BE A PARTNER . . . NOT A PATIENT
The primary mission of the Texas Cancer Center is to show you the great body of medical evidence which supports conservative (limited) treatment for patients with cancer. Patients and doctors alike have a natural desire to eliminate every last cancer cell - "Get It ALL." Research on cancer of the breast and other organs has proven that this strategy leads to treatment which is unnecessarily aggressive, i.e., serious complications with no improvement in survival. With prostatate cancer some doctors prefer to focus on disease control and not absolute cure.
Radical surgery or external radiation (like cobalt) are the most common forms of treatment. These forms of treatment cause permanent impotence in most men and incontinence in some. There is no evidence that they cure more men than more conservative forms of treatment. The Texas Cancer Center encourages men to consider implanted radioactive seeds, freezing, or hormonal therapy. Additional medical research supporting our recommendations can be found in our "Medical Research" section. Most of this research is directly linked to the National Library of Medicine.
INTRODUCTION
Prostate cancer is the most common malignancy among American men and the second leading cause of death behind lung cancer. The incidence is nearly twice as high for African-American men, and the death rate is nearly triple. About 200,000 American men are diagnosed with prostate cancer each year and about 38,000 die of the disease. Cancer deaths are few compared to the many cases because most prostate cancers grow slowly. Also most men with prostate cancer are over 60 years of age, and they are more likely to die of other causes even if their cancer is untreated. The diagnosis is increasing due to the wide spread use of the prostate-specific antigen (PSA) blood test. This test has been available since 1985. The real age-adjusted incidence of prostate cancer may also increasing.
A recent autopsy study found evidence of microscopic prostate cancer in about one third of men aged twenty to fifty. A 50-year old man has about a 40% chance of developing microscopic prostate cancer during his lifetime. He has about a 10% chance of being diagnosed with the disease, and a 2% - 3% chance of dying from prostate cancer. By the age of 80 years he has a 60% -70% chance of having microscopic cancer cells in his prostate gland. But, only about one man out of eleven (9%) will clinically apparent prostate cancer sometime during his life. Thus, there is a large gap between the number of patients with clinically diagnosed cancer and those with undetected disease. There is no other cancer with such a wide gap.
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STAGES OF DISEASE
The American Urological Association (AUA) system is most commonly used and divides prostate cancer into four stages: A D. Unfortunately cancers detected by ultrasound or from an elevated PSA do not have a logical place in this system. In 1992 the American Joint Commission on Cancer and the International Union Against Cancer (AJCC-UICC) devised a staging system based upon the TNM method. It is gaining in popularity and is often used to analyze data so that meaningful comparisons can be made. Approximate equivalents are given in parentheses. Reported fiveyear survival rates vary widely. Those reported below are approximations.
The AUA System
Stage A - The cancer cannot be felt on rectal examination. It has been found on ultrasound or in the tissue removed from a TURP.
Stage A1 - The tumor occupies less than 5% of the tissue removed and is low or medium grade. Some urologists use a slightly different definition. (T1a, N0, M0) The fiveyear survival rate is over 90%.
Stage A2 - The tumor occupies more than 5% of the tissue removed by a TURP or is of high grade or additional cancer was found after a repeat TURP. (T1b, N0, M0) The fiveyear survival rate is over 80%.
Stage B - The cancer can be felt on rectal exam.
Stage B0 - The tumor is identified by needle biopsy due to an elevated PSA. (T1c)
Stage B1 - The cancer in confined to one lobe of the prostate gland, and is less than 1.5 cm in diameter. (T2a, N0, M0) The fiveyear survival rate is about 90 95%.
Stage B2 - The cancer is confined to the prostate, but involves more than one lobe, or is more than 1.5 cm in diameter. (T2b, N0, M0) The fiveyear survival rate is about 85%.
Stage C - The cancer has extended beyond the capsule that surrounds the gland. (T3, N0, M0) The fiveyear survival rate is about 65%.
Stage D1 - The cancer has spread to lymph nodes. (any T, N13, M0) The fiveyear survival rate is about 40%.
Stage D2 - The cancer has spread to distant organs. (any T, any N, M1) The fiveyear survival rate is about 20%.
The AJCC-UICC System (abbreviated)
Primary Tumor (T)
T1 The cancer cannot be felt on rectal examination and cannot be seen on ultrasound. (Stage A)
T1a The tumor occupies less than 5% of the tissue removed. (Stage A1)
T1b The tumor occupies more than 5% of the tissue removed by a TURP. (Stage A2)
T1c The tumor was identified by needle biopsy, e. g., because of an elevated PSA. (No AUA equivalent)
T2 The tumor can be felt on rectal exam or seen on TURP and is confined to the prostate. (Stage B)
T2a The tumor involves half of a lobe or less. (Stage B1)
T2b The tumor involves more than half of a lobe, but not both lobes. (Stage B2)
T2c The tumor involves both lobes (Stage B2).
T3 The tumor has extended beyond the capsule that surrounds the gland. (Stage C)
T4 The tumor is fixed or invades adjacent structures, e.g., bladder, rectum. pelvic wall. (Stage C or D)
Lymph Nodes (N)
N0 No regional lymph nodes metastasis
N1 Metastasis to a single lymph node 2 cm or smaller. (Stage D1)
N2 Metastasis to one or more lymph nodes 2 cm or larger, but none larger than 5 cm in greatest diameter.
N3 Metastasis to a lymph node greater than 5 cm in greatest diameter.
Distant Metastasis (M)
M0 No distant metastases
M1 Distant metastases present. (Stage D2)
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TYPES OF TREATMENT
In the United States most localized prostate cancer is treated primarily with surgery and radiation therapy.
Surgery
Radical prostatectomy is the removal of the entire prostate gland, the seminal vesicles (nearby structures which secret and store a component of semen), and the pelvic lymph nodes. Since the nerves to the penis can be damaged by surgery the most common side effects is impotence (over 50%). The sensation of organism is preserved. Other complications are incontinence induced by stress such as laughing or coughing (25%) and complete incontinence (5%). Less common complications include narrowing of the urethra (ranging from less than 1% up to 25%), blood clots (1% to 12%), wound infection (from less than 1% up to 16%), swelling of the legs (1% to 5%), and death (from much less than 1% to 2%). These percentages vary greatly because they were taken from a number of different studies.
Since the early 1980's some urologists have attempted to preserve the nerves that help control erection. This change has decreased the rate of impotence to about 30%. The only study of this procedure concluded that it controlled cancer as well or better than more radical operations. The number of prostatectomies increased six-fold from 1984 to 1990. Radical prostatectomy may also be used to treat patients who have failed radiation treatment the tumor has started to grow again. Unfortunately, in these cases complications increase tenfold.
The transurethral resection of the prostate (TURP) uses a tube placed up the urethra through which small pieces of the prostate gland removed by cutting or burning the tissue. The urologist removes enough of the gland to relieve obstruction of the urethra caused by an enlarged gland. Cancer has been found in 6 to 10 percent of these procedures. With the greater use of PSA testing, cancer is now found less often, in 2 5 percent of cases. Some urologists will perform repeat a TURP, looking for additional malignancy. If more tumor is found, additional treatment is often recommend.
TURP is not generally used to treat early prostate cancer, because it seldom removes all the tumor. However, this strategy is being reevaluated. A few urologists believe the prostate cancer can be treated with repeated aggressive TURPs. TURP is acceptable treatment for patients with obstructive symptoms due to Stage C or D cancer.
The complications of TURP are minimal. Most patients retain their potency, because the capsule around the prostate is not removed. The rate of permanent urinary incontinence (as opposed to temporary incontinence) is no more than 1 percent. Narrowing of the urethra with scar tissue or regrowth of prostate tissue is rare.
Lymph Node Sampling
In some patients, it is valuable to find out if cancer has spread to the pelvic lymph nodes prior to surgery. There is about a 10% chance of lymph node metastasis from tumors of about 5 cc in volume. This increases to about 50% among tumors measuring 13 cc. Lymph nodes can removed through a major operation which enters the abdominal cavity or with a laparoscopic dissection. Laparoscopic lymph node sampling is possible through small tubes placed into abdomen, through which the surgeon can manipulate tiny instruments to remove tissue.
Most urologists believe that radical surgery cannot cure patients with lymph node involvement, and thus would not be likely to perform surgery if positive nodes were present. Most urologists also agree that patients with tumors which are both low grade and low stage do not need this staging operation.
