Management of prostate cancer

Treatment for prostate cancer may involve active surveillance, surgery, radiation therapy including brachytherapy (prostate brachytherapy) and external beam radiation therapy, high-intensity focused ultrasound (HIFU), cryosurgery, hormonal therapy, chemotherapy, or some combination. Which option is best depends on the stage of the disease, the Gleason score, and the PSA level. Other important factors are the man's age, his general health, and his feelings about potential treatments and their possible side effects. Because all treatments can have significant side effects, such as erectile dysfunction and urinary incontinence, treatment discussions often focus on balancing the goals of therapy with the risks of lifestyle alterations.

The selection of treatment options may be a complex decision involving many factors. For example, radical prostatectomy after primary radiation failure is a very technically challenging surgery and may not be an option.[1] This may enter into the treatment decision.

If the cancer has spread beyond the prostate, treatment options significantly change, so most doctors that treat prostate cancer use a variety of nomograms to predict the probability of spread. Treatment by watchful waiting/active surveillance, HIFU, external beam radiation therapy, brachytherapy, cryosurgery, and surgery are, in general, offered to men whose cancer remains within the prostate. Hormonal therapy and chemotherapy are often reserved for disease that has spread beyond the prostate. However, there are exceptions: Radiation therapy may be used for some advanced tumors, and hormonal therapy is used for some early stage tumors. Cryotherapy (the process of freezing the tumor), hormonal therapy, and chemotherapy may also be offered if initial treatment fails and the cancer progresses.[2]

Active surveillance

Active surveillance is observation and regular monitoring without invasive treatment. In the context of prostate disease this usually comprises regular PSA blood tests and prostate biopsies. Active surveillance is often used when an early stage, slow-growing prostate cancer is suspected. However, watchful waiting may also be suggested when the risks of surgery, radiation therapy, or hormonal therapy outweigh the possible benefits. Other treatments can be started if symptoms develop, or if there are signs that the cancer growth is accelerating (e.g., rapidly rising PSA, increase in Gleason score on repeat biopsy, etc.).

Approximately one-third of men who choose active surveillance for early stage tumors eventually have signs of tumor progression, and they may need to begin treatment within three years.[3] Men that choose active surveillance avoid the risks of surgery, radiation, and other treatments. The risk of disease progression and metastasis (spread of the cancer) may be increased, but this increase risk appears to be small if the program of surveillance is followed closely, generally including serial PSA assessments and repeat prostate biopsies every 1–2 years depending on the PSA trends.

Study results in 2011 suggest active surveillance is the best choice for older 'low-risk' patients.[4]

Surgery

Main article: Prostatectomy

Surgical removal of the prostate, or prostatectomy, is a common treatment either for early stage prostate cancer or for cancer that has failed to respond to radiation therapy. The most common type is radical retropubic prostatectomy, when the surgeon removes the prostate through an abdominal incision. Another type is radical perineal prostatectomy, when the surgeon removes the prostate through an incision in the perineum, the skin between the scrotum and anus. Radical prostatectomy can also be performed laparoscopically, through a series of small (1 cm) incisions in the abdomen, with or without the assistance of a surgical robot.

Radical prostatectomy

Radical prostatectomy is effective for tumors that have not spread beyond the prostate;[5] cure rates depend on risk factors such as PSA level and Gleason grade. However, it may cause nerve damage that may significantly alter the quality of life of the prostate cancer survivor.

Radical prostatectomy has traditionally been used alone when the cancer is localized to the prostate. In the event of positive margins or locally advanced disease found on pathology, adjuvant radiation therapy may offer improved survival. Surgery may also be offered when a cancer is not responding to radiation therapy. However, because radiation therapy causes tissue changes, prostatectomy after radiation has higher risks of complications.

Laparoscopic radical prostatectomy, LRP, is a new way to approach the prostate surgically with intent to cure. Contrasted with the open surgical form of prostate cancer surgery, laparoscopic radical prostatectomy requires a smaller incision. Relying on modern technology, such as miniaturization, fiber optics, and the like, laparoscopic radical prostatectomy is a minimally invasive prostate cancer treatment but is technically demanding and seldom done in the USA.

