Provenge Activated Cellular Immunotherapy Shows Promise For Treatment Of Androgen Independent Prostate Cancer
Researchers involved in a multicenter trial have demonstrated that Provenge® may improve the survival of patients with HRPC when Provenge was followed by Taxotere®.
Provenge is an active cellular immunotherapeutic agent that targets the prostatic acid phosphatase antigen. The PAP antigen is present in approximately 95% of all prostate cancers. Published phase I and II studies of Provenge in patients with prostate cancer show the approach using activated cellular immunotherapy with Provenge is safe and provides a potential benefit.
The data presented at the Prostate Cancer Foundation meeting was an update of data published in the July 1, 2006, issue of the Journal of Clinical Oncology. This phase III study randomly allocated 127 patients with asymptomatic metastatic AIPC to receive Provenge or placebo every two weeks until death or progression. Randomization was on a 2:1 basis with 82 patients in the treatment group and 45 in the control group. Patients were followed until death or for 36 months from entry on study. Thirty-four patients in the placebo group were treated with Provenge after disease progression.
- Survival at 36 months was 34% for the Provenge arm, compared with only 11% for those who received placebo .
- Median survival was 25.9 months for the Provenge arm, compared with 21.4 months for those who received placebo
- Median prostate cancer specific survival was 35.2 months for patients in the Provenge arm, compared with 23.5 months for those who received placebo.
Chemo Drugs Used To Treat Prostate Cancer
For prostate cancer, chemo drugs are typically used one at a time. Some of the chemo drugs used to treat prostate cancer include:
- Docetaxel
- Mitoxantrone
- Estramustine
In most cases, the first chemo drug given is docetaxel, combined with the steroid drug prednisone. If this does not work , cabazitaxel is often the next chemo drug tried .
Docetaxel and cabazitaxel have been shown to help men live longer, on average, than older chemo drugs. They may slow the cancers growth and also reduce symptoms, resulting in a better quality of life. Still, chemo is very unlikely to cure prostate cancer.
Other chemo drugs being studied for use in prostate cancer include carboplatin, oxaliplatin, and cisplatin.
Combination Treatment Of Docetaxel With Cape Suppresses The Proliferation And The Survival Of Docetaxel
Fig. 1
Effects of docetaxel, CAPE, and combination treatment on the proliferation of docetaxel-resistant PC/DX25 and DU/DX50 cells. The cell proliferation was determined by Hoechst 33258-based 96 well proliferation assay. PC/DX25 cells were treated with increasing concentration of docetaxel , increasing concentration of CAPE , or combination of docetaxel plus 20 M CAPE for 96 h. DU/DX50 cells were treated with increasing concentration of docetaxel , increasing concentration of CAPE , or combination of docetaxel plus 20 M CAPE for 96 h. Results were presented as mean±standard error. Experiments were repeated for at least three times. The asterisks * and *** represent p value< 0.05 and p value< 0.0001, respectively
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Lentivirus Construction And Infection
The coding sequence of ERG mRNA was synthesized and cloned into pLenti6.3 lentivirus overexpression vectors. All lentiviruses were constructed by Shanghai Obio Technology Company. After packaging, pLenti6.3-ERG lentivirus and negative control lentivirus were used to infect C4-2B cells, for the construction of ERG overexpressing C4-2B and negative control C4-2B cells. Standard biosecurity and institutional safety procedures were strictly observed.
Dr Hayley Luxton Research Impact Manager At Prostate Cancer Uk Said:
This is really exciting because it shows exactly how we can treat smarter, not harder and get the most from existing prostate cancer treatments.
There have been a lot of new treatments approved for prostate cancer in recent years, but theres still so much we dont know about how they interact with each other and who benefits most. This paves the way for men to receive more personalised, more effective treatments while experiencing fewer side effects.
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Questions To Ask Your Doctor Or Nurse
- How can chemotherapy help?
- How long will the treatment last, and how many sessions will I need?
- What are the possible side effects of chemotherapy, and how long will they last?
- Can I stop the treatment if I find the side effects difficult to deal with?
