Castration-resistant prostate cancer
Defining castrate-resistant prostate cancer has been a matter of much consideration due to:
- the heterogenous manifestations of prostate cancer progression, and
- the fact some patients who progress with a castrate-level of testosterone respond to second-line hormone manipulations.
Therefore a consensus statement has been developed by the Prostate Cancer Clinical Trials Working Group on what defines progression to ensure standard entry criteria onto a clinical trial. This in turn provides guidance to physicians treating patients outside a clinical trial. Castrate-resistant prostate cancer is defined as progressive disease despite castrate levels of testosterone. Progression can be deemed to have occurred based on changes in PSA and/or increase of measurable disease and/or increasing burden of disease on bone scan, while controlling for antiandrogen withdrawal responses. These criteria are standardised by assessments and include:
- PSA. Obtain sequence of rising values at a minimum of one-week intervals. If the patient is being deemed to have progressed by PSA alone then 2.0ng/mL must be the minimum starting value. The baseline value (#1) is the last PSA measured before increases are documented, with subsequent values obtained a minimum of one week apart. If the PSA at time point 3 is greater than that at point 2, and point 2 was greater than point 1, then PSA documented progression has been met. If the PSA at point 3 is not greater than point 2, but value at point 4 is, the patient has documented progression.
- Progression of measurable disease. Whether progression of measurable disease (such as nodal or visceral progression) is the same as the RECIST definition (target and non-target). Increasing soft tissue castrate-resistant prostate cancer can occur in the absence of a rising or even detectable PSA. Only lymph nodes greater than or equal to 2cm in diameter should be used to assess changes in size.
- Progression of disease in the prostate/ prostate bed (primary site). This should be considered. To document presence or absence of disease, all documentation of prior treatment of primary tumour is required, as are evaluations such as directed pelvic imaging (CT, MRI, positron emission tomography (PET)/CT, endorectal MRI, transrectal ultrasound). Clinical progression can be manifest by bladder outlet obstruction and/or disease extension into the bladder with ureteric obstruction.
- Bone-scan progression. This is defined as appearance of two or more new lesions. Ambiguous results may require confirmation by other imaging modalities (e.g. CT or MRI). Symptomatic progression of an isolated lesion with a castrate level of prostate cancer would also qualify as progressive disease.
Other sites of disease can also be evidence of prostate cancer progression, such as worsening epidural lesions. Radiographic and/or clinical documentation of disease in these sites would also qualify as progression.
- Is any one hormone therapy (androgen ablation) superior to another when given in the second-line setting (after relapse from first-line androgen ablation) in terms of response, progression-free survival or survival?
- Should LHRH agonist be continued when the patient is hormone refractory?
- What is the evidence for the use of bisphosphonates in the prevention of skeletal events?
- What is the evidence for the use of bisphosphonates in the treatment of bone pain?
- What is the effectiveness of unsealed radioisotopes in the management of bone pain from prostate cancer?
- Do unsealed radioisotopes improve survival in metastatic prostate cancer?
- What is the evidence that quality of life is improved with unsealed radioisotopes in prostate cancer?
- What is the toxicity of unsealed radioisotopes for treatment of metastatic prostate cancer?
- Does cytotoxic chemotherapy give a survival benefit or any other benefits in terms of quality of life improvement, control of pain or other symptoms compared to patients not receiving chemotherapy or receiving different types of chemotherapy?
Issues requiring more clinical research study
Chemotherapy-related clinical questions considered, but for which no evidence was found during systematic review
- Is there any benefit derived from chemotherapy for patients who do not have any symptoms from the prostate cancer (asymptomatic)?
- Is there any benefit derived from chemotherapy for patients who are not hormone refractory comparing chemotherapy plus hormone therapy with hormone therapy alone?
- Has the effectiveness of chemotherapy been compared to external beam radiotherapy or radio-isotopes (strontium or samarium) in a randomised study?
- Can radio-isotopes (strontium or samarium) be used at the same time as (simultaneously with) chemotherapy (combined therapy) without excessive toxicity?
- Prostate Cancer Clinical Trials Working Group, Scher HI, Halabi S, Tannock I, Morris M, Sternberg CN, et al. Design and end points of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: recommendations of the Prostate Cancer Clinical Trials Working Group. J Clin Oncol 2008 Mar 1;26(7):1148-59 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/18309951.