Lymph nodes can be removed either through a major operation, in which the abdominal cavity is opened up, or with laparoscopic surgery. Laparoscopic lymph node sampling involves placing small tubes in the abdomen, through which the surgeon can manipulate tiny instruments to remove tissue.
Laparoscopic surgery can also be performed on patients prior to various forms of radiation treatment, since there is no evidence that radiation helps men who have positive lymph nodes. These patients might benefit from early hormonal therapy.
Radiation Therapy
External Beam Radiation
Radiation is more often utilized for older patients for whom surgery would be risky. It is also suitable for those with advanced, incurable disease. Here is goal is to kill as much of the tumor as possible and slow its progress. The best results of obtained with an external beam. It requires about seven weeks of daily treatment, Monday through Friday, for a total dose of about 70 Gy.
Radiation therapy often does not eradicate the cancer. Prostate biopsies performed two years following radiation therapy are positive for cancer in 20% 30% of patients. T.A. Stamey and colleagues from Stanford University recently reported that radiation cures only 20% of patients. Five years after treatment they found rapidly increasing PSA levels (indicating probable cancer) in 80% of patients. Physicians at Stanford no longer recommend radiation for patients with curable prostate cancer.
Radiation therapy can also be used to treat symptomatic metastases to either bones or soft tissue. About 80 percent of patients respond to this treatment, but about half of those who do respond will relapse.
Radiation therapy can cause fatigue during the period of treatment, bowel injury (10%) causing rectal pain or diarrhea, bladder irritation causing urinary frequency (15%), incontinence (4%) and impotence (40% 60%).
Brachytherapy or Interstitial Radiation
"Brachy" is the Greek word for short. In this procedure radioactive seeds are placed directly into the prostate gland a very short distance from the tumor cells. The radiation is effective for only a short distance (about 5 millimeters) from the seeds. This technique causes less radiation damage to the surrounding normal tissue.
In the 1970's a surgical procedure was used to insert needles and radioactive seeds into the prostate. The needles were placed using a freehand method, which was very inaccurate. By the 1980's computerized imaging techniques permitted precise placement of the seeds and accurate calculations of the proper radiation dose. The implant is a nonsurgical procedure done on an outpatient basis. Most men are able to return to normal activity in less than 48 hours. Thus far, brachytherapy is producing results which are equivalent to those of surgery or external beam radiation therapy for patients with low or intermediate grade lesions. Patients with Gleason's score > 8, the those with T2b or T2c lesions are three times as likely to experience a rise in PSA as patients treated with surgery or external beam radiation. Brachytherapy causes fewer complications than either surgery or traditional radiation.
Chemotherapy
The drugs used currently in chemotherapy are weakly effective against prostate cancer and are usually administered after hormonal therapy has failed. They achieve a subjective response rate of 15% 30%, i.e., the patient feels better, but survival is not prolonged. Vinblastine and estramustine given together may produce a response in about 40% of patients. Suramin is an investigational drug with some promise.
Hormonal Therapy
The growth of most prostate cancers is enhanced by male hormones called androgens. Testosterone, produced by the testicles, is the most prominent type of androgen perhaps 95% of all prostate stimulating androgens. Other androgens are produced by the adrenal glands located above the kidneys. Treatment is intended to eliminate the stimulatory effect of testosterone on the prostate cancer cell. There are several ways to pursue this goal.
Removal of the testicles orchiectomy is the surest way to reduce testosterone. But, this has obvious disadvantages and other androgens remain active. Female hormones have been used for many years. Estrogens, such as diethylstilbestrol, can cause breast enlargement, blood clots, fluid retention and other complications that effect the cardiovascular system.
A new class of drugs, releasing factor antagonists, reduce the production of testosterone. These drugs include leuprolide, brand named Leupron, and goserelin acetate, brand named Zoladex. These of drugs resemble a hormone that stimulates the pituitary gland in the brain. These drugs cause the pituitary to shut off its stimulating signal to the testicles, which causes the testicles to stop making testosterone. All these treatments cause men to temporary lose their sex drive and have hot flashes.
Another class of drugs block the stimulatory effect of testosterone and other androgens on the prostate cancer cell. These drugs are called antiandrogens. Flutamide, brand name Eulexin, and bicallutamine, brand name Casodex, are two such drugs. Side effects include enlarged breasts, hot flashes, diarrhea, and reduced sex drive.
A third class of drugs inhibits the conversion of testosterone to dihydrotestosterone (DHT). DHT is actually to a greater stimulant to prostate cancer cells than testosterone itself. Finasteride, brand named Proscar, is the principle drug in this class. This class of drugs is probably the least effective. Patients with metastatic cancer experienced on a slight fall in PSA levels. A advantage of the class of drugs is preservation of potency and sex drive.
For several decades hormonal therapy has been used to treat patients with advanced prostate cancer. But, beginning in the 1990s some physicians have been using the hormonal therapy to treat patients with early, curable cancer. It is usually possible to reduce the PSA level down to less one for several months.
Complete Hormonal Block
Until recently hormonal therapy was used primarily in the treatment of advanced disease. But, in the early 1990's a few physicians began using hormonal therapy to treat patients with early prostate cancer. One form of treatment used three different drugs - one from each of the three classes mentioned above. This form of therapy has gone by several names, including complete hormonal blockade, total androgen ablation, and triple hormonal blockade. It effectively reduces the PSA level to less than 0.1 ng./ml in most patients. Patients are often treated for about a year, and then the drugs are discontinued. Normal sexual function and desire returns to most men within a few months. Many patients require no further therapy. Some patients choose to remain on Proscar, the drug with the fewest side effect. Because of the success of this treatment, some physicians are now treating patients with only two classes of drugs.
There have been no scientific studies of complete hormonal blockade. But the therapy has been successfully used on hundreds of patients in Canada, California, etc. Scientific studies have demonstrated that hormonal blockade does prolong life in men previously treated with radical prostatectomy or radiation therapy. The treatment is thought to kill prostate cancer cells both locally and throughout the body. The evidence so far suggests that hormonal blockade is effective treatment for men with early prostate cancer.
When used for patients with advanced disease, there is no convincing evidence that hormonal therapy can prolong survival. Most patients — about 85 percent — respond to treatment. Responses can be subjective (the patient feels better) and/or objective (the tumor gets smaller). Hormonal therapy can decrease the rate of tumor growth, reduce pain, and increase the quality of life. These effects may persist for a period of months to years. If one form of hormonal treatment stops working, another my be tried. But each new hormone treatment is less likely to be effective. Patients whose cancers have grown locally, but remain in the region of the prostate, are much more likely to respond to hormone manipulation (84 percent) than those who develop distant disease (20 percent).
In a recent study by the National Cancer Institute patients treated with leuprolide alone lived 29 months; those treated with both leuprolide and flutamide lived 35 months. Among patients with minimal metastatic disease this survival difference increased from 41 months to 61 months, respectively. This is one of the few studies to have demonstrated a benefit from one form of hormonal therapy over another.
Neoadjuvant Hormonal Therapy
Hormonal treatment given prior to surgery or irradiation is called neoadjuvant therapy. Though it is often used to shrink the size of the gland, hormonal treatment also kills prostate cancer cells in many men.
Hormonal Therapy for Metastatic Disease
There is no convincing evidence that hormonal therapy can prolong survival, but most patients about 85% respond to treatment. Responses can be subjective (the patient feels better) and/or objective (the tumor gets smaller). The reduction in circulating hormones often slows the growth of cancer, reduces pain, and make the patient feel better.
Hormone manipulation is used primarily in the treatment of advanced disease. It can decrease the rate of tumor growth, reduce pain, and increase the quality of life. These effects may persist for a period of months to years. If one form of hormonal treatment stops working, another my be tried. But each new hormone treatment is less likely to be effective. Response rates for hormonal therapy do not translate into survival rates. Hormone therapy is never curative, but many patients do have a prolonged survival.
In a recent study by the National Cancer Institute patients treated with leuprolide alone lived 29 months; those treated with both leuprolide and flutamide lived 35 months. Among patients with minimal metastatic disease this survival difference increased from 41 months to 61 months, respectively. This is one of the few studies to have demonstrated a benefit from one form of hormonal therapy over another.
