleason grade group is usually not assigned for prostate tissue exposed to treatment (eg, radiation therapy, androgen deprivation therapy) prior to prostatectomy.

Prognostic stage groups — The eighth edition (2017) of the AJCC/UICC staging system uses anatomic (TNM) information, along with pretreatment serum PSA and histologic grade group, to define prognostic groups for adenocarcinoma and squamous carcinoma of the prostate. The specific criteria for stage groups I through IVB are summarized in the table (table 2).

The addition of pretreatment serum PSA level and Gleason score to anatomic TNM staging to create these prognostic groups is based on multiple studies that demonstrate that these parameters are important determinants of outcome in addition to the TNM evaluation [3].

Even within these groups, there is substantial heterogeneity, which may have important implications for patient management. Additional features of the tumor that may have prognostic significance are the number and percentage of positive core biopsies, the presence of tumor perineural invasion, the presence of lymphovascular invasion, and cribriform architecture/intraductal histology. Although the eighth edition (2017) of the AJCC/UICC staging system does not take these additional factors into account, other prognostic models may incorporate some of these features. The routine use of these features and their incorporation into the staging system await further validation, but they should be considered when evaluating the patient. (See "Interpretation of prostate biopsy".)

RISK STRATIFICATION AND IMPLICATIONS FOR THE STAGING EVALUATION — As noted above, the clinical staging evaluation (based on digital rectal examination [DRE] by an experienced clinician to assess disease extent), pretreatment serum prostate-specific antigen (PSA), histologic grade group in the initial biopsy, and number and extent of cancer involvement in the biopsy cores are used to assign a prognostic stage group in the American Joint Committee on Cancer (AJCC) staging system. (See 'Staging system' above.)

NCCN risk stratification — A slightly different way of using this information to stratify males into clinical risk categories has been defined by the National Comprehensive Cancer Network (NCCN) (table 4) [4]. We use this six-tiered system of risk stratification to guide the choice of staging studies. (See 'Diagnosis' below.)

In addition, this risk stratification system has been utilized in guidelines for treatment of clinically localized prostate cancer from the American Urological Association (AUA)/American Society for Radiation Oncology (ASTRO)/Society of Urologic Oncology (SUO), which have been endorsed by the American Society of Clinical Oncology (ASCO) [5-7]. (See "Localized prostate cancer: Risk stratification and choice of initial treatment".)

ESMO — By contrast, the European Society for Medical Oncology (ESMO) and other European groups [8] use a three-tiered system for risk stratification of localized prostate cancer [9]:

●Low risk – cT1-T2a and International Society of Urological Pathology (ISUP) grade group 1 (table 3) (Gleason score ≤6) and PSA <10 ng/mL

●Intermediate risk – cT2b and ISUP grade group 2/3 (Gleason score 7) and/or PSA 10 to 20 ng/mL

●High risk – ≥cT2c or ISUP 4/5 (Gleason score 8 to 10) or PSA >20 ng/mL

Need for additional imaging — In general, assessment for soft tissue and bone metastases is appropriate for those with high- and very high-risk disease. Males with very low-, low-, and favorable intermediate-risk disease do not require further imaging with the exception of prostate MRI for those being considered for active surveillance or image-guided local therapy. Imaging for individuals with unfavorable intermediate-risk disease is controversial, and clinical practice is variable.

DIAGNOSIS — The diagnosis of prostate cancer requires a tissue diagnosis, which is generally obtained using a transrectal or transperineal approach. (See "Prostate biopsy".)

Some patients present with a very high prostate-specific antigen (PSA) level and staging studies consistent with metastatic disease, and there may be discussion about whether a confirmatory biopsy is needed. We recommend biopsy of either the prostate or a metastatic site in this situation in order to confirm the diagnosis of prostate cancer, exclude other cancer, inform treatment and prognostication, and enable current or future clinical trial eligibility.

STAGING EVALUATION — Once a diagnosis of prostate cancer is established through tissue biopsy, the extent of the staging evaluation prior to treatment should be based on multiple factors, including life expectancy, comorbidity, the presence or absence of symptoms, and risk category, which is based on the digital rectal examination (DRE), serum prostate-specific antigen (PSA), and information from the diagnostic biopsy (table 4). (See 'Risk stratification and implications for the staging evaluation' above.)

Evaluating the extent of local disease — Evaluation of local disease extent is typically accomplished with a combination of DRE and multiparametric MRI.

Digital rectal examination — DRE has clear limitations for defining local disease extent, but it is an important staging method. There can be significant interobserver variability. Although most tumors occur in the posterior portion of the prostate, some are located anteriorly and are not palpable.

Prostate MRI — There is increasing use of multiparametric MRI for staging the local extent and volume of prostate cancer, although there is no consensus on which patients should undergo MRI. Where prostate MRI is available, the authors and editors of this topic review recommend it for staging low-risk cases to ensure suitability for active surveillance and to guide further biopsy if needed. We also recommend it for males with high-risk disease for staging, particularly of the prostate/seminal vesicles and nodes. Prostate MRI can be done at the discretion of the treating clinician for males with intermediate-risk disease.

MRI technology (both hardware and software) has evolved considerably over the past two decades. The use of more powerful magnets (where available) has decreased the use of endorectal coil MRI and provides improved image resolution. (See "The role of magnetic resonance imaging in prostate cancer", section on 'Staging'.)

The International Prostate MRI Working Group developed the Prostate Imaging Reporting and Data System (PI-RADS) to standardize prostate MRI examination performance and reporting. The most recent version, PI-RADS v2.1, which was published in 2019, revises the technical parameters for image acquisition and modifies the interpretation criteria for MRI data, among other changes [10].

