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  • Review Article
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Salvage therapy for prostate cancer after radical prostatectomy

Nature Reviews Urology volume 18, pages 643–668 (2021)Cite this article

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Abstract

More than 40% of men with intermediate-risk or high-risk prostate cancer will experience a biochemical recurrence after radical prostatectomy. Clinical guidelines for the management of these patients largely focus on the use of salvage radiotherapy with or without systemic therapy. However, not all patients with biochemical recurrence will go on to develop metastases or die from their disease. The optimal pre-salvage therapy investigational workup for patients who experience biochemical recurrence should, therefore, include novel techniques such as PET imaging and genomic analysis of radical prostatectomy specimen tissue, as well as consideration of more traditional clinical variables such as PSA value, PSA kinetics, Gleason score and pathological stage of disease. In patients without metastatic disease, the only known curative intervention is salvage radiotherapy but, given the therapeutic burden of this treatment, importance must be placed on accurate timing of treatment, radiation dose, fractionation and field size. Systemic therapy also has a role in the salvage setting, both concurrently with radiotherapy and as salvage monotherapy.

Key points

  • Clinical markers of local versus distant relapse of prostate cancer following radical prostatectomy include PSA level and kinetics, pathological characteristics, genomic risk scores and imaging findings.

  • During consultation after prostatectomy, clinicians should evaluate the PSA level, the PSA doubling time, the interval to biochemical failure (PSA rises to >0.2 ng/ml), and patient comorbidities, urinary bother, continence, erectile function, changes in symptoms over time, medications and genomic risk (if possible). CT and bone scan imaging is inaccurate with PSA <5 ng/ml, and so should be avoided.

  • The ideal patients for observation are: elderly (for example, age >80), low Gleason score (for example, 6–7 (International Society of Urological Pathology grade group 1–2), long PSA doubling time (for example, >12–18 months), long interval to biochemical failure (for example, >5–10 years), low absolute PSA at time of recurrence (for example, <0.5 ng/ml), multiple medical comorbidities, high risk of death from competing causes, no distant metastases on imaging.

  • Patients with high-risk features might be good candidates for salvage radiotherapy. Androgen deprivation therapy (ADT) should be considered for those patients with PSA >0.5 ng/ml.

  • Patients with documented metastases should receive ADT alone, although patients with other high-risk features might also benefit from ADT as these features could suggest occult metastatic disease.

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Fig. 1: Considerations and treatment paradigm in the management of recurrent prostate cancer after prostatectomy.

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Acknowledgements

N.G.Z. is supported by startup funding from Penn State Cancer Institute and Penn State College of Medicine, is supported by the National Institutes of Health Grant L radical prostatectomy 1 L30 CA231572-01, is supported by the American Cancer Society – Tri State CEOs Against Cancer Clinician Scientist Development Grant, CSDG-20-013-01-CCE and received remuneration from Springer Nature for his textbook, Absolute Clinical Radiation Oncology Review.

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Authors and Affiliations

  1. Department of Radiation Oncology, Penn State Cancer Institute, Hershey, PA, USA

    Nicholas G. Zaorsky

  2. Department of Public Health Sciences, Penn State College of Medicine, Hershey, PA, USA

    Nicholas G. Zaorsky

  3. Ahmanson Translational Theranostics Division, Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA

    Jeremie Calais

  4. Nuclear Medicine Division and PET Unit, IRCCS Azienda Ospedaliero Universitaria di Bologna, Bologna, Italy

    Stefano Fanti

  5. Martini-Klinik Prostate Cancer Center, University Hospital Hamburg-Eppendorf, Hamburg, Germany

    Derya Tilki

  6. Department of Urology, University Hospital Hamburg-Eppendorf, Hamburg, Germany

    Derya Tilki

  7. Department of Urology, Koc University Hospital, Istanbul, Turkey

    Derya Tilki

  8. Department of Medical Oncology and Developmental Therapeutics, City of Hope, Duarte, CA, USA

    Tanya Dorff

  9. Department of Radiation Oncology, University Hospitals Seidman Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH, USA

    Daniel E. Spratt

  10. Department of Radiation Oncology, UCLA, Los Angeles, CA, USA

    Amar U. Kishan

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Contributions

N.G.Z., J.C., S.F., D.T., T.D., D.E.S. and A.U.K. researched data for the article, made a substantial contribution to the discussion of its content, wrote and reviewed the manuscript prior to submission.

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Correspondence to Nicholas G. Zaorsky.

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Competing interests

J.C. is supported by the Prostate Cancer Foundation (2020 Young Investigator Award 20YOUN05, 2019 Challenge Award 19CHAL02), the Society of Nuclear Medicine and Molecular imaging (2019 Molecular Imaging Research Grant for Junior Academic Faculty) and reports prior consulting activities outside of the submitted work for Advanced Accelerator Applications, Blue Earth Diagnostics, Curium Pharma, GE Healthcare, Janssen Pharmaceuticals, Progenics Pharmaceuticals, Radiomedix and Telix Pharmaceuticals. The remaining authors declare no competing interests.

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Glossary

Androgen deprivation therapy

(ADT). Also known as hormone therapy, typically includes drugs such as LHRH agonists (e.g. leuprolide) and LHRH antagonists (e.g. degarelix). Androgen receptor inhibitors (e.g. enzalutamide) and anti-androgens (e.g. bicalutamide) technically do not decrease androgen production, and technically are not ADT, but they are commonly put in the same category. Short-term ADT implies use of ADT for 3–6 months, and long-term ADT implies use for 12–36 months.

Biochemical recurrence

After prostatectomy, biochemical recurrence is historically defined by two consecutive PSA values >0.2 ng/ml. After definitive radiation therapy (i.e. for men with an intact prostate), this is defined by the nadir +2 ng/ml PSA.

