Two and a half years ago, several months before she died, Abigail Burroughs, a 21-year old senior at the University of Virginia, sat with her father as chemotherapy dripped, once again, into her body. Together, they mapped out a plan they hoped would save Abigail’s life, and the lives of other desperately-ill people.Burroughs, who was diagnosed with head and neck cancer at 19, had taken every medication her doctors could think of, to no avail. Her last chance, she believed, might be two experimental drugs, Erbitux (still not approved by the US Food and Drug Administration) and Iressa, approved in May.

The Burroughs begged the manufacturers, ImClone and AstraZeneca, respectively, to give her the drugs on a “compassionate use” basis, but  ImClone said did not have such a program at that  time. (It does now.) And  AstraZeneca, which was giving Iressa free to 22,000 people with lung cancer, said no because Abigail had the wrong kind of cancer.

These drugs might not have helped Abigail. But she and her father, Frank, became convinced that seriously ill people should be allowed to get- and even pay manufacturers for – experimental drugs once they have passed preliminary (Phase I) safety trials in humans, even if the drugs might turn out to be dangerous, or useless.  In their view, the currently-available ways to get experimental drugs  – through clinical trials,  “compassionate use” or “expanded access” programs – are tragically inadequate.

So this summer, Frank Burroughs, who now heads the Abigail Alliance for Better Access to Developmental Drugs, teamed up with the Washington Legal Foundation and sued the FDA to loosen its rules.

They want the FDA to create a new level of review called Tier 1 Initial Approval. Under this plan, patients would be able to get an experimental drug if it drug has passed Phase I trials, if the patient has been rejected from clinical trials of the drug, and if nothing else has worked. Perhaps most controversially, they also want to allow patients to be allowed to pay manufacturers for these minimally-tested medications.

Despite its powerful emotional appeal, the Tier 1 plan is creating a firestorm of opposition, including from other patient advocacy groups.

 Fran Visco, president of the National Breast Cancer Coalition based in Washington, D.C., says, “We have a system in place to prove the safety and efficacy of therapies. We can’t afford to undermine that system. The system is premised on [the idea that] drugs should not be available until they are proven safe and effective. ”

Visco points to two notorious instances in which medical interventions became widely used without adequate testing and later proved to be harmful or ineffective: bone marrow transplantation for breast cancer and hormone replacement therapy for menopause. Asked whether an individual should nonetheless be free to choose his or her own risks, she is emphatic. “When you start talking public policy, decisions have to be made. It’s not on the individual autonomy level.”

Nancy Roach, a director of the Marti Nelson Cancer Foundation based in Vacaville, CA, also opposes the Tier 1 idea, saying “it would rip the heart out of clinical research,” adding “these drugs are not candy, they are not harmless.”

At the end of a Phase I (safety trial), a drug may have been tested in only a few dozen people, she notes. (It is not until larger Phase II and Phase III trials that a drug is tested in more people and researchers study dosages and efficacy.)  “You don’t give drugs to people unless there’s a good reason to, you know how to give them, and the person has some chance of benefiting,” argues Roach.

Medical ethicist Dr. Marcia Angell, the former editor of the New England Journal of Medicine and senior lecturer on social medicine at Harvard Medical School, is also opposes to the Tier 1 idea. “New drugs are far more likely to fail than to succeed, so the chances are that a patient will be hurt by a drug rather than helped,” she says. She also rejects the idea that manufacturers need financial incentives to release them. Drug companies already “are profitable beyond any industry,” she says. “They are protected by the government. They have monopoly rights, patents, tremendous tax breaks.”

The pharmaceutical industry also vehemently opposes the Tier 1 idea. Alan Goldhammer, associate vice president for regulatory affairs for the Pharmaceutical Research and Manufacturers of America, says it would be “potentially reckless” to release drugs after only Phase I trials because at that point there is “no proof of efficacy at all.” There could also, he adds, “be potential product liability issues.”

At the FDA, Terry Toigo, director of the office of special health issues, says the agency has no comment on the lawsuit but adds, “We’re always looking to hear from people about ideas on where our system doesn’t work.”

For seriously ill patients like Abigail Burroughs, there are many parts of the system that don’t work.

It takes at least 10 years (and $800 million) for the average drug to pass through Phase I, II and III clinical trials en route to full market approval. Many patients can’t wait that long, and four out of five drugs fail along the way.

In addition to joining a clinical trial  (which can be hard to get into for medical or geographic reasons), there are a few ways to cut the waiting time, but they involve navigating a complex, bureaucratic maze. Under  “compassionate use,” also called a single patient IND (for investigational new drug), a doctor can write the manufacturer asking for a specific drug for a specific patient. The FDA reviews this request and usually approves. The company may then – but does not have to – give the drug to the patient.

Another route is the expanded access” program, in which a drug maker develops a protocol for giving the drug to an entire group of patients who meet medical criteria. If the FDA approves, the company then enrolls patients, but often there are more patients than drug available, in which case the company may set up a lottery. Drug makers can charge for “cost recovery” but usually don’t.