PI-RADS is used to characterize and assess all focal intraglandular prostate nodules seen on MRI. The system includes technical standards for scanning hardware and protocols for image acquisition and interpretation. It also provides standardized terminology for reporting and a sector map for all locations within the gland.

For PI-RADS v2 and v2.1, images should be acquired, if possible, with a 3 Tesla (3 T) magnet, and imaging at <1.5 T is specifically not recommended. Endorectal coil use is not required but is allowed if thought necessary for image quality. Diffusion weighting with high-b-value (ie, ≥1400 seconds/mm²) dynamic contrast-enhanced imaging should be routinely included. (See "The role of magnetic resonance imaging in prostate cancer", section on 'Technology'.)

PI-RADS categorizes prostate lesions based on the likelihood of cancer according to a five-point scale, defined as the following:

●PI-RADS 1 – Clinically significant cancer is highly unlikely to be present.

●PI-RADS 2 – Clinically significant cancer is unlikely to be present.

●PI-RADS 3 – The presence of clinically significant cancer is equivocal.

●PI-RADS 4 – Clinically significant cancer is likely to be present.

●PI-RADS 5 – Clinically significant cancer is highly likely to be present.

In general, clinically significant cancer can be defined as a lesion that is predicted to have a grade group of 2 or higher (table 3) with either a volume ≥0.5 mL or extraprostatic extension. In two separate studies, the probability of finding clinically significant cancer in males with PI-RADS 3, 4, or 5 lesions was 12 and 23 percent, 60 and 49 percent, and 83 and 77 percent, respectively [11,12]. Biopsy of these lesions is indicated. Given the low risk of clinically significant prostate cancer, the management of PI-RADS 3 lesions is controversial and is discussed in detail elsewhere. (See "The role of magnetic resonance imaging in prostate cancer", section on 'Management of PI-RADS 3 lesions'.)

MRI of the prostate is often obtained in males with low- and very low-risk disease to ensure that high-grade disease has not been overlooked, particularly if they are considering active surveillance [13]. (See "The role of magnetic resonance imaging in prostate cancer", section on 'Males choosing active surveillance' and "Active surveillance for males with clinically localized prostate cancer", section on 'Multiparametric MRI of the prostate'.)

For males with higher-risk disease, many studies have established the added value of prostate MRI:

●Prior to prostatectomy – MRI is useful for predicting pathologic stage at radical prostatectomy, compared with clinically based risk classification models, in addition to providing anatomic tumor localization [14,15]. Prostate MRI can also aid in planning surgical management, improving the preservation of neurovascular bundles, and reducing the rate of positive surgical margins [16]. MRI has low sensitivity but high specificity for focal microscopic extraprostatic extension and seminal vesicle invasion [17,18].

●Prior to radiation therapy (RT) – For males planning to undergo RT (or image-guided focal therapy, such as high-intensity focused ultrasound), prostate MRI can improve radiation treatment planning [19]. (See "External beam radiation therapy for localized prostate cancer", section on 'Risk stratification and the selection of the initial treatment approach' and "Cryotherapy and other ablative techniques for the initial treatment of prostate cancer".)

Guidelines from the American College of Radiology (ACR) recommend prostate MRI for all intermediate- and high-risk patients as an aid in planning local therapy [20]. Updated guidelines from the combined European Association of Urology/European Association of Nuclear Medicine/European Society for Radiotherapy and Oncology/European Society of Urogenital Radiology/International Society of Geriatric Oncology (EAU-EANM-ESTRO-ESUR-SIOG) suggest prebiopsy multiparametric prostate MRI for local staging for any risk group, although they acknowledge that the evidence is weak [8]. However, guidelines for which males should get a prostate MRI as a component of their initial staging evaluation are not available from the National Comprehensive Cancer Network (NCCN), American Society of Clinical Oncology (ASCO), or the American Urological Association (AUA)/American Society for Radiation Oncology (ASTRO) [4,5,7].

Supplemental studies based on risk stratification — Consistent with guidelines from the NCCN [4], we base our recommendations for supplemental imaging on risk stratification (table 4). Individuals with higher-risk disease, including those with high- or very high-risk or locally advanced tumors, have a high probability of harboring metastatic disease than do those with lower-risk disease (prevalence 30 to 50 percent depending on the sensitivity of the method used for disease detection) [21]. Metastases are most commonly located within the regional pelvic lymph nodes and in bone, with other sites of distant metastatic disease being rare in most patients.

Low- and very low-risk disease — In general, for asymptomatic males with low- or very low-risk cancer, especially if they have a life expectancy less than 10 years, definitive treatment is generally withheld unless there is evidence of disease progression or the development of symptoms. In such cases, no further staging workup beyond prostate MRI is indicated. (See 'Prostate MRI' above and "Initial approach to low- and very low-risk clinically localized prostate cancer".)

High- and very high-risk disease — We perform supplemental imaging to detect pelvic nodal or distant metastases for all individuals with high- or very high-risk disease. Bone imaging is needed for all, with extra attention paid to symptomatic areas. The status of the pelvic lymph nodes and presence of distant metastases can be assessed using conventional imaging (MRI, computed tomography [CT], bone scan), positron emission tomography (PET)/CT scanning using older prostate-specific radiotracers (eg, F-18 fluciclovine PET [Axumin] scan), or by PET/CT using newer, more sensitive radiotracers targeting prostate-specific membrane antigen (PSMA), such as Ga-68 PSMA-11 or Piflufolastat F-18. The choice is dependent on clinician preference and insurance coverage. However, for most patients, given the widespread availability of PSMA PET imaging, and the greater sensitivity and specificity for detection of both soft tissue and bone metastases, we suggest PSMA PET rather than conventional imaging or F-18 fluciclovine scanning. This approach is consistent with the updated 2022 NCCN guidelines. However, where PSMA PET is not available, bone scan, whole-body MRI, or PET scanning using older prostate-specific radionuclides (eg, F-18 fluciclovine) are alternatives.