- Are there any other treatments available to me?
- Who should I contact if I have any questions during my treatment and how do I contact them?
- What happens if chemotherapy doesnt work? Are there other treatments I can have later on?
- Are there any clinical trials I can take part in?
Docetaxel To Treat Prostate Cancer
Docetaxel is currently approved in the US for the treatment of head and neck cancer, gastric cancer, breast cancer, prostate cancer, and non-small cell lung cancer, and it is commercialized under the brand name Taxotere, by the pharmaceutical company Aventis Pharmaceuticals, Inc. On May 19, 2004, the FDA approved docetaxel for injection for use in combination with prednisone for the treatment of metastatic, androgen-independent prostate cancer, explain the National Cancer Insitute. Safety and efficacy were demonstrated in TAX327, a randomized, multicenter global clinical trial designed to evaluate chemotherapy with docetaxel and prednisone in the treatment of men with metastatic, hormone-refractory prostate cancer.
The study that revealed the efficacy of docetaxel included 106 patients who were treated with mitoxantrone and prednisone, weekly docetaxel and prednisone, or docetaxel once every three weeks and prednisone. The third group was the one with greater results improving survival, with a median survival of 18.9 months, compared to 16.5 months for the patients treated with mitoxantrone and prednisone. The approved dose for this indication is 75 mg/m2 docetaxel given intravenously as a one-hour infusion every 21 days on Day 1 plus 5 mg oral prednisone twice daily for 10 cycles, informed the National Cancer Institute. Adverse events included anemia, neutropenia, infection, nausea, vomiting, anorexia, and fatigue.
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Numbness Or Tingling In Fingers Or Toes
Numbness or tingling in fingers or toes is often temporary and can improve after you finish treatment. Tell your doctor if youâre finding it difficult to walk or complete fiddly tasks such as doing up buttons.
Nail changes
During treatment your nails may change colour. This gradually goes after treatment as your nails grow.
Your nail might separate from the nail bed and look white or yellow. The nail may eventually fall off but usually grows back.
Sore And Red Palms Of Hands And Soles Of Feet
You may get sore and red palms of hands and soles of feet. The skin may also begin to peel. This is called palmar-plantar or hand-foot syndrome. It usually gets better after treatment ends.
Tell your doctor or nurse about any changes to your hands or feet. They can give you advice and prescribe creams to improve any symptoms you have. It can help to:
- keep your hands and feet cool
- moisturise your hands and feet regularly
- avoid tight-fitting socks, shoes and gloves.
- dizziness
- changes to your heartbeat.
Other conditions can cause these symptoms, but it is important to get them checked by a doctor. If you cannot get through to your doctor, call the NHS urgent advice number on 111.
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Remission And The Chance Of Recurrence
A remission is when cancer cannot be detected in the body and there are no symptoms. This may also be called having no evidence of disease or NED.
A remission can be temporary or permanent. This uncertainty causes many people to worry that the cancer will come back. Although there are treatments to help prevent a recurrence, such as hormonal therapy and radiation therapy, it is important to talk with your doctor about the possibility of the cancer returning. There are tools your doctor can use, called nomograms, to estimate someone’s risk of recurrence. Understanding your risk of recurrence and the treatment options may help you feel more prepared if the cancer does return. Learn more about coping with the fear of recurrence.
In general, following surgery or radiation therapy, the PSA level in the blood usually drops. If the PSA level starts to rise again, it may be a sign that the cancer has come back. If the cancer returns after the original treatment, it is called recurrent cancer.
When this occurs, a new cycle of testing will begin again to learn as much as possible about the recurrence, including where the recurrence is located. The cancer may come back in the prostate , in the tissues or lymph nodes near the prostate , or in another part of the body, such as the bones, lungs, or liver . Sometimes the doctor cannot find a tumor even though the PSA level has increased. This is known as a PSA recurrence or biochemical recurrence.
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:
-
A PSA test every 3 to 6 months
-
A DRE at least once every year
-
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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Upfront Chemotherapy For Metastatic Prostate Cancer
In this review, we describe the historical data for chemotherapy in the perioperative and metastatic prostate cancer settings, and the recent trials that are changing the paradigm in support of docetaxel in the upfront setting.
