Edmund C. Lattime, PhD, professor of surgery, molecular genetics, microbiology & immunology, Robert Wood Johnson Medical School and associate director for education and training, The Cancer Institute of New Jersey (left), and Robert Weiss, MD, associate professor, surgery, RWJMS
What's New for the
Mid-Life Prostate?
by Eve Jacobs
|
The miseries of a growing prostate gland plague many male baby boomers long before they perceive themselves as aging. Symptoms can appear when a man is in his late 40s, according to urological surgeon Robert Weiss, and include "urinary frequency, often causing a man to get up several times each night, and urgency-difficulty in making it to a bathroom."
his urgency is not related to cancer,” he says, describing an enlarging prostate “like an orange with pulp growing inside,” that will eventually produce obstruction.
“Cancer occurs on the outside of the prostate,” he continues, which is why physicians check for nodules using a rectal exam. This should be paired with an annual PSA screening (blood test) starting at age 45 for African American men and 50 for others.
Weiss reminds baby boomers who may shy away from these tests that prostate cancer is asymptomatic in its early stages, but the blood test can often pick it up early.
The primary risk factor for prostate malignancy—which affects one in six men in the U.S. in their lifetimes—is aging. Under age 40, the incidence is one in 10,000, but it jumps dramatically to one in 38 for 40- to 59-year-olds, and one in 14 for those in their 60s.
Risk is also closely tied to race and heredity. African American men have a 61 percent higher incidence rate of this cancer than Caucasians and they are two and a half times more likely to die of the disease since their tumors tend to be found at a later stage. Men whose father or brother had prostate cancer have twice the likelihood of being diagnosed with it and those having two close relatives with the disease are four times more likely. Age at the time of diagnosis is also a factor—the risk escalates if the family member was younger than 60 at the time of detection.
Traditional treatment for prostate cancer is open surgery to remove the entire gland and sometimes certain lymph nodes, but it is a surgical procedure that many men fear—and not without reason. This surgery frequently causes problems (most often temporary) with erection and with bladder control. Robotic surgery has been popularized in the last two to three years, says Weiss, largely due to media coverage, including an article in Newsweek in June 2005 that spelled out its advantages — it’s less invasive resulting in shorter recovery and is superior from a cosmetic standpoint.
Bladder sections from a patient treated with recombinant fowlpox
producing GMCSF. Figure shows cell morphology using H&E staining (top row); CD3+ T lymphocytes (middle row) and CD4+ T helper cells (bottom row). Sections are shown at low power (left column) and high power (right column).
However, the incidence of incontinence and impotence are about the same as that for open surgery, explains the surgeon, varying by the age of the individual and not by the type of procedure. Eighty percent of men have erection problems following surgery, but many regain function—76 percent under age 60, 56 percent of those age 60 to 65, and 47 percent of those older than 65. If the patient had problems prior to surgery, his chance of regaining function will not be as good. Also, after both surgeries, half of men will experience some form of urinary incontinence—ranging from severe problems to occasional dribbling—but one year later, “just 5 percent will still experience problems,” says Weiss.
The urologist credits the six medications for benign prostate enlargement that have become available over the last 10 to15 years with radically improving treatment. Proscar and Avodart can slow or stop further growth of the prostate, and, in many cases, actually shrink the gland. They block production of DHT, a hormone that contributes to enlargement.
The other four are Alpha blockers, a type of drug originally developed for hypertension treatment. Hytrin, Cardura, Flomax and Uroxatral relax smooth muscle at the neck of the bladder, easing urine flow.
Recent findings of the Medical Therapy of Prostatic Symptoms (MTOPS) trial indicate that combining two of these drugs — Proscar and Cardura — works better than using either by itself. When taken together, the risk of progressive enlargement was reduced by 67 percent, compared with 39 percent for Cardura and 34 percent for Proscar.
When drugs fall short, Weiss recommends certain minimally invasive procedures to provide symptomatic relief. The green light laser gained FDA approval just five years ago, but has gone to the top of the patient approval charts. A thin fiber is inserted into the urethra through a cystoscope to deliver laser energy that “melts away excess tissue closing in the doughnut hole” and causing urinary problems. It is generally effective with minimal side effects.