Some believe that in the hands of an experienced surgeon, robotic-assisted laparoscopic prostatectomy (RALP) may reduce positive surgical margins when compared to radical retropubic prostatectomy (RRP) among patients with prostate cancer according to a retrospective study.[6] The relative risk reduction was 57.7%. For patients at similar risk to those in this study (35.5% of patients had positive surgical margins following RRP), this leads to an absolute risk reduction of 20.5%. 4.9 patients must be treated for one to benefit (number needed to treat = 4.9). Other recent studies have shown RALP to result in a significantly higher rate of positive margins.[7] Other studies showed no difference of robotic to open surgery.[8] A recent French study comparing standard laparoscopic to robotic to open prostatectomy showed no difference in margin status or biochemical recurrence at 5 years.[9] The relative merits of RALP and potential benefit versus open radical prostatectomy is currently an area of intense research and debate in urology. The only proven and accepted advantage to RALP is less intraoperative blood loss. Other suggested advantages beyond this lack definitive data and have not been widely accepted by the broader urological community.

Transurethral resection

Transurethral resection of the prostate, commonly called a "TURP," is a surgical procedure performed when the tube from the bladder to the penis (urethra) is blocked by prostate enlargement. In general, TURP is for benign disease and is not meant as definitive treatment for prostate cancer. During a TURP, a small instrument (cystoscope) is placed into the penis and the blocking prostate is cut away.

Cryosurgery

Cryosurgery is another method of treating prostate cancer in which the prostate gland is exposed to freezing temperatures.[10] Cryosurgery is less invasive than radical prostatectomy, and general anesthesia is less commonly used. Under ultrasound guidance, a method invented by Dr. Gary Onik,[11] metal rods are inserted through the skin of the perineum into the prostate. Highly purified argon gas is used to cool the rods, freezing the surrounding tissue at −186 °C (−302 °F). As the water within the prostate cells freezes, the cells die. The urethra is protected from freezing by a catheter filled with warm liquid. Impotence occurs up to ninety percent of the time.[12]

Orchiectomy

In metastatic disease, where cancer has spread beyond the prostate, removal of the testicles (called orchiectomy) may be done to decrease testosterone levels and control cancer growth. (See hormonal therapy, above).

Complications of surgery

The most common serious complications of surgery are loss of urinary control and impotence. Reported rates of both complications vary widely depending on how they are assessed, by whom, and how long after surgery, as well as the setting (e.g., academic series vs. community-based or population-based data). Although penile sensation and the ability to achieve orgasm usually remain intact, erection and ejaculation are often impaired. Medications such as sildenafil (Viagra), tadalafil (Cialis), or vardenafil (Levitra) may restore some degree of potency. For most men with organ-confined disease, a more limited "nerve-sparing" technique may help reduce urinary incontinence and impotence.[13]

Postoperative urinary incontinence has been reported at 16% among patients at 12 months following radical prostatectomy. Although pelvic floor muscle training has been prescribed to improve urinary continence, the evidence for efficacy in men after radical prostatectomy has come into question recently. According to information from the Men After Prostate Surgery (MAPS) randomised control trial, pelvic floor muscle training was not shown to be therapeutic or cost effective in improving urinary continence. Of the patients in the intervention group, 148 of the 196 patients reported some form of incontinence at the 12-month mark. In the control group, 151 of the 195 patients reported some urinary incontinence (EER=.755, CER=.774, RRR=.0245, ARR=.019, NNT=Not Significant).[14]

Radiation therapy

Radiation therapy, also known as radiotherapy, is often used to treat all stages of prostate cancer. It is also often used after surgery if the surgery was not successful at curing the cancer. Radiotherapy uses ionizing radiation to kill prostate cancer cells. When absorbed in tissue, Ionizing radiation such as gamma and x-rays damage the DNA in cancer cells, which increases the probability of apoptosis (cell death). Normal cells are able to repair radiation damage, while cancer cells are not. Radiation therapy exploits this fact to treat cancer. Two different kinds of radiation therapy are used in prostate cancer treatment: external beam radiation therapy and brachytherapy (specifically prostate brachytherapy).