PET imaging using PSMA-based radiotracers

Evaluation of the regional lymph nodes

Accuracy — Fluorodeoxyglucose (FDG), the usual radiotracer for PET and integrated PET/CT scanning, is excreted by the kidneys and accumulates in the bladder, creating a major problem when the goal is to image the prostatic bed and pelvis. Early studies using integrated PET/CT with prostate-specific radiotracers that target PSMA (ie, Ga-68 PSMA-11 [gozetotide], piflufolastat F-18 [F-18 DCFPyL, Pylarify]) suggested improved sensitivity and specificity for pelvic lymph node as well as distant metastases as compared with conventional imaging and other PET tracers such as FDG, although sensitivity varies according to the PSA level [22-33]. Both the radionuclide uptake and the results of cross-sectional imaging on accompanying CT are important components of the evaluation.

At least two randomized trials have confirmed the utility of PSMA PET scanning in evaluating pelvic lymph nodes in males who are planned to undergo radical prostatectomy. There are two available radiotracers, Ga-68 PSMA-11 and Piflufolastat F-18.

●GA-68 PSMA-11

•PSMA-PreRP trial – The best data using Ga-68 PSMA-11 PET imaging for detection of nodal metastases come from the PSMA-PreRP trial (NCT02919111), in which 764 males with intermediate- or high-risk localized prostate cancer who planned to undergo radical prostatectomy with pelvic lymph node dissection all had a single injection of Ga-68 PSMA-11, followed by PET/CT or PET/MRI approximately one hour later [33]. The reference standard was histologic findings at the time of surgery.

Among the 277 patients who proceeded to surgery, 75 (27 percent) were found to have pelvic lymph node metastases. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of Ga-68 PSMA-11 PET imaging for detection of pelvic nodal metastases were 40, 95, 75, and 81 percent, respectively. Notably, 5 of the 10 patients with false-positive tests (a positive scan with no evidence of nodal metastases on pathologic review of the lymphadenectomy specimen) had persistently elevated PSA levels, and a postsurgery repeat scan showed the same PET-positive lymph nodes as the presurgery scan, implying that the histopathology reference standard may have been incorrect. When these patients were included as true positives, the sensitivity, specificity, and PPV were 44, 97, and 88 percent, respectively. In unplanned subgroup analysis, there was no significant difference in the performance characteristics when individuals with intermediate-risk disease who underwent resection (49 of 166, 30 percent) were compared with those with high-risk disease (225 of 590, 38 percent) who underwent surgical resection.

Largely based on data from this trial, in December 2020, the US Food and Drug Administration (FDA) approved Ga-68 PSMA-11 (gozetotide) for PSMA-targeted PET imaging in males with prostate cancer and suspected metastases who are candidates for initial definitive therapy [34].

•Other data – The superior diagnostic accuracy of Ga-68 PSMA PET over conventional imaging can also be illustrated by the following data:

-A systematic review of predominantly retrospective reports of PSMA PET (mostly Ga-68 PSMA-11) for primary lymph node staging in intermediate- and high-risk prostate cancer included four studies comparing PSMA PET with conventional CT or MRI [35-38]; in all cases, sensitivity and specificity were superior with PSMA PET [39].

-An earlier prospective randomized trial directly compared Ga-68 PSMA-11 versus conventional imaging (CT and bone scan) for individuals with high-risk localized prostate cancer [28]. The primary outcome was accuracy of first-line imaging for identifying either pelvic nodal or distant-metastatic disease defined by the receiver-operating curve using a predefined reference-standard including histopathology, imaging, and/or biochemistry at six-month follow-up. Overall, PSMA PET/CT had a 27 percent higher accuracy for staging nodal or distant metastatic disease as compared with conventional imaging (92 versus 65 percent). First-line conventional imaging was followed by a management change less frequently than the use of PSMA PET as a first-line imaging strategy (15 versus 28 percent), and there were more patients who had equivocal findings on conventional imaging (23 versus 7 percent).

A later analysis from this trial also concluded that PSMA PET was cost effective [40].

●Piflufolastat F-18 – In the OSPREY trial, 385 patients with either high-risk prostate cancer undergoing radical prostatectomy with pelvic lymphadenectomy (cohort A) or suspected recurrent/metastatic prostate cancer on conventional imaging (cohort B) underwent integrated PET/CT using the PSMA-based radiotracer piflufolastat F-18 [31]. Among cohort A, the median sensitivity, specificity, PPV, and NPV of piflufolastat F-18 for detecting pelvic lymph node involvement were 40, 98, 87, and 83 percent, respectively. In cohort B, the median PSA value was 11.3 ng/mL, and the median sensitivity and PPV were 96 and 82 percent, respectively.

Largely based on this study, in May 2021, the FDA approved piflufolastat F-18 for PSMA-targeted PET imaging in males with suspected metastases who are candidates for initial definitive therapy and for a suspected recurrence based upon an elevated serum PSA level after definitive local therapy [41]. Availability is expected to be broader than for Ga-68 PSMA-11.