Cryosurgery
Freezing can destroy both malignant and benign tissue. In the 1960s cryosurgery was introduced to treat prostate cancer. Survival rates were at least equivalent to radical prostatectomy among patients followed for 10 years. However, these were not scientific studies. Cryosurgery was abandoned because of complications, most commonly the creation of an abnormal channel between the rectum and the bladder.
Transurethral ultrasound (TRUS) is now used to accurately guide probes within the prostate gland. Probes selectively freeze certain parts of the prostate gland. Under general anesthesia several probes are inserted into the prostate gland through the skin between the scrotum and the rectum the perineal region. Liquid nitrogen freezes the prostate gland. TRUS monitors the growing "iceball" in the prostate. The procedure requires about two hours of anesthesia (often a spinal) and two days of hospitalization. For three to ten days patients urinate through a tube placed into the bladder through the abdominal wall.
Some urologists freeze the entire prostate gland and some surrounding tissue. Their patients experience complications similar to those following radical prostatectomy. Other urologists, such as Dr. Israel Barken is San Diego, use cryosurgery to control the disease by freezing most of the gland, but not all. These patients experience few side effects. Long term results are not available, but additional treatment is required in some patients. Elevations in PSA levels can be treated with a second cryosurgery, hormonal therapy, or even surgery or radiation therapy.
This procedure is also suitable for patients with large cancers. It can relieve symptoms of obstruction. Over 20% of patients have incontinence and impotence, and about onethird of patients may have additional prostate cancer found on subsequent biopsies.
Experimental Local Treatment
These forms of treatment are in the developmental stages. They have been designed primarily for the treatment of benign prostatic hypertrophy (BPH). Their use in the treatment of cancer requires additional research.
Laser surgery
In laser surgery, a laser probe is inserted into the prostate through the urethra while the patient is under general anesthesia. It can be directed to specific parts of the gland and can heat the gland to more than 150 degrees F, causing destruction of tissue. This technique, which requires careful patient selection can be done on an outpatient basis and causes less bleeding than TURP.
Microwave thermal therapy
Microwave thermal therapy uses a microwave heat applicator inserted into the rectum while the patient is under general anesthesia. This heats the prostate gland to about 110 degrees F, causing tissue destruction. This has been used primarily to treat patients with advanced disease, and can lead to a noticeable reduction in symptoms.
Watchful Waiting
When a patient's cancer is monitored without beginning treatment immediately, the process is called watchful waiting. Clearly, watchful waiting should include regular follow up with DRE and PSA tests. This approach has been used primarily with older patients with stages A and B disease and in those who refuse radical surgery.
Some of the information about "watchful waiting" has come from patients whose enlarging prostate cancers were allowed to grow until urinary obstruction developed. In another study patients with locally progressing disease were only treated with hormonal therapy. 8 And this treatment was given only to those who developed symptoms. In few studies was an effort made to reduce the volume of a growing cancer. This approach may have led to the spread of disease in some patients as the volume of the tumor increased. Therefore, some clinical studies of watchful waiting may have achieved higher survival rates, if growing tumors had been reduced in size or otherwise treated. Patients should be followed every 3 6 months with rectal examination and PSA determinations.
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TCC ANALYSIS
Of all the malignancies prostate cancer is probably the most difficult to understand. Very few randomized trials have been performed, and these have been flawed by the small numbers of patients. Therefore, most of our information comes from retrospective studies of patients treated over the past thirty years. These studies suffer from many of the defects of retrospective trials discussed in Chapter 2 of The Cancer Breakthrough You've Never Heard of. In many studies patients were poorly treated. It is important for you to also review the "medical Research" sections below.
Is Age a Significant Factor ?
Men over 70 years of age may die of natural causes before their prostate cancer has even become noticeable. Because aggressive treatment (radical prostatectomy or radiation therapy) can cause significant side effects, conservative treatment may be suitable for men in this age group. Younger men, those with a life expectancy of more than 10 to 15 years, are more likely to experience problems or even die from their prostate cancer. Aggressive treatment is often recommended for these younger men. However, there is another important consideration. The principle complication of aggressive treatment is impotence, which is more likely to bother younger men. Thus, conservative treatment may be better for them, as well. This is especially true if the tumor is well
differentiated.
Lessons from Watchful Waiting
The risks of conservative treatment can also be evaluated by studying men who had no treatment at all, so-called watchful waiting. Many of these studies were done before PSA testing became available. Many of them were poorly conducted. In some studies patients did not have regular follow-up examinations. Some patients were not treated unless they developed bladder outlet obstruction. Investigators from Dartmouth reviewed 144 such poorly conducted studies. Surprisingly, they found no evidence that radical surgery or radiation was superior to watchful waiting. (In these studies the "treatment" was really neglect.) The Dartmouth team tried to determine if any patients benefit from aggressive treatment. They focused on men who were 60 years of age or
younger and whose tumor had a moderate Gleason grade. These were the patients who were most likely to benefit from radical surgery or radiation. But even in this select group, only 3 percent of men had
their lives prolonged by aggressive treatment. Despite poor treatment, the men in these 144 studies did remarkably well. In another study 223 Swedish men with early disease were followed for 10 years. Patients who developed symptoms from locally progressing cancer were treated with hormonal therapy only. These men lived about as long as men treated with radical surgery; 87 percent survived 10 years. Additional studies are presented below
The lesson here is that even men who were poorly treated did remarkably well. Many of these surprising results were obtained before PSA testing was available. They were obtained in men who were followed very poorly, and often treated inadequately even when their cancer progressed. Consider how much better these already good results could be, if these cancers were properly controlled.
Change in Attitude
Many physicians who advocate conservative treatment for prostate cancer are trying to control the disease. They are not trying to cure the disease by removing or destroying every last cancer cell. This is a change is treatment strategy and is difficult for some urologists and other physicians to accept. If this sounds risky, remember that even radiation therapy seldom eradicates every prostate cancer cell. It is clear that the risk of tumor spread is directly related to the
size of the tumor. Any procedure which can successfully reduce the size of the tumor may also reduce the chance of tumor spread during the follow-up period. According to the ideas presented here, patients who have survived a tumor of a specific size without developing distant spread can probably prevent the spread of cancer cells from a
smaller tumor. There is no evidence concerning prostate cancer which violates this simple principle. If the tumor can be controlled locally, though not necessarily eradicated, the spread of disease can usually be prevented. Thus, conservative treatment, such as complete hormonal blockade, cryosurgery, or radiation seed implantation, becomes a reasonable option.
The Importance of Follow-up
Digital rectal examinations (DRE) and PSA testing are important parts of follow-up. Following any form of treatment the blood level may fall to near 0 ng./ml. Recurrent or progressive disease may be present, if the PSA level begins to rise. Appropriate additional treatment can be started. A goal of treatment should be to keep the PSA level as low as possible. Treatment should continue if the PSA level approaches the highest level measured prior to treatment. There is no medical evidence that prostate cancer will spread, if the tumor is well controlled. Periodically, men will need to take a "holiday" off of hormonal treatment. This will give men a break from the unpleasant side effects of the treatment. As mentioned above, PSA levels are not reliable while men are receiving hormonal treatment. A drug holiday also permits PSA
measurements which more accurately reflect the size and activity of the cancer.
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TREATMENT OPTIONS
The following treatment options are recommended. Keep in mind that conservative treatment is best suited to the treatment of early cancer. Even so, I would encourage you to ask your doctor about the most conservative options available to you in your specific case. "Standard treatment" refers to the treatment recommended as accepted medical practice.
Stage A1
At this stage, the tumor occupies less than 5 percent of the tissue removed, and is of low or medium grade. Standard treatment is watchful waiting. Repeat TURP is becoming less common. But if additional cancer following a repeat TURP, the patient is classified A2.
Stage A2
At this stage, the tumor occupies more than 5 percent of the tissue removed, or is of high-grade, or significant additional cancer was found after a repeat TURP or biopsy. Radical prostatectomy or radiation therapy is standard treatment for patients who have more than 10 years of life expectancy, and have an intermediate or high-grade tumor. But, the benefits of aggressive therapy are so small that patient preference should play a significant role in decisions about treatment.
Patients who are over 65 70 years of age and all those with well differentiated tumors may wish to consider watchful waiting. I believe that patients should first receive a course of hormonal therapy. The should begin their period watchful waiting with a PSA of less than 0.10 ng/ml. Other treatment options include cryosurgery, laser surgery, repeat aggressive TURP, or microwave thermal therapy.
