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MANAGEMENT OF BIOCHEMICAL RECURRENCE AFTER RADICAL PROSTATECTOMY & RADIATION THERAPY

MANAGEMENT OF BIOCHEMICAL RECURRENCE AFTER RADICAL PROSTATECTOMY & RADIATION THERAPY

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MANAGEMENT OF BIOCHEMICAL RECURRENCE AFTER RADICAL PROSTATECTOMY & RADIATION THERAPY

  1. 1. GAURAV NAHAR DNB UROLOGY(STD.) MMHRC, MADURAI Evaluation and Management of Prostate-specific Antigen Recurrence After Radical Prostatectomy for Localized Prostate Cancer
  2. 2. INTRODUCTION Radical prostatectomy(RP)- the primary curative procedure for the treatment of localized prostate cancer. Approximately one third of all patients still demonstrate disease recurrence after surgery. For the majority, first sign of recurrent disease is a rising PSA level without either clinical or radiographic evidence of disease—the so-called ‘PSA recurrence’ or ‘biochemical failure’.
  3. 3. Rising PSA levels after RP may be due to 1. a local recurrence in the prostatic bed, 2. occult distant metastases or 3. a combination of both. Quite difficult to identify recurrent lesions accurately at an early stage of PSA recurrence. Local recurrence may be cured using salvage external-beam radiotherapy, whereas distant metastases require systemic hormonal therapy.
  4. 4. Majority of patients with PSA recurrence after RP- relatively young and healthy; hence treatment for PSA recurrence should aim not only to improve survival but also to preserve the quality of life.
  5. 5. PSA is a glycoprotein produced primarily by epithelial cells lining the acini and ducts of prostate gland. Serum PSA levels are normally very low. Elevated serum PSA level-d/t disruption of normal prostatic architecture- an important marker of many prostate diseases- BPH, prostatitis, and prostate cancer.
  6. 6. Treatment options T1/T2 disease • The standard approaches for men with organ- confined T1/T2 prostate cancer are – radical prostatectomy (RP) – external beam radiation therapy (EBRT), – brachytherapy, and – active surveillance Choice of therapy is largely a matter of patient preference. No evidence that cure rate is different with RP, EBRT, or brachytherapy when patients are stratified based upon prognostic characteristics.
  7. 7. Intermediate- or high-risk T1/T2 prostate cancer For these patients definitive treatment rather than active surveillance Intermediate-risk disease- EBRT, brachytherapy, or RP High-risk disease- ADT plus EBRT or RP plus adjuvant EBRT
  8. 8. Advantages of main treatment for early prostate cancer: EBRT Effective long term control with high dose Rx Low risk of urinary incontinence Wide range of ages When combined with hormonal therapy, offers a chance of cure in high-risk of disease Treatments can eradicate extension of tumor beyond the margins of prostate
  9. 9. Advantages of main treatment for early prostate cancer: Brachytherapy Cancer control rate equal to surgery and EBRT for organ-confined tumor Quicker than EBRT (one treatment) Available for cure in a wide range of ages and in those with comorbidities
  10. 10. Advantages of main treatment for early prostate cancer: Radical Prostatectomy Effective long-term cancer control Prediction of prognosis can be more precise based on pathologic features in specimen Pelvic lymph node dissection is possible through the same incision PSA failure easy to predict
  11. 11. Advantages of main treatment for early prostate cancer: Active Observation Reduces overtreatment Avoids or postpones treatment-associated complications Has no effect on work or social activities
  12. 12. Contraindications to main treatment options for early prostate cancer RP: High operative risk, ‘medical age’ of 70 or more, neurogenic bladder, morbid fear of surgery Active observation: High grade tumors, pt preference, expected survival of 10 or more years.
  13. 13. DEFINITION OF PSA RECURRENCE AFTER RP PSA usually reaches an undetectable level within 21– 30 days after radical prostatectomy. Persistently detectable or subsequent rising serum PSA levels (typical limit of detection is 0.05 ng/ml) after RP indicate either residual prostate cancer or recurrence.
  14. 14. AUA Guideline Update Panel recommended using a cut point ≥ 0.2 ng/mL, with a second confirmatory level ≥ 0.2 ng/mL, to define surgical failure. Memorial Sloan-Kettering Cancer Center (MSKCC) demonstrated best cut point to predict the probability of metastatic progression was > 0.4 ng/mL, followed by another rise.
  15. 15. EAU guidelines on prostate cancer: serum PSA level of >0.2 ng/ml- residual or recurrent disease & major risk of progression when the PSA level reaches 0.4 ng/ml. Prostate-Specific Antigen Working Group recommendation: PSA value ≥ 0.4 ng/mL, 8 weeks or more after RP and rises on a subsequent measurement. Eight weeks is ample time to allow PSA levels to clear, given a half-life of 2 to 3 days.
