Prostate cancer diagnosis and treatment progress and controversies
1. Prostate cancer, cut or wait? Radical prostatectomy vs. watchful waiting
The results of a Swedish randomized controlled trial with 15 years of follow-up showed that radical prostatectomy reduced prostate cancer deaths in patients with early-stage prostate cancer compared to watchful waiting, and that this advantage was clearly present in low-risk patients and patients under 65 years of age. Do these results raise new questions about the treatment of prostate cancer? Are there new challenges to the watchful waiting approach?
Radical prostatectomy has become the most important surgical treatment for prostate cancer in the West. Approximately 60,000 men in the United States are treated for prostate cancer each year with this approach. At the same time, watchfulwaiting has also become increasingly important in recent years because of its lesser impact on patients’ quality of life due to the longer natural course of early-stage prostate cancer. In the 2010 edition of the NCCN Prostate Cancer Guidelines, it is stated that watchful waiting is the only recommended initial treatment strategy for patients with low-risk prostate cancer with a life expectancy of less than 10 years and very low-risk prostate cancer with a life expectancy of less than 20 years.
In fact, there are few clinical studies comparing the prognosis of patients with prostate cancer with radical prostatectomy versus watchful waiting, and even fewer reports of long-term follow-up studies. So what is the best treatment strategy for patients with prostate cancer, especially those with early-stage prostate cancer?
Bill-Axelson and his research team are solving this mystery step by step through a fifteen year long randomized controlled clinical study. Between October 1989 and February 1999, 695 patients with early-stage prostate cancer (mean age 64.7 years) were randomly assigned to a radical resection group (347) and a watchful waiting group (348). And the causes of death were assessed by histological analysis of tissue sections and radical resection specimens to compare the impact of different treatments on patient prognosis. The authors’ team analyzed and published the follow-up results in several phases (2002, 2005, 2008, 2011), the most recent one ending in 2009, and their findings were published in the May 5, 2011 issue of the New England Journal of Medicine (Bill-Axelson, Holmbergetal. 2011).
The authors first published the results of this study in 2002. At that time, the average follow-up period was 6.2 years, which was short relative to the natural course of early-stage prostate cancer. The study found that radical prostatectomy reduced prostate cancer mortality by 50% and distant metastases by 37% compared to watchful waiting, but there was no significant difference in overall mortality between radical prostatectomy and watchful waiting.
Although these results suggest that radical prostatectomy may reduce death and metastasis due to prostate cancer itself, the lack of a significant difference in overall mortality makes this approach superior. The effect of radical prostatectomy on reducing overall mortality was further demonstrated with longer follow-up years. In the 2005 study (mean follow-up 8.2 years), it was shown that radical prostatectomy significantly reduced mortality due to prostate cancer itself, overall mortality, and distant metastasis and local progression of the cancer (Bill-Axelson, Holmbergetal. 2005).
In this latest study, the results continue to show that radical prostatectomy reduces prostate cancer mortality and that this advantage is clearly present in both low-risk patients and patients younger than 65 years of age. However, for patients older than 65 years of age, the benefit of radical prostatectomy appears to be less pronounced. Also, it was found that in patients who underwent radical prostatectomy, the mortality rate was seven times higher in patients with extraperitoneal tumor growth than in those without, so it may be beneficial for patients with extraperitoneal growth to receive local or systemic adjuvant therapy (Bill-Axelson, Holmbergetal. 2011).
From the results of this study, it seems that the advantages of radical prostate cancer resection are becoming clearer step by step as the years of follow-up gradually increase, while watchful waiting seems to be progressively lacking clinical evidence to support it. In the actual clinical process, it is always a difficult choice for the clinician to properly grasp the indications and select the appropriate therapy. As emphasized in the NCCN 2010 Guidelines, “low risk” and “low life expectancy” are important points to consider when selecting watchful waiting therapy. For this study, the most recent follow-up was nearly 15 years (much longer than 10 years), so should the treatment plan for patients who choose watchful waiting change accordingly as their actual years of survival increase?