Salvage radiation therapy

Radiation therapy prescribed to the prostate bed, with or without the pelvic lymph nodes, in the setting of a rising PSA after prostatectomy. The historical definition for salvage radiotherapy is with PSA of ≥0.2 ng/ml with a second confirmatory value. ‘Early salvage’ refers to radiotherapy with PSA < 0.5 ng/ml. ‘Very early salvage’ refers to radiotherapy with PSA 0.01–0.2 ng/ml.

Prostate bed

The prostate bed has the following boundaries: the anterior: the posterior edge of the pubic bone, or the posterior 1–2 cm of the bladder wall (when above the superior edge of the pubic symphysis); the posterior: the anterior rectal wall, or the mesorectal fascia (when above the superior edge of the pubic symphysis); the lateral: levator ani muscles, obturator internal, sacrorectogenitopubic fascia; and the inferior: 8–12 mm below the vesicourethral anastomosis. Prior to surgery, the prostate bed is the volume occupied by the prostate and seminal vesicles. After surgery, it consists of the inferior portion of the bladder and proximal urethra, which are joined by the vesiculourethral anastomosis.

X-ray attenuation coefficients

A value that characterizes how easily a material can be penetrated by X-rays, in m2/kg. Soft tissue often has the same attenuation coefficient as a tumour, so the tumour cannot readily be seen on a CT scan (which uses X-rays), unless the tumour is large (> several cm) and/or contrast material is used.

Bone scintigraphy

Commonly called a bone scan, or radiolabelled diphosphonate Technetium-99m (99mTc) scan, which evaluates for bone metastases.

Adjuvant radiation therapy

Post-prostatectomy radiation therapy prescribed to the prostate bed, with or without the pelvic lymph nodes, for adverse pathological features, including positive margins, extracapsular extension (pT3a) or seminal vesicle invasion (pT3b), with an undetectable PSA (historically <0.2 ng/ml).

Surrogate end point

An indicator used in place of a more traditional ‘hard’ end point (such as survival), which might be more difficult, or take too long to reach to identify if a treatment works in the context of a clinical trial.

Hard end point

End points including death or quality of life.

Image-guided radiation therapy

An integral component of radiotherapy systems that obtains imaging coordinates of a target and/or healthy tissues before or during treatment, detects and corrects for random and systematic errors that occur in patient setup and organ motion, and increases accuracy and precision. Multiple types of image-guided radiation therapy systems exist. 2D and 3D systems detect movements interfractionally (that is between two radiotherapy sessions), novel 4D systems detect movements intrafractionally (that is during one radiotherapy session).

Intensity-modulated radiotherapy

(IMRT). An advanced form of high-precision radiation that conforms the treatment volume to the shape of the tumour. The dose distribution created by IMRT is characterized by a concavity or invagination of the edge of the high doses away from the rectum, rather than a straight edge through the rectum as seen with 3D-CRT.

Pelvic lymph node radiotherapy

Also called whole-pelvis radiotherapy, this is a treatment that additionally includes the following nodal regions: common iliacs, presacral (S1–3), external or internal iliacs, obturators, typically to a dose of 45–50 Gy in 2-Gy fractions. The volume generally starts at L5–S1 (although some start at L4–L5) and ends inferiorly at the femoral heads and top of the pubic symphysis.

Gross tumour volume

(GTV). This is the demonstrable extent and location of the malignant growth; it consists of the macroscopic primary tumour, which for prostate cancer has historically been defined as the entire gland as well as any visualized extension into surrounding normal tissues, the regional lymph nodes, or distant metastases based on clinical data. For post-prostatectomy radiotherapy, there is typically not a measurable GTV.

Clinical target volume

(CTV). This volume encompasses the gross tumour volume (GTV) as well as areas at risk of microscopic or subclinical cancer involvement. The CTV can include a margin around the prostate GTV and adjacent regions at risk of having subclinical disease. For post-prostatectomy radiotherapy, the two most common CTVs are the prostate bed ± the pelvic lymph nodes. For post-prostatectomy radiotherapy, the CTV typically does not include the GTV, as the disease is microscopic and cannot be seen on imaging.

Planning target volume

(PTV). This volume encompasses the CTV plus an additional margin to account for patient movement, setup error and organ movement. For post-prostatectomy radiotherapy, this margin is typically 3–10 mm.

α to β ratio

The α to β ratio describes the shape of the cell survival curve and the gradient of the two components of cell kill, α and β. The α to β ratio is used to describe the dose response of radiation on different tissues. Prostate cancer cells have a relatively low α to β ratio of 1.5, implying that those cells are more sensitive to doses delivered in larger fraction sizes. In the radiobiological linear quadratic equation, the α to β ratio is the dose at which cell killing as a result of the linear and quadratic components is equal.

2 Gy equivalent dose

(EQD2). Radiotherapy can be given with conventional fractionation (1.8–2.0 Gy per day up to ~60–70 Gy), with hypofractionation (2.1–3.0 Gy per day, up to ~50 Gy), or ultrahypofractionation/stereotactic body radiation therapy (~5–12 Gy per day, up to ~30–50 Gy). However, the overall, or isoeffective, dose is thought to be similar with all approaches, and the EQD2 helps to provide a rough estimate of this total dose if it had been delivered in 2-Gy fractions.

Partin table

A mathematical formula that predicts pathological stage using retrospective prostatectomy data.

Microscopic cell kill

Killing of cells that are not visible on imaging, including micrometastatic disease in the bloodstream.

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Zaorsky, N.G., Calais, J., Fanti, S. et al. Salvage therapy for prostate cancer after radical prostatectomy. Nat Rev Urol 18, 643–668 (2021). https://doi.org/10.1038/s41585-021-00497-7

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