Prostate Cancer

7. FOLLOW UP

The rationale for following up patients is to assess immediate- and long-term oncological results, ensure treatment compliance and allow initiation of further therapy, when appropriate. In addition, follow-up allows monitoring of side effects or complications of therapy, functional outcomes and an opportunity to provide psychological support to PCa survivors, all of which is covered in Chapter 8.

For patients the most critical aspect of PCa is the diagnosis, the ensuing treatment and follow-up. These must be discussed between the patient and the clinician for co-decision on the treatment and the planned follow-up, including modalities, periodicity and how this will be communicated to the patient. The patient must be prepared for different potential outcomes of the follow-up, e.g., PSA levels, and what to expect from these. Otherwise, f.i., even a very small increase in PSA levels can cause unnecessary fear, even panic.

7.1. Follow-up: After local treatment

7.1.1. Definition

Local treatment is defined as RP or RT, either by IMRT plus IGRT or LDR- or HDR-brachytherapy, or any combination of these, including neoadjuvant and adjuvant therapy. Unestablished alternative treatments such as HIFU, cryosurgery and focal therapy options do not have a well-defined, validated, PSA cut-off to define BCR but follow the general principles as presented in this section. In general, a confirmed rising PSA is considered a sign of disease recurrence.

7.1.2. Why follow-up?

The first post-treatment clinic visit focuses on detecting treatment-related complications and assist patients in coping with their new situation apart from providing information on the pathological analysis. Men with PCa are at increased risk of depression and attention for mental health status is required [1279,1280]. Tumour or patient characteristics may prompt changing the follow-up schedule. Follow-up of men diagnosed with PCa may allow early treatment of disease and treatment-related problems. The use of salvage treatment should be considered in light of the expected life-expectancy, especially when below 10 years in asymptomatic patients.

7.1.3. How to follow-up?

The procedures indicated at follow-up visits vary according to the clinical situation. A disease-specific history is mandatory at every follow-up visit and includes psychological aspects, signs of disease progression, and treatment-related complications. Evaluation of treatment-related complications in the post-treatment period is highlighted in Sections 6.1.2.4 and 8.2. The examinations used for cancer-related follow-up after curative surgery or RT are discussed below.

7.1.3.1. Prostate-specific antigen monitoring

Measurement of PSA is the cornerstone of follow-up after local treatment. While PSA thresholds depend on the local treatment used, PSA recurrence almost always precedes clinical recurrence [975,1281]. The key question is to establish when a PSA rise is clinically significant since not all PSA increases have the same clinical value (see Section 6.3) [977]. No prospective studies are available on the optimal timing for PSA testing.

7.1.3.1.1. Active surveillance follow-up

Patients included in an AS programme should be monitored according to the recommendations presented in Section 6.2.1.3.

7.1.3.1.2. Prostate-specific antigen monitoring after radical prostatectomy

Following RP, the PSA level is expected to be undetectable. Biochemical recurrence is any rising PSA after prostatectomy as defined in Section 6.3. Prostate-specific antigen level is expected to be undetectable
2 months after a successful RP [1282]. Prostate-specific antigen is generally determined every 6 months until 3 years and yearly thereafter but the evidence for a specific interval is low [485] and mainly based on the observation that early recurrences are more likely to be associated with more rapid progression [977,1283,1284]. A rising PSA may occur after longer intervals up to 20 years after treatment and depends on the initial risk group [898]. A yearly PSA after 3 years is considered adequate considering the fact that a longer interval to BCR is correlated with a lower EAU-BCR risk score but around 50% of recurrence should be expected beyond 3 years. As mentioned in Section 6.3.2 no definitive threshold can be given for relapse after RP. Persistently measurable PSA in patients treated with RP is discussed in Section 6.2.6.