Other minimally invasive procedures include TURP (it has been performed for
several decades), which Weiss calls the “gold standard” for the treatment of urinary retention, in which excess prostate tissue is cut away piece by piece using an instrument inserted through a cystoscope; transurethral needle ablation (TUNA), approved in 1996, in which radiofrequency waves destroy excess tissue with heat; and transurethral microwave thermotherapy (TUMT), which destroys excess tissue with microwaves. Although TURP is highly effective, patients need both spinal, epidural or general anesthesia and a hospital stay. The other procedures are usually done on an outpatient basis.
“Most men will get improvement from these minimally invasive procedures, although the tissue can grow back over five to 10 years,” explains Weiss. “But there’s no danger to going back and repeating the procedure.” The surgeon also treats malignancies of the kidney and bladder. Among recent advances is “kidney-sparing surgery,” in which a tumor and surrounding kidney tissue are removed, saving healthy kidney that continues functioning. Also, Weiss is using the laparoscope instead of an open procedure for some kidney cancer surgeries.
For bladder cancer, the biggest advance has to be the highly specialized procedure which fashions a new bladder or “neobladder” out of intestines. Traditionally, a patient has had an outside bag or “ileal conduit” to collect the urine after having the bladder removed. The neobladder is an inside bladder which functions in a
similar manner to the original bladder.
“The patient can swim, play tennis, do anything,” he says. “The surgical procedure is more complicated, but the patient benefits by having a far superior quality of life.”
There is also breaking news in bladder cancer treatment — a vaccine trial is currently being conducted by Weiss and cancer researcher Edmund Lattime, PhD, whom Weiss calls “a pioneer” in this field. They have already enrolled 10 patients in the protocol. [See “The Birth of A Cancer Vaccine”] Coming round again to issues surrounding prostate cancer screening, Weiss describes a new mechanical imager he has helped develop to improve the digital rectal exam. “It’s a sensor similar to a finger,” he explains, “with micro-sensors on the tip to do the exam. It feels hard spots and soft, and creates a computer image.” This project has been supported by an NIH small business grant; and 200 patients have already been recruited for examinations.
“The images show the contour of the prostate,” he continues. “The idea is that primary doctors could use it to capture information on the computer screen, and then print it out for comparison year to year.”
With baby boomers like Weiss addressing the concerns of their generation with a creative mindset, boomer medicine can only continue getting healthier.
The Birth of a Cancer Vaccine
A cancer vaccine in your lifetime may not be quite as pie-in-the-sky as you think. Just ask researcher Edmund Lattime, PhD, himself a boomer, about the possibility, and you will be swept up in the swell of his optimism.
The future has arrived and it is now.
But why has it taken so long? Vaccines for most of our worst childhood infections have been around so long that we barely give them their due. Are the cancer guys just slow on the uptake?
Although the idea of a cancer vaccine surfaced in the ’60s and ’70s, “early attempts were less than successful,” Lattime states. “No one understood the complexities of the immune response. Tumor cells were ground up and mixed with adjuvants [other ingredients to boost the immune system], then injected into animal models, but these early vaccines lacked efficacy.”
The cancer researcher calls the immune system spectacular—its ability to differentiate good from bad, and to learn at birth what is self, what non-self.
For infectious diseases, the time to immunize is soon after birth, before a baby comes into contact with common germs. Driven into our brains is the vaccination schedule for infants—chock-full for the first 24 months of life with boosters given in the teen years.
But cancer vaccines are different, Lattime explains: “They are intended to treat, not to prevent.”
Why not prevent? “Cancer cells are self—they develop through a series of small genetic changes which differ from tumor to tumor. Viruses and bacteria are not self. When you deal with cancer, you have to be very careful what it is you are immunizing to.”
