Four years ago, Ellen Pinzur, a Cambridge woman who had been a lifetime smoker, got a most unwelcome surprise.

When she went to her gynecologist for a routine exam, he suspected she had a fibroid, a benign growth in the uterus. He sent her for an ultrasound. Sure enough, she did have a fibroid.    

But that was the good news.The test also showed that Pinzur, now 52, had bladder polyps. She had them removed, then several months later, had a checkup by cystoscopy, in which a urologist inserts a lighted tube through the urethra to see inside the bladder while the patient is under local anesthesia.

The polyps were gone, but they had “seeded” her bladder with cancerous tumors. Unlike many people who get bladder cancer, Pinzur did not have the telltale sign of blood in her urine.

In hopes of boosting the odds of beating her cancer, Pinzur joined a study in which tuberculosis bacteria, of all things, are squirted into the bladder to trigger an influx of white blood cells that attack both the TB and cancer cells. (The risk of TB spreading to other parts of the body is low.)

Perhaps because of this unusual therapy, Pinzur has been cancer-free now for two years.

The therapy she had is but one of a number of new techniques that scientists are working on to improve both treatment and diagnosis of bladder cancer, which will strike 54,200 Americans this year and kill 12,100. Men are four times more likely to get bladder cancer than women because smoking is a major trigger for the cancer, and historically, men have smoked more than women.

If caught early, while the cancer is a shallow spot in the lining of the bladder, the 5-year survival rate is 95 percent; for cancers that have invaded muscle tissue and spread throughout the body, 5-year survival is 50 to 60 percent.

But the most striking thing about bladder cancer is that it recurs in 70 percent of cases, no matter what doctors do. For the 500,000 Americans who have it, this means a lifetime of monitoring – including cystoscopy every three to 12 months.

This is not only unpleasant, it’s expensive – much more so than caring for someone with breast or prostate cancer, notes Dr. Ihor Sawczuk, vice chairman of urology at Columbia University’s College of Physicians and Surgeons.

But nearly a dozen new tests now on the market or under development could lighten this burden.

The goal of all these tests is “to make cystoscopy unnecessary,” says Dr. Kevin R. Loughlin, a urologist at Brigham and Women’s Hospital. So far, he cautions, none of the tests has replaced cytology – a noninvasive exam in which a pathologist looks through a microscope at cells shed from the bladder into the urine. If he or she sees any suspicious cells, the patient must then undergo cystoscopy, the more invasive test.

But cytology, the current “gold standard,” is not a perfect test. In fact, it picks up only about 40 percent of cancers, and is worst at spotting the most common, early stage bladder cancers.

The hope is the new tests can do much better.

Today , for instance, Matritech, Inc. of Newton will present its case to the US Food and Drug Administration, arguing for expanded approval of its already-marketed test, NMP22, which measures a protein made in the nucleus of cells in urine. High levels of NMP22 indicate high turnover of cells, a sign of cancer. The company wants doctors to use the test not just to monitor people who have cancer, as is now the case, but to test those who merely show symptoms, like having blood in the urine. In Japan, the NMP22 test is already approved for wider screening.

Overall, the test is 70 percent sensitive, which means it finds 70 percent of tumors at all stages of cancer combined.

That also means it misses 30 percent. And while that’s better than cytology, it’s still underwhelming to some urologists.

“It’s not the greatest test in the world,” says Dr. Michael O’Donnell, director of the bladder cancer center at Beth Israel Deaconess Medical Center. “I did a 6-month pilot trial at our institution and abandoned it.” The test often said patients had cancer when they didn’t and missed it in those who did have it.

Even if it were 80 percent sensitive, “that just isn’t good enough in my mind,” adds Loughlin of the Brigham.

Still, in one Italian study published last year, NMP22 was a better cancer detector than a marker called BTA. Another 1998 study found NMP22 was just as sensitive as a marker called telomerase, and that both were more sensitive than BTA. A Cleveland Clinic study published in January, showed the test was 100 percent sensitive. And a Spanish study, published this month suggested that NMP22 combined with another marker, CYFRA 21-1, can help reveal whether cystoscopy is needed.

For instance, if a patient scores low on the NMP22 test, it may be safe to postpone the invasive exam for a few months or do it under local anesthesia in the doctor’s office. If a patient scores high, it suggests the procedure should be done in a hospital under anesthesia, so that if the urologist does see cancer, he or she can remove it right then and there.

The NMP22 test may also tip the balance when other tests are ambiguous, notes Dr. Eric J. Sacknoff, a urologist at Cambridge Urological Associates. If the NMP22 score is high and a bladder X-ray is negative, for instance, that may indicate there is indeed a cancer, but higher up in the urinary system.

Ultimately, it’s not just better detection but better treatment that’s needed to turn the tide in bladder cancer.

At the Beth Israel, for instance, urologist O’Donnell is expanding the trial that Pinzur participated in to 70 centers nationwide. It’s already been shown that treating bladder cancer patients with TB seems to prevent recurrence in about 60 percent of cases. O’Donnell hopes that adding alpha interferon may improve those odds. So far, though, his study hasn’t followed patients long enough to tell.

