New ESMO clinical practice guideline for prostate cancer

In December, the European Society for Medical Oncology (ESMO) published a new clinical practice guideline for the diagnosis, treatment, and follow-up of local and locoregional prostate cancer (PCa).

The guideline provides key recommendations and algorithms for managing localised PCa, and covers diagnosis, staging, risk assessment, treatment and disease monitoring. Algorithms for the management of localised disease and biochemical recurrence are provided.

On the issue of screening, ESMO recommends that population-based prostate-specific antigen (PSA) screening can be considered based on national risks and benefits, but adds that population screening is associated with a risk of overdiagnosis.

Diagnosis

PSA testing, digital rectal examination (DRE) and imaging remain central to selecting men for biopsy. According to the guidelines, moderately elevated PSA concentrations (3-10ng/ml) have limited specificity for detection. PSA-density (PSA-D) can add value in predicting clinically significant disease.

New blood and urine tests may be considered within risk-stratification pathways, but ESMO points out that comparative studies are lacking.

Predictive models or risk-stratified algorithms incorporating different clinical parameters such as age, PSA level, PSA-D, family history, DRE findings, biomarkers, MRI, can facilitate patient selection, improve prediction of clinically significant disease and reduce diagnosis of indolent tumours.

However, the guideline stresses that risk calculators are calibrated to the relevant population.

MRI is recommended before initial or repeat prostate biopsy. Targeted biopsies have a higher detection rate for clinically significant PCa and a decreased detection rate for clinically insignificant disease compared with systematic biopsies.

The guideline states that, in contrast to transrectal biopsy, transperineal biopsy results in fewer adverse events (AEs) relating to infection and sepsis, and it can be carried out without antibiotic prophylaxis, which aligns with antibiotic stewardship.

When MRI is positive (PI-RADS ≥4), both targeted and systematic biopsies are required if a high reliability for diagnosis of clinically significant disease is a priority. If reducing the detection of clinically insignificant disease is a priority, targeted biopsy without systematic biopsy may be sufficient.

The guideline advises that perilesional sampling of the MRI lesion improves detection of clinically significant disease. If MRI is equivocal (PI-RADS 3), biopsy should be carried out if there is a high suspicion of PCa or if PSA-D is >0.15.

When multiparametric MRI is of good quality and negative (PI-RADS ≤2) and clinical suspicion of PCa is low, biopsy may be omitted.

The guideline states that PSA-D can help to risk stratify patients with a negative MRI for further diagnostic work-up following a non-suspicious MRI result. PSA-D >0.15-0.2 signals a higher risk of missed significant PCa in patients with normal MRI findings.

In patients at high risk of locally advanced or metastatic disease when systematic biopsy will likely be diagnostic, MRI should not delay diagnosis and treatment. Systematic biopsy can be sufficient in these cases.

High-resolution ultrasound (US) based on a 29 MHz transducer can be used as an alternative to MRI for diagnosis.

In terms of genetic testing, the guidelines point out that germline testing is not routine clinical practice and is generally reserved for patients with de novo metastatic PCa or a family history of breast, ovarian, pancreatic and/or high risk prostate cancer, and for relatives of patients diagnosed with PCa at a young age.

ESMO advises that PSA testing every two to four years may be considered in individuals aged ≥40 years who carry germline mutations that could increase PCa risk. However, more studies are needed to understand the possible role of polygenic risk scores in screening and early detection pathways, the document states.

See Table 1 for a summary of recommendations related to diagnosis.

Staging and risk assessment

Localised disease is classified as low, favourable intermediate, unfavourable intermediate, high or very high risk as a guide to prognosis and therapy. ESMO points out that this classification is less applicable to PCa diagnosed via MRI-targeted biopsies and needs to be adapted for current diagnostic pathways.

Patients with low risk disease do not require further imaging for staging, but MRI can inform discussions on active surveillance. Patients with favourable intermediate risk disease do not require further imaging for staging, unless there is a suspicion of disease underestimation.

Patients with International Society of Urological Pathology (ISUP) grade group ≥3 or high risk disease should undergo imaging for detection of nodal or metastatic disease.

Prostate-specific membrane antigen (PSMA) positron emission tomography (PET)-computed tomography (CT) and possibly whole-body MRI have better accuracy than CT or bone scintigraphy, but they have not been shown to improve clinical outcomes.

