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Hormone Therapy For Prostate Cancer Not Working

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What Is Hormonal Therapy For Prostate Cancer

Hormone Therapy & Advanced Therapies for Prostate Cancer, Celestia Higano, MD | 2021 Mid-Year Update

Hormonal therapy for prostate cancer is a treatment to lower the levels of the hormone testosterone in the body. Prostate cancer needs testosterone to grow. Testosterone is mainly made by the testicles. Hormonal therapies reduce the amount of testosterone in the body, or stop it reaching the prostate cancer cells.

Testosterone is important for:

  • muscle development and bone strength.

Hormonal therapies are drugs that can be given as injections or as tablets.

Detection Of Intracellular Reactive Oxygen Species Dcfh2

Intracellular ROS formation was assessed by measuring the fluorescence of DCF, the oxidation product of the non-fluorescent probe 2,7-dichlorodihydrofluorescein diacetate . Briefly, cells were grown in 96-well plates at a density of 2.0×105 cells per mL were treated with the IC25 and IC50 of AgNPs and G-AgNPs for 24h. Three hours prior to completion of treatment, 150 µM tert-butyl hydrogen peroxide was used as positive control. Then, cells were incubated with 10 µM DCFH2-DA for 30 minutes at 37 °C, in the dark. Live cells were then imaged with filter set appropriate for fluorescein using a fluorescence microscope OLYMPUS IX51 . The oxidation of DCFH2-DA was detected by the increase in fluorescence which is proportional to the amount of intracellular ROS generated. The intracellular mean fluorescence intensity was quantified using the ImageJ software .

Intermittent Hormonal Therapy For Locally Advanced Prostate Cancer

Intermittent hormonal therapy is where you stop taking the drugs and after a while start taking them again. This may be an option for locally-advanced prostate cancer. It gives you a break from the side effects of hormonal therapy.

Intermittent hormonal therapy is not suitable for everyone and should only be done on your doctors advice. Your doctor can explain more about this. They usually measure your PSA level using the PSA test every 3 months. If it goes up to a certain level or you get symptoms, your doctor will advise you to start hormonal therapy again.

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Clinical Trials And New Treatments

A clinical trial is a type of medical research. It helps researchers and medical teams to find new and improved ways of preventing, diagnosing, treating and managing health problems such as prostate cancer. Clinical trials often test new medicines, medical procedures or medical equipment. There are clinical trials looking at new treatments for prostate cancer and new ways of using existing treatments. If you decide to take part in a clinical trial, you may be able to have a newer treatment that isn’t yet widely available.

To find out more about taking part in a clinical trial, ask your doctor or nurse, or speak to our specialist Nurses.

Read more about clinical trials or speak to your doctor or nurse.

Clinical trials gave us hope and my dad felt that he was doing some good too A personal experience

Combined Androgen Blockade: Pro And Con

Prostate Cancer

Pro:

Crawford ED, Eisenberger MA, McLeod DG, et al. A Controlled Trial of Leuprolide With and Without Flutamide in Prostatic Carcinoma. New England Journal of Medicine 1989 321:41924. PMID: 2503724.

Con:

Eisenberger MA, Blumenstein BA, Crawford ED, et al. Bilateral Orchiectomy With or Without Flutamide for Metastatic Prostate Cancer. New England Journal of Medicine 1998 339:103642. PMID: 9761805.

Two large meta-analyses that reviewed many studies comparing combined androgen blockade to monotherapy concluded that the combination offered only a small survival advantage and even that finding was inconsistent between the two analyses. One analysis, which reviewed 27 randomized studies involving 8,275 men, estimated that combined androgen blockade improved five-year survival by only 2% to 3%, at most. However, an advantage of only 2% to 3%, when applied to thousands of men undergoing treatment, translates into hundreds of lives extended obviously an important benefit to the men who gain months and even years of life as a result. That is why I use combined therapy for all of my patients who undergo hormone treatments.

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How Does Hormone Therapy Help Prostate Cancer

Hormone therapy can control or shrink cancer and reduce symptoms. It may help you feel better and improve your quality of life for a while, but it cannot cure cancer. Most men with advanced prostate cancer receive hormone therapy. If your cancer has spread when you are diagnosed, you can start hormone therapy right away.

When should you switch treatment for prostate cancer?

But if prostate cancer cells start to grow and grow, the level of PSA may increase. In this case, your doctor may need to change your treatment. They will discuss it with you. After a few months or years, the hormone treatment usually stops working and the cancer begins to grow again.