After all, watchful waiting has undeniable advantages as a treatment with a low impact on patients’ quality of life. We are looking forward to more clinical experience and clinical studies to provide strong evidence on how to find the appropriate use of this therapy in clinical work.
2. Progress in the treatment of metastatic prostate cancer
Prostate cancer is an androgen receptor-dependent disease, so blocking the androgen receptor has been an important tool in the treatment of this disease. However, although most patients can benefit from androgen deprivation therapy, tumors inevitably continue to progress after one to four years due to multiple factors; once the cancer enters a hormone-refractory state, the patient’s life expectancy is limited. Fortunately, chemotherapies such as polyene paclitaxel (Docetaxel) have been found to extend the life span of patients to some extent. Now, the advent of abiraterone acetate appears to be a boon for patients with metastatic prostate cancer.
Oncogenomic studies have found that within desmoid-resistant prostate cancer, a specific molecular alteration leads to the upregulation of androgen biosynthetic enzymes, which causes an increase in androgen levels within the tumor, which in turn also leads to an increase in blood androgen measurements. If we can find the key step in the androgen synthesis process and block it with drugs, can we achieve better androgen reduction and thus slow down the progression of the disease?
Abiraterone acetate, a precursor drug of abiraterone, is a selective inhibitor of androgen synthesis, which blocks androgen synthesis in adrenal, testicular and tumor cells by blocking cytochrome P450c17 (CYP17, a key enzyme in testosterone synthesis).
In its Phase 1 and 2 clinical trials, abiraterone acetate showed significant anti-cancer effects in patients with progressive destructive resistant prostate cancer. In this Phase 3 trial, the team hopes to demonstrate that the use of abiraterone acetate and prednisone to inhibit androgen synthesis can improve the overall survival of patients with advanced prostate cancer.
Nearly 1,200 patients with advanced prostate cancer who had already received polytene paclitaxel chemotherapy as part of their prior treatment were enrolled in the trial. They were given prednisone twice daily along with the trial drug (abiraterone acetate) or placebo. The primary observed endpoint of the trial was overall survival, and secondary observed endpoints included time to PSA re-elevation, survival without disease progression, and PSA response rate.
After a mean follow-up of one year, the overall survival rate was significantly higher in the trial group than in the placebo group, and the mean survival time was 4 months longer than in the placebo group. The trial group still had significant advantages in the secondary observed endpoints of time to PSA re-elevation, survival without disease progression, and PSA response rate.
It is also worth noting that the treatment effect of the trial group persisted in the vast majority of subgroups of this trial: the effect of the combination of abiraterone acetate and prednisone was not altered by a number of factors, such as patient regional origin, age, basal PSA level, and basal alkaline phosphatase level, and its effect was quite generalized.
Although the incidence of common side effects such as fatigue and weakness, back pain, and nausea did not differ significantly between the test and control groups, the incidence of side effects due to elevated salt corticosteroids (fluid retention, hypertension, hypokalemia, etc.) was significantly higher in the test group than in the placebo group.
Through this study, it was demonstrated that androgen production inhibition using abiraterone acetate can improve the overall survival rate and prolong the life span of patients with desmoresistant advanced prostate cancer who have received chemotherapy.
3. Can reductase inhibitors prevent prostate cancer? U.S. FDA warns of prostate cancer risk with 5-alpha reductase inhibitors
It is reported that recently, the U.S. Food and Drug Administration (FDA) warned medical professionals of labeling changes for 5-alpha reductase inhibitors (5-ARIs), said drugs include dutasteride and finasteride.
The instructions for these drugs now warn that patients taking these drugs are at an increased risk of being diagnosed with high-grade prostate cancer.
Dutasteride and finasteride, two drugs marketed for the treatment of benign prostatic hyperplasia, have been studied for prostate cancer prevention in high-risk men, but have not been approved by the FDA.
