Robert B. Den, MD
Mark Hurwitz, MD
BASICS
DESCRIPTION
• Rising PSA after treatment, referred to as biochemical recurrence, is nearly always the first indication of recurrent prostate cancer. The site of recurrence—local, regional, distant, or a combination of sites, however, cannot be discerned by PSA level alone
• Definitions of biochemical recurrence following radiation:
– ASTRO definition: 3 consecutive rises in PSA (backdating)
– Phoenix definition: PSA nadir + 2 ng/mL
EPIDEMIOLOGY
Incidence
• Most men with clinically localized disease will not experience recurrence. However, given the widespread use of radiation therapy for treatment of prostate cancer, biochemical recurrence is not an uncommon problem in routine clinical practice.
• 5-yr rates of biochemical recurrence ∼5–40% depending on risk stratification criteria
Prevalence
The time from biochemical recurrence to clinical recurrence is typically measured in years. Therefore prevalence is relatively high as compared to incidence.
RISK FACTORS
• Risk of recurrence is associated with original risk stratification including clinical stage, PSA, and Gleason score.
• A rise in PSA of >2 points in the year preceding diagnosis is associated with increased risk for both recurrence and prostate cancer–specific mortality
• Gleason score 4 + 3 = 7 vs. 3 + 4 = 7 and/or ≥50% positive biopsies in intermediate-risk patients
• Lower doses of radiation
• Lack of use of androgen deprivation therapy in high-risk patients
Genetics
New tests linking tumor-specific genetic profiles to adverse risk in prostate cancer including risk of recurrence after prostatectomy have recently become clinically available. Their ultimate clinical value remains to be fully defined. In regard to biochemical recurrence following radiation therapy, the utility of such tests to guide further therapy is not yet known.
PATHOPHYSIOLOGY
• >95% of prostate cancers are adenocarcinoma
• Rare variants such as TCC, small cell carcinoma, and sarcomas are not associated with elevation of PSA
ASSOCIATED CONDITIONS
Symptoms of urinary outlet obstruction can occur but are uncommon during the initial period of biochemical recurrence.
GENERAL PREVENTION
• Optimized radiation therapy including dose escalation with daily image guidance to ensure proper targeting with external beam radiation and use of proper brachytherapy techniques
• Use of androgen deprivation in combination with radiation for high risk and selected intermediate risk patients
DIAGNOSIS
HISTORY
• Prior radiation treatment information should be obtained including type of radiation, technique, and dose prescribed. For prostate brachytherapy postimplant dosimetry analysis should be reviewed to determine if there were underdosed regions.
• Thorough assessment of general health with emphasis on urinary and bowel function is important in guiding the advisability of potential salvage therapies.
PHYSICAL EXAM
General physical exam including rectal exam
DIAGNOSTIC TESTS & INTERPRETATION
Lab
• PSA.
– In addition to total PSA, PSA kinetics may be helpful in identifying patients at greater risk of development of distant vs. local recurrence.
– Patients with short time to PSA nadir after treatment and short doubling times (PSADT) are at greater risk of subsequent diagnosis of metastatic disease (PSDAT <3–6 mo)
• Testosterone establishes baseline for future hormonal intervention
• Basic metabolic panel
• CBC
Imaging
• Bone scan
• CT of abdomen and pelvis
• Pelvic/prostatic MR. Magnetic resonance spectroscopic imaging may improve results over MR alone
• New techniques for PET/CT including use of 18F-NaF may be useful in select cases
• Other imaging as clinically indicated
Diagnostic Procedures/Surgery
• Prostate biopsy should be considered if more than 2 yr have elapsed since completion of radiation therapy and additional local therapy is being contemplated.
– As the full effects of radiation are not manifested for 24–30 mo, biopsy before this time is not indicated.
• Approximately 20% of patients who have postradiation biopsies will have no clinical evidence of disease with additional long-term follow-up. Conversely, given the limitations of sampling, local recurrence may be present despite negative biopsy.
• Biopsy to assess findings concerning for distant metastases as clinically indicated.
Pathologic Findings
• Discerning posttreatment change from residual disease in irradiated prostate tissue can be difficult.
– Immunohistochemical analysis with basal cell-specific keratin monoclonal antibodies can aid in differentiating benign and malignant glands since only benign glands display basal cell immunoreactivity.
DIFFERENTIAL DIAGNOSIS
• PSA bounce phenomenon
– 35% incidence after brachytherapy
– Less common with external beam radiation
• Testosterone rebound after completion of androgen deprivation with associated rise in PSA
TREATMENT
GENERAL MEASURES
• Efforts should be made to discern if biochemical recurrence is due to presence of local vs. distant disease or a combination of both.
• In the presence of metastatic disease androgen ablation is the standard choice.
• In cases of only localized disease there are many more options including observation, androgen ablation or salvage therapies including radical prostatectomy or cryotherapy.