  16. 16. EAU guidelines for follow-up of prostate cancer after treatment with curative intent, PSA measurement + DRE at 3, 6 and 12 months after treatment, then every 6 months until 3 years, and thereafter annually. 45% developed recurrence in first 2 years after RP, 76% within first 5 years, and the remaining 23% >5 years after surgery. Hence a prolonged PSA follow- up is necessary after RP.
  17. 17. No definite consensus regarding PSA cut-off point for defining PSA recurrence after RP, a PSA level of 0.2 ng/ml on conventional assays is the most acceptable cut-off point for PSA recurrence based on a clinical point of view.
  18. 18. PSA RECURRENCE AFTER RADIATION THERAPY Biochemical failure after radiation therapy (ASTRO) as three consecutive PSA rises, optimally separated by 3 months between measurements, beginning at least 2 years after the start of radiation therapy. Time of failure is midpoint between the nadir and the first confirmed rise, or any rise significant enough to trigger therapy.
  19. 19. ASTRO Phoenix Criteria recommend that biochemical failure be defined as a PSA rise of 2 ng/mL above the post-treatment nadir, whether or not the patient received hormonal therapy in conjunction with radiation therapy. The date at which that level was reached would be the date of relapse.
  20. 20. FACTORS PREDICTING PSA RECURRENCE AFTER RP Local extent of disease on a DRE (T stage), serum PSA level and Gleason score from prostate biopsy specimens- all are important factors for predicting pathological stage (pT stage) for clinically localized prostate cancer. Partin Tables combine clinical stage, Gleason score, preop PSA level to predict pathologic stage: 1. Organ confined 2. Extracapsular (extraprostatic) extension 3. Seminal Vesicle invasion 4. Lymph node mets
  21. 21. Pretreatment risk stratification for prostate cancer
  22. 22. Using Partin tables, information regarding the probability of various pathological stages, such as organ-confined disease, extraprostatic extension, and seminal vesicle or lymph node involvement, is provided pre-operatively. Such pathological stages can serve as an excellent surrogate for outcome after RP.
  23. 23. For majority of patients, biochemical relapse occurs far earlier than the development of radiographically evident findings or findings on physical examination or by biopsy. Low pretreatment PSA levels, lower-grade tumors, low clinical or pathologic staging, late time from definitive local therapy to PSA relapse, and long PSADTs generally indicate a low likelihood of developing distant radiographically apparent metastases.
  24. 24. Serum PSA level between 10 and 20 ng/ml- intermediate risk for PSA recurrence, while serum PSA level >20 ng/ml represent a high-risk for developing PSA recurrence after RP. Gleason grade ≥4, or a Gleason score >7 on RP specimens is predictive of a high-risk for PSA recurrence.
  25. 25. Histopathological determinants and molecular markers have been evaluated to predict PSA recurrence and survival. p53 tumor suppressor gene expression, bcl-2 protooncogene expression, expression of Ki-67 & p27, apoptotic index, DNA ploidy and tumor angiogenesis (microvessel density):- all are possible predictive factors of PSA recurrence after RP.
  26. 26. TESTS TO DETERMINE SITE OF RECURRENCE Current methods of detecting recurrence whether in prostatectomy bed, an irradiated gland, or metastatic sites such as bone or lymph nodes, are of very limited value. Bone Scintigraphy: Bone scintigraphy will only detect metastatic disease that interferes with normal osteoblast/osteoclast interactions to produce abnormal bone deposition. Areas of marrow involvement that do not impact bone metabolism will remain undetected.
  27. 27. No single PSA value predicts scan positivity, although PSAs will be well above 20 to 30 ng/mL before bone scintigraphy reflects metastatic disease. Tracer uptake in areas of trauma, infection, or inflammation can easily be mistaken for metastatic disease.
  28. 28. CT SCAN: CT scans are not sufficiently sensitive for detecting local recurrence until increasing rate of PSA becomes >20 ng/ml per year. CT is suboptimal for detection of metastasis as it has a lower limit of detection of 0.5 cm & the scans are nonspecific, making it difficult to distinguish scar tissue or fibrosis from tumor.
  29. 29. Sensitivity & specificity of MRI and MR spectroscopy are improving; most useful for detecting nodal and bony metastases. But not sufficiently useful early in the course of PSA recurrence. Positron emission tomography (PET-CT using FDG, 18F choline, 11C choline, 11C acetate), a biochemical imaging modality, still investigational, cannot accurately distinguish post-operative scars from local recurrence.