Ultrasensitive PSA assays remain controversial for routine follow-up after RP. Men with a PSA nadir < 0.01 ng/mL have a high (96%) likelihood of remaining relapse-free within 2 years [1285]. In addition, post-RP PSA levels > 0.01 ng/mL in combination with clinical characteristics such as ISUP grade and surgical margin status may predict PSA progression and can be useful to establish follow-up intervals [1284]. However, up to 86% of men were reported to have PSA values below 0.2 ng/mL at 5 years after an initial PSA nadir below 0.1 ng/mL within 6 months after surgery [1286]. Lastly, PSA and associated PSA-DT [1287] calculated prior to 0.2 ng/mL may help identify suitable candidates for early intervention [1288]. Prostate-specific antigen monitoring after SRT to the prostatic fossa is done at similar intervals and an early and rapid PSA rise predicts more rapid progression [1283] and is correlated to metastases-free and PCa-specific survival [1289].

7.1.3.1.3. Prostate-specific antigen monitoring after radiotherapy

Following RT, PSA drops more slowly as compared to post RP. A nadir < 0.5 ng/mL is associated with a favourable outcome after RT although the optimal cut-off value remains controversial [1290]. The interval before reaching the nadir can be up to 3 years, or more. At the 2006 RTOG-ASTRO Consensus Conference the Phoenix definition of radiation failure was proposed to establish a better correlation between definition and clinical outcome (mainly metastases), namely, an increase of 2 ng/mL above the post-treatment PSA nadir [976]. This definition also applies to patients who received HT [976].

7.1.3.2. Digital rectal examination

Local recurrence after curative treatment is possible without a concomitant rise in PSA level although very rarely [1291]. This has only been proven in patients with unfavourable undifferentiated tumours. Prostate-specific antigen and DRE comprise the most useful combination for first-line examination in follow-up after RT but the role of DRE was questioned since it failed to detect any local recurrence in the absence of a rising PSA in a series of 899 patients [1292]. In a series of 1,118 prostatectomy patients, no local histologically proven recurrence was found by DRE alone and PSA measurement may be the only test needed after RP [1293,1294].

7.1.3.3. Transrectal ultrasound, bone scintigraphy, CT, MRI and PET/CT

Imaging techniques have no place in routine follow-up of localised PCa as long as the PSA is not rising. Imaging is only justified in patients for whom the findings will affect treatment decisions, either in case of BCR or in patients with symptoms (see Section 6.3.4 for a more detailed discussion).

7.1.3.4. Functional follow-up

All local treatments for PCa may cause short- and long-term side effect of various degree that will affect the patients’ QoL. For quality control, and in order to help the patient in choosing the optimal treatment for him, it is essential that the functional outcomes of any treatment given is measured and registered by validated and reproducable methods. In order to adress side effects and their impact of QoL specific tools or ‘patient-reported outcome measures’ (PROMs) have been developed and validated for men with PCa. These questionnaires assess common issues after PCa diagnosis and treatment and generate scores which reflect the impact on perceptions of HRQoL. For further discussion on this see Section 8.3.

7.1.4. How long to follow-up?

Most patients who fail treatment for PCa do so within 7 years after local therapy [503]. Patients should be followed more closely during the initial post-treatment period when risk of failure is highest. PSA measurement, disease-specific history and DRE (if considered) are recommended every 6 months until 3 years and then annually. Whether follow-up should be stopped if PSA remains undetectable (after RP) or stable (after RT) remains an unanswered question, but it seems fair that follow-up is only done to the point that if a recurrence is found the patient is fit enough for salvage therapy.

Risk assessment to predict metastases-free and PCa-specific survival after recurrence after primary treatment may guide individual decisions on a need for longer follow-up [903,977,1295]. Even in men with a PSA-DT less than 10 months after RP who choose to defer treatment, a median metastasis-free survival of 192 months and OS of 204 months from RP was observed, indicating the relatively long disease-free intervals observed in men with a rising PSA after local treatment [1296].

Symptomatic recurrence without a PSA rise is extremely rare, however, the symptoms typical for recurrent disease may vary and are poorly defined by published data. In case of the following symptoms PSA testing should be performed to exclude a possible cancer recurrence in particular in men not followed up by regular testing of their PSA levels: skeletal pain, haematuria, progressive voiding complaints, progressive lower body oedema, progressive bowel complaints or complaints of fatigue, sarcopenia or unexplained weight
loss [1297].

