Many novel therapies are available for use in patients with metastatic castration-resistant prostate cancer (mCRPC), some of which convey substantial progression-free survival and overall survival benefits. Delaying disease progression and providing palliation of symptoms are primary therapeutic aims of treating patients with mCRPC; therefore, ensuring that the benefit-to-harm ratios are acceptable to patients, through systematic measurement of patient-reported outcomes (PROs) using validated tools, is vital. In this Perspectives, we appraised the published reports from clinical trials testing treatments of mCRPC over the past 5 years and found that PROs were either not being measured routinely, or if used, were often not reported adequately, thus hampering evaluation of the true effects of many of these treatments on patients' quality of life. Improvements are needed because data collected directly from patients, not just physician-collected safety data and adverse events, are crucial to inform clinical decision-making on treatment options.
Free Castration Stories
Objectives:Describe the etiology of prostate cancer. Review the pathophysiologic basis of prostate cancer.Outline how to properly manage a patient affected by prostate cancer.Summarize how an optimally functioning interprofessional team would coordinate care to enhance outcomes for patients with prostate cancer. Access free multiple choice questions on this topic.
Newer diagnostic modalities include free and total PSA levels, PCA3 urine testing, Prostate Health Index scoring (PHI), the"4K" test, exosome testing, genomic analysis, MRI imaging, PIRADS scoring, and MRI-TRUS fusion guided biopsies.[10]
Free and Total PSA: The percentage of free PSA in the blood can be a useful indicator of malignancy. A free PSA percentage is considered valid if the total PSA is between 4 and 10 ng/ml. The free PSA percentage is calculated by multiplying the free PSA level by 100 and dividing it by the total PSA value.
It's been suggested that a superior test would be totally independent of any bias from the medical history, family history, or even the PSA level, allowing such information to be considered by each clinician using their own clinical judgment. Many clinicians prefer those tests which are totally independent of the PSA level and do not require significant patient clinical data yet still offer statistically equivalent and valid results (negative predictive value, etc.), leaving them free to interpret the test report using knowledge of the patient's clinical history and PSA results. A preferred test would be one that the patient could perform at home, is based on genetics, requires minimal staff time to arrange and administer, does not require a prostatic massage, produces few "unreportable" errors that force patients to repeat the process, and still provide over 90% negative predictive value for Gleason pattern 4 disease since lower grade disease is not generally treated.
The "4K" Test measures serum total PSA, free PSA, intact PSA, and human kallikrein antigen 2. It includes clinical DRE results as well as information from any prior biopsies. These results are compared to a very large, age-matched database, and a percentage risk of "significant" prostate cancer is calculated. Clinically significant prostate cancer is usually defined as Gleason 3+4=7 or higher disease. A risk analysis of 10% or more would typically suggest proceeding with a biopsy. Interestingly, the "4K" test has not been shown to be any better than PSA testing alone when used for tracking active surveillance patients.[144]
The Prostate Health Index (PHI) is a blood test that includes free PSA, total PSA, and the [-2] proPSA isoform of free PSA. A formula is used to combine these test results mathematically to give the PHI score. This PHI score appears to be superior to PSA, free and total PSA, and PCA3 in predicting the presence of prostate cancer.[149]
[F-18]-fluorodeoxyglucose (F-18-FDG) PET scans are designed to target rapidly growing cells like cancers that absorb glucose faster than normal tissues. F-18-FDG scans use a tagged glucose analog radiotracer molecule which becomes incorporated into malignant cells. The Fluorine-18 tracer ligand then makes the tissue visible on PET scans. F-18-FDG has been available since the late 1990s and has been widely used for various malignancies. However, its use in urology has been limited by its relatively high renal excretion, which acts to hide many malignancies of the urinary tract and the relatively slow metabolic activity of prostate cancer. Higher grade, castration-resistant, and neuroendocrine prostate cancers, which are faster growing and incorporate more F-18 tagged glucose, will tend to show up better on F18-FDG PET scans.[183][184] Nevertheless, F-18-FDG is generally not considered optimal for prostate cancer PET/CT scanning for these reasons, as well as the relatively high uptake overlap with normal prostatic tissue, BPH, and prostatitis. However, it can be useful in detecting recurrences and staging other fast-growing urological malignancies such as testicular and renal cancer and bladder carcinomas.[185][186][187] F-18-FDG is not a PSMA-based scan, and its half-life is 110 minutes. It is not currently recommended by the NCCN for prostate cancer imaging.[185]
In 1941, Urologist Charles Huggins MD from the University of Chicago discovered that androgen deprivation (castration) would cause prostate glands to atrophy and prostate cancer to regress.[239][240] He was awarded the Nobel Prize for Medicine in 1966 for this discovery which is the basis for all hormonal (testosterone deprivation-based) treatments used in prostate cancer. This was the first effective systemic therapy for prostate cancer, and it still is extremely useful in putting cancer into remission. This beneficial hormonal effect typically lasts an average of about two years, but virtually all prostate cancers will eventually escape and regrow.
