Relevance Of Trial Data In Real
After decades without significant progress in the treatment landscape of mHSPC, the results of the above-mentioned trials are welcome. Nevertheless, we need to cautiously interpret these results, taking into consideration the between-study heterogeneity in study populations, and how well they reflect our patient population .
Justification For A New Guideline
Clinicians treating men with advanced prostate cancer are challenged with the rapidly evolving prostate cancer landscape given the approval of new classes of agents for use in various prostate cancer disease states. The increasing complexity of advanced prostate cancer management underscores the need for the current clinical practice guideline, developed to provide a rational basis for treatment of patients with advanced disease, based on currently available published data. To assist in clinical decision-making, guideline recommendations are furnished according to disease state across the entire continuum of advanced prostate cancer.
About The 5th Annual Prostate & Urologic Cancer Symposium:
The Prostate & Urologic Cancers Symposium is held through the University of Oklahoma and the Stephenson Cancer Center to provide new insights in the treatment of prostate and urologic cancers. This single-day program consists of lectures and case discussions highlighting a multidisciplinary approach to urologic cancer care and integration of new technology in the evaluation and treatment of patients with prostate and/or urologic cancers. Dr. Cookson presented this lecture during the 5th iteration of this summit in 2019.
Please visit our collection page to view additional educational activtities from this symposium.
Michael S. Cookson, MD, MMHC
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Possible Future Treatment Strategy As Per The Clinical And Biological Characteristics
The treatment strategies should be determined as per cancer and patient characteristics as well as patient preference. We showed the possible treatment strategy for patients with mCSPC as per patient subgroups . Group 1: elderly and/or fragile patients with very limited life expectancy ADT alone or best supportive care. Group 2-a: patients with low-volume, low-risk disease, favorable response to ADT, and life expectancy < 10 y ADT alone, because long-term OS, about 10 years, is expected with ADT alone in this patient group. Adverse events caused by upfront combination therapies may exceed their efficacy in those patients. Group 2-b: patients with the same cancer characteristics as group 2-a patients and having longer life expectancy upfront combination therapies using docetaxel or ARPIs, with or without prostatectomy or EBRT to the prostate together with ADT. Metastases-directed radiotherapy may be also indicated. Complete eradication of cancer and cure may be anticipated with these aggressive combination treatments in these patients. Group 3: patients with high-volume, high-risk, or unfavorable response to ADT upfront combination therapies using docetaxel or ARPIs. Group 4: patients carrying DDR gene mutations poly polymerase inhibitors or platinum-based chemotherapy. The prognostic and predictive biomarker-based decision will enable optimal personalized treatment.
If Treatment Does Not Work
Recovery from cancer is not always possible. If the cancer cannot be cured or controlled, the disease may be called advanced or terminal.
This diagnosis is stressful, and for many people, advanced cancer may be difficult to discuss. However, it is important to have open and honest conversations with your health care team to express your feelings, preferences, and concerns. The health care team has special skills, experience, and knowledge to support patients and their families and is there to help. Making sure a person is physically comfortable, free from pain, and emotionally supported is extremely important.
People who have advanced cancer and who are expected to live less than 6 months may want to consider hospice care. Hospice care is designed to provide the best possible quality of life for people who are near the end of life. You and your family are encouraged to talk with the health care team about hospice care options, which include hospice care at home, a special hospice center, or other health care locations. Nursing care and special equipment, including a hospital bed, can make staying at home a workable option for many families. Learn more about advanced cancer care planning.
After the death of a loved one, many people need support to help them cope with the loss. Learn more about grief and loss.
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From Personalized To All
A systematic review and meta-analyses of the aggregate data of the CHAARTED, GETUG-AFU15, and STAMPEDE trials indicated that the upfront use of docetaxel showed better OS in patients with mCSPC than in those with ADT alone . As per the STAMPEDE trial, upfront docetaxel improved the OS irrespective of the metastatic tumor burden . For low-volume patients, the median OS was 93.2 mon and 76.7 mon for upfront docetaxel and ADT alone, respectively . This HR was consistent with that in high-volume patients , suggesting that upfront docetaxel would be beneficial for all patients with mCSPC, irrespective of the metastatic burden, and this treatment may be for all-comers.