Ultimately, says Loughlin of the Brigham, the best treatment for bladder cancer will probably be gene therapy to correct messages from errant genes on chromosomes 9 and 17. And the best way to prevent it is not to smoke. Scientists believe that bladder cancer begins when genes on one or both of these chromosomes are damaged by tobacco and other carcinogens.

So far, he says, that research is still in its infancy. But “this is where the real, major advance is going to be.”< SIDEBAR

SMOKERS AT HIGHER RISK YOU MAY BE AT RISK FOR BLADDER CANCER IF YOU ARE OVER 50, MALE OR SMOKE. IN FACT, MEN ARE FOUR TIMES MORE LIKELY THAN WOMEN TO GET BLADDER CANCER, PROBABLY BECAUSE, HISTORICALLY, THEY’VE BEEN MORE LIKELY TO SMOKE. MEN ALSO TEND TO URINATE LESS FREQUENTLY THAN WOMEN, WHICH MEANS THAT WHATEVER TOXINS OR CARCINOGENS ARE IN THE URINE STAY IN THE BLADDER LONGER. 

Smoking causes nearly half of bladder cancer deaths in men and more than a third in women. Others at risk include those who are exposed to chemicals called aromatic amines. Painters, as well as people who work in the leather, rubber, dye, and aluminum industries often use these compounds.

In recent years, the incidence of bladder cancer has been rising slowly, for unclear reasons.

One sign of possible bladder cancer is blood in the urine, either enough to see with the naked eye, or traces detected through urine testing. But this doesn’t always indicate cancer. It can also be – in fact, it usually is – a sign of infection or inflammation anywhere in the urinary tract, prostate problems, or a kidney stone. Or sometimes, simply having eaten beets can give the urine a reddish hue.

Still, if you have blood in your urine, you should call your doctor.

The drug thalidomide, which was banned in the United States after it caused serious birth defects in 10,000 babies worldwide four decades ago, can produce dramatic improvements in people with a cancer of the bone marrow, according to a study being published today.The study is a “significant advance” in treatment for myeloma, Dr. Kenneth Anderson, a myeloma specialist at Boston’s Dana-Farber Cancer Institute, said yesterday.   Myeloma, a cancer that arises in the bone marrow and that crowds out normal tissue so that the marrow can no longer make healthy blood cells, is diagnosed in almost 14,000 Americans a year. It is “notoriously difficult” to treat, Anderson said in an editorial accompanying the report in the New England Journal of Medicine. Typically, only 29 percent of people diagnosed with it survive for five years, despite treatment.

The new study, done at the University of Arkansas for Medical Sciences, involved 84 patients who had relapsed despite aggressive treatment, including marrow transplants and high-dose chemotherapy.

When given thalidomide in doses of up to 800 milligrams a day, 32 percent of patients improved at least somewhat, as gauged by lower levels of a myeloma-related protein in blood or urine tests. Two patients had complete remissions, meaning that their cancer was undetectable.

One year after starting treatment, about 22 percent of patients were alive without relapse; a total of 58 percent were alive, although some had progression of cancer. It is not clear how long the responses had lasted, although in some cases, the responses appeared to be “durable,” Anderson and his co-author, Dr. Noopur Raje, said in the editorial.

The lead researcher, Dr. Seema Singhal, formerly in Arkansas and now codirector of the myeloma and lymphoma program at the South Carolina Cancer Center at the University of South Carolina, said in a telephone interview that “the results are extremely encouraging.”

She added:  “You kind of like to believe in magic, and once in a while it happens.”

Magic might be a description of thalidomide, because, at least in myeloma, scientists are less sure now about how it might work than they were when the study began.

Initially, Singhal and her colleagues decided to try thalidomide because it is an angiogenesis inhibitor, meaning it can block the chemical signals that trigger formation of blood vessels around tumors.

But in this study, many patients who responded to thalidomide did not show a reduction in the density of blood vessels that nourish tumors in the bone marrow. That could merely be a sampling problem: Every time a doctor conducts a biopsy on a small piece of bone marrow to study, there is a chance that the section sampled has more, or fewer, cancer cells and blood vessels than the rest of the marrow.

On the other hand, said Anderson of Dana-Farber, it may also be that thalidomide is acting in other ways. For instance, it may directly attack myeloma cells, or the so-called stromal cells of the marrow on which they grow. It might work by keeping myeloma cells from attaching to stroma cells. It might block chemical signals that help myeloma cells grow. Or it might nudge T-cells to attack myeloma cells.

The fact that thalidomide not only seems to work in advanced myeloma but that it also may have several ways of acting is part of the excitement, Anderson said.

After it was banned by the Food and Drug Administration in the 1960s because it caused birth defects in the babies of pregnant women, who took it for morning sickness, thalidomide was approved last year for a type of leprosy.

But the drug, made by Celgene, was approved with severe restrictions, including the stipulation that every person, male or female, who uses it must be enrolled in a government-monitored registry.

In addition, only doctors who have received training may prescribe it. Because it can cause birth defects, women must undergo pregnancy tests before using the drug, and both men and women must agree to use contraception.