The use of freezing technology to kill cancer cells is not new; it was first used in London in the 19th century for breast and cervical cancers. Modern cryotherapy required the development of closed circulation liquid Nitrogen probes, and one of the first uses of this new technology was for benign prostatic hyperplasia in 1966.[281]
Cryotherapy provides very good tissue ablation and destruction but has some complications and is very technology-dependent. Early use of this technology was delayed due to the size of the original Nitrogen probes, the development of urethral injuries, and the inability to monitor the exact location of the probes and ice-ball in real-time. These problems were solved by technological advances, including the use of transrectal ultrasound to visualize the size and shape of the ice ball, more precise freezing probe placement, the use of multiple strategically placed interstitial temperature sensors to prevent over-freezing, simultaneously utilizing multiple smaller probes based on Argon gas for freezing instead of the harder to use liquid nitrogen, adding a thaw cycle to the protocol, and the standard placement of urethral warming catheters to protect the urethra from injury.[282]
Using two freeze/thaw cycles instead of just one, rapid freezing to -40 C with slow thawing, and appropriate use of hormonal therapy to shrink larger prostates (greater than 60 gm) before treatment appear to improve the cancer-free results. Hormonal therapy can help reduce the prostate size but does not otherwise improve survival outcomes with cryotherapy.[282]
Cryotherapy has shown it can control tumors resistant to all other therapies, which will still be susceptible to ablation by alternating freeze-thaw cycles that disrupt cell membranes resulting in tissue destruction. In such cases, it is important to be sure that the malignancy is still confined to the prostate. Since cryotherapy cannot treat nodal involvement, lymph node dissections may be needed.[285]
The role of stereotactic radiotherapy in prostate cancer is less well defined than standard external beam radiation. With stereotactic therapy, the individual fractionated dosages are higher, typically 7 to 8 Gy each, which allows for a much reduced total treatment time, usually only about a week. Higher fractionated dosages beyond 8 Gy are not recommended as they have been associated with increased toxicity and side effects. Stereotactic radiotherapy is less suitable for patients with very large prostate volumes (greater than 75 to 100 mL) or prior TURP surgery. Most experts prefer real-time tracking, and early reports suggest using urethral catheterization during treatment planning and simulation improves urethral identification. Newer SABR delivery systems include gantry devices that are currently undergoing clinical trials. It is hypothesized that using SABR for metastatic cancer may be reasonable to reduce the seeding of additional tumors, which may ultimately increase overall and progression-free survival. This strategy has already been shown to improve survival in metastatic non-small cell lung cancer but is still theoretical for use in prostate cancer.[294][305][306]
Lutetium 177 vipivotide tetraxetan is now FDA approved for use in metastatic castrate-resistant prostate cancer in patients with positive gallium 68 PSMA-11 PET/CT scans who have failed hormonal therapy and at least one course of docetaxel or cabazitaxel. The technology binds a beta particle source with a PSMA-specific binder into a unique radioligand which seeks out PSMA-expressing cells and exposes them and their immediate microenvironment to beta radiation. The treatment has a good safety profile and is relatively well tolerated. It has been found to extend progression-free and overall survival in this extremely difficult group of patients by about 4 or 5 months.[197][198]
Polyadenosine diphosphate-ribose polymerases (PARP) are a type of enzyme that helps repair DNA damage in cells. PARP inhibitors, such as olaparib and rucaparib, prevent cancer cells from repairing DNA damage which facilitates apoptosis. They are considered a type of targeted therapy as they work best in patients with DDRG germline or somatic mutations. Olaparib showed a median survival benefit of about five months (more than double the median progression-free survival) compared to enzalutamide or abiraterone treatment alone and was most effective in patients with BRCA2 mutations on germline testing.[346] Rucaparib demonstrated a 63% PSA response rate.[363] Patients with PALB2, BRIP1, and RAD51B mutations responded quite well to rucaparib therapy, while those with ATM, CDK12, and CHEK1 germline mutations were generally refractory to the drug.[345][364] Both PARP inhibitors have demonstrated the ability to extend overall survival and make prostate cancer more radiosensitive in early clinical trials.[345][346][347][348][349][363][365][366] This may greatly increase their usefulness and efficacy in the future once this aspect of their clinical effect has been adequately studied.[365] Olaparib and rucaparib are FDA-approved for use in men with metastatic castrate-resistant prostate cancer who have BRCA1, BRCA2, or ATM mutations that have progressed after enzalutamide or abiraterone therapy. 2ff7e9595c
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