These recent clinical trials suggest that early combination therapies are consistently associated with better outcomes than ADT alone, irrespective of the tumor burden and risk category. Thus, recent clinical guidelines recommend a combination of docetaxel or ARPIs with ADT as first-line therapy for all patients with mCSPC., The era of ADT alone may end and upfront combination therapies are becoming a standard of care as the initial treatment for all-comers with mCSPC.
Docetaxel: The Role Of Chemotherapy In Mhspc
Until 2004, chemotherapy played a peripheral role in the treatment of metastatic prostate cancer, with mitoxantrone and alkylating agents used for symptomatic benefit in the castrate-resistant setting . Docetaxel was the first cytotoxic agent to demonstrate a survival benefit, as reported in the TAX 327 trial . The question was then asked whether docetaxel would provide a similar, proportional benefit to survival if used earlier in the disease spectrum.
The benefit of adding docetaxel to lifelong ADT for mHSPC was established by three phase III trials: CHAARTED, STAMPEDE and GETUG-AFU 15. The key characteristics and results of these three trials are shown in Table .
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Definitive Treatment Is Beneficial Only In Patients With Low
Not only systemic pharmacotherapy, but radiation to the prostate also improves OS in low-volume disease. The recent high-quality RCTs, STAMPEDE and Hormonal Therapy Versus Hormonal Therapy Plus Local External Radiation Therapy in Patients With Primary Diagnosed Metastasized Prostate Cancer , concluded that adding radiation therapy to the prostate in mCSPC patients receiving ADT did not further improve their OS, the primary endpoint. In contrast, subgroup analyses by metastatic burden in the STAMPEDE trial showed OS benefit for patients with low-volume disease . The HORRAD trial also showed a similar trend without statistical significance in patients with < 5 metastatic lesions. Meta-analysis of 2 RCTs that involved 2493 patients suggested that ADT plus EBRT to the prostate was associated with improved OS as compared to ADT alone in men with low-volume metastatic burden however, this result was not observed in those with high-volume disease . Prostatectomy may also improve the oncologic outcomes in patients with oligometastatic prostate cancer. The definitive treatments, either radiation or prostatectomy, may be associated with survival benefit in patients with low metastatic burden. The results of several ongoing clinical trials on the benefit of prostatectomy and radiation to the prostate are expected to provide more information on this subject.
Advanced Prostate Cancer Metastatic Hormone
This course series Advanced Prostate Cancer gives clinicians a complete view on clinical aspects, diagnosis, and treatments of prostate cancer. This course series contains five courses, each of them addresses an important topic in diagnosis, treatment, and management of prostate cancer. Each course is accredited by the European Accreditation Council for Continuing Medical Education for 1 to 3 European CME credits. The five courses are:
Course 1: Basis of ADT Course 2: Hormone-sensitive nmPCaCourse 3: Metastatic hormone-sensitive PCaCourse 4: Non-metastatic CRPC Course 5: Metastatic CRPC
This course Metastatic Hormone-Sensitive Prostate Cancer is the third part of the course series.
The development of this course has been supported by Jansen with a concession of an unrestricted educational grant.
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Genetic And Biochemical Biomarkers
A variety of markers have been studied for their ability to prognosticate patients and even predict response to treatment in the mCRPC setting. The most extensive data have come from analyses of circulating tumour cells. The rapidly evolving treatment landscape has meant that drugs commonly used in the castrate-resistant setting are now used in the mHSPC setting, and previously identified genetic aberrations in the mCRPC setting may have prognostic and/or predictive value earlier in the treatment paradigm. While this topic warrants a brief discussion, there is currently insufficient evidence in this field to suggest that genetic markers should guide treatment in the mHSPC setting.
Circulating tumour cells and AR splice variant 7 have been proposed as prognostic and predictive biomarkers in patients with mCRPC treated with enzalutamide and abiraterone acetate . Theoretically, the poor response in AR-V7-positive patients in the castrate-resistant setting may indicate that docetaxel will be more beneficial than androgen targeting in these patients. Results from small studies have suggested support for this hypothesis , although larger randomised trials and improved isolation and analysis of CTC will be required to validate these results.
Active Surveillance And Watchful Waiting
If prostate cancer is in an early stage, is growing slowly, and treating the cancer would cause more problems than the disease itself, a doctor may recommend active surveillance or watchful waiting.