External beam radiation therapy

External beam radiation therapy uses a linear accelerator to produce high-energy x-rays that are directed in a beam towards the prostate. A technique called Intensity Modulated Radiation Therapy (IMRT) may be used to adjust the radiation beam to conform with the shape of the tumor, allowing higher doses to be given to the prostate and seminal vesicles with less damage to the bladder and rectum. External beam radiation therapy is generally given over several weeks, with daily visits to a radiation therapy center. New types of radiation therapy such as IMRT have fewer side effects than traditional treatment. Eleven centers in the United States are now using proton therapy for prostate cancer, which uses protons rather than X-rays to kill the cancer cells. Researchers are also studying types of stereotactic body radiotherapy (SBRT) to treat prostate cancer.[15]

External beam radiation therapyfor prostate cancer is delivered by a linear accelerator, such as this one.

Brachytherapy

Permanent implant brachytherapy is a popular treatment choice for patients with low to intermediate risk features, can be performed on an outpatient basis, and is associated with good 10-year outcomes with relatively low morbidity.[16] It involves the placement of about 100 small "seeds" containing radioactive material (such as iodine-125 or palladium-103) with a needle through the skin of the perineum directly into the tumor while under spinal or general anesthetic. These seeds emit lower-energy X-rays which are only able to travel a short distance. Although the seeds eventually become inert, they remain in the prostate permanently. The risk of exposure to others from men with implanted seeds is generally accepted to be insignificant.[17] However, men are encouraged to talk to their doctors about any special temporary precautions around small children and pregnant women.[18]

Uses

Radiation therapy is commonly used in prostate cancer treatment. It may be used instead of surgery or after surgery in early stage prostate cancer (adjuvant radiotherapy). Radiation treatments also can be combined with hormonal therapy for intermediate risk disease, when surgery or radiation therapy alone is less likely to cure the cancer. Some radiation oncologists combine external beam radiation and brachytherapy for intermediate to high-risk situations. Radiation therapy is often used in conjunction with hormone therapy for high-risk patients.[19] Others use a "triple modality" combination of external beam radiation therapy, brachytherapy, and hormonal therapy. In advanced stages of prostate cancer, radiation is used to treat painful bone metastases or reduce spinal cord compression.

Radiation therapy is also used after radical prostatectomy either for cancer recurrence or if multiple risk factors are found during surgery. Radiation therapy delivered immediately after surgery when risk factors are present (positive surgical margin, extracapsular extension, seminal vessicle involvement) has been demonstrated to reduce cancer recurrence, decrease distant metastasis, and increase overall survival in two separate randomized trials.[20]

Side effects

Side effects of radiation therapy might occur after a few weeks into treatment. Both types of radiation therapy may cause diarrhea and mild rectal bleeding due to radiation proctitis, as well as potential urinary incontinence and impotence. Symptoms tend to improve over time except erections which typically worsen as time progresses.

A new method to reduce rectal radiation injury in prostate cancer patients involves the use of an absorbable spacer placed between the prostate and rectum.

MRI showing hydrogel spacer pushing the rectum away from the prostate during radiotherapy.

Such spacers are commercially available in some regions, and are undergoing clinical trials in others.[21] By temporarily altering the anatomy these products have the potential to allow for improved cancer targeting while minimizing risk to neighboring healthy tissues. Prostate Rectum Spacers should be compatible with all prostate cancer radiotherapy treatments including 3D conformal, IMRT and stereotactic radiation and brachytherapy.