What is intermittent androgen deprivation for prostate cancer?

What is intermittent ADT? The researchers investigated whether a technique called intermittent androgen deprivation could delay the development of hormonal resistance. In case of intermittent androgen deprivation, hormone therapy is given in cycles with pauses between drug administrations, rather than continuously.

Other Treatments To Manage Symptoms

If your prostate cancer has spread to the bones or other parts of your body, you may get symptoms such as pain.

Or if the cancer inside your prostate is pressing on your urethra , you may get urinary problems. There are treatments to help manage symptoms. These are sometimes called palliative treatments. They include:

  • pain-relieving drugs such as paracetamol, ibuprofen, codeine or morphine
  • radiotherapy to slow down the growth of the cancer and reduce symptoms
  • drugs called bisphosphonates to treat bone problems such as pain
  • medicines or surgery to make it easier to urinate.

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Adverse Effects And Their Impact On Survival

For most men, ADT has an impact on quality of life, and for some, the adverse effects of ADT are significant enough to cause them to discontinue therapy before completing the recommended length of treatment. Numerous adverse effects result from induced hypogonadism-sexual dysfunction, hot flashes, weight gain, mood lability, sleep disturbance, gynecomastia, shrinkage of genitalia, decrease in bone density, depression, and cognitive decline.

Increased risk of fracture secondary to ADT may also contribute to the survival equation when balancing the risks and benefits of treatment. Androgen suppression has been shown in numerous studies to decrease bone mineral density. ADT for prostate cancer is now one of the leading causes of osteoporosis in this country. Large population-based retrospective series have demonstrated an increased risk of fracture in men who received ADT. Although the cause of increased fracture risk is also due to greater fall risk secondary to metastatic disease and treatment-related frailty, decreased bone density from prolonged androgen suppression is certainly a major contributor. It is well-accepted that hip fractures in the elderly have an impact on survival similarly, aside from the obvious associated morbidity, skeletal fractures in men with prostate cancer have also been shown to increase mortality.

How Might Hormone Therapy Make Me Feel

Intermittent Hormone Therapy for Prostate Cancer 101 | Ask a Prostate Expert, Mark Scholz, MD

Hormone therapy itself can affect your mood. You may find that you feel more emotional than usual or just different to how you felt before. Some men find that they cry a lot. You may also get mood swings, such as getting tearful and then angry. Just knowing that these feelings are caused by hormone therapy can help.

Everyones different some men are surprised by the side effects and how upsetting they find them. Others have fewer symptoms or are not as worried by them.

Some of the other side effects of hormone therapy are hard to come to terms with. Physical changes, such as putting on weight, or changes to your sex life, might make you feel very different about yourself. Some men say they feel less masculine because of their diagnosis and treatment.

If youre starting hormone therapy very soon after being diagnosed with prostate cancer, you might still feel upset, shocked, frightened or angry about having cancer. These feelings are normal, and its okay to feel this way.

Things in your day-to-day life can change because of the hormone therapy. Your relationships with your partner, family and friends might change. Or you might be too tired to do some of the things you used to do.

Some men experience low moods, anxiety or depression. This could be directly caused by the hormone therapy itself, or because youve been diagnosed with prostate cancer. It could also be due to the impact that treatment is having on you and your family.

What can help?

Talking about it

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Figure : How Hormone Therapy Affects The Androgen Cascade

The male sex hormones are known as androgens. Probably the best known hormone in this family is testosterone. Most androgens are produced in the testicles.

Androgens fuel the growth of prostate cells, including prostate cancer cells. Hormone therapy also known as androgen-deprivation therapy seeks to cut off the fuel supply. But different therapies work in different ways.

A. The hypothalamus releases pulses of LHRH, which signals the pituitary gland to release the hormones FSH and LH.

B. LH travels through the bloodstream. When it reaches the testicles, it binds to specialized cells that secrete testosterone into the bloodstream.

C. In the prostate, the enzyme 5-alpha-reductase converts testosterone and other types of androgens into dihydrotestosterone , which stimulates the growth of prostate cells and fuels the growth of cancer, if it is present.

Centrally acting agents

LHRH agonists flood the pituitary gland with messages to crank out LH. This causes a temporary surge of testosterone until receptors in the pituitary are overloaded. Then testosterone levels drop sharply.