The intention should be to remove or destroy all of the tumor, or as much as safely possible. Tumor growth or recurrence could be monitored with frequent DREs and PSA examinations. If the tumor returns or continues to grow, additional tumor could be removed with a additional treatment. Patients should understand the great importance of frequent followup examinations, as outlined below. This approach should be considered experimental. Both the patient and the doctor should be willing to accept the risk of disease progression.
Stage B0, B1 and B2
At stage B, the tumor is confined to the prostate gland. The treatment options are the same as those listed above for stage A2.
Stage C
At this stage, the cancer has extended beyond the capsule that surrounds the gland. Radiation therapy is the primary treatment for most patients, although it is uncertain whether this can increase patient survival. Patients in whom the entire tumor can be removed may consider a radical prostatectomy. Hormonal therapy should also be tried. If the tumor shrinks some patients may be candidates for surgery. But, there is no evidence that surgery prolongs survival.
Stage D
At this stage, the cancer has spread to lymph nodes (D1) or distant organs (D2). The primary therapy is hormone manipulation or castration. TURP can relieve obstruction. Chemotherapy is rarely used.
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MEDICAL RESEARCH
History of Treatment
During the late 1880's several surgeons performed a variety of operations, which removed all or part of the prostate and occasionally part of the bladder. In 1904 Hugh Young at Johns Hopkins Hospital, assisted by Halsted, performed a radical prostatectomy. The incision was made between the anus and the scrotum -- called a perineal incision. The seminal vesicles, nearby structures which store sperm, were also removed. But, unlike Halsted's radical mastectomy for breast cancer, Young's radical prostatectomy did not remove the regional lymph nodes. Most patients had disease which was too advanced for surgery, and few urologists mastered this operation. It was never widely performed.
By 1925, urologists at the Mayo Clinic began to recognize the pelvic lymph nodes as the earliest site of tumor spread. But, urologists seldom tried to remove them surgically, because patients with positive lymph nodes were not considered curable. By 1937 Young reported a 50% five-year survival rate following radical perineal prostatectomy. In the mid-1930's transurethral resection became accepted in the treatment of cancer, which obstructed the flow of urine. In 1941 Huggins reported that prostate cancer was responsive to male hormones. Castration and female hormones became accepted treatment for patients with advanced disease.
In 1945 another prostatectomy technique was introduced. An incision was made through the lower abdomen, and the prostate was approached from behind the pubic bone. Urologists used this incision to operate on the bladder, so they were familiar with this approach. The retropubic prostatectomy became a popular operation for prostate cancer.
Radiation treatment was used with mixed results in the early part of this century. By the 1950's megavoltage irradiation was able to delivery sufficiently high doses of radiation to effectively treat most stages of the disease.
Between 1984 and 1990 the rate of radical prostatectomy increased nearly six-fold in the United States.(1) This has occurred for several reasons. First, the incidence of prostate cancer has been increasing. Second, PSA testing has increased the detection of prostate cancer. Third, nerve-sparing surgery has reduced the incidence of impotence following radical prostatectomy. Fourth, randomized trials have suggested that radical prostatectomy is more effective that radiation therapy in treating cancer confined to the prostate.(2) Nevertheless, the number of patients in this trial was too small to arrive at firm conclusions.
Understanding Prostate Cancer
Of the malignancies covered in this book prostate cancer is probably the most difficult to understand. Very few randomized trials have been performed, and these have been flawed by the small numbers of patients. Therefore, most of our current information comes from retrospective studies of patients treated over the past twenty years. These studies suffer from the defects of retrospective trials discussed in Chapter 2.
There is an additional difficulty with prostate cancer. Patients may not have their entire prostate or even their entire tumor removed. Tumor growth or recurrence may not be detected. Important questions are unanswered. How large was the tumor? Was it entirely removed? When did it recur? What happened to patients whose recurrences were promptly treated? Without this information it is difficult for urologists to accurately evaluate the results of treatment.
In contrast, in other parts of the body conservative treatment almost always involves complete removal of the cancer. The tumor can be precisely measured by a pathologist. Recurrent cancer is also easy to detect and measure. A mass can be felt or seen through a scope, e.g., cancer of the bladder, cervix or rectum. This accurate information allows physicians to compare the consequences of different types of treatment and to judiciously advise their patients.
An example of this difficulty is reported by Matzkin et al. from the University of Miami.(3) In 1994, they reviewed nine papers dealing with untreated stage A1 disease. They reported progression of the cancer -- either locally or distantly -- in 2% to 50% of patients. These wide ranging results illustrate the difficulty of dependable information about this disease.
There is an additional problem with current statistics about prostate cancer. Digital rectal examination, transrectal ultrasound (TRUS), and PSA tests are the primary tools to measure the disease. Most of the clinical studies urologists now rely on were done prior to the widespread use of the PSA blood test and transrectal ultrasound. Using only the digital rectal examination urologists had difficulty evaluating the progression of prostate cancer. Surgical treatment was usually withheld until urinary obstruction developed.
The Importance of Follow-up
Let us consider the practical significance of all this. Most patients today are diagnosed with early prostate cancer. They have an elevated PSA or cancer is found on a TURP for benign prostatic enlargement. These patients may wish to consider no further treatment, just watchful waiting. What is a urologist likely to recommend?
Urologists from Johns Hopkins Medical School recently said,". . . 15 to 20 per cent of patients with untreated A1 disease develop metastatic disease with an average follow-up of 10 years."(4) This statistic is sufficient to encourage the most stouthearted to pursue aggressive treatment. But, let us consider the source of these numbers.
The 20% figure comes from a 1986 Mayo Clinic study reported in 1986.(5) Fifteen men with stage A1 were followed for 10 years. Three of these patients (20%) developed metastatic disease; all three were alive when the study ended. In spite of these high rate of tumor spread, the Mayo doctors suggested that "careful ongoing surveillance of young men with stage A1 prostatic cancer seems mandatory." However, there is no evidence in this study that these patients had regular follow-up examinations. The PSA and ultrasound tests were not generally available and were not mentioned in the study. I have reviewed over a dozen studies concerning men with stage A1 prostate cancer. Few studies have clearly described a regular follow-up program. Patients with early prostate cancer may have developed metastatic disease, because they are not carefully followed. Growing cancer was not promptly detected and removed.
The success of careful follow-up evaluation is clear. Several urologists have treated their patients who have stage A1 disease with a second TURP. Ziegler and colleagues from the University of Saarlandes, Homburg/Saar, Germany, performed a second TURP on 120 patients with stage A1 disease.(6) Twenty-six percent had residual tumor, and 74% had none. The 89 patients who were tumor-free were followed closely. None has developed prostate cancer and none has died. Patients with residual tumor were treated according to their age and physical condition. (check follow-up)
Consider those patients who have stage A1 prostate cancer. About 80% of them will have residual cancer in their prostate gland after radical prostatectomy.(7) Some of them with have both a higher stage and a higher grade of disease. This suggests that patients who are treated with a second TURP do not have all of their cancer removed by the second operation.
Major Study Analyzes Watchful Waiting
A thorough study of prostate cancer was conducted by the Prostate Patient Outcomes Research Team (PPORT), a multiinstitutional, multispeciality group based at Dartmouth Medical School.(8),(9) This group considered the entire English language medical literature on prostate cancer from 1966 through 1991 and selected 144 articles for review. The PPORT study found only one study out of 144 that fulfilled its five standard of quality. All the other papers had substantial flaws. Even in this often-quoted study, the frequency of follow-up examinations was not considered among the five standards of quality. The authors compared the treatment efficiency of aggressive treatment (radical prostatectomy or radiation therapy) versus watchful waiting.
This study found no definitive evidence that either form of aggressive therapy was superior to watchful waiting for most patients with stage A or B cancer. They concluded that if the benefits of radical surgery or radiation therapy could be obtained with a simple pill, it is likely that the Food and Drug Administration would not approve the sale of the drug, because it would be considered ineffective. This is even more remarkable when you consider that the FDA's position would be negative, even for a theoretical drug with no side effects.
They concluded that all men with well-differentiated tumors and all men over 75 years of age were unlikely to benefit from aggressive therapy. The concluded that the benefits of aggressive therapy were so small that the preferences of patients should be considered. ["small enough that the choice of therapy is sensitive to the patient's preferences for various outcomes."]