7.1.5. Summary of evidence and guidelines for follow-up after treatment with curative intent

7.2. Follow-up: During first line hormonal treatment (androgen sensitive period)

7.2.1. Introduction

Androgen deprivation therapy is used in various situations: combined with RT for localised or locally-advanced disease, as monotherapy for a relapse after a local treatment, or in the presence of metastatic disease often in combination with other treatments. All these situations are based on the benefits of testosterone suppression either by drugs (LHRH agonists or antagonists) or orchidectomy. Inevitably, the disease will become castrate-resistant, although ADT will be maintained.

This section addresses the general principles of follow-up of patients on ADT alone. Section 6.5.7 includes further information on other drug treatments. Furthermore the specific follow-up needed for every single drug is outside the scope of this text, as is follow-up after chemotherapy.

To detect disease- and treatment-related complaints, regular clinical follow-up is mandatory and cannot be replaced by imaging or laboratory tests alone. Complementary investigations must be restricted to those that are clinically helpful to avoid unnecessary examinations and costs.

7.2.2. Purpose of follow-up

The main objectives of follow-up in patients receiving ADT are to ensure treatment compliance, to monitor treatment response, to detect side effects early, and to guide treatment at the time point of clinical progression. After the initiation of ADT, it is recommended that patients are evaluated every 3 to 6 months. This must be individualised and each patient should be advised to contact his physician in the event of troublesome symptoms. This is even more important for patients who receive a combination of ADT and other potent medication, e.g., ARPI, for their disease.

7.2.3. General follow-up of men on ADT

Patients under ADT require regular follow-up, including monitoring of serum testosterone, creatinine, liver function and metabolic parameters at 3 to 6 month intervals. Men on ADT can experience toxicity independent of their disease stage. Androgen deprivation therapy reduces bone density gradually, increasing the risk of fractures [1298]. It is therefore essential to asses bone density before and during treatment with ADT with or without a combination with other drugs.

As the consequenses of ADT are so varying, a structured follow-up including lab results, radiology and QoL, may be of value both for the patient and for the treating physician [1299].

7.2.3.1. Testosterone monitoring

Testosterone monitoring should be considered standard clinical practice in men on ADT. Many men receiving medical castration will achieve a castrate testosterone level (< 20 ng/dL), and most a testosterone level < 50 ng/dL. However, approximately 13–38% of patients fail to achieve these levels and up to 24% of men may experience temporary testosterone surges (testosterone > 50 ng/dL) during long-term treatment [1282] referred to as ‘acute on-chronic effect’ or ‘breakthrough response’ [1300]. Breakthrough rates for the
< 20 ng/dL threshold were found to be more frequent (41.3%) and an association with worse clinical outcomes was suggested [1300].

The timing of measurements is not clearly defined. A 3 to 6-month testosterone level assessment has been suggested to ensure castration is achieved (especially during medical castration) and maintained. In case a castrate testosterone level is not reached, switching to another agonist or antagonist or to an orchiectomy should be considered. In patients with a confirmed rising PSA and/or clinical progression, serum testosterone must be evaluated in all cases to confirm a castration-resistant state. Ideally, suboptimal testosterone castrate levels should be confirmed with an appropriate assay [1301,1302]. After ADT cessation (intermittent treatment or temporary ADT use as with EBRT) testosterone recovery is dependent on patient’ age and the duration of ADT [1303,1304].

7.2.3.2. Liver function monitoring

Liver function tests will detect treatment toxicity (especially applicable for NSAA), but rarely indicate disease progression. Men on combined ADT should have their transaminase levels checked at least yearly but in particular in the first 6 months of treatment initiation since liver function disorders were observed relatively early in the majority of patients in larger trials [1305]. In view of potential liver toxicity a more frequent check is needed with some drugs (including abiraterone acetate) [1306]. Alkaline phosphatase may increase secondary to bone metastases and androgen-induced osteoporosis, therefore it may be helpful to determine bone-specific isoenzymes as none are directly influenced by ADT [1307].