In general, however, once a drug is approved for one use, it may legally be prescribed for others as well. In addition to its promise in myeloma, thalidomide is also being studied as a treatment for AIDS-related ulcers and a virulent type of brain tumor called a glioblastoma.

Four years ago, Betty Frizzell, a retired schoolteacher from Cookeville, Tenn., was diagnosed with pancreatic cancer, one of the deadliest malignancies there is.

Normally, people with advanced tumors, like Frizzell’s, live only about five months after they are diagnosed. Frizzell, now 64, is thriving on a diet of fruits and vegetables plus a regimen of dietary supplements including pancreatic enzymes and – believe it or not – coffee enemas.She does get a bit tired of carrot juice, she says, and the coffee enemas – two in the morning, two at night – are “very time consuming.” But she’s convinced it’s worth it: “I’m sure I wouldn’t be alive today if I had not chosen this route.”

“Pancreatic cancer strikes almost as many people as leukemia, yet so far, less progress has been made,” says Dr. Robert Mayer , director of the center for gastrointestinal cancer at the Dana-Farber Cancer Institute in Boston.

In fact, pancreatic cancer is so tough to detect that by the time it is discovered, survival is often counted in weeks: 36 to 40 weeks if the cancer hasn’t spread to nearby organs, 16 to 20 weeks if it has. This year, 28,600 Americans will be diagnosed with the disease and 28,600 will die of it, according to the American Cancer Society.

That’s why the mere hint of good news, even from a tiny study of a wacky-sounding therapy involving mega-doses of dietary supplements and coffee enemas, is making the mainstream medical establishment sit up and take notice.

In the July issue of the journal Nutrition and Cancer, a pair of New York private practitioners, Drs. Nicholas Gonzalez and Linda Lee Isaacs, reported their findings on a preliminary study of 11 patients, including Frizzell, with inoperable pancreatic cancer. In all 11, pancreatic cancer was confirmed by a biopsy.

The patients, who followed a dietary regimen at home developed by Gonzalez and Isaacs, lived a median of 17 months after diagnosis, nearly triple the usual survival rate.

The regimen included mega-doses of vitamins and minerals plus pancreatic digestive enzymes such as trypsin and chymotrypsin.

Patients ate no red meat or poultry, had fish several times a week, plus eggs and whole grains. And twice a day, they gave themselves coffee enemas (admittedly bizarre, especially given the fact that a decade ago coffee was thought to possibly cause pancreatic cancer; it has since been shown not to.)

Gonzales suspects that caffeine taken rectally may relax muscles of the liver and gallbladder ducts, causing “toxins,” including byproducts from the body’s attempts to destroy cancer cells, to spill into the intestines. Drinking coffee doesn’t have the same effect, he says. (For what it’s worth, he adds, decaf doesn’t, either; what appears to work is one tablespoon of ground coffee, brewed or percolated, per pint of water.)

Odd as the regimen sounds, it “certainly warrants further investigation,” says Dr. Jeffrey White, who heads the office of cancer complementary and alternative medicine at the National Cancer Institute. In fact, his office recently decided to give $1.4 million over five years to researchers at Columbia University College of Physicians and Surgeons to test the regimen.

Even the director of the new study, Dr. John Chabot, vice chair of the department of surgery at Columbia, doesn’t have the faintest idea why the Gonzalez-Isaacs regimen might work.

“Frankly, when I first read” about it, “I said, ‘That can’t possibly work.’ Then I read the pilot data. . .[ and] said, ‘There really might be something there. I had to come to grips with it myself. I have no idea how or why it might work, but the data are compelling enough that I can’t ignore it.”

In fact, he adds, “it doesn’t matter what the underlying theory is about why it works because I think that’s something for us to investigate once we demonstrate that it works.”

 If it does. The pilot findings could be due to “selection bias,” notes Dr. Karen Antman, who heads Columbia’s cancer center. The people who were able to find Gonzalez and Isaacs and to follow the strict regimen may, for instance, have been more highly motivated or healthier than other patients.

And she can’t imagine why coffee enemas would help: “I don’t get it.” But the mere fact that some patients are alive after three years when they “should have had a median survival of four to six months” means doctors should test the regimen, not just argue with advocates of alternative therapies, she says.

Barrie Cassileth, chief of integrative medicine at Memorial Sloan-Kettering Cancer Center in New York, agrees. Variations on the Gonzalez-Isaacs regimen have been around for decades and have been “something everyone has scoffed at, including me,” she says.

What’s new is that Gonzalez “is going about the situation very systematically, trying to collect research data. That is impressive. . .I support him 100 percent and I will continue to let patients know about this study” at Columbia, she says.

She wishes the coffee enema part could be dropped because “that’s what makes people laugh at it.”

But the researchers say that, to be valid, the new study has to replicate the whole regimen because nobody knows which parts, if any, may help.

Gonzalez concedes that he, too, was initially taken aback by the idea of coffee enemas. “When I first heard about coffee enemas, I thought that was the single weirdest thing I ever heard of,” he says.

