His and Her Health

In the last decade, the incidence of death from cancer has pretty much stabilized. However, prostate cancer, due to its earlier diagnosis and more aggressive treatment techniques, has shown the greatest improvement in life expectancy than any other malignancy. On the other hand, there has been tremendous controversy over PSA testing and whether or not PSA testing truly improves life expectancy of patients if the disease is caught early and treated aggressively.

I think statistics from the National Institute of Health showing that of all the major cancers, prostate cancer in the last decade, has certainly demonstrated that earlier diagnosis and more aggressive treatment has demonstrated the best survival figures of any other malignancies. I personally think that this information is misinformation, much of which is to decrease the cost of male healthcare and without consideration for men who may in the future develop this disease.
Several years ago, I wrote a Prostate Cancer Month article talking about the direction of prostate cancer research and treatment. Much of what I had to say has, in fact, become true, again demonstrating major advancements in the diagnosis and treatment of prostate cancer. These items include surgical advances such as robotic radical prostatectomy and medical therapy with the first therapeutic cancer vaccine approved by the Food and Drug Administration, Provenge. I would now like to talk about prostate cancer as it is today and where we are going in the future.

Prostate Cancer Today

As it stands right now, most men 50 years or older are receiving annual or fairly regular digital rectal exams by their physicians with PSA blood tests. In many cases, those men at higher-than-normal risk are beginning their screening process at 40 years of age. African-American males or families in which the father and/or brothers have had prostate cancer are screening at 40 years of age rather than 50. Many general practitioners and most urologists are interpreting these laboratory tests in several different ways: 1)The absolute value in relationship to the age and race of the patient. 2)The change over time. 3)The PSA density, i.e. that amount of PSA that is produced per cubic centimeter of prostate tissue. For example, a small gland should have a much lower production of PSA, and if the PSA is higher than one would think for that size gland, suspicion for cancer is increased. 4)Physicians are doing regular digital rectal exams, their skills have improved, and any deviation from the norm becomes a reason for prostate biopsy, i.e. asymmetry, firmness, nodularity and irregularities. The combination of PSA and digital rectal exams on a regular basis can diagnose prostate cancer at an early stage in 98% of patients. The earlier the better. The more aggressive the therapy, the better the cure and/or the survival. 5) Biopsy techniques have also improved. Almost every urologist is using sonography to assist in biopsying the various areas of the prostate that need to be sampled. The number of biopsies considered the standard has also increased, and most urologists are doing more than 10 biopsies and many are doing as many as 18 or 24 biopsies. Increasing the number of biopsies tends to increase the chance of hitting an area that will show a malignancy. The procedure can be done under local anesthesia, and less and less are using sedation.

Once the biopsy is taken, pathologists have learned a standardized way of reading the biopsy specimens. Their skills have increased, and the ability of pathologists to consistently read cancer and read it at the same grade has improved. Using the Gleason scoring system, most pathologists pretty much will agree on the Gleason stage of a particular cancer. The staging is determined by looking at the best and worst cancer from a particular core of tissue, grading it from 0-5 and then adding the worst and best scores together to give a Gleason grading score. Most cancers are 5, 6 or 7, relatively well differentiated, closer to normal tissue than not, slow in developing, slow in metastasizing and allowing for a big window to make the diagnosis of cancer while it is still curable.

Fifteen percent of the cancers are extremely rapidly growing, quite undifferentiated leading to poor results with the therapies we have today and a relatively rapid demise in many within two years. The undifferentiated tumors, usually Gleason 8, 9 and 10, do not produce PSA as the well-differentiated tumors, and frequently the PSAs in these cases are low or normal. Unfortunately, our abilities to diagnose undifferentiated Gleason 8, 9 and 10 tumors early is poor and the treatments are even worse. Thankfully, the majority of us who get prostate cancer have the well-differentiated, more easily diagnosable and treatable type of cancer.

After a diagnosis is made, the next step is to determine how far the cancer has spread. Most of our treatments, including surgery, radiation therapy and cryoablation or freezing therapy, are only good for cancers localized to the prostate gland. Once it spreads beyond the prostate, treatment of the entire body with either hormonal manipulation or chemicals is necessary. Fortunately at this time, more than 90% of our malignancies are localized and aggressive surgical, radiation and cryosurgical approaches can either cure or sustain life for an extended period of time.

Localized cancer, particularly in the younger age group, 60 to 65, was relatively healthy and able to live at least 15-20 years, are excellent candidates for surgical techniques. The advantage of surgery is that the cancer is out and injury to the neurovascular bundle is more easily salvaged. Robotic techniques have become the dominant way of handling surgical prostate cancer and now represents more than 70% of surgical techniques.