7.2.3.3. Serum creatinine and haematological parameters

Estimated glomerular filtration rate monitoring is good clinical practice as an increase may be linked to ureteral obstruction or bladder retention. A decline in haemoglobin is a known side effect of ADT. A significant decline after 3 months of ADT is independently associated with shorter progression-free and OS rates and might explain significant fatigue although other causes should be considered [1308]. Anaemia is often multi-factorial and other possible aetiologies should be excluded. An early decrease in haemoglobin 3 months after ADT initiation predicted better survival whereas a decrease beyond 6 months was associated with poor outcome in the SPCG-5 population [1309]. Radiotherapy to more extensive bone metastases locations may result in myelosuppression and haematological toxicity [1310,1311].

7.2.3.4. Monitoring of metabolic complications

The most severe complications of androgen suppression are metabolic syndrome, cardiovascular morbidity, mental health problems, and bone resorption (see Section 8.2.4.5).

All patients should be screened for diabetes by checking fasting glucose and HbA1c (at baseline and routinely) in addition to checking blood lipid levels. Men with impaired glucose tolerance and/or diabetes should be referred for an endocrine consultation. Prior to starting ADT a cardiology consultation should be considered in men with a history of cardiovascular disease and in men older than 65 years. Men on ADT are at increased risk of cardiovascular problems and hypertension and regular checks are required [1312]. More profound androgen ablation resulted in a higher cardiovascular toxicity [1313] and cardio-respiratory fitness decreased even after 6 months of ADT [1314]. Although LHRH antagonists have been suggested to provide a more favourable cardiovascular toxicity profile compared to LHRH agonists, the prematurely closed PRONOUNCE study found no difference at 12 months in major adverse cardiovascular events between men receiving degarelix or leuprolide [1315].

7.2.3.5. Monitoring bone problems

Androgen deprivation therapy increases the risk of osteoporosis. A combination of ADT with apalutamide, darolutamide, enzalutamide, abiraterone plus prednisone or docetaxel increases the fracture risk even more [1141,1316,1317]. Administration of ADT for more than a year, as compared to less than one year, showed a higher risk of osteoporosis (HR: 1.77 and 1.38, respectively) [1318]. Several scores (e.g., Fracture Risk Assessment Tool [FRAX score], Osteoporosis Self-Assessment Tool [OST], Osteoporosis Risk Assessment Instrument [ORAI], Osteoporosis Index of Risk [OSIRIS], Osteoporosis Risk Estimation [SCORE]) can help identify men at risk of osteoporotic complications but validation of these scores in the ADT setting is required (see Section 8.3.2.2) [1319-1321].

Routine bone monitoring for osteoporosis should be performed using dual emission X-ray absorptiometry (DEXA) scan [1322-1324]. Presence of osteoporosis should prompt the use of bone protective agents. The criteria for initiation of bone protective agents are mentioned in Section 8.3.2.2. If no bone protective agents are given, a DEXA scan should be done regularly, at least every 2 years [1325].

A review summarising the incidence of bone fractures showed an almost doubling of the risk of fractures when using ADT depending on patients’ age and duration and type of ADT with the highest incidence in older men and men on additional novel ARPI medication across the entire spectrum of disease [1326]. In case of an osteoporotic fracture a bone protective agent is mandatory. Vitamin D and calcium levels should be regularly monitored when patients receive ADT and patients should be supplemented if needed (see Section 8.3.2.2).

7.2.3.6. Monitoring lifestyle, cognition, fatigue and sexual function

Lifestyle (e.g., diet, exercise, smoking status, etc.) affects QoL and potentially outcome [1307]. During follow-up men should be counselled on the beneficial effects of exercise to avoid ADT-related toxicity [1327]. Androgen deprivation therapy may affect mental and cognitive health and men on ADT are three times more likely to report depression [1328]. Attention to mental health should therefore be an integral part of the follow-up scheme. Men on ADT may experience complaints of fatigue possibly related to systemic inflammation [1329]. Reduced cognitive performance and fatigue may arise within 6 months after initiation of ADT but can improve over time [1330]. Another apect of starting ADT is that it leads to sexual dysfunction, causing > 80% of couples to cease sexual activity completely. This aspect affects patients as well as their partners and couple counselling should be considered [1331].