Until 20 years ago or so, the coffee enema was actually listed in the Merck Manual as a general treatment to help people feel better, though not for any particular disease. Since then, it has gained some notoriety, mostly as a new-age remedy for depression and other ailments; coffee enemas have been widely publicized on the Internet and by Hollywood stars such as Janet Jackson.

Michael Lerner, president of Commonweal, a health and environmental research institute in Bolinas, California, has researched what scientific literature there is on coffee enemas and, while not an advocate, notes that they were part of a cancer treatment developed decades ago by Dr. Max B. Gerson, a German physician. But solid data on efficacy is scarce, Lerner says.

Cassileth of Sloan-Kettering agrees, noting that repeated enemas could weaken colon function, triggering constipation. Coffee enemas could also remove potassium from the body and trigger potentially fatal electrolyte imbalances, as well as dehydration, she says, though Gonzalez says this is unlikely.

As for the pancreatic enzymes, Gonzales thinks they may have a direct anti-cancer effect, though this is unproved.

The design of the new study is simple. Columbia researchers are seeking a relatively small group of people – 72 to 90 patients – with pancreatic cancer at Stages II, III or IV, that is, cancer that is confirmed by biopsy to have spread beyond the pancreas.

Half the patients will then be randomly assigned to get the dietary regimen through Gonzalez and Isaacs and half to a chemotherapy drug, gemcitabine, which improves quality of life but prolongs it only slightly.

About 30 patients have been interviewed, but all want the dietary regimen, not gemcitabine. There’s another problem, too. Ideally, says Mayer of Dana-Farber, the researchers should not lump together three stages of cancer. If one group lives longer but has more people with less advanced cancer, it will be impossible to know whether the treatment was better or the patients were simply less sick.

Meanwhile, Betty Frizzell just keeps growing organic veggies in her garden, making her own bread and cooking Sunday dinner every week for 14 people. (Then she prepares her own meal.)

Her big problem now is that the government “is fixing to build a big interstate highway” on half of her 90-acre farm. She fears “it will be harder to fight the federal government than pancreatic cancer.”

More on pancreatic cancer

To find out about joining the new pancreatic cancer study, call Dr. John Chabot at Columbia University, 212-305-9468 begin_of_the_skype_highlighting              212-305-9468      end_of_the_skype_highlighting .

You can also read about the trial of nutritional therapy on the Web. Go to the National Cancer Institute’s Web site at http://wwwicic.nci.nih.gov/ and then click on PDQ, clinical trials database, PDQ clinical trials user’s guide, then PDQ clinical trials search form. Under diagnosis, click on “pancreatic cancer, exocrine.” The study is number 24 on the list.

To learn more about alternative cancer therapies in general, take a look at:

• “The Alternative Medicine Handbook,” by Barrie R. Cassileth, published by W.W. Norton & Co.
• “Choices in Healing: Integrating the Best of Conventional and Complementary Approaches to Cancer,” published by the MIT Press.

By this time Dr. Candace Jennings, 50, an orthopedic surgeon from Ipswich, figured she’d be back to work and blessed again with plenty of energy for her husband and sons, 7 and 13.

But even though it’s been a year since she finished chemotherapy and radiation for breast cancer, she’s only got half the energy she used to have. She tried to go back to work but had to give it up – “the energy demand was too much,” she says. And her doctors, while sympathetic, haven’t offered much hope.”Somebody’s got to solve cancer fatigue,” she says passionately. “It really affects your self-esteem,” especially if you’re used to being productive. “When you can barely get out of bed to go to the bathroom, it’s very hurtful.”

In recent years, cancer specialists have made huge strides in combatting the nausea, vomiting, and pain that often accompany cancer and its therapy, but treatment for the fatigue that can last long after treatment lags far behind. In fact, it’s a huge, under-recognized, problem for many of the 8 million Americans who’ve had cancer.

Two years ago, an organization called the Fatigue Coalition – a group of doctors, nurses, and advocates funded by Ortho Biotech to study cancer fatigue – surveyed 419 patients and found that fatigue, not pain, was the most common complaint, although half had completed treatment more than a year earlier.

In May, the group presented its latest data at a cancer conference in Atlanta. Again, fatigue was the big complaint, even two years after treatment; 76 percent of the 379 patients queried had debilitating fatigue at least once a week.

That’s “absolutely staggering,” says Dr. Russell Portenoy, head of pain medicine and palliative care at Beth Israel Medical Center in New York and chairman of the coalition.

It’s “inexcusable,” he adds, that so many cancer patients think they must simply accept feeling wiped out, and that doctors don’t take their complaints more seriously.

 But this is beginning to change. The M.D. Anderson Cancer Center in Houston recently opened a special facility to treat cancer fatigue. Memorial Sloan-Kettering Cancer Center in New York is planning one, too, and so is New York’s Beth Israel.

And though the research is preliminary, there are signs that better treatments will become available as scientists begin to untangle the many causes of cancer-related fatigue.

