To Treat or Not To Treat, Early Stage Prostate Cancer

Over 200,000 men will be diagnosed with prostate cancer this year. The majority of these men (90%) will have localized disease. It has been established that early prostate cancer is over diagnosed and over treated. The dilemma for most of these men will be whether to treat or not to treat.

The Scandinavian Prostate Cancer Group Study has provided evidence that after a median follow-up of 12.8 years, patients treated with surgery (prostatectomy) had a greater survival than patients treated with watchful waiting by about 5% (87.5% vs. 82.1%). Metastasis was also less likely to be found in the treated group by 6% (19.3% treated vs. 26% not treated). This survival benefit was restricted to men younger than 65 years of age, Gleason score <7.

This survival benefit may not be relevant in men identified by PSA screening, as in the Scandinavian study 88% of patients had palpable tumors, implying a more advanced stage. In the US the median age at diagnosis of prostate cancer is 67, fewer than 50% have palpable tumors, and the lead time associated with prostate cancer detection from PSA screening has been estimated to be as long as 10 years. The only reason to question therapy is the price one has to pay in side effects and decrease quality of life issues. Prostatectomy is associated with erectile dysfunction and urinary incontinence.

Advancements in the delivery of radiation therapy, including image guided and focusing techniques, have allowed for improvements in the rates of disease control similar to surgery. Large, randomized studies comparing the two modalities in early stage disease are lacking. Radiation therapy is associated with bladder irritability, bowel symptoms and at some point erectile dysfunction as well. Adjuvant hormone therapy, shown to benefit patients receiving radiation therapy, increases the side effect profile with vitality and hormonal function issues.

Treatment-related symptoms are exacerbated by obesity, large prostate size, high PSA score, and older age. These changes influence satisfaction with treatment outcomes in patients and their partners. In the end, the decision to treat or not to treat is a personal one with one’s urologist acting as coach. The question to ask: “…is the promised benefit at the end of the road worth the price paid in decrease quality of life en route?”

“Quality of Life” Trumps Plain Survival

There is a growing consensus among physicians and patients that survival in prostate cancer with quality of life beats plain survival. Prostate cancer comes in basically two patterns of behavior (low-risk and high-risk), and the vast majority diagnosed by screening today (85%) is a low-risk, indolent cancer which takes many years to develop. The problem is that the words “cancer” and “indolent” don’t fit well with most people’s conceptions of cancer as a disease, and this falls into the patterned behavior of urologists who are trained to take “cancers” out. Active surveillance of low-risk prostate cancer has been shown by various studies to be clinically acceptable and maintain quality of life.

There is little probability that a cancer that can be cured will not be cured if active surveillance is carried out. In the words of the late oncologic urologist Dr. Whitmore: “If the prostate cancer is curable is treatment necessary, and if treatment is necessary is cure possible?” The undercurrent of his allusion implies that we are dealing with two different diseases, and we actually don’t know if one morphs into the other. Many men are found to have died with prostate cancer from other causes rather than of it. The concept that low-risk prostate cancer does not kill people is not being taught to patients.

Of course once active surveillance is chosen close follow-up is necessary to avoid the charge, in our litigious environment, that a window of opportunity was missed. The decision of when to turn from surveillance to treatment will always be a point of contention, but this can be reached jointly by patient and physician as they assess the objective findings being followed.

As patients become more educated, they are less likely to go through “knee-jerk” treatment after diagnosis. Over-diagnosis and over-treatment are likely to increase with the American Urological Association recommendation to begin screening at age 40. Autopsy series reveal that 30% of men in their 30′s have histologic evidence of prostate cancer. Treating young people with low risk disease condemns them to a decreased quality of life, when the latency period of their disease could be quite prolonged. There is enough evidence to suggest that active surveillance is a sound initial strategy in low-risk prostate cancer.

The Prostate Story

The prostate has become a common focus of discussion in health related media outlets, but it would not be wrong to assume that most people don’t know what the prostate is. The prostate is a male reproductive organ about the size of a golf ball, growing around the urethra (the urinary channel) as it leaves the bladder. Its function is to make semen, the nutrient fluid in which the sperm lives.

The prostate can be the cause of many problems in men and the consternation is compounded by the confusion surrounding the media cacophony about screening for prostate cancer and the usefulness of PSA (prostate specific antigen) in this regard. Prostate cancer is one of the most commonly diagnosed cancers among men in the United States. Prostate cancer is not only prevalent, but also slow growing. Only 0.6% of diagnosed prostate cancer patients die within 5 years. (NCI SEER data) This makes it difficult to decide how and if to treat the prostate cancer. The main question becomes: is the cancer significant enough to require treatment? Not all prostate cancers are the same. Age, Gleason score, stage, co-morbidities, all contribute to outcomes. The AUA has come out publicly with the statement that prostate cancer is over diagnosed and over treated and active surveillance is an acceptable option.