– In general candidates for local salvage therapy should have original clinical stage tumor T-1, T2 NX/N), life expectancy of >10 yr, and a PSA <10 ng/mL (1)
– Patient who are not ideal candidates for salvage therapy should be treated by androgen deprivation or observation
MEDICATION
First Line
• Hormonal therapy (androgen deprivation):
– LHRH agonists: Leuprolide, goserelin, triptorelin
Suppress LH and FSH release by the pituitary
– LHRH antagonists: Degarelix (only 1 FDA approved in US;
Suppress LH and FSH release by the pituitary
– Antiandrogens: Flutamide, bicalutamide, nilutamide, directly block the activity of androgens on the androgen receptor
– LHRH agonists can be used alone or in combination with oral antiandrogens
– When LHRH agonist therapy is initiated, a release of testosterone is induced (androgen flare) that may exacerbate symptoms from metastatic lesions. In particular, patients with spinal metastasis may be in jeopardy of cord compression
Flare avoided by initiating antiandrogen therapy 2 wk prior to 1st LHRH agonist injection
– Orchiectomy remains an infrequently utilized option for androgen ablation
Second Line
Alternate androgen deprivation therapy or clinical trial
SURGERY/OTHER PROCEDURES
• Radical prostatectomy is rarely performed following prostate radiation due to high rates of morbidity (2)
– However, surgery can be considered in carefully selected cases for relatively young healthy patients with established local recurrence
– 5- and 10-yr rates of freedom from biochemical recurrence with salvage radical prostatectomy range up to 59% and 37% respectively with disease-specific survival as high as 83% at 10 yr
– Common toxicities include bladder neck contracture (17–47%), rectal fistula (7–20%), and erectile dysfunction in nearly all patients
ADDITIONAL TREATMENT
Radiation Therapy
• Administration of additional radiation therapy in most instances should be limited to research protocols.
– The most commonly investigated approach is salvage brachytherapy following external beam radiation failures.
– 5-yr freedom from biochemical recurrence has been reported between 25–75% and disease-specific survival between 74–100%. Wide variation in reported outcomes is likely due to variation in risk criteria across studies.
– Crude rates of grade ≥3 GU and GI complications average 13% and 5%, respectively. Rates may be higher in elderly patients.
Additional Therapies
• Thermal ablative therapies including cryoablation and high-intensity focused ultrasound remain investigational.
• Cryotherapy in particular has shown promise in selected series.
– 5–10-yr freedom from biochemical recurrence with cryotherapy ranges between 34–59%.
– Rates of ≥3 GU and GI complications average approximately 10% and 3% across reported series.
• Focal ablative therapies that attempt to identify the site of recurrence and ablate the site are investigational (3).
Complementary & Alternative Therapies
Low-fat diets and diets high in polyphenols as found in broccoli, turmeric, pomegranate, and green tea may be beneficial
ONGOING CARE
PROGNOSIS
PSA doubling time of less than approximately 6 mo and in particular 3 mo has been linked to increased risk of prostate cancer–specific mortality
COMPLICATIONS
• Urinary outlet obstructive symptoms
• Proctalgia due to rectal invasion is typically seen only with advanced stages of recurrence
FOLLOW-UP
Patient Monitoring
• Dependent in part on subsequent treatment
• Every 3–6 mo including general and prostate exam and PSA
Patient Resources
American Cancer Society. http://www.cancer.org/cancer/prostatecancer/detailedguide/prostate-cancer-treating-recurrence
REFERENCES
1. NCCN Practice Guidelines Version 1. 2014 http://www.nccn.org/. Accessed January 6, 2014
2. Punnen S, Cooperberg MR, D’Amico AV, et al. Management of biochemical recurrence after primary treatment of prostate cancer: A systemic review of the literature. Eur Urol. 2013;64(6):905–915.
3. Valerio M, Ahmed HU2, Emberton M2, et al. The role of focal therapy in the management of localised prostate cancer: A systematic review. Eur Urol. 2013. pii: S0302–2838(13)00557–5. doi: 10.1016/j.eururo.2013.05.048.
ADDITIONAL READING
Kanthabalan A, Arya M, Punwani S, et al. Role of focal salvage ablative therapy in localised radiorecurrent prostate cancer. World J Urol. 2013;31(6):1361–1368.
See Also (Topic, Algorithm, Media)
• Prostate Cancer, Biochemical Recurrence (Elevated PSA) Following Cryotherapy
• Prostate Cancer, Biochemical Recurrence (Elevated PSA) Following Radical Prostatectomy
• Prostate Cancer, Metastatic (Clinical and Pathologic N+, M+)
• PSA Elevation, General Considerations
• PSA, Bounce
• PSA, General Considerations
• Reference Tables: TNM: Prostate Cancer
CODES
ICD9
• 185 Malignant neoplasm of prostate
• 790.93 Elevated prostate specific antigen [PSA]
• V15.3 Personal history of irradiation, presenting hazards to health
ICD10
• C61 Malignant neoplasm of prostate
• R97.2 Elevated prostate specific antigen [PSA]
• Z92.3 Personal history of irradiation
CLINICAL/SURGICAL PEARLS
• Risk stratification, morbidities associated with the primary course of radiation, and PSA kinetics posttreatment are important to consider in selecting the best management option.
• Participation in clinical trials should be encouraged in areas such as this where no consensus exists.