Comparison to surgery

Multiple retrospective analyses have demonstrated that overall survival and disease-free survival outcomes are similar between radical prostatectomy, external beam radiation therapy, and brachytherapy.[22] Rates for impotence when comparing radiation to nerve-sparing surgery are similar. Radiation has lower rates of incontinence compared with surgery, but has higher rates of occasional mild rectal bleeding.[23] Men who have undergone external beam radiation therapy may have a slightly higher risk of later developing colon cancer and bladder cancer.[24]

Since prostate cancer is generally a multifocal disease, the traditional prostatectomy eliminates all local lesions by removing the entire prostate. However, it has been hypothesized that an "index lesion" might be responsible for disease progression. Therefore, focal therapy targeted towards the index lesion might effectively treat prostate cancer while preserving the remainder of the gland. Interventional radiologists have started to treat prostate cancer with minimally invasive therapies such as cryoablation, HIFU, radiofrequency ablation, and photodynamic therapy that permit focal therapy by utilizing image guidance. These therapies are still in beginning or experimental stages; however, because they preserve tissue, they can potentially reduce adverse treatment outcomes such as impotence and incontinence. A small prospective study published in European Urology in February 2015 assessed the focal treatment of index lesions with HIFU in patients with multifocal prostate cancer and found that the majority of men returned to baseline genitourinary function and 86% of men were free of clinically significant prostate cancer at one year.[25] Small, nonrandomized cohort studies with a median range follow-up 17–47 months have shown that cryoablation, HIFU, and phototherapy are associated with low rates of adverse effects and early disease control rates of 83%-100% based on negative biopsies.[26]

Patients who might particularly benefit from focal therapy with HIFU are men with recurrent cancer after the gland has been removed. Cancer recurrence rates after surgical resection can be as high as 15-20%. MR imaging improves early detection of cancer, so MR-guided therapies can be applied to treat recurrent disease. Additionally, for men who have already failed salvage radiation treatment and have limited therapeutic options remaining, interventional therapies might offer more chances to potentially cure their disease. While recent studies have demonstrated the feasibility of these treatments, additional work is needed to further evaluate which patients are best suited for these procedures and determine long-term efficacy.[27]

High intensity focused ultrasound

High intensity focused ultrasound (HIFU) was first used in the 1940s and 1950s in efforts to destroy tumors in the central nervous system. Since then, HIFU has been shown to be effective at destroying malignant tissue in the brain, prostate, spleen, liver, kidney, breast, and bone.[28]

HIFU for prostate cancer utilizes ultrasound to ablate/destroy the tissue of the prostate. During the HIFU procedure, sound waves are used to heat the prostate tissue, thus destroying the cancerous cells. In essence, ultrasonic waves are focused on specific areas of the prostate to eliminate the prostate cancer, with minimal risks of affecting other tissue or organs. Temperatures at the focal point of the sound waves can exceed 100 °C (212 °F).[28] However, many studies of HIFU were performed by manufacturers of HIFU devices, or members of manufacturers' advisory panels.[29]

Contraindications to HIFU for prostate cancer include a prostate volume larger than 40 grams, which can prevent targeted HIFU waves from reaching the anterior and anterobasal regions of the prostate, anatomic or pathologic conditions that may interfere with the introduction or displacement of the HIFU probe into the rectum, and high-volume calcification within the prostate, which can lead to HIFU scattering and transmission impairment.[30]

A 2012 UK trial of focal HIFU on 41 patients reported no histological evidence of cancer in 77% of men treated (95% confidence interval: 61 - 89%) at 12 month targeted biopsy, and a low rate of genitourinary side effects.[31] However, this does not necessarily mean that 77% of men were definitively cured of prostate cancer, since systematic and random sampling errors are present in the biopsy process, and therefore recurrent or previously undetected cancer can be missed.[32]

A 2016 report on a multicenter French study of HIFU for PC confined to a single prostate lobe showed encouraging results.[33]

Life-style changes

Prostate enlargement can cause difficulties emptying the bladder completely. This situation, in which there is residual volume in the bladder is prone to complications such as cystitis and bladder stones, also commonly found in patients with benign prostate hyperplasia. It was often suggested to change the voiding position of symptomatic males, however study results showed heterogeneity. A meta-analysis of people with prostate enlargement and healthy males showed a significant reduction of residual volume, while a trend towards an improved urinary flow rate and decreased voiding time was found.[34] The effect of changing ones position is thought to arise from relaxation of the pelvic musculature, which are contracted in the standing position thereby influencing urodynamics.