In some cancer patients, perhaps 15 percent, depression and anxiety are likely causes of fatigue, says Dr. William Breitbart, a psychiatrist and internist at Sloan-Kettering. But for many more, it’s the other way around – they get depressed because of their lack of physical energy.

Sometimes, fatigue is caused by the cancer itself as tumors compete with healthy tissue for nutrients. In other cases, it’s the treatments that cause fatigue – chemotherapy and radiation, or even relatively nontoxic immune-boosting drugs.

In fact, the fatigue caused by immune-modifying drugs like the interferons, the interleukins, and tumor necrosis factor is so common and so profound that researchers suspect the natural forms of these substances, called cytokines, which are made as the body tries to fight cancer, are also triggers of fatigue.

In one small study, Dr. Donna Greenberg, a Massachusetts General Hospital psychiatrist, found that a cytokine called IL-1 rose in prostate cancer patients several weeks after radiation, just as fatigue increased, though she cautions that the connection between the two events is still unclear.

Other studies on cytokines and fatigue have had ambiguous results, says Barbara Piper, an associate professor of nursing at the University of Nebraska Medical Center who works with the Oncology Nursing Society to study cancer fatigue. Despite the embryonic understanding of the physiology of fatigue, researchers are finding ways to fight it.

At Sloan-Kettering, Breitbart has just completed a study showing that the psychostimulant drugs, Ritalin and Cylert, when used alone, improved fatigue significantly over a placebo in people with AIDS, which like cancer, can cause exhaustion.

The once-banned drug thalidomide may help, too, he says, perhaps by combatting the fatigue-inducing effects of tumor necrosis factor.

Anecdotal evidence suggests that steroid drugs like dexamethasone or prednisone may also temporarily boost energy in cancer patients, says Beth Israel’s Portenoy. A drug called amantadine, already used to treat fatigue in people with multiple sclerosis, may help, too.

At M.D. Anderson, Dr. Tejpal Grover will study yet another drug, Provigil, recently approved by the US Food and Drug Administration for narcolepsy, a disorder in which patients suffer sudden sleep attacks. No one knows quite how it works, he says, but it seems to have stimulating effects like Ritalin.

When fatigue is due to anemia, which can be caused by the cancer itself or cancer therapy, iron supplements, blood transfusions, or drugs that boost red blood cells such as Procrit, made by Ortho Biotech, often help considerably.

Fatigue has also been linked to low white blood cell counts, which occur when chemotherapy damages the bone marrow. There are drugs that stimulate white-cell growth, but they are usually used to protect against infection, not to boost energy.

In some patients, fatigue lifts when infections and chronic pain are treated. And addressing fairly common problems like an underactive thyroid gland, which could be overlooked in a person with a larger problem like cancer, also helps.

The bottom line, says Dr. Wendy S. Harpham, a doctor in Dallas who, like Candace Jennings, had to give up her practice when cancer struck, is that fatigue is one of the toughest adaptations that many patients have to make.

In some ways, she says, “the adjustment to my energy limitations has been harder than managing many of the other challenges of survivorship.”

Jennings echoes that. Giving up her practice was difficult, she says, though she’s found deep satisfaction as a part-time volunteer high school biology teacher. Exercise helps, too. And so do friends, who boost energy by helping keep her morale up.

A year ago, as she was finishing chemo, her friends took cuttings from their own yards and planted a “recovery garden” in hers. Recently, they got together to celebrate the flourishing garden and Jennings’ courage. Not only could their energy prove contagious, the garden’s may, too. It’s doing so well, she says, “it’s as if it’s imbued with some kind of magic.”

Drug-free ways to fight weariness

In addition to new drug strategies to combat cancer fatigue, researchers are exploring non-drug approaches.

A number of studies have shown that exercise – even gentle walking several times a week – seems to boost energy, says Paula Rieger, a nurse practitioner at the University of Texas MD Anderson Cancer Center and president-elect of the Oncology Nursing Society.

Using energy wisely – saving it for the things you really care about – also helps, says Dr. Donna Greenberg, a Massachusetts General Hospital psychiatrist. “Be thrifty with energy,” she says. Delegate jobs – like grocery shopping – that someone else could do. Go to one social event, not two. If you’re freshest in the morning, do the important things then, and then rest.

And try to avoid self-criticism for feeling tired. “People are harsh on themselves for not being able to fulfill obligations and for needing help,” Greenberg says. “Fatigue is invisible and there’s no lab test for it. That means that people often question whether their fatigue is physical or emotional, and it’s hard to know whether to push yourself or rest.”

Many tired patients also assume that their fatigue is a sign that their cancer is progressing. Often, that’s not true.

Learning to expect fatigue also takes some of the worry out of it, cancer researchers say. Keeping a diary of the ebb and flow of energy can help, too, particularly in helping tease apart the different patterns of fatigue.

If you’re reasonably energetic and motivated in the morning, but then fade, that’s a sign you’re not depressed but simply run out of energy.

If you can hardly get out of bed in the morning and have lost interest in doing normal things, that’s a clue you may be depressed. Depression is highly treatable with anti-depressant medications and psychotherapy.