The men most likely to benefit from aggressive treatment are those age 60 years and younger with moderately differentiated cancer (Gleason grade 5 through 7). If these patients are followed for 10 years, about 2% of those treated aggressively will die of cancer or its treatment, and about 5% of those followed with watchful waiting will die of prostate cancer. Thus, of all the patients with prostate cancer, only 3% may have their lives prolonged by aggressive treatment. But, men with prostate cancer are much more likely to die from other causes. Of men who are diagnosed with prostate cancer at age 60, about 25% of men are likely to die from other causes within five years. This increases with age. About 60% for those age 75 are likely to die from other causes. In other words, the potential benefit of aggressive treatment decreases with age -- from a survival advantage of about 3% at age 60 to about 0% at age 75 years. The Prostate Patient Outcomes Research Team points out that some informed patients may be reluctant to trade several years of good quality life in the near future for a 3% survival advantage in the distant future. They agree that this choice rightly belongs to the patient.
If you are still inclined to do everything possible to eradicate the cancer, consider one more problem with the PPORT report. The authors stated,"We assumed that patients received no treatment for local progression of disease unless symptoms or findings of bladder outlet obstruction occurred." These patients apparently received little if any follow-up evaluation -- not even a yearly rectal examination. This treatment was called "watchful waiting," but there was nothing watchful about it. If these patients had been carefully followed with rectal examinations, PSA blood tests, and ultrasounds, progressive disease could have been detected and treated much sooner. The entire theme of this book concerns the importance of the early detection and removal of progressive or recurrent disease. The success of conservative treatment relies upon regular follow-up examinations. The availability of the transrectal ultrasound and PSA blood test can only improve the results of watchful waiting and other conservative measures. The 3% survival advantage of aggressive treatment may decline to 1% or less, as patients take advantage of modern detection procedures. Patients must understand, however, that these tests are not prefect. Very rarely prostate cancer may spread in patients with a normal rectal examination, a normal PSA, and a normal ultrasound.
Studies from Other Institutions
Doctors at the Karolinska Institute and Memorial Sloan-Kettering Cancer Center (MSKCC) reviewed the medical literature since 1980 regarding the treatment of prostate cancer. They compared the results of radical prostatectomy, external radiation, and deferred treatment (waiting -- though not necessarily watchful).(10) The disease specific survival at 10 years was 93% for radical prostatectomy, 74% for external radiation, and 84% for deferred treatment. These results are not from randomized studies and could be biased for the reasons discussed in Chapter 2. There was no uniform way to compare the patients for tumor grade and stage. Radiation has usually been used on patients with more advanced disease. Furthermore, the frequency of follow-up examinations was not determined. The differences in survival may reflect tumor growth among untreated patients. Also, many of the patients with smaller tumors may have been treated with radical prostatectomy.
Surgeons from MSKCC hospitals treated 75 patients with stage B prostate cancer from 1946 to 1986 and followed them for 15 years.(11) Initially patients had a digital rectal exam every three months. Twenty-three patients developed evidence of progressive disease and were treated with TURP. The fifteen-year survival of these patients was equal to or better than the expected survival of normal men of similar age. The authors claimed that "no deliberate selection was evident;" however the study was not a review of the hospital's entire experience. Some urologists believe that the patients in this study were not a representative sample, but rather patients remembered by Dr. Whitmore.
This treatment was very similar to that recommended in this book. But these impressive results were obtained without reduction of the initial tumor volume, without any treatment during the first year after diagnosis and without the aid of PSA or TRUS. I believe that the careful follow-up of these patients contributes to these good results. Only five patients developed distant metastases without first demonstrating local progression of disease. This further suggests that the tumor is unlikely to spread if the size of the prostate cancer can be kept under control.
Patients who are over seventy are likely to die of other causes, before prostate cancer becomes a threat to survival. Patients of any age with well-differentiated cancers are unlikely to die of prostate cancer. Therefore, the patients who are most likely to benefit from aggressive treatment are younger (less than 65 years of age) with moderately or poorly-differentiated tumors. Unfortunately, some studies have also suggested that patients with poorly differentiated cancer also do poorly following aggressive treatment. When Hugh Jewett reviewed the experience of Johns Hopkins Hospital with 447 patients treated with radical prostatectomy, none of his patients with poorly differentiated tumors survived fifteen years free of disease.(12) In 1994, urologists at the same institution reviewed their experience with 63 similar patients treated in the prior ten years.(13) Distant metastases only developed in the seven patients with positive pelvic lymph nodes. They concluded that these patients may benefit from an attempt at cure. A review article in the New England Journal of Medicine also concluded that men with grades 1 and 2 cancer may receive a small survival benefit from aggressive treatment. But,"the relative benefit of aggressive treatment for grade 3 cancer is "less clear."(14)
A Middle Ground
Many articles portray the options as aggressive therapy, on one hand, and watchful waiting, on the other. I believe that patients should consider some of the choices between these two extremes. Dr. Sonda from the University of Michigan said,"Some urologists believe that prostate cancer can be cured be repeated aggressive resection."(15) Unfortunately, it is often difficult to determine the precise location of some prostate cancers even with ultrasound. Furthermore, a cancer located in the periphery of the gland would be difficult to reach with a TURP scope. Therefore, few urologists agree with this statement.
At one time urologists felt that TURP might cause prostate cancer to spread. This is another reason that TURP has never been considered a suitable operation for patients with prostate cancer. In 1947 it was shown that much of the fluid used to wash out the small chips of resected tissue made its way into the blood stream. It was feared that the surgeon who cut through cancer may also wash some cancer cells into the blood stream and increase the dissemination of prostate cancer. This fear has been disproved.(16) A TURP may make a subsequent prostatectomy technically more difficult. But it does not increase the complication rate of a later radical prostatectomy.(17)
During the 1980's some studies suggested that TURP caused prostate cancer to spread. Patients treated with radiation therapy seemed to do worse if they were diagnosed with a TURP as opposed to a rectal biopsy. It was suggested that TURP caused the dissemination of cancer cells. This supported an attitude that inadequate initial therapy may do more harm than good. Several studies failed to confirm this association. Doctors at Baylor College of Medicine in Houston showed that those patients who were first treated with TURP had done poorly, because many had more advanced disease in the first place. Many of them had required a TURP because their cancer was so large that it obstructed urine flow. Doctors at Memorial Hospital in New York also concluded that TURP did not adversely affect patients with prostate cancer.(18) Today there is general agreement that patients with Stage A or B disease are not harmed by a TURP prior to radiation therapy, i.e., that TURP does not cause prostate cancer cells to spread.(19)
If prostate cancer is diagnosed from a TURP, many urologists recommend a second TURP or transrectal ultrasound guided biopsy. A follow-up TURP usually finds additional prostate cancer in about 30% of patients. But, a follow-up radical prostatectomy usually finds additional cancer in about 60% of patients. This suggests that 30% of patients may have their prostate cancer missed by a second TURP. Some urologists have been concerned by this finding. But, this may not be surprising. The initial TURP was not intended to be curative cancer operation. Furthermore, recall the high incidence of microscopic prostate cancer found at autopsy in men of all ages.
In summary, most prostate cancer is out of the reach of the TURP scope. But, some patients can be treated with a TURP. They may wish to consider having additional tumor removed prior to a period of watchful waiting.
Other treatment options include cryosurgery, microwave thermal therapy, and retropubic prostatectomy. Some urologists have speculated about even less aggressive prostate surgery, perhaps "enucleation." Unfortunately lesser surgery may have as many complications as radical surgery, so this approach has not been seriously tested. I believe that the spread of prostate cancer is largely determined by its size. I would encourage urologists to search for additional ways to reduce the bulk of a prostate cancer prior to a period of watchful waiting.
Even if countless studies affirm a policy of watchful waiting, it will always carry a degree of risk. A patient may experience local tumor growth and later develop distant tumor spread. He will always wonder,"What would have happened if . . .?" As the patient and the doctor embark on this uncertain voyage, they must remain in constant contact. New information, procedures and diagnostic tests should be promptly incorporated into the follow-up plan. Ian Thompson has said that each patient has a "window of curability."(20) Reliable information suggests this to be true for prostate cancer and other solid tumors. The patient and the doctor must be willing to share the responsibility for vigorous follow-up care and for the outcome of their treatment decision.