Active surveillance. Prostate cancer treatments may seriously affect a person’s quality of life. These treatments can cause side effects, such as erectile dysfunction, which is when someone is unable to get and maintain an erection, and incontinence, which is when a person cannot control their urine flow or bowel function. In addition, many prostate cancers grow slowly and cause no symptoms or problems. For this reason, many people may consider delaying cancer treatment rather than starting treatment right away. This is called active surveillance. During active surveillance, the cancer is closely monitored for signs that it is worsening. If the cancer is found to be worsening, treatment will begin.
ASCO encourages the following testing schedule for active surveillance:
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A PSA test every 3 to 6 months
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A DRE at least once every year
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Another prostate biopsy within 6 to 12 months, then a biopsy at least every 2 to 5 years
Treatment should begin if the results of the tests done during active surveillance show signs of the cancer becoming more aggressive or spreading, if the cancer causes pain, or if the cancer blocks the urinary tract.
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Risk Of Bias Assessment
Two investigators independently assessed risk of bias using predefined criteria. Disagreements were resolved by consensus. For randomized trials and cohort studies, methodologists adapted criteria for assessing risk of bias from the U.S. Preventive Services Task Force. Criteria for randomized trials included use of appropriate randomization and allocation concealment methods, baseline comparability of groups, blinding, attrition, and use of intention-to-treat analysis. For cohort studies on prognostic factors, criteria included methods for assembling cohorts, attrition, blinding assessment of outcomes, and adjustment for potential confounding.
The methodology team assessed systematic reviews using AMSTAR 2 criteria. Criteria included use of pre-specified methods, appropriate search methods, assessment of risk of bias, and appropriate synthesis methods. Studies were rated as âlow risk of bias,ââmedium risk of bias,â or âhigh risk of biasâ based on the presence and seriousness of methodological shortcomings.
Studies rated âlow risk of biasâ are generally considered valid. âLow risk of biasâ randomized trials include clear descriptions of the population, setting, interventions, and comparison groups a valid method for allocation of patients to treatment low dropout rates and clear reporting of dropouts blinding of patients, care providers, and outcome assessors and appropriate analysis of outcomes.
Improving How Long Patients Live
The ENZAMET trialfunded in part by the drugs manufacturer, Astellas Pharma, as well as government health agencies in Canada and Australiaenrolled more than 1,100 men with hormone-sensitive metastatic prostate cancer. The men were randomly assigned to ADT combined with enzalutamide or with any of three other androgen-blocking drugs.
At a median follow-up of nearly 3 years, men who received ADT plus enzalutamide had a 33% reduced risk of death, with 80% still alive compared with 72% of men treated with ADT plus another antiandrogen drug, reported the trials lead investigator, Christopher Sweeney, M.B.B.S., of the Dana-Farber Cancer Institute.
Men in the enzalutamide group also had better clinical progression-free survival , which the research team defined as the time until the return of disease-related symptoms, the detection of new metastases on imaging scans, or the initiation of another cancer treatment for prostate cancer, whichever came first. At 3 years, 63% of men in the enzalutamide group were alive without clinical progression of their disease, compared with 33% in the standard treatment group.
Although enzalutamide appeared to be effective regardless of whether men had high- or low-volume disease, one apparent differentiating factor was planned early treatment with docetaxel. Nearly half of the men in both treatment groups received early treatment with docetaxel and, for those men, enzalutamide was not associated with longer overall survival.
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Tailoring Treatment Aims To The Individual Goal
As alluded to earlier in the review, treatment of the mHSPC patient must take into context the overriding individual treatment aim. For most patients, metastatic prostate cancer is an incurable disease. The aim is to transform mHSPC into a manageable chronic illness so that the patient dies with the cancer, rather than of it.
For the young patient with few comorbidities presenting with mHSPC, the risk of dying from metastatic prostate cancer is significant. The likely treatment aim is to prolong OS with respect to the cancer. In the absence of a clearly superior agent and prospective sequencing data, the strategy is to maximise the lines of therapies that can be utilized in the patients treatment course. The reasoning of the treating oncologist may be to administer docetaxel in the upfront setting, taking into account that the more tolerable oral antiandrogens can be added on more easily than docetaxel at a later point should the patient become increasingly frail from the disease and/or other underlying comorbidities.