As the clinical impact of upstaging with PSMA-PET-CT or whole-body MRI compared with conventional imaging is unknown, patients with localised disease on conventional imaging should not be denied radical local treatment solely because metastatic lesions are identified on novel imaging techniques only, ie, if no correlates are observed on the bone windows or lymph nodes (LNs) of the CT scan.

Genomic and pathology-based signatures are not yet recommended for clinical practice.

See Table 2 for a summary of recommendations related to staging and assessment.

Management of localised disease

The guidelines stipulate that there is no single best option for the optimal management of localised PCa. Patients should be informed about the benefits and harms of all treatments within the context of their personal preferences and comorbidities.

Given the range of therapies and their side effects, patients should be offered consultation with both a urologist and a radiation oncologist. Treatment options with curative intent include radical prostatectomy (RP), external beam RT (EBRT), and brachytherapy.

Watchful waiting (WW) with delayed hormone therapy on symptomatic progression is an option for patients who are not suitable for, or are unwilling to undergo, treatment with curative intent.

Active surveillance is appropriate for patients with low risk disease and selected patients with intermediate risk disease, typically involving repeat PSA tests, MRI and biopsies, with curative treatment as an option for patients with evidence of disease progression.

To date, no clear data exist regarding optimal frequency of follow-up for patients undergoing active surveillance. Moreover, there are no clear data on the assessments that should be carried out at each follow-up visit,

The guideline states that the role of LN dissection during RP remains controversial. Extended pelvic LN dissection (PLND) provides the highest accuracy of LN staging relative to imaging.

Data from two randomised controlled trials with short term follow-up did not show improved biochemical recurrence (BCR)-free survival after extended PLND versus limited PLND.

An updated analysis of one of these trials with longer follow-up confirmed the absence of improved BCR-free survival, but did report improved metastasis-free survival (MFS) in the extended PLND arm.

The combination of RP with systemic treatments, particularly neoadjuvant therapy, has been evaluated in several trials. A systematic review concluded that neoadjuvant ADT is associated with a reduction in tumour size, downstaging and a reduced rate of positive surgical margins, but no improvement in cancer control.

Recent phase 2 studies have explored next-generation hormonal therapies in combination with ADT, and have found an effect on downstaging and a higher rate of minimal residual disease in the interventional arm.

No data are available on short or mid term cancer control outcomes. Ongoing phase 3 trials are exploring the same strategy. Currently, no evidence supports the use of perioperative ADT outside of clinical trials.

No survival data have been published on RP versus RT+ADT in high risk prostate cancer, but the ongoing phase 3 SPCG-15 trial, which is comparing primary RP with primary RT+ADT for locally advanced disease, will provide evidence in this setting.

The guideline states that, for radical prostate RT, dose escalation using intensity-modulated RT improves biochemical control with acceptable toxicity. Most studies, however, have not demonstrated MFS or overall survival (OS) benefit.

Multiple phase 3 studies have shown non-inferiority for moderate hypofractionation compared with schedules over seven to eight weeks, especially in patients with intermediate risk disease. SBRT has been shown to be non-inferior for biochemical control in patients with ISUP grade group 2 intermediate risk disease, although with a slightly higher risk of genitourinary (GU) side effects.

ESMO advises that the role of prophylactic pelvic nodal RT remains unclear, with trials reporting contrasting results in terms of oncological benefit.

Patients treated with RP for intermediate or high risk disease might require post-operative RT (adjuvant and salvage) with or without ADT. Studies have suggested that salvage prostate bed RT is preferred over adjuvant RT.

Patients with high risk characteristics benefit from long term ADT (two years) alongside prostate bed RT in terms of MFS, but no OS benefit has been reported. The optimal duration of concomitant ADT (six versus 24 months) in the salvage setting remains a matter of debate and should be individualised based on cancer risk and comorbidities.

While focal ablative treatments have recently emerged as therapeutic options in localised prostate cancer, the guideline states that, to date, no prospective randomised studies have compared focal ablation with RP or RT, and, therefore, these alternative options should only be offered within a clinical trial or prospective registry.

See Table 3 for a summary of recommendations on managing localised disease.