Medical Research since 1995
Fowler and associates of the Massachusetts General Hospital studied the treatment recommendation of urologists and radiation oncologists and concluded, " . . . while urologists and radiation oncologists do agree on a variety of issues regarding detection and treatment of prostate cancer, specialists overwhelmingly recommend the therapy that they themselves deliver."(21)
Screening Recommendations
F. Labrie and associates of Laval University in Quebec City, Canada, began a randomized trial of prostate cancer screening in 1988.(22) By 1997, 46,193 men had entered the study - 38,056 were screened and 8,136 were not. There were only 5 prostate cancer deaths among the men who were screened. But, among those who were not screened, 137 men had died of prostate cancer. This represents a 69 percent decrease in prostate cancer deaths among men who were screened and promptly treated. It is clear from this study that prostate cancer screening can save lives. Also, the type of treatment is not nearly as important as the importance of early detection.
Brachytherapy or Interstitial Radiation
The Northwest Tumor Institute in Seattle has a very large experience with this technique. H. Ragde and L. Korb reported 10-year results of 152 patients with T1 to T3, low to high grade prostate cancer.(23) All patients received Iodine-125 brachytherapy with or without external beam radiation. Only 3 patients died of prostate cancer, and 66 percent of patients were free of disease after 10 years. The authors concluded that their results were comparable to those of radical prostatectomy.
J. Sharkey and colleagues of the Urology Health Center in New Port Richey, Florida have used brachytherapy to treat 1,048 patients since 1991.(24) After five to nine years, over 90 percent of their patients have stable PSA levels of less than 1.5 ng./ml. This result has been confirmed by a negative biopsy rate of 90 percent in 600 men. Incontinence occurs in less than 1 percent of patients, and impotence occurs in about 10 percent.
In the May 13, 1996, issue of Fortune magazine, Andy Grove, then chairman of Intel, explained his choice of interstitial radiation to treat his stage B prostate cancer. P.C. Walsh, a urologist at Johns Hopkins in Baltimore wrote an editorial which was critical of Groves' decision.(25) Walsh stated,"It is now clear that most patients who received digitally directed interstitial radiotherapy under that protocol are dying of the disease." My letter-to-the-editor was published in the Journal of Urology.(26) I pointed out that Walsh referred to a study conducted between 1970 and 1985 of men with advance disease - 72 percent had tumors larger than 2 cm. Local failure occurred in 48 percent of men, and only 18 percent of these men had additional hormonal treatment. It is not surprising that this group of men did poorly. Today most men are treated with early disease. Local recurrence is promptly detected and treated. Walsh's editorial reflected his strong bias favoring radical surgery and was of little help to men wrestling with the complex decision.
Complete Hormonal Blockade
Urologists in the U.S., Canada and Europe are investigating the use of hormonal treatment for early prostate cancer. As early as 1977, the South Sweden Prostate Cancer Study Group treated men with localized disease using either immediate estrogen therapy or delayed treatment.(27) By 1993, there was no difference in overall survival between the groups, but the risk of dying of prostate cancer was higher in the deferred treatment group. Between 1985 and 1993, the Medical Research Council in England treated 934 men with localized prostate cancer. Men were randomly assigned to immediate hormonal blockade or deferred treatment - treatment which was delayed until symptoms developed.(28) Overall survival was longer in men who received immediate treatment, and there was a 21 percent reduction is deaths due to prostate cancer.
Since 1989, S.B. Strum and associates of the Prostate Cancer Research Institute in Los Angeles have used hormonal blockade - an antiandrogen and a LHRH agonist.(29) They have treated 255 men and achieved undetectable PSA levels in 216. Some men who maintained an undetectable PSA level for more than one year elected to discontinue hormonal blockade. PSA levels remained low for an average of about 3 years. Only one patient developed a prostate cancer recurrence which was not responsive to further hormonal treatment.
Combination Treatment
N.N. Stone and R.G. Stock of Mount Sinai Medical Center in New York reported that hormonal therapy given before and after brachytherapy can reduce the size of the prostate and improve local control.(30) Patients with high risk disease had results that were similar to those of men with low risk cancer. Two years after treatment, 62 men agreed to have prostate biopsies; 60 (97 percent) were negative for tumor. Hormonal therapy given prior to radiation also prolongs overall survival.(31)
A. D'Amico and associates from the Joint Center for Radiation Therapy in Boston treated 1,586 men with 3-dimensional conformal external beam radiation.(32) Hormonal blockade was provided to 276 men for six months surrounding the radiotherapy. Men with intermediate and high risk cancer were much less likely to fail if they were treated with hormonal blockade. When given prior to radical prostatectomy, endocrine treatment reduces the incidence of positive surgical margins, but it does not improve survival.
Cryosurgery
J.K. Cohen and associates of the Medical College of Pennsylvania in Pittsburgh treated 383 patients with cryosurgery. Five years later 71 percent had a negative biopsy and 60 percent of patients had a PSA of < 1 ng./ml.(33)
Watchful Waiting
The results of pure watchful waiting are not good and few men now choose this option. As discussed above, there are now good alternatives to aggressive surgery and radiation. Sweden and Denmark have reliable cancer registries. They have found a high rate of prostate cancer deaths among men who postpone treatment. Men below the age of 75, who are diagnosed with nonmetastatic prostate cancer, have a greater than 50 percent chance of dying of prostate cancer if they do not receive immediate treatment.(34) Furthermore, as mentioned above, the screening study from Quebec City found a 69 percent reduction in prostate cancer deaths among men who were screened and immediately treated.
Texas Cancer Center Treatment Analysis
The Texas Cancer Center supports the increased use of conservative treatment for cancer of the prostate. Men should chose the type of treatment they prefer, since there is no evidence that overall survival is affected by this decision.
Medical References
1. LU-Yao G, McLerran D, Wasson J, et al. An assessment of radical prostatectomy. JAMA 269:2633-6, 1993.
2. Paulson DF. Randomized series of treatment with surgery versus radiation for prostate adenocarcinoma. NCI Monographs 1988, No.7:127-31.
3. Matzkin H, Patel JP, Altwein JE, Soloway MS. Stage T1a carcinoma of prostate. Urol 1994; 43:11-21.
4. Brendler CB, Walsh PC. The role of radical prostatectomy in the treatment of prostate cancer. CA - Can J Clin 1992; 42:212-22.
5. Blute ML, Zincke H, Farrow GM. Long-term followup of young patients with stage A adenocarcinoma of the prostate. J Urol 1986; 136:840-3.
6. Ziegler M, Becht E, Zwergel T, et al, Incidental carcinoma of the prostate: diagnostic second transurethral resection and therapeutic consequences. In Altwein JE, Faul P, Schneider W. (Eds.) Incidental Carcinoma of the Prostate. Springer-Verlag: Berlin. 1991, pp.128-132.
7. Marberger M. Incidental discovery of prostatic carcinoma with transurethral resection and the possible consequences. In Altwein JE, Faul P, Schneider W. (Eds.) Incidental Carcinoma of the Prostate. Springer-Verlag: Berlin. 1991, pp.114-118.
8. Fleming C, Wasson JH, Albertsen PC et al. A decision analysis of alternative treatment strategies for clinically localized prostate cancer. JAMA 1993;269:2650-2568.
9. Wasson JH, Cushman CC, Bruskewitz RC et al. A structured literature review of treatment for localized prostate cancer. Arch Fam Med 1993;2:487-493.
10. Adolfsson J, Steineck G, Whitmore Jr WF. Recent results of management of palpable clinically localized prostate cancer. Cancer 1993; 72:310-22.
11. Whitmore Jr WF, Warner JA, Thompson IM. Expectant management of localized prostatic cancer. Cancer 1991; 67:1091-6.
12. Jewett HJ. Radical perineal prostatectomy for palpable, clinically localized, non-obstructive cancer: experience at the Johns Hopkins Hospital, 1909 - 1063. J Urol 1980;124:492-494.
13. Partin AW, Lee BR, Carmichael M, Walsh P, Epstein P. Radical prostatectomy for high grade disease: a reevaluation 1994. J Urol 1994;151:1583-6.
14. Chodak GW, Thisted RA, Gerber GS, et al. Results of conservative management of clinically localized prostate cancer. N Engl J Med 1994; 330:242-8.