●Flotufolastat F-18 – In the LIGHTHOUSE study, among 356 patients with unfavorable intermediate-risk or high/very high-risk prostate cancer who were candidates for initial definitive therapy, sensitivity for identification of an involved hemipelvis region was between 23 and 30 percent among three readers, and specificity was at least 93 percent [42]. Based on these results, flotufolastat F-18 was approved by the US FDA for patients with suspected metastasis who are candidates for initial definitive therapy.

Can a negative PSMA PET be used to avoid pelvic nodal dissection? — The results of both the PSMA-PreRP and OSPREY trials were remarkably similar in that both had limited sensitivity (40 percent in both trials) but high specificity (95 and 98 percent) for detecting pelvic lymph node metastases. (See 'Accuracy' above.)

Given the high specificity but relatively low sensitivity, clinicians taking care of patients with high-risk prostate cancer who undergo PSMA-based PET scanning prior to prostatectomy can use a positive PET scan as a "true positive," while a negative scan cannot be used to exclude disease or inform nodal dissection. However, in the absence of knowing the true clinical impact of the PET/CT results on long-term outcomes, in our view, a PET scan that shows only low-volume nodal disease should not necessarily change clinical management (ie, if a radical prostatectomy was planned, it should still be done, even if the PET scan is positive).

Pelvic lymph node dissection (PLND) is the only accurate means for assessing pelvic lymph node involvement, and it represents the "gold standard" in the evaluation of nodal stage in prostate cancer. For those treated with radical prostatectomy, PLND is generally performed concurrently. However, this approach can add morbidity to the surgery and is usually limited to those patients at significant risk for lymph node involvement based on the local extent of disease, serum PSA, and histologic grade group (generally for those with intermediate- or high-risk disease (table 4)). (See "Radical prostatectomy for localized prostate cancer", section on 'Indications for lymph node dissection'.)

In this group, PSMA PET is still recommended to evaluate for distant metastases. Given the better accuracy of PSMA PET for detection of pelvic nodal metastases than other older tests, it is relevant to ask whether a negative PSMA PET in this setting can be used to avoid PLND [43]. The issue of whether a negative PSMA PET could be used to avoid the need for PLND was directly addressed in a meta-analysis of data from 27 studies (2832 participants, mixed populations of risk strata) in which the reference standard was pelvic lymph node dissection [44]. On a per patient basis, the sensitivity, specificity, PPV, and NPV for predicting nodal metastases were, respectively, 58, 95, 79, and 87 percent. Over a lymph node involvement range of 5 to 40 percent, PPV increased from 59 to 91 percent, while NPV decreased from 99 to 84 percent. The authors concluded that the high NPV in males with a lower risk of lymph node involvement might be clinically useful for reducing the number of unnecessary pelvic lymph node dissections, but that for high-risk patients, a negative PSMA PET/CT is insufficiently reliable.

A more extensive discussion of PSMA PET/CT for detection of distant metastases in males with high-risk prostate cancer is provided below, and there is a separate discussion of the use of these radiotracers in males with a rising PSA after definitive local therapy. (See 'Evaluation for distant metastases' below and "Rising serum PSA following local therapy for prostate cancer: Diagnostic evaluation", section on 'Ga-68 and F-18 PSMA PET/CT'.)

Evaluation for distant metastases

Accuracy — There is accumulating evidence of the better diagnostic accuracy of PSMA-based PET scans than other imaging techniques including bone scans, 18F-sodium fluoride (NaF) PET/CT, and whole-body MRI for detection of bone metastases [28,31,45-49]. The best data come from a prospective randomized multicenter study in which 302 males with high-risk localized prostate cancer before curative intent surgery or radiotherapy in Australia were randomly assigned to conventional imaging with CT and bone scanning or Ga-68 PSMA-11 PET/CT [28]. Males who had no more than two unequivocal distant metastases on first-line imaging had second-line imaging from the alternate group; second-line imaging was performed in 96 percent of the males originally assigned to conventional imaging and in 92 percent of those randomly assigned to PSMA PET/CT. The primary outcome was accuracy of first-line imaging for identifying either pelvic nodal or distant metastatic disease, as assessed by the area under the curve (AUC) of the receiver operating characteristic curve. The AUC was calculated as the mean of the estimated sensitivity and specificity.

Of the 295 males with sufficient follow-up, 87 (30 percent) had pelvic nodal or distant metastatic disease. PSMA PET/CT had a significant, 27 percent greater accuracy than conventional imaging to detect metastatic disease (92 versus 65 percent). Both sensitivity (85 versus 38 percent) and specificity (98 versus 91 percent) were greater for PSMA PET/CT. Subgroup analysis also showed the superiority of PSMA PET/CT for detection of pelvic lymph node metastases (AUC 91 versus 59 percent) and for distant metastases (AUC 95 versus 74 percent).

Compared with conventional imaging, first-line PSMA PET/CT resulted in a change in planned management for nearly twice as many patients (28 versus 15 percent), and there were fewer equivocal findings (7 versus 23 percent). Nearly one-half of the treatment modifications after first-line PSMA PET/CT involved a change from potentially curative to palliative-intent therapy. Among males undergoing second-line imaging with PSMA PET/CT, a management change occurred in 27 percent (versus 5 percent of those undergoing second-line conventional imaging after a negative PSMA PET/CT).

Limitations of the study included the definition of metastatic disease at six months (the reference standard could include histopathologic confirmation, findings on radiographic imaging, or PSA response) and the lack of information on the effect of any change in management on long-term outcomes [50].

A later analysis from this trial also concluded that PSMA PET was cost effective [40].