The robotic techniques allow for three-dimensional visualization intraoperatively through small puncture wounds in the lower abdomen. The hospital stays are usually less than 24 hours and the postoperative morbidity and pain are significantly reduced over the previous open radical prostatectomies. It appears that even though robotic surgery costs more, potency, bleeding and incontinence appears to be better using these techniques.

Radiation techniques continue to be improved. However, no matter the manner radiation is performed, injuries to the neurovascular bundle do occur and potency problems occur in 70% of the patients within 2-5 years after surgery. Most people using radiation therapy have excellent urinary control, but if there are control problems, particularly if severe, the ability to correct the problem is significantly reduced over a surgical technique with the same problem.

Cryoablation of the prostate is definitely increasing in frequency and is the procedure of choice in patients who have radiation failure, rising PSA and no evidence of extraprostatic disease. It also does not have the serious local side effects that radiation therapy has, i.e. radiation to the bladder and rectum with associated urgency, frequency, blood in the urine, rectal discomfort, diarrhea and rectal bleeding.

Disease outside the prostate must be treated systemically. At this time, hormonal manipulation with LHRH drugs such as Lupron, Eligard and Trelstar are the standard. These drugs are given intramuscularly or subcutaneously on a 1-6-month basis, reducing the testosterone which normally stimulates prostate cancer, but when dropped below 21 ng/dL optimizes the effects of the drug in suppressing the cancer and causing tumor palliation. A 1-year implant known as Vantas, which is placed just under the skin in the medial aspect of the arm, is equally as effective.

The addition of an antiandrogen such as Casodex may help some men, particularly if LHRH alone does not suppress the PSA. If patients are on combination therapy of an LHRH agonist and/or antiandrogens such as Casodex and the PSA rises, discontinuation of the antiandrogen frequently will improve the PSA for anywhere from 1-2 years after discontinuation. A new drug known as an LHRH antagonist, Degorelix, is starting to be used and will be discussed in the section on future advancements in prostate cancer.

Research in chemotherapy specific for prostate cancer has progressed with multiple new chemotherapeutic agents available. Doxorubicin, Taxotere and Taxol are the mainstay and can be used in those patients who fail hormonal manipulation. Theoretically, the chemotherapeutic agents work best when the tumor is growing rapidly, and taking hormones first will slow the growth of the cancer, not allowing the chemotherapy to be as effective. Many people are now giving chemotherapy earlier before growth is slowed by hormonal manipulation.

The Future of Prostate Cancer.

In June, 2010, the FDA approved the very first cancer vaccine, known as Provenge, developed and manufactured by a company called Dendreon Pharmaceuticals. There was significant controversy over the approval of this drug, mainly because the studies were presented as a compilation and not as individual studies, and many of the members of the advisory board to the FDA were involved in other prostate cancer vaccine clinical trials. Thanks to the support of patients with prostate cancer, the drug was finally approved by the FDA for various positive reasons. Firstly, the drug causes minimal-to-no harm, has minimal adverse events and almost no serious side effects. From the FDA’s point of view, this is their most important function is to improve a drug that is safe for the public. Secondly, if you looked at the statistical information related to survival, it was shown that at two years the Provenge-treated group survived five months longer than the placebo-treated group. This may not seem like a long time but in terms of cancer can be a lifetime, and when compared to other chemotherapies for prostate cancer, this survival figure is almost two times the increase in life expectancy.

The Provenge studies were performed on about 1400 patients, all with advanced prostate cancers of all grades; most of whom had bony metastases, all of whom had been treated with hormonal manipulation and/or chemotherapy, all having failures with rising PSAs. The outlook for these patients was bleak, and in general 88% of these patients will die within two years. As stated before, Provenge statistically improved the life expectancy of the patients by five months in a group of patients, most of whom would have died. Safety was never an issue. Side effects are minimal and tolerable, and serious side effects are few and far between.

The drug is made specifically for each patient. A three-hour process known as a leukophoresis occurs as specific white blood cells are removed from the patient similar to giving blood for transfusion purposes. This blood is sent to Morristown, New Jersey, where a 48-hour process occurs in which the patient’s dendritic cells are mixed with killed prostate cancer cells that have a protein molecule on the surface membrane representing the PAP antigen. PAP equals prostate alkaline phosphatase. After two days of incubation, the dendritic cells are stimulated to the PAP antigen, are processed by removing the cancer cells and sent back as quickly as possible to the physician site, where the dendritic cells or drug is infused back into the patient over a one-hour period of time. This process occurs three times, two weeks apart. The dendritic cells then multiply in the body acting as clones of activated cells, going after PAP-positive or prostate cancer cells and assisting in the destruction and killing of these cells no matter where they may be in the body. This therapeutic vaccine does not prevent cancer but is only to treat cancer of the prostate in those patients who have advanced disease and rising PSA after standard hormonal therapy.