  30. 30. PROSTASCINT (Antibody based imaging/ Immunoscintigraphy): Approved by the U.S. FDA to detect occult metastatic disease in early prostate cancer, also indicated for a rising PSA and a negative or equivocal standard metastatic evaluation when there is a high clinical suspicion of metastatic disease. Based on a murine antibody, 7E11, combined with indium-111 to target the internal domain of PSMA, a transmembrane type II glycoprotein found on normal prostate tissue and prostate cancers.
  31. 31. PREDICTING LOCAL Vs SYSTEMIC RECURRENCE Combination of Gleason score, pathological stage and serum PSA velocity 1 year after surgery best distinguished local recurrence from distant metastases. PSADT and Gleason score are highly prognostic for clinical outcome.
  32. 32. TREATMENT OF PSA RECURRENCE Depends on the site of recurrence: namely local, systemic or a combination of both. Treatment options for presumed local recurrence include external beam radiotherapy and, for presumed distant metastasis, hormonal therapy. Observation only is also one of the treatment options regardless of recurrence site.
  33. 33. Routine tests cannot identify site of recurrence untilnPSA reaches 20–50 ng/ml, at which level effectiveness of radiotherapy can no longer be expected. Therefore, treatment is mainly selected according to the pathological findings of RP specimen and post-operative serum PSA parameters.
  34. 34. OBSERVATION: Natural course from PSA recurrence to development of metastatic disease or prostate cancer-specific death is quite long. Hence observation with delayed hormonal therapy for symptomatic or metastatic disease can be a valid treatment option.
  35. 35. RADIATION THERAPY: Salvage radiotherapy is the recommended terminology for curative-intended radiation for post-operative PSA recurrence as opposed to adjuvant radiotherapy administered shortly after RP based on adverse pathological findings. Candidates must have a life expectancy of >10 years, since salvage radiation therapy is sometimes associated with high morbidity.
  36. 36. Preoperative PSA level, pre-radiotherapy PSA level and seminal vesicle involvement are significant risk factors for actuarial biochemical disease-free survival following post-operative radiotherapy. ASTRO Consensus Panel demonstrated a serum PSA level of 1.5 ng/ml as the threshold level for optimal success rates. European Consensus Group recommended a PSA level of 1.0–1.5 ng/ml as appropriate cut-off point to initiate salvage radiotherapy for presumed local recurrence.
  37. 37. Dose of radiation: ASTRO Consensus Panel- 64.8Gy radiation to the prostatic bed. European Consensus group- 64 Gy, with 1.8-2.0 Gy per fraction. Predictors of disease progression following salvage radiotherapy: negative/close margins, an absence of extracapsular extension, presence of seminal vesicle invasion, a Gleason score of 8–10, a pre- radiotherapy PSA level >2.0 ng/ml, a PSA doubling time of ≤10 months.
  38. 38. Hormonal therapy may increase sensitivity to irradiation, may be effective for possible distant metastases in such patients. But the European Consensus Group mentioned that hormonal therapy is not standard in patients receiving salvage radiotherapy.
  39. 39. HORMONAL THERAPY: Androgen deprivation therapy by surgical(B/L scotal orchiectomy) or medical castration using a LH-RH agonist or antiandrogens may improve survival. PSA level at which hormonal therapy should be initiated remains unclear, though time to metastatic disease was delayed on starting at PSA level ≤5 ng/ml than at PSA level ≤10mg/dl.
  40. 40. INTERMITTENT HORMONAL THERAPY- this concept introduced to avoid the side effects of hormonal therapy. Long-term efficacy remains unclear. Finasteride may have an ability to delay disease progression patients in PSA recurrence after RP; long-term studies are required.
  41. 41. CONCLUSION Clinical state of “Rising PSA/Biochemical recurrence” after RP- second in size only to localized disease. Unique in that patients are characterized by an absence of symptoms, radiographic findings or pathologic findings—standard measures of treatment effects.
  42. 42. PSADT is one of the most common elements for stratifying patients & allocating Rx. Patients can be divided into three groups based on prognosis:  low-risk patients are unlikely to develop metastases or symptoms or die of their disease and should be managed expectantly;  intermediate-risk patients receive androgen deprivation or can be considered for investigational approaches designed to slow the disease to the point where the patient dies of other causes; and  high-risk patients (those with PSADTs of ≤9 months) can be considered for androgen deprivation or ideally, enrolled in a clinical trial(TAX3503- Docetaxel 10 cycles; Mitoxantrone & Prednisone).
  43. 43. Thank You

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