Disrupted sleep can also lead to fatigue, so sleep “hygiene” – sticking to a regular sleep-wake cycle and avoiding caffeine and other stimulants in the evening – helps.

And diet can help, too. Make sure you’re getting enough calories and that you plan meals that appeal to you.

For years now, the incidence of some types of lymphoma – the cancer that killed former US Sen. Paul Tsongas, Jackie Onassis and Jordan’s King Hussein – has been among the fastest rising of all cancers, and no one is quite sure why.

The death rate has been increasing, too. This year, 64,000 Americans will get lymphoma and 27,000 will die from it.Yet lymphoma, which springs up in the core of the immune system – in B and T cells in the blood, lymph nodes, and lymph vessels – may be the cancer with the brightest hopes for treatment, and even cure.

There’s good reason for this. In solid tumors such as breast cancer, cancer cells are packed together with normal cells; in the liquid cancers – leukemia and lymphoma – some cancerous cells float freely in the blood.

This makes them “easier to capture,” says Dr. David Rosenthal, head of the Harvard University Health Services and immediate past president of the American Cancer Society.

Over the years, the ability to study these cells has yielded a detailed knowledge of markers on the cell surface, against which promising new drugs called monoclonal antibodies are being targeted.

Lymphoma comes in two basic types – Hodgkin’s disease, which has four subtypes, and non-Hodgkin’s, which has 30 subtypes “and more as we get smarter,” says Dr. Morton Coleman, director of the center for lymphoma and myeloma at New York Presbyterian Hospital-Cornell Medical Center.

Chemotherapy and radiation work well for Hodgkin’s, which unlike non-Hodgkin’s, has been declining in incidence. Ten years after diagnosis, 77 percent of Hodgkin’s patients are alive, according to the American Cancer Society.

With the most common form of the aggressive non-Hodgkin’s lymphoma, chemotherapy can cure about 50 percent of patients. Of those who aren’t cured initially, 50 percent can be cured with high dose chemotherapy and bone marrow transplants.

“These data are really quite convincing,” says Dr. Lawrence Shulman, vice-chairman for clinical services for adult oncology at the Dana-Farber Cancer Institute.

Paradoxically, it’s the less aggressive forms of non-Hodgkin’s lymphoma that have been incurable. However, some of these do respond to monoclonal antibodies and to relatively new chemotherapy drugs like Fludara, Leustatin and Nipent.

The work that led to the development of monoclonal antibodies against lymphoma began years ago, when researchers discovered that all B cells carry a marker called CD20 on their surface, notes Dr. Andrew Zelenetz, chief of the lymphoma service at Memorial Sloan-Kettering Cancer Center in New York.

A year and a half ago, Rituxan, made by Genentech, Inc. and IDEC Pharmaceuticals, was approved by the Food and Drug Administration for a cancer called follicular lymphoma.

Rituxan works by finding and destroying all cells, normal and malignant, that carry the CD20 marker. Afterwards, stem cells in the bone marrow create a new crop of B cells. In some patients, the new crop is cancer-free. In others, it contains both healthy and malignant cells. But because Rituxan has few side effects, treatment can be repeated.

Rituxan has now been used in 15,000 patients, many of whom had relapsed after other therapy. So far, half have responded favorably, and six percent of those get a complete remission, meaning that cancer is undetectable. The benefits last about a year.

Just behind Rituxan in the pipeline is Bexxar, made by the Coulter Pharmaceutical Co. and expected to be approved later this year. It’s like Rituxan, but has a radioactive compound (I-131) attached. In trials with patients who have relapsed after other treatment, it produces a favorable response in 70 percent; of those, 30 percent had a complete remission for three years.

In patients who have not had prior treatment, Bexxar seems to produce a whopping 100 percent response rate – with 70 percent in complete remission. But Dr. Bruce Cheson, head of the medicine section in the division of cancer treatment and diagnosis at the National Cancer Institute, is cautious: “Patients relapse – no one is cured.”

Because it makes a patient’s body radioactive for a few days, Bexxar will probably have to be given in a hospital in some states, says Dr. James Levine, a lymphoma specialist at Beth Israel Deaconess.

But other states, including Massachusetts, have recently redrafted their regulations to comply with new requirements of the federal Nuclear Regulatory Commission. The NRC has concluded that at the doses suggested, such drugs drugs do not present a danger to people in close proximity to patients and therefore can be given on an outpatient basis.

Also in the pipeline is another radioactive monoclonal antibody called Y2B8, which contains yttirum and has some of the advantages of both Rituxan and Bexxar. The manufacturer, IDEC, says it will probably seek FDA approval in mid-2000.

Yet another drug, Oncolym, is aimed at a different cellular marker, HLAdr. It’s being developed by Techniclone Corp. and will be marketed by Schering AG of Germany; it could be on the market within a year and a half. Still another, LymphoCide, by Immunomedics Inc., is aimed at a different marker, CD22.

Beyond the new antibodies, scientists are trying to find other ways to treat lymphoma, including so-called antisense RNA compounds to block a gene called Bcl2 that often goes awry in lymphoma, customized vaccines to prevent relapse, and new variations on bone marrow transplants.