In December 2020, the FDA approved Ga-68 PSMA-11 for PSMA-targeted PET imaging in males with prostate cancer and suspected metastases who are candidates for initial definitive therapy [34]. In May 2021, the FDA approved piflufolastat F-18 for PSMA-targeted PET imaging in the same population.

Clinical implications — If clinically relevant, CT-guided biopsy is an option to confirm suspicious findings on PSMA PET. If confirmed, the finding of soft tissue or bone metastases using these more sensitive tests may upstage the tumor, and as a result, this may alter the treatment plan (either from systemic to locoregional treatment, or vice versa) in up to one-half of cases [51-53]. However, an important point is that while PSMA PET has the potential to stage individuals more accurately than conventional imaging using CT and bone scan by identifying otherwise occult soft tissue and bone metastases, the impact on long-term outcomes are just beginning to be studied [54]. Whether and how findings on PET/CT should impact treatment remains controversial [50].

In particular, careful consideration should be given to changing potentially life prolonging therapies that were developed in trials that utilized conventional imaging, based upon the results of next-generation imaging such as PSMA PET/CT. As an example, a patient with low-volume metastatic hormone-sensitive prostate cancer based on conventional imaging and no prior prostate radiation who appears to have more extensive metastatic disease on next-generation imaging should not be denied RT to the prostate that has proven benefit based on conventional imaging definition of low- versus all high-volume disease. (See "Overview of systemic treatment for recurrent or metastatic castration-sensitive prostate cancer", section on 'Prostate-directed therapy'.)

Other tests to evaluate the regional nodes

F-18 fluciclovine PET — Where PSMA-based PET scans are unavailable, nodes and distant metastases can be staged using older prostate-specific radiotracers with PET (eg, F-18 fluciclovine PET [Axumin]). Early studies utilizing F-18 fluciclovine PET/CT or PET/MRI during initial staging suggested a high specificity but low sensitivity for detection of lymph node metastases in previously untreated prostate cancer [55-57]. As an example, in one study of 68 males with high-risk or unfavorable intermediate-risk prostate cancer who underwent F-18 fluciclovine PET/MRI prior to surgery that included pelvic lymphadenectomy, the per patient sensitivity and specificity of PET for detection of lymph node metastases were 55 and 85 percent, respectively [57]. However, compared with conventional imaging, F-18 fluciclovine had a significantly higher sensitivity on both a patient-based (55 versus 33 percent) and a region-based (55 versus 19 percent) analysis, detecting metastases in seven more patients and 22 more regions, with similar high specificity. Similar results have been noted with F-18 choline PET/CT [58].

Cross-sectional imaging — Conventional imaging using CT or MRI is of limited value in the detection of involved pelvic lymph nodes, mainly because of limited sensitivity. One meta-analysis concluded that pooled sensitivity for detection of nodal metastases was 0.42 and 0.39 for CT and MRI, respectively, although specificity was 0.82 for both modalities [59].

Other tests for evaluate for distant metastases

Technetium-99 bone scan — A positive radionuclide bone scan in a high-risk patient in the absence of a pattern consistent with trauma, arthritis, or an alternative explanation on plain radiographs is thought to have a relatively high sensitivity for metastases. Males with a positive or equivocal bone scan are usually further evaluated with plain radiographs. A positive radionuclide bone scan that is confirmed by plain radiographs or MRI indicates the presence of distant metastases. If radiographic findings are inconclusive, an MRI or a CT scan of the bone can be performed; an alternative is whole-body next-generation imaging using PET/CT or MRI.

There is a large body of evidence supporting the use of technetium-99 radionuclide bone scan ("bone scan") for staging of prostate cancer; however, the yield is low in the setting of low levels of serum PSA and low Gleason grade group disease [60-62]. As an example, in a review of 23 studies that examined the role of staging bone scans at initial diagnosis, the detection rates for males with serum PSA levels of <10 ng/mL, 10.1 to 19.9 ng/mL, and 20 to 50 ng/mL were 2, 5, and 16 percent, respectively [60]. Detection rates for Gleason scores of ≤6, 7, and ≥8 were 4, 10, and 29 percent, respectively. Combining the Gleason grade group and serum PSA concentration with the clinical stage may be particularly useful to predict the likelihood of a positive bone scan. As an example, in one series, only 3 of 308 males with Gleason grade group 2 tumors, a serum PSA concentration ≤50 ng/mL, and a clinical stage ≤T2b had a positive bone scan [61]. (See "Localized prostate cancer: Risk stratification and choice of initial treatment".)

F-18 fluciclovine PET — The performance of F-18 fluciclovine relative to radionuclide bone scanning for detection of bone metastases in prostate cancer was addressed in a report of 106 males with metastatic disease who underwent both scans [63]. F-18 fluciclovine PET detected more bone metastases and had a lower rate of false-positive findings. The sensitivity, specificity, PPV, and NPV for bone scan were 79, 86, 45, and 96 percent, respectively, while for F-18 fluciclovine PET, they were 100, 98, 89, and 100 percent, respectively.

Axial skeleton MRI — A role for axial skeleton MRI in the initial staging evaluation is not yet established. We do not order axial skeleton MRI unless there are equivocal findings on PSMA PET/CT, bone scan, or cross-sectional imaging, or findings that suggest the possibility of epidural tumor extension or spinal metastases for which radiation therapy might be needed.

MRI of the axial skeleton may be more sensitive than radionuclide bone scan for detection of occult metastases [64]. However, experience is limited in the United States, and MRI is not widely used as a component of the initial staging workup of males with newly diagnosed prostate cancer.