The GnRH antagonist jams receptors in the pituitary gland so that it cannot respond to the pulses of LHRH sent by the hypothalamus. This prevents the LH signal from being sent and no testosterone is made in the testicles.

DES inhibits secretion of LHRH from the hypothalamus.

Peripherally acting therapies

Orchiectomy removes the testicles, preventing testosterone production.

Evidence For Combining Hormone Therapy And Radiation Treatment

Bolla M, Collette L, Blank L, et al. Long-Term Results with Immediate Androgen Suppression and External Irradiation in Patients with Locally Advanced Prostate Cancer : A Phase III Randomised Trial. Lancet 2002 360:1036. PMID: 12126818.

Bolla M, Gonzalez D, Warde P, et al. Improved Survival in Patients with Locally Advanced Prostate Cancer Treated with Radiotherapy and Goserelin. New England Journal of Medicine 1997 337:295300. PMID: 9233866.

DAmico AV, Schultz D, Loffredo M, et al. Biochemical Outcome Following External Beam Radiation Therapy With or Without Androgen Suppression Therapy for Clinically Localized Prostate Cancer. Journal of the American Medical Association 2000 284:12803. PMID: 10979115.

DAmico AV, Manola J, Loffredo M, et al. Six-Month Androgen Suppression Plus Radiation Therapy Versus Radiation Therapy Alone for Patients with Clinically Localized Prostate Cancer: A Randomized Controlled Trial. Journal of the American Medical Association 2004 292:8217. PMID: 15315996.

Denham JW, Steigler A, Lamb DS, et al. Short-Term Androgen Deprivation and Radiotherapy for Locally Advanced Prostate Cancer: Results from the Trans-Tasman Radiation Oncology Group 96.01 Randomised Controlled Trial. Lancet Oncology 2005 6:84150. PMID: 16257791.

Nesslinger NJ, Sahota RA, Stone B, et al. Standard Treatments Induce Antigen-Specific Immune Responses in Prostate Cancer. Clinical Cancer Research 2007 13:1493502. PMID: 17332294.

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Hormone Therapy: Immediate Versus Delayed

Medical Research Council Prostate Cancer Working Party Investigators Group. Immediate Versus Deferred Treatment for Advanced Prostatic Cancer. British Journal of Urology 1997 79:23546. PMID: 9052476.

Messing EM, Manola J, Sarosdy M, et al. Immediate Hormonal Therapy Compared with Observation after Radical Prostatectomy and Pelvic Lymphadenectomy in Men with Node-Positive Prostate Cancer. New England Journal of Medicine 1999 341:17818. PMID: 10588962.

Messing EM, Manola J, Yao J, et al. Immediate Versus Deferred Androgen Deprivation Treatment in Patients with Node-Positive Prostate Cancer after Radical Prostatectomy and Pelvic Lymphadenectomy. Lancet Oncology 2006 7:4729. PMID: 16750497.

Nair B, Wilt T, MacDonald R, Rutks I. Early Versus Deferred Androgen Suppression in the Treatment of Advanced Prostatic Cancer. Cochrane Database of Systematic Reviews 2002 CD003506. PMID: 11869665.

Therapies That Interfere With Androgen Function

Prostate Cancer

Taken daily as pills, antiandrogens bind to the androgen receptor proteins in the prostate cells, preventing the androgens from functioning. In addition to preventing a flare reaction, antiandrogens may be added to your treatment plan if an orchiectomy, LHRH agonist or LHRH antagonist is no longer working by itself. Commonly prescribed antiandrogens include flutamide and bicalutamide .

Enzalutamide is a newer type of antiandrogen that blocks the signal that the receptor normally sends to the cells control center to trigger growth and division. This antiandrogen may be used to treat castration-resistant prostate cancer.

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Surgical procedures to remove the diseased prostate are usually necessary. Surgical procedures are not always necessary. If the disease is caused by bacterial infections, a doctor can treat the symptoms using alpha-blockers or surgery. Physical therapy, relaxation exercises, and warm baths are all recommended. A physician may also prescribe antibiotics to cure the infection. A bacterial infection can also cause a recurrence of the condition.

An enlarged prostate can be uncomfortable for both men and women. Some of the symptoms of an enlarged male reproductive organ include a weakened urine stream, urgent need to urinate, and urinary tract infections. BPH can also cause damage to the kidneys. A sudden inability to urinate can be life-threatening, as it can lead to bladder and kidney damage. Unfortunately, most men with enlarged prostrates put up with the symptoms for years before they seek treatment. However, many of the men with symptoms finally decide to go to a doctor for proper gynecological evaluation and to begin enlarged prostatic therapy.