7.2.4. Methods of follow-up in men on ADT without metastases

7.2.4.1. Prostate-specific antigen monitoring

Prostate-specific antigen is a key marker for following the course of androgen-sensitive non-metastasised PCa. Imaging should be considered when PSA is rising > 2 ng/mL or in case of symptoms suggestive of metastasis.

7.2.4.2. Imaging

In general, asymptomatic patients with a stable PSA level do not require further imaging, although care needs to be taken in patients with aggressive variants when PSA levels may not reflect tumour progression [1332]. New bone pain requires at least targeted imaging and potentially a bone scan. When PSA progression suggests CRPC status and treatment modification is considered, imaging, by means of a bone and CT scan, is recommended for restaging. Detection of metastases greatly depends on imaging (see Section 6.3.4).

7.2.5. Methods of follow-up in men under ADT for hormone-sensitive metastatic PCa

In metastatic patients it is of the utmost importance to counsel about early signs of spinal cord compression, urinary tract complications (ureteral obstruction, bladder outlet obstruction) or bone lesions that are at an increased fracture risk. The intervals for follow-up in M1 patients should be guided by patients’ complaints and can vary. Since most men will receive another anti-cancer therapy combined with ADT such as ARPI, chemotherapy or local RT, follow-up frequency should also be dependent on the treatment modality. The specific points related to follow-up during the castrate-resistant situation are detailed in Section 6.5.12.

7.2.5.1. PSA monitoring

In men on ADT alone, a PSA decline to < 4 ng/mL suggests a likely prolonged response and follow-up visits may be scheduled every 3 to 6 months provided the patient is asymptomatic or clinically improving. This applied to men on ADT monotherapy as well as after ADT plus docetaxel [1118]. Depending on symptoms and risk assessment, more frequent visits may be indicated. Treatment response may be evaluated based on a change in serum PSA level [1117,1118] and bone- and CT scan although there is no consensus about how frequently these should be performed [1260]. A rise in PSA level usually precedes the onset of clinical symptoms by several months. A rising PSA should prompt assessment of testosterone level, which is mandatory to define CRPC status, as well as restaging using imaging. However, it is now recognised that a stable PSA during ADT is not enough to characterise a non-progressive situation [1333].

7.2.5.2. Imaging as a marker of response in metastatic PCa

Treatment response in soft-tissue metastases can be assessed by morphological imaging methods using the Response Evaluation Criteria in Solid Tumours (RECIST) criteria. However, these criteria cannot be used in bone where response assessment is difficult [1334,1335].

When bone scan is used to follow bone metastases, a quantitative estimation of tracer uptake at bone scan can be obtained through automated methods such as the Bone Scan Index [1336]. Nonetheless, bone scan is limited by the so-called ‘flare’ phenomenon which is defined by the development of new images induced by treatment on a first follow-up scan which, after longer observation, actually represent a favourable response. Flare is observed within 8 to 12 weeks of treatment initiation and can lead to a false-positive diagnosis of disease progression. Computed tomography cannot be used to monitor sclerotic bone lesions because bone sclerosis can occur under effective treatment and reflects bone healing. Magnetic resonance imaging can directly assess the bone marrow and demonstrate progression based on morphologic criteria or changes in apparent diffusion coefficient. A standardisation for reporting is available [1337]. The ability of PET/CT to assess response has been evaluated in a few studies. Until further data are available, MRI and PET/CT should not be used outside trials for treatment monitoring in metastatic patients [1338].

Men with metastasised PCa on ADT should also in the absence of a PSA rise be followed up with regular imaging since twenty-five percent of men with, or without, docetaxel in the CHAARTED trial developed clinical progression without a PSA rise [1333]. One in eight men with a PSA < 2 ng/mL showed clinical progression [1333]. The addition of docetaxel to ADT in the CHAARTED trial population did not reduce the incidence of clinical progression at low PSA values and this rate was similar for both low- and high-volume disease as per CHAARTED criteria [1333]. However, the optimal timing and image modality to be used remain unclear, as is the real clinical value of any findings.

7.2.6. Guidelines for follow-up during hormonal treatment