MRI of the axial skeleton was compared with standard sequential workup in a series of males considered to be at high risk for bone metastases [65]. The study included males with newly diagnosed prostate cancer with a biopsy Gleason score ≥8 and a PSA ≥20 ng/mL, a rapidly rising PSA within three years after radical prostatectomy, or a rapidly rising PSA during androgen deprivation therapy. Bone metastases were identified in 41 of 66 males (62 percent). Screening axial skeleton MRI identified metastases in 7 of 23 males (30 percent) who were considered negative and in 8 of 17 males (46 percent) considered equivocal for the presence of bone metastases by other strategies, and the initial treatment plan was modified in 15 patients (22 percent) as a consequence of the MRI findings.

There are limited data comparing the diagnostic accuracy of axial skeleton MRI versus PSMA PET/CT. One pooled analysis concluded that high-quality MRI (defined as an MRI equipped with multisequence, diffusion weighting imaging and two or more imaging planes with a magnet strength of 1.5 Tesla [1.5 T]) had a sensitivity of 0.96 (95% CI 0.90-1.02) and a specificity of 0.90 (95% CI 0.81-0.99) on a per patient basis, while 3 T high-quality MRI had a sensitivity of 0.94 (95% CI 0.86-1.02) and a specificity of 0.94 (95% CI 0.86-1.02), respectively, for bone metastases in patients with prostate cancer [66]. In the network analysis of MRI versus PET/CT using a variety of radiotracers, 68Ga-PSMA PET/CT had the highest diagnostic value with the best superiority index (4.56 [95% CI 0.11-11.00]), followed closely by 3 T high-quality MRI (4.43 [95% CI 0.14-11.00]), 1.5 T high-quality MRI (3.38 [95% CI 0.11-9.00]), and then, 18F-NaF PET/CT, 11C-choline PET/CT, and 18F-choline PET/CT.

Whole-body MRI — Where available, whole-body MRI may be used for staging of both nodal and distant metastatic disease in high-risk patients, but PSMA PET is preferred, if available. While whole-body MRI is used frequently for staging of both nodal and distant metastases in high-risk individuals in parts of Europe (including the United Kingdom), it is recommended by ASCO only when conventional imaging is negative in a patient with clinically high- or very high-risk prostate cancer or when the results of conventional imaging are suspicious or equivocal, for clarification of disease extent or detection of additional sites of disease, if this could potentially alter management [67]. We prefer PSMA PET.

Systematic analyses, prospective clinical studies, and meta-analyses of whole-body MRI compared with other modalities for detection of bone metastases have shown at least comparable (and in some cases superior) diagnostic accuracy compared with bone scan plus CT, F-18 choline PET/CT, and F-18 NaF PET/CT [48,68-71]. As examples:

●In one meta-analysis of 27 studies of males with prostate cancer, whole-body MRI was superior to choline PET/CT and bone scan for detection of bone metastases on a per patient basis (pooled sensitivities for choline PET/CT, whole-body MRI, and bone scan were 91, 97, and 79 percent, respectively, while the corresponding specificities were 99, 95, and 82 percent, respectively) [68].

●In a second pooled analysis of 32 studies (1507 patients) examining the utility of diffusion-weighted MRI in detecting bone metastases in a variety of patients, the pooled sensitivity, specificity, and area under the curve (AUC) for detection of bone metastases on a per patient basis were 95 percent, 92 percent, and 0.98, respectively [71].

●Few data have compared whole-body MRI versus PSMA PET/CT. One small prospective study compared the diagnostic accuracy of 68Ga-PSMA PET/CT with that of 18F-fluoride-based PET/CT and whole-body MRI for the detection of bone metastases in 55 individuals with prostate cancer, 20 classified as having bone metastases [48]. The sensitivity, specificity, and overall accuracy for PSMA PET (100, 100, and 100 percent) was significantly better than that for whole-body MRI (80, 83, and 82 percent).

Recommendations of expert groups — There are variable recommendations from expert groups on the use of new imaging modalities as compared with conventional imaging for initial staging of prostate cancer for bone metastases:

●The most recent NCCN prostate cancer guidelines state that CT, MRI, PET/CT or PET/MRI with F-18 NaF C-11 choline, F-18 fluciclovine, Ga-68 PSMA-11, or F-18 piflufolastat PSMA can be considered for evaluation of equivocal results on initial bone imaging [4]. Soft tissue imaging of the pelvis, abdomen, and chest can include chest CT and abdominal/pelvic CT or abdominal/pelvic MRI (preferred over CT for pelvic staging). Alternatively, Ga-68 PSMA-11 or F-18 piflufolastat PSMA PET/CT or PET/MRI can be considered for bone and soft tissue (full body) imaging.

Because of the better sensitivity and specificity of PSMA PET tracers for detecting micrometastatic disease compared with conventional imaging (CT, MRI) at initial staging, conventional imaging is not a necessary prerequisite to PSMA PET, which can serve as an equally effective, if not more effective, front-line imaging tool.

●Guidelines from the Royal College of Radiologists/Royal College of Physicians also support the use of F-18 choline PET/CT or Ga-68 PSMA-11 PET/CT for equivocal conventional findings on bone scan [72].

●On the other hand, 2020 guidelines from ASCO on the use of these newer imaging tests are broader [67]:

•The guidelines endorse the use of next-generation imaging (ie, PET, PET/CT, PET/MRI, or whole-body MRI) in patients with a high risk of metastatic disease when conventional imaging (defined as CT, bone scan, and/or prostate MRI) is negative.