The bottom line is that lymphoma “is the area where there has been the most progress” in basic science, much of which is already being translated to new therapies says Dr. Jerome Groopman, chief of experimental medicine at Beth Israel Deaconess Medical Center.

Indeed, there are “more exciting treatments currently being explored for patients with lymphoma than probably for any other tumor,” says Cheson of NCI.

“Given the rapid pace of development,” adds Coleman of New York, “I fully anticipate that the overwhelming majority of patients will be cured within the next decade.”

Concern over rare tumor

A year and a half ago, Zenar Ambrozik thought he’d had a stroke – he became incontinent and began stumbling badly.

Ambrozik, now 81, was rushed from his Wakefield home to Melrose-Wakefield Hospital, where he had a brain scan. “They said, ‘Oh, boy. There’s something in your brain,’ ” he says.

There certainly was. At Massachusetts General Hospital, where he was later seen, doctors found a kind of brain tumor that is rare – it strikes 3,000 Americans a year – but it is increasing so fast some experts fear it could become the most common brain tumor.

It’s called brain lymphoma, or primary central nervous system lymphoma, and it’s a strange cancer indeed. It also appears highly sensitive to a therapy pioneered at MGH.

Between 1973 and 1991, brain lymphoma increased 10-fold nationwide; researchers initially thought it might be linked to better diagnosis or perhaps to AIDS.

But neither of those would completely explain the increase, says Dr. Tracy Batchelor, director of neuro-oncology at MGH.

Brain lymphoma appears to be a subtype of non-Hodgkin’s lymphoma, a systemic cancer that affects B cells of the immune system. But brain lymphoma is confined to the nervous system and the tumors are “biologically very distinct,” says Dr. Michael Grossbard, an MGH lymphoma specialist. They “don’t get out into the rest of the body.”

In other words, people with brain lymphomas don’t usually have systemic lymphoma, even though the latter can spread to the brain. “Even when systemic lymphomas do spread to the brain, they look very different from primary brain lymphomas,” says Dr. John W. Henson, executive director of the MGH brain tumor center.

Nobody knows where brain lymphomas arise, but it’s probably some “cryptic location elsewhere,” says Dr. Fred Hochberg, an MGH neuro-oncologist. What is clear is that brain lymphomas are highly lethal. “This kills people within four months if it’s not treated,” he says.

Historically, doctors used whole-brain radiation, which temporarily eradicated tumors, but caused memory loss and did not have a long-term survival benefit. The new treatment – high dose methotrexate – does seem to work, MGH doctors say. In fact, Zenar Ambrozik is back to playing golf and says his progress has been “fantastic.”

Over the last three years, MGH has treated 30 patients and 80 percent went into remission. Half relapse after two years, but half of those can achieve remission again with re-treatment.

“This is very unusual for brain tumors,” says Batchelor. “This is a uniquely sensitive tumor.” The team is now working with nine other medical centers to broaden their research.

More information

For more information, you may contact:

• Cure for Lymphoma Foundation, 212-213-9595 begin_of_the_skype_highlighting              212-213-9595      end_of_the_skype_highlighting; on the Web it’s www.clf.org.

• Lymphoma Foundation of America, 800-500-9976 begin_of_the_skype_highlighting              800-500-9976      end_of_the_skype_highlighting or 310-204-7040 begin_of_the_skype_highlighting              310-204-7040      end_of_the_skype_highlighting; on the Web, it’s www.lymphoma.org.

The worst part of Colleen Combes’ breast cancer treatment three years ago, besides losing her hair, was the awful mouth sores caused by chemotherapy.

These ulcers “were like canker sores that had broken open, only much worse. They were everywhere – on my tongue, the inside of my lips, my cheeks. It was very painful. I couldn’t eat. It was difficult to talk,” says Combes, a 41-year old Rockland woman currently on leave from her job in a law firm.But in January, when Combes’ cancer had spread and she needed a stem cell transplant (a major procedure akin to a bone marrow transplant), things were different. She had no mouth sores despite the even higher doses required in the second round of chemotherapy.

Just before the transplant, Combes agreed to participate in a test of a new drug to prevent mouth sores. She still doesn’t know for sure whether she got the drug or a placebo, but she had “no mouth sores, nothing. I was ecstatic.” Perhaps because of this, she says, she also went home sooner than most patients.

Until recently, the main reason doctors had to limit or stop chemotherapy in many patients was damage to the bone marrow or immune system – the body’s infection-fighting equipment.

Now, that problem has become more manageable, thanks to drugs that protect the marrow, and mouth sores and other oral complications are becoming the number-one treatment-limiting issue, says Dr. Stephen Sonis, chief of oral medicine, oral maxillofacial surgery and dentistry at Brigham and Women’s Hospital in Boston.

“It’s a major, major problem,” agrees Dr. Jerome Groopman, chief of experimental medicine at Beth Israel Deaconess Medical Center.

This year alone, 1.2 million new cases of cancer will be diagnosed among Americans. About 400,000 patients will develop oral complications from their treatment, many to the point where they’ll need morphine or will have to stop treatment altogether, which can affect survival.