However, these studies looking at prostate cancer prevention have found that said drugs increase the incidence of high-grade prostate cancer.
While the risk of prostate cancer appears to be low, physicians must be aware of this safety information, according to the FDA. The known benefits can be more accurately weighed against the potential risks as clinicians consider starting or continuing treatment with 5-ARIs.
The decision to release new safety data was based on the results of the FDA review of the Prostate Cancer Prevention Trial (PCPT) and the Reduction of Prostate Cancer Events (REDUCE) trial of dutasteride. These two trials evaluated the use of these drugs as chemopreventive agents. The trials showed that while the overall rate of prostate cancer diagnosis decreased, the incidence of high-grade prostate cancer increased in both cases, and some experts questioned the use of these drugs in such cases.
The FDA’s Oncologic Drugs Advisory Committee discussed data from the PCPT and REDUCE trials on December 1, 2010, and recommended that these drugs not be approved for the indication of prophylaxis.
Reducing cancer risk, however, was evaluated by the PCPT for 7 years with 5 mg daily finasteride versus placebo, and the trial showed that the cumulative incidence of prostate cancer decreased from 24.4% in the placebo group to 18.4% in the finasteride group over the study period.
Over the 7-year period, the rate of prostate cancer in the finasteride and control groups was 3.5% and 4.9%, respectively, representing an absolute risk reduction of 1.4%. The reduction in risk was limited to prostate cancers with a Gleason score (GS) ≤6. The incidence of prostate cancer with a GS score of 8-10 was increased in the finasteride group relative to the placebo group, i.e., 1.1% versus 1.8%.
Similarly, the REDUCE trial evaluated the effect of 0.5 mg daily dutasteride versus placebo on reducing the risk of prostate cancer in men over 50 years of age over a 4-year period. The results showed that prostate cancer was detected significantly less in men in the dutasteride group compared to the placebo group, with a 22.8% relative risk reduction (p<0.001).
The overall risk reduction was limited to prostate cancers with a GS score ≤6. In contrast, the incidence of cancer with a GS score of 8-10 was increased in the dutasteride group relative to the placebo group, i.e., 0.5% versus 1%.
However, a review of these findings published in ClinicalCancerResearch in 2009 suggested that finasteride does not cause high-grade prostate cancers, but only makes them easier to diagnose (ClinCancerRes. 2009;15:4694-4699).
Study author Christopher Elliott, MD, of the Department of Urology at Stanford University in California, told MedscapeMedicalNews at the time that their findings suggest that the PCPT findings linking finasteride use to increased diagnosis of high-grade prostate cancer are likely the result of detection bias rather than an increase in new high-grade prostate cancers . These results suggest that concerns that finasteride is contributing to the development of high-grade prostate cancer are likely unfounded.
Information for Clinicians
In new guidelines issued in February 2009, the American Society of Clinical Oncology and the American Urological Association jointly recommended that both dutasteride and finasteride be considered for asymptomatic men at reduced risk for prostate cancer. The guidelines note that some men may benefit from discussing the benefits and risks of 5-ARIs for prostate cancer prevention with their physicians.
The FDA is also currently issuing the following additional information to healthcare professionals.
1. Please be aware that 5-ARIs may increase the risk of high-grade prostate cancer.
2. Before starting treatment with 5-ARIs, perform appropriate evaluation to rule out other urologic conditions, including prostate cancer that may resemble BPH.
3. Please note that treatment with 5-ARIs may reduce prostate-specific antigen (PSA) values by approximately 50% at 6 months; however, individual patients with 5-ARIs may experience varying degrees of decrease in PSA values. Therefore, any definite rise in PSA values during treatment with 5-ARIs may indicate the presence of prostate cancer, and further evaluation should be performed even if the man’s PSA levels are within the normal range for a population not using 5-ARIs.