15. Sonda LP. Second-look prostate resection for incidental carcinoma of the prostate. In Altwein JE, Faul P, Schneider W. (Eds.) Incidental Carcinoma of the Prostate. Springer-Verlag: Berlin. 1991, pp.109-13.
16. Zelefsky MJ, Whitmore WF, Leibel SA, Wallner KE, Fuks Z. Impact of transurethral resection on the long-term outcome of patients with prostate carcinoma. J Urol 1993; 150:1860-6.
17. Neerhut GJ, Wheeler TM, Dunn JK, Scardino PT. Residual tumor after transurethral resection of the prostate: features of incidentally found prostate cancer in transurethral and radical prostatectomy specimens. In Altwein JE, Faul P, Schneider W. (Eds.) Incidental Carcinoma of the Prostate. Springer-Verlag: Berlin. 1991, pp.119-121.
18. Zelefsky MJ, Whitmore Jr WF, Leibel SA, Wallner KE, Fuks Z. Impact of transurethral resection on the long-term outcome of patients with prostatic carcinoma. J Urol 1993; 150:1860-4.
19. Stamey TA, McNeal JE. Adenocarcinoma of the prostate. in Walsh P.C., Retik, A. B., Stamey T.A., Vaughan Jr. E. D. (eds.) Campbell's Urology, Vol. II, 6th Ed. Philadelphia: W. B. Saunders Co., 1992.
20. Thompson IM. Observation alone in the management of localized prostate cancer: the natural history of untreated disease. Urol 1994; 43:41-6.
21. Fowler FJ Jr, McNaughton Collins M, Albertsen PC, Zietman A, Elliott DB, Barry MJ Comparison of recommendations by urologists and radiation oncologists for treatment of clinically localized prostate cancer. JAMA. 283:3217-3222, 2000.
22. Labrie F, Candas B, Dupont A, and others. Screening decreases prostate cancer death: First analysis of the 1988 Quebec prospective randomized controlled trial. Prostate 38:83-91, 1999.
23. Ragde H, Korb L. Brachytherapy for clinically localized prostate cancer. Semin Surg Oncol 18:45-51, 2000.
24. Sharkey J, Chovnick S, Behar R, Otheguy J, Rabinowitz R. Re: radical prostatectomy for localized prostate cancer provides durable cancer control with excellent quality of life: a structured debate. J Urol 165:192-193, 2000.
25. Walsh PC. Editorial comment: Taking on prostate cancer. J Urol 156:1518-1548, 1996.
26. Evans RA. RE: Editorial comment: Taking on prostate cancer. J Urol 156:1528-1529, 1996.
27. Lundgren R, Nordle O, Josefsson K. Immediate estrogen or estramustine phosphate therapy versus deferred endocrine treatment in nonmetastatic prostate cancer: a randomized multicenter study with 15 years of followup. The South Sweden Prostate Cancer Study Group. J Urol 153:15480-1586, 1995.
28. The Medical Research Council Prostate Cancer Working Party Investigators Group. Immediate versus delayed treatment for advanced prostate cancer: initial results of the Medical Research Council Trial. Br J Urol 79:235-246, 1997.
29. Strum SB, Scholtz MS, McDermed JE. Intermittent androgen deprivation in prostate cancer patients: factors predictive of prolonged time off therapy. The Oncologist 5:45-52, 2000.
30. Stone NN, Stock RG. Neoadjuvant hormonal therapy improves the outcomes of patients undergoing radioactive seed implantation for localized prostate cancer. Mol Urol 3:239-244, 1999.
31. Adolfsson J. The natural history of early prostate cancer and the impact of endocrine treatment. Eur Urol 36:3-8, 1999.
32. D'Amico A, Schultz D, Loffredo M, Dugal R, Hurwitz M, Kaplan I, and others. Biochemical outcome following external beam radiation therapy with or without androgen suppression for clinically localized prostate cancer. JAMA 284:1280-1283, 2000.
33. Cohen JK, Miller RJ, Benoit R, Rooker GM, Merlotti L. Five year outcome of PSA and biopsy following cryosurgery as primary treatment for localized prostate cancer. J Urol 159 (suppl):252, 1998.
34. Labrie F. Screening and early treatment of prostate cancer are accumulating strong evidence and support. Prostate 43:215-222, 2000.
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3. Petersen NC, Bodenham DC, Lloyd OC: Malignant melanoma of the skin. Br J Plast Surg 1962; 15:49-116.
4. Wong CK: A study of melanocytes in the normal skin surrounding malignant melanomata. Dermatologica 1970; 141: 215-225.
5. Cochran AJ: Histology and prognosis in malignant melanoma. J Path 1969; 97: 459-468.
6. Olsen G: The malignant melanoma of the skin: new theories based on a study of 500 cases. Acta Chir Scand [Suppl.] 1966; 365: 1-220.
7. Morton DL. Current management of malignant melanoma. Ann Surg 1990; 212: 123-124.
8. Cascinelli N, van der Esch EP, Breslow A, Morabito A, Bufalino R: Stage I malignant melanoma of the skin: the problem of resection margins. Europ J Cancer 1980; 16: 1079-1085.
9. Schmoeckel C, Bockelbrink A, Bockelbrink H, Braun-Falco O: Low- and high-risk malignant melanoma - III. Prognostic significance of the resection margin. Eur J Clin Oncol 1983; 19: 245-249.
10. Heenan PJ, Weeramanthri T, Holman CDJ, Armstrong BK: Surgical treatment and survival from cutaneous malignant melanoma. Aust NZ J Surg 1985; 55: 229-234.
11. Heenan PJ, English DR, Holman CDJ, et al. The effects of surgical treatment on survival and local recurrence of cutaneous malignant melanoma. Cancer 1992; 69:421-6.
12. Pitt TTE: Aspects of surgical treatment for malignant melanoma: The place of biopsy and wide excision. Aust NZ J Surg 1977; 47: 757-766.
13. Ackerman AB, Scheiner AM: How wide and deep is wide and deep enough? Human Path 1983; 14: 743-744.
14. Cascinelli N, van der Esch EP, Breslow A, Morabito A, Bufalino R: Stage I malignant melanoma of the skin: the problem of resection margins. Europ J Cancer 1980; 16: 1079-1085.
15. Elder DE, Guerry D, Heiberger R, LaRossa D et al: Optimal resection margin for cutaneous malignant melanoma. Plast Reconstr Surg 1983; 71: 66-72.
16. Aitken DR, Clausen K: Klein JP, James AG. The extent of primary melanoma excision. A re-evaluation-how wide is wide? Ann Surg 1983; 198: 634-641.
17. Aitken DR, James AG, Carey LC: Local cutaneous recurrence after conservative excision of malignant melanoma. Arch Surg 1984; 119: 643-646.
18. Lehman JA, Cross FS, Richey DG: Clinical study of forty-nine patients with malignant melanoma. Cancer 1966; 19: 611-9.
19. O'Rourke MGE, Altmann CR. Melanoma recurrence after excision is a wide margin justified? Ann Surg 1993; 217:2-5.
20. Seigler HF. Clinicopathologic factors relating to surgical margins for cutaneous melanoma . Ann Surg 1993; 217:1.
21. Brown M, Goldsmith LA. Excision margins for melanoma in awkward places lie the eyelid. JAMA 1993, 269:588-589. (Letter)
22. Balch CM, Milton GW, Cascinelli N, Sim FH. Elective Lymph Node Dissection: Pros and Cons. In: Balch CM, Houghton AN, Milton GW, Sober AJ. Cutaneous Melanoma. Philadelphia: J. B. Lippincott, 1992.
23. McCarthy WH, Shaw HM, Cascinelli N, Santinami N, Belli F. Elective lymph node dissection for melanoma: two perspectives. World J Surg 1992;16:203-213.
24. Sutherland CM, Mather FJ. Prophylactic lymph node dissection for malignant melanoma: What to do while we wait. J Surg Oncol 51:1-4, 1992.
25. Balch CM, Soong S-J, Milton GW, et al. A comparison of prognostic factors and surgical results in 1,786 patients with localized (stage I) melanoma treated in Alabama, USA and New South Wales, Australia. Ann Surg 1982; 196:677-684.
26. Veronesi U, Adamus J, Bandiera DC, et al. Delayed regional lymph node dissection in stage I melanoma of the skin of the lower extremities. Cancer 1982; 49:2420-2430.