Traditionally, androgen deprivation therapy has been the standard initial treatment for metastatic hormone-sensitive prostate cancer , with chemotherapy utilized in the castration-resistant setting. Data reported from three recent clinical trials shed new light on the role of upfront docetaxel in advanced or mHSPC. Two of these studies-CHAARTED and STAMPEDE-showed significant improvement in overall survival, while the third study, GETUG-AFU 15, showed no statistical difference. The CHAARTED study showed a 13.6-month survival improvement and the STAMPEDE study showed a 10-month survival improvement with ADT plus docetaxel, compared with ADT alone, in the hormone-sensitive setting. These numbers are remarkable when compared with the 2.9-month survival benefit from docetaxel in the metastatic castration-resistant setting, which has been the standard setting for the use of docetaxel in advanced prostate cancer. In this review, we describe the historical data for chemotherapy in the perioperative and metastatic prostate cancer settings, and the recent trials that are changing the paradigm in support of docetaxel in the upfront setting.
Fgf2 Secreted From Endothelial Cells To Pca/ecs Co
To determine which factor contributes to the expression of ERG in prostate cancer cells co-cultured with HUVEC, we conducted cytokines array according to the manufacturers protocol. As shown in Figures 4A, B, a series of cytokines were elevated in the culture media of 22Rv1 co-cultured with HUVEC compared with 22Rv1 cultured alone. Among these factors, IL-6, IL-8, RANTES, and bFGF have been identified as cytokines that are associated with chemotherapy resistance . Next, we examined the effect of IL-6, IL-8, CCL5, and FGF2 in the regulation of ERG expression by adding them to the culture media of prostate cancer cells, respectively. As demonstrated in Figure 4C, FGF2 upregulated the expression of ERG in 22Rv1 and C42B cells by western blotting analysis, while IL-6, IL-8, and CCL5 did not . Interestingly, the expression of FGF2 increased in HUVEC co-cultured with prostate cancer cells compared with HUVEC cultured alone measured by qPCR and ELISA analysis . Moreover, blocking FGF2 by using PD173074 could reverse the enhancing effects of HUVEC on ERG expression and docetaxel resistance in prostate cancer cells .
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Dealing With Prostate Cancer
Being diagnosed and living with prostate cancer can change how you feel about life. If you or your loved one is dealing with prostate cancer you may feel scared, stressed or even angry. There is no right way to feel and everyone reacts differently.
Visit our wellbeing hub for information to help support you in looking after your emotional, mental, and physical wellbeing. If you are close to someone with prostate cancer, find out more about how you can support someone with prostate cancer and where to get more information.
Erg Is A Key Mediator For Endothelial Cell
Recent studies have revealed that ERG can promote resistance to docetaxel in different prostate cancer cell lines . Accordingly, the expression of ERG in 22Rv1 and C42B cells co-cultured with HUVEC was determined, respectively. Interestingly, qPCR and western blot assay demonstrated that the expression of ERG increased in prostate cancer cells with prolonged co-culture time . This finding indicated that endothelial cells could induce ERG expression in prostate cancer cells in an AR independent manner. To investigate whether ERG expression has an impact on docetaxel resistance, we constructed ERG overexpressing C4-2B cells by lentiviral transfection. Cell viability assays revealed that ERG overexpression enabled more C4-2B cells to survive upon the same dose of docetaxel while knocking down ERG could restore their sensitivity to docetaxel . Annexin V/PI assay was used to assess apoptosis following docetaxel treatment in C4-2B with or without ERG overexpression. The percentage of apoptotic cells was much lower in C4-2B-ERG cells than that in C4-2B cells . Consistently, cleaved-caspase3 and cleaved-PARP also decreased in C4-2B-ERG cells compared with C4-2B cells by western blot analysis . Collectively, these data suggested that endothelial cells enhance the docetaxel resistance of prostate cancer cells through increasing ERG expression.