Frequent exercise such as brisk walking can delay the progress of prostate cancer [35][36]

Hormonal therapy

Hormonal therapy in prostate cancer. Diagram shows the different organs (purple text), hormones (black text and arrows), and treatments (red text and arrows) important in hormonal therapy.

Hormonal therapy uses medications or surgery to block prostate cancer cells from getting dihydrotestosterone (DHT), a hormone produced in the prostate and required for the growth and spread of most prostate cancer cells. Blocking DHT often causes prostate cancer to stop growing and even shrink. However, hormonal therapy rarely cures prostate cancer because cancers that initially respond to hormonal therapy typically become resistant after one to two years. Hormonal therapy is, therefore, usually used when cancer has spread from the prostate. It may also be given to certain men undergoing radiation therapy or surgery to help prevent return of their cancer.[37]

Hormonal therapy for prostate cancer targets the pathways the body uses to produce DHT. A feedback loop involving the testicles, the hypothalamus, and the pituitary, adrenal, and prostate glands controls the blood levels of DHT. First, low blood levels of DHT stimulate the hypothalamus to produce gonadotropin-releasing hormone (GnRH). GnRH then stimulates the pituitary gland to produce luteinizing hormone (LH), and LH stimulates the testicles to produce testosterone. Finally, testosterone from the testicles and dehydroepiandrosterone from the adrenal glands stimulate the prostate to produce more DHT. Hormonal therapy can decrease levels of DHT by interrupting this pathway at any point. There are several forms of hormonal therapy:

The most successful hormonal treatments are orchiectomy and GnRH agonists. Despite their higher cost, GnRH agonists are often chosen over orchiectomy for cosmetic and emotional reasons. Eventually, total androgen blockade may prove to be better than orchiectomy or GnRH agonists used alone.

Each treatment has disadvantages that limit its use in certain circumstances. Although orchiectomy is a low-risk surgery, the psychological impact of removing the testicles can be significant, and sterility is certain. The loss of testosterone can cause hot flashes, weight gain, loss of libido, enlargement of the breasts (gynecomastia), impotence, penile atrophy, and osteoporosis. GnRH agonists eventually cause the same side effects as orchiectomy but may cause worse symptoms at the beginning of treatment. When GnRH agonists are first used, testosterone surges can lead to increased bone pain from metastatic cancer, so antiandrogens or abarelix is often added to blunt these side effects. Estrogens are not commonly used because they increase the risk for cardiovascular disease and blood clots. In general, the antiandrogens do not cause impotence, and usually cause less loss of bone and muscle mass. Ketoconazole can cause liver damage with prolonged use, and aminoglutethimide can cause skin rashes.

Estrogen therapy

Estrogens have been used in the treatment of prostate cancer.[42] The estrogens that have been used include diethylstilbestrol, fosfestrol (diethylstilbestrol diphosphate), ethinyl estradiol, ethinyl estradiol sulfonate, polyestradiol phosphate, and estradiol undecylate, as well as the combined estrogenic and nitrogen mustard alkylating antineoplastic agent estramustine.[42][43] Newer estrogens with improved tolerability and safety like GTx-758 have also been studied.[44][45] Estrogens are effective in the treatment of prostate cancer because they are functional antiandrogens.[43][46] They both suppress testosterone concentrations to castrate levels via their antigonadotropic activity[43][46] and they reduce the percentage of free and bioavailable testosterone by increasing sex hormone-binding globulin production and levels.[44][46] Estrogens have been found to be equivalent in effectiveness to androgen deprivation therapy with castration and non-steroidal antiandrogens.[46] However, they significantly increase cardiovascular mortality, and for this reason, are now little used in prostate cancer.[46] Although the most commonly employed estrogens like diethylstilbestrol and ethinyl estradiol are associated with increased cardiovascular mortality, it is notable that certain estrogens, namely polyestradiol phosphate, have been found not to do so; this is attributed to different degrees of effect of the various estrogens on hepatic protein synthesis.[46]