27. Sim FH, Taylor WF, Pritchard DJ, Soule EH. Lymphadenectomy in the management of stage I malignant melanoma: a prospective randomized study. Mayo Clin Proc 1986; 61:697-705.
28. Balch CM, Murad TM, Soong S-J, et al. A multifactorial analysis of melanoma: Prognostic histopathological features comparing Clark's and Breslow's methods. Ann Surg 1978; 188:732-742.
29. Balch CM, Soong S-J, Shaw HM, Urist MM, McCarthy WH. Analysis of prognostic factors in 8500 patients with cutaneous melanoma. In: Balch CM, Houghton AN, Milton GW, Sober AJ. Cutaneous Melanoma. Philadelphia: J. B. Lippincott, 1992.
30. McCarthy WH, Shaw HM, Thompson JF, Milton GW. Time and frequency of recurrence of cutaneous stage I malignant melanoma with guidelines for follow-up study. Surg Gynecol Obstet 1988; 166:497-502.
Medical Research since 1995
All of the studies of malignant melanoma fall into two categories: those that like at treatment of the primary lesion, and those that look at treatment of the lymph nodes.
The Primary Lesion
Since 1995, Mohs micrographic surgery has become accepted treatment in several academic medical centers. J.A. Zitelli and colleagues of Shadyside Medical Center in Pittsburgh conducted a prospective study of 535 patients treated for melanoma using the Mohs technique.(1) Eighty-three percent of lesions were successfully excised with a 6 mm margin; a 1.2 cm margin was required to remove 97 percent of all lesions. They achieved 5-year survival rates which were equivalent to patients treated by standard wide-margin surgery. Local recurrences from inadequate excision of the primary tumor were very rare (0.5 percent). The authors recommend Mohs micrographic surgery when narrow margins are desired
S.N. Snow and associates of the Mohs Surgery Clinic in Madison, Wisconsin, treated 179 patients with melanoma from 1981 to 1991.(2) They concluded that the Mohs technique was effective treatment for patients with melanomas of thin and intermediate thickness. For deeper lesions the number of cases was insufficient to evaluate.
By 1998, K. M. Keaton and associates at the M. D. Anderson Cancer Center studied 278 patients with thick melanomas, i.e., deeper than 4 mm.(3) The median tumor thickness for their patients was 6 mm. After a median follow-up of 257 months, the local recurrence rate was 27%. These investigators found that neither local recurrence nor excisional margin significantly affected overall survival. They concluded that a 2 cm margin of excision was adequate for patients with thick lesions (> 4 mm).
D.A. Hudson and associates of the University of Cape Town, South Africa, treated 106 patients with stage I melanoma of the face.(4) Margins of excision ranged from less than 1 cm to greater than 2 cm. Seven patients developed local recurrences, but these were not influenced by the size of the excision margin. The authors concluded that stage I melanoma of the face should be treated with a complete excision, microscopically confirmed by a pathologist. They found that this could be achieved with margins of excisions of less than 1 cm.
Erroneous Conclusions
Many studies have now proven that a narrow margin of excision - and the local recurrence which may follow - does not adversely affect survival. This conflicts with the prevailing paradigm and some investigators are now resorting to faulty research techniques to support their erroneous beliefs.
X. D. Dong and associates of Duke University Medical Center studied 648 patients who developed local recurrence following the removal of the original melanoma.(5) The Duke investigators reported that 48.5% of these patients died within five years of their local recurrence. (They did not compare this mortality rate to that of patients who remained free of local recurrence.) They concluded that this mortality rate was high and that local recurrence caused the melanoma to spread. They suggested that patients may benefit from more aggressive local therapy, e.g., wider margins of excision.
This study is seriously flawed, because there are at least two types of local recurrence. First, cancer cells may have already spread to a distant organ (metastasis), before the original melanoma was removed. As the metastasis grows it may shed additional cancer cells into the blood stream, where they eventually make there way back to the site of surgery. (Experimental research has shown that cancer cells are attracted to tissue, which has been injured by surgery.) This first type of local recurrence has a very bad prognosis, because the cancer has already spread. Modern scans and other tests may not detect the distant metastasis until is almost an inch in size. This may be months after the local recurrence is first seen. Thus, the distant metastasis appears to follow - and thus be caused by - the local recurrence. But, this is incorrect.
The second type of recurrence involves cancer cells left behind in the skin following the removal of the original melanoma. I prefer to call this "local persistence." Local persistence is not a threat to patient survival. Patients who are able to prevent the spread of disease from their original melanoma, are able to prevent the spread of disease from a recurrent - or persistent - melanoma. This is precisely the way breast cancer behaves. Even in the well-known NSABP lumpectomy trial, patients who developed local recurrence were 4.6 times as likely to develop distant metastases as those who remained free of local recurrence. But, the NSABP investigators concluded correctly that local recurrence was the indicator of a poor prognosis, but not its cause.
X. D. Dong and associates of Duke University combined patients with two types of local recurrence in their study. It is not surprising that these patients had a poor prognosis. Many of them already had distant metastases and developed local recurrence from the distant disease. Some of the patients had local persistence and their survival was not affected. But, they were lost in this faulty study. Contrary to the study from Duke, aggressive local therapy has no affect on patient survival.
The Regional Lymph Nodes
Sentinel Lymph Node Biopsy
Sentinel lymph node biopsy is a new technique which removes only those few lymph nodes which are close to the melanoma - those nodes where the melanoma is most likely to spread. Before surgery a dye in injected into the skin around the melanoma. The dye flows into the nearest (sentinel) lymph node(s) and a scan identifies the node(s) in question. The is called lymphatic mapping. A blue colored dye allows the surgeon to see the sentinel lymph node while performing the biopsy. By removing very few lymph nodes the surgeon can determine the status of all the nodes in the region. If cancer cells are found in the sentinel node, the surgeon usually removes most of the remaining regional nodes. This technique causes few effects and can be performed on any patient about whom there is any question of lymph node spread. For most patients it has largely eliminated the decades long debate about the value of elective lymph node dissection in patients with melanoma. Regrettably, there is much we can learn from this debate - lessons that are now ignored.
Surprising New Information about Elective Lymph Node Dissection (ELND)
In 1996, Intergroup Melanoma Trial published the results of a randomized trial of 740 patients with localized melanoma, 1.0 to 4.0 mm thick.(6) Half of the patients received an ELND. The other half was observed. If the lymph nodes enlarged with cancer cells, they were removed. Among the patients to benefit from an ELND were those with very thin lesions, 1.0 - 2.0 mm. This was surprising, because these patients were the least likely to have positive regional lymph nodes. Why did ELND benefit only those patients least likely to have positive lymph nodes? The authors of this study offered no explanation for their surprising results. In 1995, I commented on similar data that had already been published from another study. I also offered an explanation for these paradoxical results.
The Texas Cancer Center believes that all available medical evidence continues to support the increased use of limited surgery for malignant melanoma.
1. Zitelli JA, Brown C, Hanussa BH. Mohs micrographic surgery for the treatment of primary cutaneous melanoma. J Am Acad Dermatol 37:236-45, 1997.
2. Snow SN, Mohs FE, Oriba HA, Dudley CM, Leverson CM, Hetzer M. Cutaneous malignant melanoma treated by Mohs surgery. Review of the treatment of 179 cases from the Mohs Melanoma Registry. Dermatol Surg 23:1055-60, 1997.
3. Heaton KM, Sussman JJ, Gershenwald JE, Lee JF, Reintgen DS, Mansfield PF, Ross MI. Surgical marg and prognostic factors in patients with thick (> 4 mm) primary melanoma. Ann Surg Oncol 5:322-8, 1998.
4. Hudson DA, Krige JE, Grobbelaar AO, Morgan B, Grover R. Melanoma of the face: the safety of narrow excision margins. Scand J Plast Reconstr Surg Hand Surg 32:97-104, 1998.
5. Dong XD, Tyler D, Johnson JL, DeMatos P, Seigler HF. Analysis of prognosis and disease progression after local recurrence of melanoma. Cancer 88:1063-1071, 2000.
6. Balch CM, Soong S--J, Bartolucci AA, et al. Efficacy of an elective regional lymph node dissection of 1 to 4 mm thick melanomas for patients 60 years of age and younger. Ann Surg 224:255-266, 1996.
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