The main marker used to screen for prostate cancer is the PSA. However this elevated in benign conditions as often as it is in the presence of prostate cancer. The PSA is a protein made by prostate cells, which can be found in increased amounts in the blood in conditions where the vascularity of the prostate increases. This can occur in both malignant as well as inflammatory conditions, as in prostatitis. The PSA is not diagnostic of prostate cancer, but taken in context with other clinical information obtained during evaluation, can help in diagnostic and treatment related decision-making by experienced physicians.

Although there is debate regarding the role of diet in prostate cancer, some clear trends have emerged:

  • Prostate cancer rates vary widely between countries and ethnicities.
  • Prostate cancer rates are higher in societies with “Western” diets and lifestyles.
  • These higher cancer rates follow the adoption of Western eating practices.

Prostate cancer has been shown to have a genetic component with a three-fold increase in incidence in first-degree relatives. However, environmental factors also play an important and possibly a decisive role in the appearance of this disease. There is a three-fold increased incidence in prostate cancer between Asians (88/100,000) and Blacks in the US (233/100,000). What are the main dietary differences between Western and developing countries? The emphasis is on animal-based foods in the former, versus plant-based foods in the latter.

There is a large amount of evidence pointing to animal derived fat as playing a role in the development of prostate cancer. What are the mechanisms for this? The first mechanism involves a hormone that increases cancer cell growth. This is a growth hormone called Insulin-like Growth Factor 1 (IGF-1). It turns out that consuming animal-based foods increases the blood level of this growth hormone.

Vitamin D metabolism has also been implicated in prostate cancer. Our bodies can make all the Vitamin D we need by exposure to the sun. This Vitamin D gets transformed to the active form 1,25 D in the kidney. This active form of Vitamin D is 1,000 times more active than the non-active form, and acts in preventing cells in becoming diseased. Animal protein-containing foods cause a significant decrease in 1,25 D. Another cause of decreased 1,25 D is too much calcium in the diet. All these variable pathways can interact in unexpected ways to lead to adverse effects in these intricate networks. The take home-message regarding diet, to quote Michael Pollan, the healthy food advocate:
“Eat food. Not too much. Mostly plants.”

Urinary Tract Infections

Definitions

Urinary Tract Infections (UTI) –  are caused by the presence of bacteria in the urine (bacteriuria), which is normally free of bacteria.

Pyuria - The presence of white blood cells (WBC’s) in the urine, indicative of an inflammatory response to bacterial invasion.

Acute Pyelonephritis - is a clinical syndrome of chills, fever, and flank pain that is accompanied by bacteriuria and pyuria, indicating an acute infection of the kidney.

Chronic Pyelonephritisdescribes a shrunken, scarred kidney, secondary to recurrent inflammatory insults over various periods of time.

Cystitis is inflammation of the bladder, whether bacterial or otherwise. Bacterial cystitis as opposed to nonbacterial cystitis can be a useful differentiating term.

Urethritisthis refers to inflammation in the urethra, rather than the bladder. Symptoms from one are very difficult to differentiate from the other. Pure urethritis in the female – unlike that in the male – is very rare.

Recurrent Infections are due to either reinfection with a new organism after an infection-free period, or to bacterial persistence or recurrence caused by the same organism from a persistent focus within the urinary tract.

Most Common Causes of Persistent UTI

  • The infective organism is resistant to the antibiotic selected
  • The development of resistance in a previously susceptible organism
  • Poor renal function, which prevents antibiotic concentration in the urine
  • The presence of stones or abnormal tissue leading to high concentrations of bacteria
  • Urinary reflux
  • Predisposing genetic factors that increase chance of bacterial attachment to host
  • Chronic bacterial prostatitis (infection of the prostate)
  • Foreign bodies
  • Urethral diverticula and infected urethral glands
  • Fistulas to the bladder from colon or other infectious collections

Routes of InfectionMost bacteria enter the urinary tract from the fecal reservoir in a retrograde manner, via ascent through the urethra into the bladder.

Bacterial Adherence and ColonizationStudies have demonstrated that for infection to occur bacteria have to adhere to host tissue and this is done through hair-like protein appendages on bacteria called pili, which adhere to receptor sites on cells. The virulence of bacteria depends on the strength of this interaction, which is affected by both bacterial and host factors and maybe genetically determined.

Principles of Antimicrobial Therapy

Initial Elimination of BacteriaElimination of bacteria occurs within hours if the proper antimicrobial agent is used.

Duration of TherapyIn women with uncomplicated UTI’s, 3 days of full-dose therapy has been shown to be as effective as longer courses. In the presence of mitigating circumstances, such as recurrence, chronicity, age older than 65, diabetes or pregnancy, a 7-day regimen should be considered. In complicated infections, or infections of the kidney, 14- to 21-day regimens should be used.