How To Tell If Hormone Therapy Is Working

If you are taking hormone therapy for prostate cancer, you will have regular PSA tests. If hormone therapy is working, your PSA levels will stay the same or may even go down. But, if your PSA levels go up, this may be a sign that the treatment is no longer working. If this happens, your doctor will discuss treatment options with you.

If you are taking hormone therapy for breast cancer, you will have regular checkups. Checkups usually include an exam of the neck, underarm, chest, and breast areas. You will have regular mammograms, though you probably wont need a mammogram of a reconstructed breast. Your doctor may also order other imaging procedures or lab tests.

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Intermittent Or Continuous Therapy

Once prescribed, hormone therapy used to continue for life, but scientists are now reevaluating that strategy and investigating whether hormone therapy can be taken intermittently, with so-called holidays from treatment. The thinking is that this may not only help restore quality of life as, for example, returning libido and sexual health but also delay the hormone resistance that eventually develops in men taking hormone therapy.

Clinical trials evaluating whether intermittent therapy is as effective or more effective than continuous therapy are now under way, so it is too early to say for sure.

The Future Of Hormone Therapy For Prostate Cancer

Reducing Side Effects of Hormone Therapy for Prostate Cancer | Prostate Cancer Staging Guide

Some experts aren’t sure how much further we can improve hormone therapy for prostate cancer.

“I’m not saying that we’ve reached the end of what we can do with hormonal therapy,” Thrasher tells WebMD, “but there are only so many ways to shut down the hormonal effects. The cancer will still eventually escape.”

Brooks argues that, overall, prostate cancer is only moderately affected by hormones. “You can only do so much manipulating the levels of hormones,” says Brooks. “We have to find better ways to fight the basis of the cancer cells.”

Thrasher and Brooks have more hope that the next breakthroughs will come with different approaches, like chemotherapy or vaccines.

But Holden remains optimistic about the future of hormone therapy for prostate cancer.

“Cancer cells eventually figure out how to survive, how to overcome a specific hormone therapy,” he says. “But if we have enough types of drugs and can keep changing the hormone therapy, we might be able to keep the cancer cells in a state of confusion. We could change therapies before they have a chance to adapt.”

“It’s like an endless chess game,” he says. “You may not ever win, but you might be able to prolong the game indefinitely. I think that hormone therapy still has a lot of promise. We just need to develop better anti-androgens, and more varieties of them.”

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How Testosterone Helps Prostate Cancer Grow

Testosterone travels through the bloodstream and eventually reaches prostate cancer cells, where it helps the cancer grow. Up to a point, the more testosterone the cancer cells have, the more the cancer can grow and eventually spread to other parts of the body. Hormone therapy is designed to prevent testosterone from fueling the growth of these cancer cells.

Secondary Treatment Following Relapse

Hormone therapy may also be used as a secondary or salvage treatment when PSA levels rise following initial prostate cancer treatment, indicating the cancer has returned. This situation is known as biochemical recurrence. The salient points to keep in mind are that hormone therapy is most often used as a salvage treatment when PSA doubling time is less than six months, indicating that the cancer is aggressive or may have already metastasized.

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What Type Of Hormone Therapy Works Best

Unfortunately, understanding the details of hormone therapy for prostate cancer can be difficult. Which drug or combination of drugs works best? In what order should they be tried? Research hasn’t answered these questions yet.

“Right now, there’s a level of art to figuring out which agents to use,” says Durado Brooks, MD, MPH, director of prostate cancer programs at the American Cancer Society. “We don’t have clear evidence yet.”

LHRH agonists remain the usual first treatment. But in some cases, doctors are trying anti-androgens first. Anti-androgens may be especially appealing to younger men who are still sexually active, since these drugs don’t completely shut down sex drive. When anti-androgens stop working — based on PSA tests — a person then might shift onto an LHRH agonist.

Other doctors prefer to begin therapy with a combination of two or even three drugs, especially for patients with symptoms or advanced disease, says Holden.

Researchers originally hoped that combined androgen blockade would significantly add to the benefits of LHRH agonists. However, the results, to date, have been mixed. Some studies have shown slightly longer survival with combined androgen blockade, but the results haven’t been as dramatic as many experts had hoped. Other studies have shown no benefit. A possible explanation may be the type of anti-androgen used, but further studies are needed to answer this question.

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