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Treating Smarter Not Harder: Thousands Of Men Could Be Spared Side Effects Of Docetaxel Chemotherapy
Results from an international study funded by Prostate Cancer UK could change the way we treat advanced prostate cancer, enabling healthcare teams to target those men who will benefit most from chemotherapy, and to reduce side effects in others.
A key part of our research strategy is developing better treatments. Often, this means developing new medicines that are more effective at treating prostate cancer.
But it also means finding better ways to use existing treatments, so that men with prostate cancer can live longer lives with fewer side effects.
As part of this work, and thanks to your support, weve invested more than £2.5m into researchers analysing the results of the STAMPEDE trial, which aims to find the best way to treat men with advanced prostate cancer .
Now, new analysis of STAMPEDE and two other trials has showed that some men with advanced prostate cancer benefit much more than others from the chemotherapy docetaxel.
Men with large prostate tumours, who also had many secondary tumours, were almost three times as likely to be alive after five years when given docetaxel chemotherapy alongside the usual hormone therapy.
Presented at the American Society of Clinical Oncology conference, the results pave the way for more personalised treatments, enabling healthcare teams to target docetaxel at those who will benefit the most, while moving others more quickly onto different treatments that will work for them.
To Put That Into Context
]William K. Oh, MDIcahn School of Medicine at Mount SinaiNew York, New York
STAMPEDE trial
STAMPEDE is a multi-stage, multi-arm, randomized controlled trial that is evaluating the effect of the addition of various agents to ADT in men with high-risk nonmetastatic or mHSPC. This ongoing trial commenced in 2005 and has enrolled almost 7,000 patients from more than 100 centers across the United Kingdom and Switzerland. The survival data from 917 patients with newly diagnosed M1 disease in the control arm have recently been reported. Among this group of M1 prostate cancer patients, there was a median age of 66 years, a median PSA of 112 ng/mL, 62% with bone-only metastases, and 26% with both bone and soft tissue metastases the median failure-free survival was 11 months and median overall survival was a disappointing 42 months, despite active treatments being available in the castration-resistant setting.
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Endothelial Cells Promote The Proliferation Of Prostate Cancer Cells With Or Without Docetaxel Treatment
We established a co-culture system to investigate the effect of endothelial cells on the growth of prostate cancer cells . 22Rv1 and C4-2B cells were cultured with or without HUVEC. CCK8 assays revealed that 22Rv1 and C4-2B cells co-cultured with HUVEC increased cell proliferation capability compared with the corresponding monoculture group, respectively . Moreover, as shown in Figures 1D, E, 22Rv1 or C4-2B cells co-cultured with HUVEC incorporated more EdU than the monoculture group . To investigate whether HUVEC has a synergistic impact on docetaxel resistance in prostate cancer cells, we measured cell viability of 22Rv1 and C42B cultured with or without HUVEC after 48h of docetaxel treatment at the indicated concentration. Interestingly, 22Rv1 and C42B co-cultured with HUVEC demonstrated lower sensitivity to docetaxel than the monoculture group . Collectively, these results indicated that endothelial cells may enhance the proliferation of prostate cancer cells before and after docetaxel treatment.
Endocrine Therapy And Prostate Cancer
Male hormones, specifically testosterone, fuel the growth of prostate cancer. By reducing the amount and activity of testosterone, the growth of advanced prostate cancer is slowed. Hormone therapy, known as androgen ablation or androgen suppression therapy, is the main treatment for advanced prostate cancer. It is the first line of treatment for metastatic prostate cancer.
In many patients, endocrine therapy provides temporary relief of symptoms of advanced prostate cancer. Endocrine therapy may reduce tumor size and levels of prostate specific antigen in most men. PSA is a substance produced by the prostate gland that, when present in excess amounts, signals the presence of prostate cancer.
However, hormone therapy is not without side effects. Some of the more serious side effects include loss of sex drive, impotence, weakened bones , and heart problems.
Eventually, most patients with advanced prostate cancer stop responding to hormone therapy. Doctors call this castrate-resistant prostate cancer.
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