Redefining Hormone Sensitive Disease In Advanced Prostate Cancer
Thomas W. Flaig
1Division of Medical Oncology, University of Colorado Denver School of Medicine, 12801 E. 17th Avenue, Room L18-8117, Aurora, CO 80045, USA
Abstract
Prostate cancer is the most common cancer among men in the United States. For decades, the cornerstone of medical treatment for advanced prostate cancer has been hormonal therapy, intended to lower testosterone levels, known as Androgen Deprivation Therapy . The development of hormone-resistant prostate cancer remains the key roadblock in successful long-term management of prostate cancer. New advancements in medical therapy for prostate cancer have added to the hormonal therapy armamentarium. These new therapeutic agents not only provide a survival benefit but also show potential for reversing hormonal resistance in metastatic CRPC, and thus redefining hormonally sensitive disease.
1. Background
2. History of Androgen Deprivation Therapy in Prostate Cancer
Given the multiple sources and associated biosynthesis pathways of androgen productions, hormonal therapy in prostate cancer is achieved through multiple mechanisms with several different classes of agents .
| Class | |
| Goserelin, leuprolide, triptorelin, histrelin acetate | |
| GnRH antagonists | |
| Bicalutamide, nilutamide, flutamide, **cyproterone acetate | MDV3100, TOK-001 |
| Glucocorticoids | Prednisone, Dexamethasone, others |
3. Current Advancement in Hormonal Therapy
4. Discussion
Disclosure
References
Copyright
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Searches And Article Selection
A research librarian conducted searches in Ovid MEDLINE , Cochrane Central Register of Controlled Trials , and Cochrane Database of Systematic Reviews . An updated search was conducted prior to publication through January 20, 2020. The methodology team supplemented searches of electronic databases with the studies included in the prior AUA review and by reviewing reference lists of relevant articles.
The methodology team developed criteria for inclusion and exclusion of studies based on the Key Questions and the populations, interventions, comparators, outcomes, and settings of interest. The population was patients with advanced prostate cancer as described in Table 3. Treatments included first and second line antiandrogens, immunotherapy, chemotherapy, radiation therapy, surgery, radiopharmaceuticals, and surveillance strategies. Comparisons were against placebo, no therapy, or another active intervention and intermittent versus continuous therapy. Outcomes included overall survival , prostate cancer mortality, progression-free survival , prostate-specific antigen progression-free survival , failure-free survival, metastases-free survival, time to metastases, time to progression, skeletal events, and adverse events.
In Five Years A Major Treatment Shift
In men diagnosed with metastatic hormone-sensitive prostate cancer, the cancer is typically driven to grow and spread by androgens that are produced largely in the testes. For many years, treatments that block androgen production have been a mainstay for men initially diagnosed with metastatic prostate cancer.
Starting in 2014, that began to change after a large clinical trial showed that adding the chemotherapy drug docetaxel to ADT improved how long men with hormone-responsive disease lived. Shortly after, another clinical trial showed that adding abiraterone to ADT also improved survival in these men, although primarily in men with many metastatic tumors, known as high-volume disease.
However, docetaxel, which works by directly killing cancer cells, can have substantial side effects, and some patients arent healthy enough to tolerate it. And abirateronewhich blocks androgen production throughout the bodycan also cause side effects, including those that affect the liver. It also has to be given in combination with the steroid prednisone, which carries its own toxicity.
Doing so, Dr. Chi said during a presentation of the TITAN data at the ASCO meeting, might help stave off the typically inevitable development of hormone-resistant cancer, which is more difficult to treat and a key driver of prostate cancer deaths.
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Treatments For Metastatic Castration
Castration-sensitiveprostate cancer is cancer that is being controlled by keeping thetestosterone level as low as would be expected if the testicles were removed. Metastatic prostate cancer is prostate cancer thathas spread to other parts of the body.
The goal of treatment is to help you live longer and try toimprove your quality of life. Yourhealthcare team will suggest treatments based on your needs and work with youto develop a treatment plan.
Treatment optionsfor metastatic castration-sensitive prostate cancer may include a combinationof the following:
- hormone therapy
- watchful waiting