4. It should be known that 5-ARIs are not approved for prostate cancer prevention.
5. Any adverse events related to 5-ARIs should be reported to the FDA’s MedWatch notification system.
4. Is testosterone useless in the treatment of prostate cancer? Studies of testosterone therapy in untreated prostate cancer
Testosterone therapy has long been a contraindication to prostate cancer treatment because of the belief that higher serum testosterone levels can cause accelerated prostate cancer growth. This has recently been challenged by evidence. A small sample study was conducted to examine the effects of testosterone therapy in men with untreated prostate cancer.
Materials and Methods
Testosterone-deficient patients were treated with testosterone therapy, actively monitored for active prostate cancer, and prostate biopsy, serum prostate-specific antigen and prostate volume results were reported.
Results
A total of 13 men with testosterone-deficient prostate cancer men received testosterone therapy for a median duration of 2.5 years (range, 1.0 to 8.1 years). The mean age was 58.8 years. The initial biopsy Gleason score was 6 in 12 cases and 7 in 1 case. Mean serum total testosterone concentrations ranged from 238-664 ng/dl (p<0.001). There was no change in mean prostate-specific antigen after testosterone treatment (5.5±6.4: 3.6±2.6ng/ml, p=0.29). There was no change in prostate volume. Follow-up biopsies averaged 2. 54% of follow-up biopsies did not reveal cancer. 2 biopsies showed increased prostate cancer grade but showed no progression at 1 subsequent biopsy and radical prostatectomy. No progression of limited prostate cancer or distal disease was seen.
Conclusion
Short- to intermediate-term testosterone therapy in patients with untreated prostate cancer was not associated with prostate cancer progression. These results are consistent with the saturation model (i.e., treating the fastest growing prostate cancer with low concentrations of androgens). Long-term contraindication of testosterone therapy in patients with untreated or low-risk prostate cancer or prostate cancer without metastasis or recurrence should be reevaluated.
5. The birth of a prostate cancer vaccine: Provenge (sipuleucelT), a prostate cancer vaccine
The FDA approved Provenge, a prostate cancer vaccine from Dendreon Pharmaceuticals, Inc.
Unlike vaccines in the traditional sense, Provenge is a new type of autologous cellular immunotherapy drug for patients with advanced prostate cancer that mobilizes the patient’s own immune system to fight the disease.
Results from a clinical trial with 512 subjects showed that patients treated with Provenge had a 4.1 month longer overall survival than the control group. To meet the FDA’s post-marketing surveillance requirements for the drug, Dendreon will continue to enroll 1,500 patients in four more clinical trials to further test the drug’s safety. In the clinical trial involving 512 men, those treated with Provenge had an average survival time of 25.8 months, compared to 21.7 months for those in the control group. The main side effects of Provenge are fever, chills, fatigue and pain. It is a so-called therapeutic vaccine for prostate cancer that has already been diagnosed.
An article in the June 2011 issue of Nature Medicine said that DNA raised from healthy cells was used to develop a new vaccine. This vaccine was used in rats with prostate cancer and had a cure rate of up to 80 percent. The researchers believe that this approach has the potential to be applied to the development of vaccines for other cancers and have begun research on a vaccine for melanoma. Affirming the effectiveness of this therapy.
6. Advances in prostate cancer screening: ASCOGU: PSA ≥ 3ng/ml should be biopsied
A large screening study showed that men with initial prostate-specific antigen (PSA) levels <3ng/ml suggest a low risk of prostate cancer and a low risk of death from long-term prostate cancer.
At the American Society of Clinical Oncology Genitourinary Oncology Forum (ASCOGU) held February 17-19, Professor Monique Roobol of Erasmus University Medical Center in Rotterdam, the Netherlands, reported that an initial PSA screening value <3ng/ml suggested a risk of prostate cancer incidence of less than 6% over the next 11 years, with 23 deaths and a mortality rate of 0.15%. The median time between initial PSA value and diagnosis of prostate cancer was more than 8 years for those with the lowest initial PSA values. The results of these studies suggest that PSA can be used as a screening indicator for prostate cancer. Prostate biopsy should be performed for initial PSA levels ≥3ng/ml.