Asymptomatic Bacteriuria (the presence of bacteria in the urine)Older people frequently have this condition, without the symptoms of a UTI. This condition does not require treatment in the absence of symptoms. Treating these patients only clears their urine of bacteria for short periods and then they become recolonized. Multiple treatments lead to the development of resistant organisms.

Factors Increasing Severity of Infection

  • Urinary obstruction
  • Renal or bladder stones
  • Catheter drainage
  • Diabetes
  • Spinal cord injury or neurogenic bladders
  • Pregnancy
  • Acute bacterial prostatitis (prostate infections)

Bladder Infections

Uncomplicated Cystitisclinical symptoms include dysuria (burning), frequency, urgency, voiding of small volumes, or sensation to void without much urine, and suprapubic and lower abdominal pain. The presumptive diagnosis can be made on urinalysis, but urine culture remains the definitive test. Short course of antibiotic therapy adequate in women with uncomplicated infections, but should be avoided in men.

Reinfectionscause has to be identified and corrected. Specific risk factors have been identified for reinfections in women, including the first UTI before age of 15 years and maternal history of UTI’s. In women, diaphragm-spermicide and tampon use have been associated with increase risk of UTI and vaginal colonization with E. coli bacteria. Spermicides containing the active ingredient nonoxynol-9 may provide a selective advantage in reducing colonization. Thus, spermicidal agents should be discontinued in women with recurrent UTI’s.

Postmenopausal women have frequent reinfections. Estrogen replacement frequently restores the normal vaginal environment.

Low-Dose Prophylaxislong term, low-dose therapy can be given to prevent reinfection. The success of prophylactic therapy depends on the effect of the antimicrobial agent on the vaginal and fecal reservoirs of pathogenic bacteria. One a day dosing for 6 weeks is a common regimen. In some cases 6-12 months are needed.

Post-Intercourse Prophylaxissexual activity has been established as an important risk factor for acute cystitis in women. Post-intercourse therapy with antimicrobials in women with “honeymoon cystitis” taken as a single dose post intercourse reduces the rate of infection.

Urinary Tract Infections During Pregnancybecause pregnant women with bacteriuria are at an increased risk to develop kidney infections, this should be looked for and treated when found. Selection of an antibiotic to treat the bacteriuria must be made with special consideration to maternal and fetal toxicity.

Urinary Tract Stones

Overview:

Treatment of urinary tract stones dates back to antiquity and has relied mostly on open surgery. The treatment did not come into the “space age” until the early 1980’s with the introduction of extracorporeal shock-wave lithotripsy (ESWL), and the miniaturization of instruments to allow access to the ureter. This has almost eliminated open stone surgery today.

Predicting Factors:

Genetics

25% of patients with kidney stones have a family history of stones. In a longitudinal study of 37,999 male health professionals, a family history of stones was more than three times higher in men with kidney stones than in non-formers. The lack of evidence associating environmental factors with kidney stones also favors the influence of genetic components to kidney stone formation.

Age and Sex

The peak incidence is from the twenties to the forties. The proportion of male to female incidence is 3:1. Increased urinary citrate concentrations was found in the urine of women, and is thought to provide a protective effect from calcium stones. Patients with recurrent stones tend to have lower levels of urinary citrate.

Extrinsic Factors

Geography

The prevalence of urinary calculi is higher in those who live in mountainous, desert, or tropical areas. Geography, however, represents just one factor among a multitude of others – such as dietary habits, temperature, and humidity – superimposed on the
intrinsic factors that predispose to stone formation.

Climactic and Seasonal Factors

The incidence of urinary calculi is higher during the summer months. High temperatures increase perspiration, which may result in concentrated urine and this promotes crystallization. An alternative viewpoint is that increased exposure to sunlight causes
increased production of vitamin D leading to increased calcium excretion in the urine.

Water Intake

It is an accepted truism that increase water intake and increased urinary output decreases the incidence of urinary calculi in those predisposed to form stones. This has been verified by the incidence of stone formation and its relationship to fluid intake.

Diet

Dietary intake of various foods may result in greater urinary excretion of substances that have an effect on the incidence of urinary calculi. However, the underlying intrinsic tendency to form stones also has to be present. Increased oxalate, calcium or sodium in the urine of patients predisposed to stone formation, can lead to an increased incidence of stones. Increase ingestion of animal proteins can also lead to increased urinary concentrations of calcium, oxalate and uric acid.

Physical Activity

Urinary calculi are much more likely to be found in individuals who are sedentary. The risk of calcium oxalate and uric acid stone formation increases after a space flight, because of the microgravity environment of space.