Imagine, in general, vaccine or immunotherapy works better with lesser tumor or antigen loads. This vaccine will probably be used and researched on prostate cancer that has not advanced to the stages that were originally used to develop Provenge. Patients with biochemical failure, i.e. rising PSAs, after local therapy such as surgery, radiation or cryoablation with no evidence of metastases may be a better group to use the therapeutic vaccine on than the more advanced group for whom the FDA has now approved the drug.

There is no doubt the drug is expensive, at approximately $31,000 a dose or around $100,000 for three treatments. The one production facility is only at 25% of capacity. Several other production facilities are being built, and as the capacities increase and the expenses of developing this drug have been covered, I am sure the cost will go down in time. On the other hand, in those patients who have no further direction to go with their prostate cancer, Provenge is potentially a miracle drug. Medicare is now in the process of approving payment for this particular drug, and many of the other private insurance carriers are beginning to review and authorize treatment.

Immunotherapy obviously is exciting. Research in new chemotherapeutic agents and combinations thereof continue to occur and will improve our armamentarium of prostate cancer treatments. Combining immunotherapy with chemotherapy also may produce synergistic results.
Surgical techniques continue to improve as does the equipment developed by manufacturers.

Robotic radical prostatectomy is a procedure that requires fairly extensive training and a long learning curve. Most of the residents in urology in the United States are learning this procedure during their five or six years of surgical training. The numbers of cases being done has dramatically increased, and I expect the majority of prostate cancer operations to be done robotically in the next five years. As the residents get better, do more cases and as more and more physicians doing robotic surgery get more and more experience, the procedure will be quicker and safer with even less morbidity and better outcomes. Urinary control and sexual function will be less of a postoperative problem and blood loss will be minimal. These robotic techniques are being not only used for prostate cancer but also in kidney cancer and other urological intra-abdominal problems such as stone disease, adrenal tumors, urinary tract obstructions, etc.

Radiation therapy techniques continue to improve, and a new technique known as high-density radiation therapy is becoming available to us for the treatment of prostate cancer. In this case, the patient receives two very high doses of interstitial radiation. Cannulas or needles are placed in the prostate gland through sonographic guidance. Into the cannulas, very high-dose for short periods of time of radioactive seeds are utilized.

This short-duration, high-dose radiation sandwiches the standard external beam radiation, i.e. interstitial radiation followed by external beam radiation for 30-40 days followed by a second dose of high-dose radiation therapy. Whether this will be better than the standard radiation techniques is not known, but it appears to give at least as good survival with less side effects than the traditional brachytherapy.

As stated in the previous section, LHRH agonist with or without antiandrogens is the treatment of choice for patients with extraprostatic disease. Recently, an LHRH agonist known as Degorelix has been developed and marketed. Its major advantage is that you do not get the acute testosterone rise for 3-4 days, which in some cases can be detrimental to the patient, and rapid castration with levels below 50 ng/dL within seven days rather than 28 days for LHRH agonist.

The patients in which this drug is indicated includes those patients who have significant urinary obstruction, patients with obstruction to the kidneys and hydronephrosis, extensive painful bone metastases particularly if the bone metastases are compressing the spinal cord, and patients who have brain metastases. I admit this represents a small percentage of patients, but the drug can miraculously resolve their symptomatic metastases without the potential serious side effects of an LHRH agonist or an LHRH agonist with radiation therapy.

The diagnosis and treatment of prostate cancer has come a long way. Thirty-five years ago, 95% of patients with prostate cancer presented with metastatic disease involving the bone, living a relatively short, uncomfortable existence. Today, almost all of our patients have localized disease and are potentially curable. The National Cancer Institute has statistics showing that urologists are doing a great job in increasing the survivals of our patients with prostate cancer. Patients are doing a great job by having regular digital rectal exams and PSA tests by their physicians.

Surgery has dramatically improved with the techniques of robotics, and immunotherapy may be the answer to some of our unfortunate patients who no longer respond to chemotherapy or hormonal manipulation. Earlier use of prostate cancer vaccines may improve overall survivals even more. (September, 2010)