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docetaxel (n = 593), and another was ADT combined with
docetaxel and zoledronic acid (n = 593). Patients were
included with either M1 or N1 or had at least two of the
following adverse criteria: T3/4, PSA 40 ng/ml, or Gleason
8–10. In addition, relapsed patients after local treatment
were included if they had one of the following criteria: PSA
4 ng/ml with PSA DT <6 mo, PSA 20 ng/ml, N1, or M1. No
stratification was used regarding metastatic disease vol-
ume. The key findings are summarised in .
In the three trials, toxicity was mainly haematologic with
approximately 12–15% grade 3–4 neutropenia and 6–12%
grade 3–4 febrile neutropenia. Concomitant use of granu-
locyte colony-stimulating factor receptor was shown to be
helpful, and its use should be based on available guidelines
. Based on these data, docetaxel combined with ADT
should be considered as a new standard for men presenting
with metastases at first presentation, provided they are fit
enough to receive the drug ).
3.4. Follow-up during hormonal treatment
The main objectives of follow-up in men on ADT are to
ensure treatment compliance, to monitor treatment re-
sponse and side effects, and to identify the development of
CRPC. Clinical follow-up is mandatory on a regular basis and
cannot be replaced by laboratory tests or imaging modali-
ties. It is of the utmost importance in metastatic situations
to advise patients about early signs of spinal cord
compression and to check for occult cord compression,
urinary tract complications (ureteral obstruction, bladder
outlet obstruction), or bone lesions that pose an increased
fracture risk. Treatment response may be assessed using the
change in serum PSA level as a surrogate end point for
survival . Asymptomatic patients with a stable PSA level
do not require further imaging. summarises the
guidelines for follow-up during hormonal therapy. New-
onset bone pain requires a bone scan, as does PSA
progression suggesting CRPC status, if a treatment modifi-
cation is considered. The Prostate Cancer Clinical Trials
Working Group (PCWG2) clarified the definition of bone
scan progression, at least for patients enrolled in clinical
trials, as the appearance of at least two new lesions that
are later confirmed. Suspicion of disease progression
indicates the need for additional imaging modalities guided
by symptoms or possible subsequent treatments.
The measurement of serum testosterone levels should
also be considered part of clinical practice for men on LHRH
therapy. The timing of testosterone measurements is not
clearly defined. A 3- to 6-mo assessment of the testosterone
level might be performed to evaluate the effectiveness of
treatment and to ensure that the castration level is being
maintained. If this is not the case, switching to another type
of LHRH analogue, LHRH antagonist, surgical orchiectomy,
or addition of an antiandrogen can be attempted. In
Table 1 – Guidelines for imaging and second-line therapy after treatment with curative intent
Local salvage treatment LE GR
BCR after RP
Offer patients with a PSA rise from the undetectable range and favourable prognostic factors (pT3a or lower, time to BCR >3 yr,
PSA DT >12 mo, Gleason score 7) surveillance and possibly delayed salvage radiotherapy.
3 B
Treat patients with a PSA rise from the undetectable range with salvage RT. The total dose of salvage RT should be at least 66 Gy
and should be given early (PSA <0.5 ng/ml).
2 A
BCR after RT
Treat highly selected patients with localised PCa and a histologically proven local recurrence with salvage RP. 3 B
Due to the increased rate of side effects, perform salvage RP in experienced centres. 3 A
Offer or discuss high-intensity focused ultrasound, cryosurgical ablation, and salvage brachytherapy with patients without evidence
of metastasis and with histologically proven local recurrence. Inform patients about the experimental nature of these approaches.
3 B
Systemic salvage treatment
Do not routinely offer ADT to asymptomatic men with BCR. 3 A
Do not offer ADT to patients with a PSA DT >12 mo. 3 B
If salvage ADT (after primary RT) is started, offer intermittent therapy to responding patients. 1b A
ADT = androgen-deprivation therapy; BCR = biochemical recurrence; GR = grade of recommendation; LE = level of evidence; PCa = prostate cancer;
PSA = prostate-specific antigen; PSA DT = prostate-specific antigen doubling time; RP = radical prostatectomy; RT = radiotherapy.
Table 2 – Key findings: hormonal treatment combined with chemotherapy in men presenting with metastatic disease
Study Population Patients, n Median FU, mo Median OS, mo HR p value
ADT + D ADT
Gravis et al M1 385 50 58.9 54.2 1.01 (0.75–1.36) 0.955
Gravis et al HV 7% 82.9 60.9 46.5 0.9 (0.7–1.2) 0.44
Sweeney et al M1 HV 5% 790 28.9 57.6 44 0.61 (0.47–0.8) <0.001
STAMPEDE M1 (61%), N+ (15%), relapse 1184
43
593 D 81 71 0.78 (0.66–0.93) 0.006
593 D + ZA 76 NR 0.82 (0.69–0.97) 0.022
M1 only 725 + 362 D 60 45 0.76 (0.62–0.92) 0.005
ADT = androgen deprivation therapy; D = docetaxel; FU = follow-up; HR = hazard ratio; HV = high volume; NR = not reported; ZA = zoledronic acid.
* HV indicates either visceral metastases or more than four bone metastases with at least one outside the spine and pelvis.
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