Extensive disease

Palliative care for advanced stage prostate cancer focuses on extending life and relieving the symptoms of metastatic disease. As noted above, abiraterone is showing some promise in treating advance-stage prostate cancer. It causes a dramatic reduction in PSA levels and tumor sizes in aggressive advanced-stage prostate cancer for 70% of patients.[40][41] Chemotherapy may be offered to slow disease progression and postpone symptoms. The most commonly used regimen combines the chemotherapeutic drug docetaxel with a corticosteroid such as prednisone. One study showed that treatment with docetaxel with prednisone prolonged life from 16.5 months for those taking mitoxantrone and prednisone to 18.9 months for those taking docetaxel + prednisone.[47] Bisphosphonates such as zoledronic acid have been shown to delay skeletal complications such as fractures or the need for radiation therapy in patients with hormone-refractory metastatic prostate cancer.[48] Xofigo is a new alpha emitting pharmaceutical targeting bone metastasis. The phase II testing shows prolonged patient survival times, reduced pain, and improved quality of life.

Bone pain due to metastatic disease is treated with opioid pain relievers such as morphine and oxycodone. External beam radiation therapy directed at bone metastases may provide pain relief. Injections of certain radioisotopes, such as strontium-89, phosphorus-32, or samarium-153, also target bone metastases and may help relieve pain.

Alternative therapies

As an alternative to active surveillance or definitive treatments, other therapies are also under investigation for the management of prostate cancer. PSA has been shown to be lowered in men with apparent localized prostate cancer using a vegan diet (fish allowed), regular exercise, and stress reduction.[49] These results have so far proven durable after two-years' treatment. However, this study did not compare the vegan diet to either active surveillance or definitive treatment, and thus cannot comment on the comparative efficacy of the vegan diet in treating prostate cancer.[50]

Many other single agents have been shown to reduce PSA, slow PSA doubling times, or have similar effects on secondary markers in men with localized cancer in short term trials, such as pomegranate juice or genistein, an isoflavone found in various legumes.[51][52]

The potential of using multiple such agents in concert, let alone combining them with lifestyle changes, has not yet been studied. A more thorough review of natural approaches to prostate cancer has been published.[53]

Neutrons have been shown to be superior to X-rays in the treatment of prostatic cancer. The rationale is that tumours containing hypoxic cells (cells with enough oxygen concentration to be viable, yet not enough to be X-ray-radiosensitive) and cells deficient in oxygen are resistant to killing by X-rays. Thus, the lower Oxygen Enhancement Ratio (OER) of neutrons confers an advantage. Also, neutrons have a higher relative biological effectiveness (RBE) for slow-growing tumours than X-rays, allowing for an advantage in tumour cell killing.[54]

Prevention

Neither selenium nor vitamin E have been found to be effective in preventing prostate cancer.[55]

Trade-offs

The trade-off dilemma refers to the choice between the expected beneficial and harmful effects in terms of survival and quality of life for a particular treatment. An example of such trade-off in prostate cancer treatment includes urinary and bowel symptoms and waning sexual function.[56] How common these symptoms are and the distress they cause varies between types of treatment and individuals.[57]

One option is to trade off an intact sexual function for the possibility of a prolonged life expectancy by not having curative treatment. The choice involves a trade-off so it is of central importance for the person and the physician to have access to information on established treatment benefits and side effects. A Swedish study found that the willingness to do this kind of trade-off varied considerably among men.[56] While six out of ten were willing to consider a trade-off between life expectancy and intact sexual function, given the present knowledge of treatment benefits for clinically localized prostate cancer, four out of ten stated that they would under all circumstances choose treatment irrespective of the risk for waning sexual function. Access to valid empirical information is crucial for such decision making. Key factors here are an individual’s feeling towards the illness, their emotional values and religious beliefs. A substantial proportion of people and physicians, experience stress in judging the trade-off between different treatment options and treatment side-effects which adds to the stress of cancer diagnosed, a situation made worse in that eight out of ten people with prostate cancer have no one to confide in except their spouse and one out of five live in total emotional isolation.[58]

References

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