Those like Combes who have stem cell or bone marrow transplants, which involve high-dose chemotherapy, are at special risk: 75 to 80 percent get severe oral complications, says Dr. Philip Fox, former clinical director of the National Institute of Dental and Craniofacial Research at NIH and now research and development director at Amarillo Biosciences Inc. in Amarillo, Tex.

Indeed, oral complications from cancer treatment are emerging as such a major problem that the National Institutes of Health recently launched a public education campaign to raise consciousness of the issue among patients, doctors and dentists.

Like cancer cells, cells that constitute the mucosal lining of the mouth have a quick turnover rate. This means that, like cancer cells, they are easily killed by chemotherapeutic agents.

As cells in the mouth die, they release molecules called cytokines, which cause inflammation that further damages mouth tissue. The resulting breaks and ulcers then make it easy for germs from the mouth to enter the bloodstream and cause systemic infection, particularly since the immune defenses are also hurt by chemotherapy.

In other words, once the lining of the mouth is damaged, patients lose a key “physical barrier” to infection, says Groopman. On top of that, patients often have so much pain from mouth sores that they can’t eat or absorb much-needed nutrients.

With head and neck cancers, which will be diagnosed in about 30,000 Americans this year, the main problem is the radiation that patients get after surgery. Radiation can destroy saliva glands, as well as blood vessels and bones in the mouth and jaw.

Saliva is essential, not just because it lubricates the mouth but because it contains proteins that fight viruses, yeast and bacteria. Without saliva, patients have difficulty swallowing, chewing, speaking and fighting infection, which means tooth decay can become rampant.

In addition, radiation can damage blood vessels and the jawbone to such a degree that if a person later needs a tooth extracted, the bone may never heal. Taken together, this means that patients with head and neck cancer should get major dental work done before radiation.

But it’s chemotherapy, because it affects more people, that’s an even larger concern, specialists say, and some drugs, especially fluorouracil (5-FU), cytarabine, methotrexate, and some combinations of drugs, are particularly damaging.

On the plus side, scientists have “learned more about mucositis, or mouth sores, in the last two years than in the prior 50,” notes Sonis. As a result, a number of new drugs to prevent or treat mucositis are now in testing.

At the University of Connecticut Health Center in Farmington, Dr. Douglas Peterson, head of oral diagnosis, has completed a study in stem cell transplant patients of a drug called misoprostol, already on the market for stomach ulcers. Taken in mouthwash form within two hours of the start of chemotherapy, he says, the drug may reduce oral tissue injury. Other data, however, suggests that in tablet form, the drug can make mucositis worse.

At the Fred Hutchinson Cancer Research Center in Seattle, Dr. Mark Schubert, director of oral medicine, along with Sonis and others, is testing a new antimicrobial drug, IB367. The idea, says Schubert, is to see if by killing oral bacteria and yeast, the drug can reduce the severity of mucositis. This is the drug Colleen Combes, the breast cancer patient, thinks she had.

Elsewhere, researchers are testing growth factors called KGF-1 and KGF-2, designed to stimulate oral mucosal cells called keratinocytes. Others are testing TGF-beta3, a drug that stops cells from dividing and hence might help cells in the mouth escape the damage from chemotherapy drugs.

Still others are testing an amino acid called glutamine that, when swished in the mouth, might help mucosal tissue to regrow. Also under study is benzydamine, a drug that may block inflammation of mouth tissue, and Il-11, a drug that may block mucositis in multiple ways.

For patients like Combes, these and other drugs in the works hold the promise not only of increasing quality of life during and after cancer treatment but, because they may enable more people to complete treatment, may boost the chances of survival.

It’s not easy to get yourself to the dentist when you’ve just been told you have a life-threatening disease. “People with cancer have a gazillion things to think about,” says Sonis of the Brigham. “It’s like sitting under a dump truck and getting unloaded on. But to the extent that they can be proactive and get to the dentist, it’s a huge help.”

Treat the mouth before therapy

If you’re facing chemotherapy for any kind of cancer or radiation for head and neck cancer, it’s important to get major dental work done before you start treatment, according to the National Institutes of Health.

With radiation in particular, treatment can damage oral tissues so severely that dental work later, including tooth extractions and gum surgery, may be difficult or impossible.

During cancer treatment, mouth care is also crucial, which means you should:

• Brush teeth gently with an extra-soft toothbrush or foam sponges. Brush after every meal and at bedtime.

• Floss once a day to remove plaque, unless your oncologist says your blood platelet levels are so low that the risk of bleeding is too great.

• Rinse your mouth often with water or salt water and ask your oncologist or dentist if you should use a fluoride gel or rinse as well.

• Don’t use mouthwashes that contain alcohol, as most commercial mouthwashes do.

• Use a saliva substitute such as Biotene to help keep your mouth moist.

• Eat soft, easy-to-chew foods.

• Don’t eat spicy, sour or crunchy foods.

• Eat foods that are warm but not too hot or cold.

• Avoid alcoholic drinks.

• If you smoke or chew tobacco, quit and ask your oncology team for help if you need it.