Stress

Studies show that stress can also be a factor significantly associated with stone disease.

Metabolic Factors

Urinary stones occur due to the formation of crystals and crystal aggregates in the urine. Normal individuals have inhibitors of crystal formation and growth in the urine in the form of compounds like citrate, magnesium and certain proteins. There is a
fine balance between the various physical and chemical factors that keep crystals in solution. This balance can be affected at multiple points to lead to crystal formation and aggregation, which leads to stone development. Bacterial infections may promote stone formation by increasing crystal adherence.

Clinical Presentation

Acute Stone Episode

Pain is the most common presenting symptom and it tends to occur during the night or early morning hours. Pain tends to be colicky, appears in the flank and radiates to the area of the groin. Urinary frequency or urgency is noted, as the stone gets closer to the
bladder. Localized ureteral irritation can affect the gastrointestinal tract and produce associated bloatiness, nausea, vomiting or diarrhea. Fever, if present, can indicate associated infection, which makes the presentation a medical emergency. The urine in most patients reveals the presence of microscopic or gross hematuria.

Medical Therapy

Treatment of existing stones is either medical if small enough to pass, or procedural if too large. This will be carried out under the supervision of an urologist. The secondary purpose of medical therapy is to prevent new stone formation. So, who needs medical
therapy?

  • Patients in whom the initial episode involves multiple stones.
  • Patients who have had a stone recurrence within 1 year of follow-up.
  • Patients who have risk factors for recurrence.

General Measures of Prevention

Hydration

Historical data strongly suggest that hydration is effective in preventing stone formation. An increase in urine volume of only one cup per day was associated with a protective effect. Ideally, the fluid intake should be enough to maintain a urine output of 2.5-3 quarts a day. Interestingly, a large study of 81,000 women, showed a decrease incidence of stone formation in women drinking 8 oz. of wine daily, but showed an increase incidence if drinking similar amounts of grapefruit juice. Also another study found the consumption of one bottle of beer a day reduced the risk of stone formation by 40%.

For more information on how sugary drinks may increase kidney stones, please go here.

Diet

Epidemiologic studies have shown that the incidence of renal stones is higher in populations in which protein intake is greater. Proteins increase urinary calcium, oxalate, and uric acid excretion and the mathematically calculated probability of stone formation even in normal subjects. In two large studies, the prevalence of stone disease and the incidence of new stone formation were directly associated with weight and body mass index. This association was greater in women. This observation suggests that
weight reduction may be one method of preventing stone disease.

Dietary Calcium

Contrary to popular belief, a higher intake of dietary calcium was strongly associated with a decreased risk of kidney stones. The intake of supplemental calcium was positively associated with risk. This may be due to the timing of the calcium ingestion or to factors other than the calcium in diary products. This suggests that dietary calcium restriction is inappropriate for patients with calcium stones, and may even be detrimental.

Dietary Sodium

Increased dietary sodium leads to increased calcium in the urine. Patients with recurrent stones do not ingest more sodium, but they are more sensitive to it. Avoiding excessive sodium is a good strategy in avoiding recurrent calcium stone formation.

Dietary Oxalate

Only about 10% of urinary oxalate comes from dietary sources. The rest comes from liver metabolism and the conversion of ascorbic acid (40%). Thus it appears prudent to avoid an excess of vitamin C in patients with recurrent calcium oxalate stone formation.

Dietary Fiber

Patients with calcium oxalate stones eat less dietary fiber than healthy subjects. Fiber binds intestinal calcium and decreases calcium absorption. Fiber also decreases intestinal transit time.

Summary

  • High fluid intake
  • Limit meat intake
  • Substitute whole wheat bread for white bread
  • Eat natural fiber cereals
  • Sodium restriction
  • Limit oxalate-rich foods and vitamin C
  • DO NOT restrict dairy products, but avoid overindulgence
  • Increase intake of citrate (lemonade) or citrus fruits

Special Situations

Prostatic Calculi

Prostatic stones occur frequently in men older than 50 years. They are asymptomatic and found incidentally during work-up for other conditions. This is an aging process and typically has no clinical significance. The stones are usually calcium phosphate. Symptoms, when present, may be due prostatic enlargement (BPH), chronic prostatitis, or terminal urinary bleeding or spotting. In some cases bloody ejaculate or perineal discomfort is noted.

Stones in Pregnant Women

Although pregnancy does not predispose to calculi, physiologic dilatation of the ureters and renal pelvis allow preformed calculi to move or migrate resulting in renal colic and hematuria. Ultrasound has become the cornerstone of evaluation in pregnancy. The first trimester is the most significant risk period for radiation exposure. If indicated, resolution of obstruction with stents under ultrasound monitoring is the way to go. Pregnancy is an absolute contraindication for lithotripsy in any form and should be delayed until after the delivery.