But the vaccine researcher’s excitement is well-founded now. After 25 years, scientists can say they understand quite a lot about how the immune system works, and how it interfaces with cancer cells. “We have learned that to be ‘successful,’ cancer cells have to be very smart.”
In fact, they have to be smart enough to:
- Mastermind a series of genetic changes;
- Metastasize, which is a complex series of events where small foci of cells break off from a tumor, get into the blood stream and/or lymphatic system, and get back into tissue and grow;
- Actively evade the immune system.
They evade the immune system via multiple mechanisms including the production of cytokines (proteins) that directly modulate the immune system by mimicking normal immune regulation. “The tumors have found ways to turn on suppressive cytokines or make the cytokines themselves,” he explains.
So cancer vaccine researchers have changed their course. They are looking for ways not only to enhance the immune system but also to block factors that inhibit its functioning optimally.
Lattime says they have learned to focus their attention on the area where the tumor develops because that’s where the initial immunological interactions are occurring. “The original response, or lack of it, takes place at the tumor site in what we call the tumor microenvironment,” he explains “This means that targeting this compartment can allow the development of an immune response via modulating the initial phase of the tumor-host interaction.”
His team has focused on the microenvironment of bladder cancer in humans and mice. What they discovered is that “while you can prevent a tumor from growing by immunizing the mouse under the skin before giving the tumor, if you first give the tumor to the mouse and then try to immunize it — the mouse doesn’t produce the same effective immunity.”
But what’s more, when the team gave an immunization directly into the tumor—surprisingly it worked. “The mouse developed an immune response,” he says. “So we looked at which cells and which factors were turned on in the microenvironment, and through a combination of vaccine plus modulation of these regulatory cells and mechanisms, we were able to induce an immune response that resulted in the tumors regressing.”
The questions the research team tackled are many and complex. How can you change the tumor microenvironment? How do you distinguish which cells and factors are needed to help the immune system fight the tumor? Do you stimulate the good factors or turn off the bad ones?
Lattime and urological surgeon Robert Weiss have started treating bladder cancer patients with a vaccine—there are 10 patients so far in the clinical trial. The researchers know they need to modify the tumor microenvironment. They have discovered which cells are deficient, and know that they need to recruit and activate these deficient cells.
Their strategy is to take an altered fowl pox virus—a close relative of vaccinia, used by Edward Jenner to immunize against smallpox—to carry immune stimulating proteins to the tumor site. The virus “infects” the cancerous bladder and turns on a gene that over a period of weeks produces immune factors needed to fight the cancer.
“Placing a vaccine directly into the bladder delivers the immune enhancing cytokines where the critical tumor-host interaction takes place,” says Lattime. The phase I trial is studying the side effects and the best doses of the vaccine therapy.
“We know this works,” he continues. The researcher says the team has already demonstrated in a mouse model that they can get the virus into the bladder, it is safe, the gene is transferred to the tissues, the factor is being made and the cells are being brought in and activated.
This Phase I trial—sponsored by the National Cancer Institute (NCI)—will demonstrate that the vaccine is also safe for humans. The team is recruiting patients with advanced bladder cancer, who are scheduled to have their bladders removed, allowing the scientists to study what has actually transpired at the tumor site.
Patients get four weekly doses of virus, delivered into the bladder with a catheter, the last one given four to five days before surgery. There are three different regimens, with each group of three to six patients receiving escalating doses.
Lattime explains that a superficial bladder cancer — on the lining of the bladder that has not invaded the deeper layers — can be removed by the surgeon. But the cancer often recurs. “These are the patients we hope to treat with the vaccine in the future,” he says, which may be as soon as two years.
“This is the first time this is being done —it’s our science, our vaccine — and we are very excited about it,” says the researcher proudly.
In addition, the team is working on a vaccine for pancreatic cancer — one of the malignancies with few treatment options — and has developed an effective approach to deliver that vaccine. It is currently under review by the NCI.
In conclusion, Lattime praises the new vaccine for cervical cancer, which is unlike the vaccines he is working on because it is a preventative. “Since the cause of the cancer is a virus, in this case the medical community has a real opportunity for prevention.”