Management of very high risk disease

Patients with metastatic disease on PSMA-PET-CT, but non-metastatic disease on conventional imaging, might best be managed as patients with very high risk locally advanced disease. There is currently no level of evidence for adjuvant or neoadjuvant androgen receptor pathway inhibitors (ARPIs) other than abiraterone, or for such treatment intensification in patients undergoing surgery.

Surgery in this situation lacks the possibility for treatment intensification with an ARPI and is likely to be followed by further multimodal treatments (RT or hormonal therapy).

The guideline includes an algorithm for the management of very high risk or cN1 disease.

For a summary of the recommendations on managing very high risk disease, see Table 4.

Management of pN1 disease

Pathological LN involvement at the time of RP and PLND is an adverse prognostic factor. In patients with pN1 disease, persistently detectable post-operative PSA is associated with poor outcomes.

Treatment options for pN1 disease after RP and PLND include observation (if PSA is undetectable) with treatment upon disease progression, adjuvant ADT and/or adjuvant RT, but the guideline stresses that there is a lack of RCT data in this setting.

For a summary of the recommendations on managing pN1 disease, see Table 5.

Management of persistent PSA after RP

Patients with persistent PSA after RP (PSA >0.1ng/ml six to nine weeks after surgery) should have repeat staging to determine the possibility of salvage RT. Whenever possible, PSMA-based imaging should be used. The role of salvage RT and metastasis-directed therapy is uncertain in patients with distant metastases.

In the absence of distant metastases, the guideline recommends that salvage RT may be used, and the addition of ADT should be considered, although there is a lack of data in this clinical scenario. The document acknowledges that there is controversy around the dose and duration of ADT in patients with PSA elevations following a period of undetectable PSA after RP.

See Table 6 for a summary of recommendations on managing persistent PSA after RP.

Management of biochemical recurrence

Following local treatment, PSA tests should be carried out on a regular basis. ESMO recommends PSA testing every six months during the first three years and annually beyond that. For patients undergoing radical RT and ADT, testosterone recovery needs to be monitored together with PSA, and closer follow-up might be warranted during this process, eg, every six months. Late recurrences are observed so long-term follow-up is warranted, according to the guideline.

After local treatment, biochemical recurrence (BCR) is defined as a PSA rise in the absence of disease on imaging. After RT, BCR is defined by the Phoenix criteria of PSA nadir +2ng/ml.

After RP, BCR is defined as a rising PSA level that is confirmed by a second rise, after having been non-detectable (<0.1ng/ml) after RP. The advice from ESMO is that these definitions should primarily be viewed as a means of standardising reporting of outcomes and not as hard limits for triggering action.

A short PSA doubling time (<6-12 months) and initial ISUP grade group 4-5 are associated with increased prostate cancer-specific mortality after RP, whereas after RT, early development of BCR (<18 months) and initial ISUP grade group 4-5 are linked to increased mortality. Genomic classifiers are an option to risk stratify patients with BCR to treatment or surveillance. Patients without these risk characteristics may not require salvage treatment.

The guideline acknowledges that differentiation of locoregional from systemic disease in patients with BCR is difficult with conventional imaging. PSMA-PET imaging has demonstrated superior sensitivity and specificity.

After RP, MRI is not recommended to detect local recurrence at low or very low PSA ranges. However, after RT, MRI has good sensitivity for detecting local, intraprostatic recurrence in early BCR.

For PET-CT-detected nodal or metastatic recurrences, the guideline states that elective nodal RT with inclusion of the prostate bed (if not previously treated) provides the best oncological outcomes.

No OS benefit has been seen with early versus deferred ADT in patients with PSA failure after local therapy. In fact, early ADT has been shown to adversely affect quality of life. Intermittent ADT has demonstrated a more favourable toxicity profile with no difference in OS.

The guideline states that post-operative RT following RP may be given as adjuvant RT in patients with undetectable post-operative PSA or as salvage RT in patients with persistent or rising PSA.

Histological proof of local recurrence by biopsy is recommended before local salvage treatment after initial organ-sparing treatment, if MRI or PSMA-PET shows suspicion of local recurrence. In this setting, treatment options are salvage RP, SBRT or salvage ablation with high intensity focused ultrasound (HIFU), cryotherapy, or laser therapy.

For a summary of the recommendations on managing very high risk disease, see Table 7.

An algorithm for the treatment of patients with BCR is included in the guideline.