•They also endorse one of these tests when conventional imaging is suspicious or equivocal.

•For males presenting initially with demonstrable metastatic disease on conventional imaging, next-generation imaging can clarify the burden of disease and potentially shift the treatment intent from multimodality management of oligometastatic disease to systemic anticancer therapy, alone or in combination with targeted therapy for palliative purposes. (See "Overview of systemic treatment for recurrent or metastatic castration-sensitive prostate cancer", section on 'Metastasis-directed therapy for oligometastatic disease'.)

Importantly, all of these recommendations predated the FDA approval of Ga-68 PSMA-11 and piflufolastat F-18 for imaging in males with prostate cancer and suspected metastases who are candidates for initial definitive therapy.

Intermediate-risk disease — We do not perform supplemental staging studies to evaluate for soft tissue and bone metastases in patients with favorable intermediate-risk disease. Clinical practice is variable in unfavorable intermediate-risk disease, and guidelines from expert groups are disparate.

Benefit of supplemental imaging — In general, the risk of nodal and distant metastases is very low in most males with favorable intermediate-risk disease and low in those with unfavorable intermediate-risk disease. The following data are available:

●In an analysis of 8591 males undergoing radical prostatectomy for intermediate-risk prostate cancer, 80.2 percent (n = 6883) were performed with pelvic lymph node dissection, of which 198 (2.9 percent) were histologically positive for pelvic nodal metastases [73]. When stratified according to risk, 1.2 percent of favorable-risk and 4.7 percent of unfavorable-risk tumors were node-positive. However, there were differences in the lymph node positivity rates among the subgroups with favorable (0 to 1.3 percent) and unfavorable (3.5 to 5 percent) intermediate-risk categories. Additional factors associated with a higher lymph node positivity rate included ≥50 percent positive cores, ≥35 percent involvement of at any core, and an unfavorable genomic classifier result, none of which is considered in the risk stratification system.

●Additional data are available from an analysis derived from the Surveillance, Epidemiology and End Results (SEER) database that included patients newly diagnosed with prostate cancer between 2010 and 2016 [74]. Of the 145,939 assessable for analysis of pelvic lymph node metastases by conventional imaging, 4559 harbored clinical nodal disease, including 13 (0.02 percent), 18 (0.08 percent), 63 (0.3 percent), 512 (2.8 percent), and 3954 (14.9 percent) of those with low, favorable intermediate-, unfavorable intermediate-, high-risk, and very high-risk disease, respectively. These resulted in a number needed to image (NNI) of 4619, 1182, 319, 35, and 7, respectively. Of the 181,109 patients assessable for analysis of distant metastases, 8920 (4.9 percent) harbored distant metastases, including 50 (0.07 percent), 45 (0.1 percent), 161 (0.5 percent), 1290 (5.1 percent), and 7374 (22 percent) of those with low-, favorable intermediate-, unfavorable intermediate-, high-, and very high-risk disease, respectively. These resulted in NNIs of 1347, 602, 174, 20, and 5, respectively.

●In a review of 88 patients with favorable intermediate-risk prostate cancer who underwent Ga-68 PSMA-11 PET/CT prior to radical prostatectomy and lymph node dissection, the preoperative PET/CT showed suspicious uptake in the lymph nodes in only 4 (5 percent); of the two patients found to have pathologic lymph node involvement, only one had a positive Ga-68 PSMA-11 PET/CT scan [75]. The sensitivity, specificity, PPV, and NPV of Ga-68 PSMA-11 PET/CT for identifying lymph node involvement were 50, 97, 25, and 99 percent, respectively.

Guidelines from expert groups — Guidelines from expert groups (including those from the NCCN [4], the AUA/ASTRO, and ASCO [5,7]) recommend that supplemental imaging studies to assess bone and soft tissue be used to assess for regional adenopathy or distant metastases in patients with high- and very high-risk disease, but there is some disagreement about whether patients with intermediate-risk disease require additional imaging:

●NCCN guidelines suggest bone and soft tissue imaging for all individuals with unfavorable intermediate-risk, high-, or very high-risk disease, but not for favorable intermediate-risk disease [4].

●In 2018 guidelines from ASCO and the AUA/ASTRO/Society of Urologic Oncology (SUO) also suggest that clinicians consider nodal evaluation by cross-sectional imaging (CT or MRI) of the abdomen and pelvis or PSMA PET for all males with unfavorable intermediate-, high-, or very high-risk disease [5,7].

●On the other hand, 2022 guidance from the AUA/ASTRO suggest that males with intermediate risk disease do not need supplemental imaging, regardless of their subcategory [76].

GERMLINE GENETIC TESTING AND TUMOR TISSUE TESTING — Germline genetic testing is appropriate for many males with prostate cancer, especially if there is a family history of breast, ovarian, pancreatic, or other gastrointestinal tumors, or if there is cribriform or intraductal pathology.

Consistent with National Comprehensive Cancer Network (NCCN) and American Society of Clinical Oncology (ASCO) guidelines, we also suggest molecular and biomarker analysis of tumor tissue for males with low- and favorable intermediate-risk disease if the results would impact clinical decision making (eg, life expectancy is 10 years or more, and active surveillance is being considered).

A substantial number of males with prostate cancer, particularly those with intraductal/cribriform histology, carry germline mutations that might affect therapy and screening for additional tumors. Guidelines from the NCCN advocate germline testing for males with very low-, low-, and intermediate-risk disease if the family history is positive or there is intraductal pathology [4]. Guidelines from ASCO and the American Urological Association (AUA)/American Society for Radiation Oncology (ASTRO) also recommend referral for genetic counseling for males with high-risk localized prostate cancer and a strong family history of specific cancers (eg, breast, ovarian, pancreatic, and other gastrointestinal tumors, lymphoma) [5,76]. Criteria for genetic testing are discussed elsewhere. (See "Genetic risk factors for prostate cancer", section on 'Who needs referral for genetic evaluation'.)

Several tissue-based molecular assays have been developed in an effort to enhance prognostic estimation and improve decision making in males with newly diagnosed prostate cancer, especially those considering active surveillance. NCCN and ASCO guidelines both endorse biomarker analysis of tumor tissue for males with low- and favorable intermediate-risk disease if life expectancy is 10 years or more and active surveillance is being considered [4,77]. This subject is discussed in detail elsewhere. (See "Molecular prognostic tests for prostate cancer", section on 'Clinical utility and guidelines from expert groups'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Diagnosis and management of prostate cancer".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Prostate cancer (The Basics)")

●Beyond the Basics topics (see "Patient education: Treatment for advanced prostate cancer (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Diagnosis – The diagnosis of prostate cancer requires a tissue diagnosis, which is generally obtained with transrectal biopsy. (See 'Diagnosis' above.)

●Staging – The most commonly used staging system for prostate cancer is that developed jointly by the American Joint Committee on Cancer (AJCC) and the Union for International Cancer Control (UICC) (table 1 and table 2). (See 'Staging system' above.)

●Staging evaluation – The extent of the staging evaluation should be based on multiple factors, including life expectancy, comorbidity, the presence or absence of symptoms, and risk category (table 4) (see 'Risk stratification and implications for the staging evaluation' above):

•Role of prostate MRI – Where available, we recommend prostate MRI for staging low-risk cases to ensure suitability for active surveillance and to guide further biopsy if needed. We also recommend it for males with high-risk disease for staging, particularly of the prostate/seminal vesicles and nodes. Prostate MRI can be done at the discretion of the treating clinician for males with intermediate-risk disease. (See 'Prostate MRI' above.)

•Low/very low risk – For asymptomatic males with low- or very low-risk cancer (table 4), especially if they have a life expectancy less than 10 years, no further staging workup beyond prostate MRI is indicated. (See 'Low- and very low-risk disease' above.)

•High/very high risk

-We perform supplemental imaging to detect pelvic nodal or distant metastases for all individuals with high- or very high-risk disease (table 4). Given the preferential spread to bone, bone imaging is indicated for all of these patients, with particular attention to symptomatic areas. (See 'High- and very high-risk disease' above.)

-For most patients, given the widespread availability of prostate-specific membrane antigen (PSMA) positron emission tomography (PET), and the greater sensitivity and specificity for detection of both soft tissue and bone metastases, we suggest PSMA PET rather than conventional imaging (CT, bone scan) or F-18 fluciclovine scanning. This approach is consistent with the updated 2022 National Comprehensive Cancer Network (NCCN) guidelines. However, where PSMA PET is not available, bone scan, whole-body MRI, or PET scanning using older prostate-specific radionuclides (eg, F-18 fluciclovine) are alternatives. (See 'PET imaging using PSMA-based radiotracers' above.)

-Given the high specificity but relatively low sensitivity, clinicians taking care of patients with high-risk prostate cancer who undergo PSMA-based PET/CT prior to prostatectomy can use a positive PET scan as a "true positive," while a negative scan cannot be used to exclude disease or inform nodal dissection. However, in the absence of knowing the true clinical impact of the PET/CT results on long-term outcomes, in our view, a PET scan that shows only low-volume nodal disease should not necessarily change clinical management (ie, if a radical prostatectomy was planned, it should still be done, even if the PET scan is positive). (See 'Can a negative PSMA PET be used to avoid pelvic nodal dissection?' above.)

-A role for axial skeleton MRI in the initial staging evaluation is not yet established. We do not order axial skeleton MRI unless there are findings on other studies that suggest the possibility of epidural tumor extension or spinal metastases for which radiation therapy might be needed. (See 'Axial skeleton MRI' above.)

-Where available, whole-body MRI may be used for staging of both nodal and distant metastatic disease in high-risk patients, but PSMA PET is preferred, if available. (See 'Whole-body MRI' above.)

•Intermediate risk – Given the relatively low risk of nodal and distant metastatic disease, we do not perform supplemental staging studies to evaluate for soft tissue and bone metastases in patients with intermediate-risk disease, especially those with favorable intermediate-risk disease, although clinical practice is variable and guidelines from expert groups are disparate. (See 'Intermediate-risk disease' above.)

●Germline and tumor tissue genetic testing

•Germline genetic testing is appropriate for all patients with prostate cancer, especially if there is a family history of breast, ovarian, pancreatic, or other gastrointestinal tumors, or if there is cribriform or intraductal pathology regardless of family history.

•We also utilize molecular and biomarker analysis of tumor tissue for males with low- and favorable intermediate-risk disease if the results would impact clinical decision making (eg, life expectancy is 10 years or more, and active surveillance is being considered). (See 'Germline genetic testing and tumor tissue testing' above.)

ACKNOWLEDGMENTS — The editorial staff at UpToDate would like to acknowledge Philip W Kantoff, MD, who contributed to an earlier version of this topic review.

We are saddened by the death of Nicholas Vogelzang, MD, who passed away in September 2022. UpToDate gratefully acknowledges Dr. Vogelzang's role as Section Editor on this topic, and his dedicated and longstanding involvement with the UpToDate program.