Companies can also try to rush drugs through the FDA under the “accelerated approval” program, as occurred with AstraZeneca’s Iressa.  In this scenario, the company gets approval on the basis of “surrogate markers,” such as regression of a tumor, rather than demonstrated clinical benefit, such as increased survival.

Companies can also ask for a “priority review” if a new drug would be a significant improvement over drugs already on the market. And they can “fast track” a drug by submitting data on a rolling timetable, as the research marches along, not just at the end of the process.

For many patients, this system works well enough. For others, including Ruth-Ann Santino of Arlington, it doesn’t. Two years ago, Santino “wrote the world” to put pressure on ImClone to give her Erbitux, says her husband, Fred Santino. The Santinos even heard of  another patient who appeared to have gotten the drug from ImClone.

 But Ruth-Ann Santino never did. She died in May, 2001.

Dean Gordanier is a tax lawyer, fitness buff, father of three and, at age 54, a veteran of the roller-coaster ride of hope and despair that is becoming a way of life for growing numbers of people with cancer, thanks to the promise, and the heartbreak, of a new generation of cancer drugs.Many of these drugs, which oncologists call “targeted therapies,” are breathtaking scientifically. With names like Gleevec, Avastin, Iressa, Rituxan, Herceptin, even the still-nameless drug known as SU11248, these drugs are the closest scientists have come yet to the holy grail of cancer treatment – knocking out cancer cells with great specificity without wreaking too much havoc on the rest of the body.

Some of these drugs target specific enzymes called kinases that act as switches that control cell functions; in some cancer cells, kinases are locked in the “on” position. Others are monoclonal antibodies that attack  markers on the surface of cancer cells. And some starve tumors of blood supply by attacking proteins that make blood vessels grow.

“I am so unbelievably excited about the science because it is like standing on the Nina, the Pinta or the Santa Maria. You can see the New World coming,” says Dr. George Demetri, director of the Center for Sarcoma and Bone Oncology at the Dana-Farber Cancer Institute in Boston.

Gordanier is excited, too, as well he might be, since these drugs have saved his life – twice. But he is wary as well. Like any seeming miracle treatment, targeted therapies are fabulous if, and while, they work. But because cancer cells are wily and can mutate to escape a drug’s action, even the most promising drug may stop working after a while. 

In the fall of 1999, Gordanier went to his doctor complaining of acid indigestion. Two days after Christmas, he had tests that showed a grapefruit-sized lump in his belly. It turned out to be a potentially deadly kind of stomach cancer called GIST (gastrointestinal stromal tumor).

In early January, 2000, Gordanier signed a consent form “acknowledging that life is uncertain and evisceration has its risks,” as he wryly put it in his diary, and underwent a drastic form of surgery called a “Whipple” in which doctors removed the tumor, 90 percent of his stomach, his spleen, 70 percent of his pancreas and his transverse colon.

But by September, his pain- and his cancer – were back. Doctors tried chemoembolization, or squirting chemotherapy drugs directly into the blood supply of his tumors, which had now spread to his liver. It didn’t work. In late February and early March of 2001, he simply “waited to die,” as he wrote in his diary.

Then he got lucky, joining a clinical trial of Gleevec for GIST. (In May, 2001, the US Food and Drug Administration approved Gleevec for chronic myeloid leukemia. The FDA went on to approve Gleevec for GIST in February, 2002.)

“I have been saved by the bell,” Gordanier wrote in his journal. “It looks like Gleevec will allow me to struggle on with a good possibility of a successful outcome, if you define success (as I do) as being able to live and work without pain and to enjoy each day as it comes and for what it brings.”

But 18 months later, by December, 2002, Gleevec had stopped working, as it does in about 75 percent of people after two years.

Once again, death loomed perilously close until Gordanier’s doctor referred him to Demetri. Demetri suggested  SU11248, an experimental new drug also called Sugen, for the company that developed it. (It is now made by Pfizer.) Since mid-January, Gordanier has been taking SU11248. So far, it’s working.

“It’s a holding action,” says Gordanier. “The cancers will mutate. But I will be alive as long as the doctors can keep one step ahead of the tumors.”

As Gordanier and others with life-threatening illnesses have learned the hard way, it’s crucial to ask questions about any new drug, even an apparent wonder drug that sounds like the best, or only, option.

“With any kind of experimental drug, you want to know two things: how likely is it to help, and what kind of harm can it cause?” says Gordanier. “If the likelihood of buying more time is low and severe side effects are a real possibility, it’s hard to decide whether to risk whatever good weeks or months you have left- no matter how desperate you are.”

For instance, even when a new drug is successful by statistical standards, the impact in real life may be minimal. Avastin, for instance, garnered big headlines at the recent meeting of the American Society of Clinical Oncology because it proved an important principle: That blocking a tumor’s blood supply can slow tumor growth.

But the drug only prolongs life for an average of five months in colon cancer patients. Whether that is a lot or a little “depends on what the five months are like. Is the five months likely to be spent in the intensive care unit of a hospital or at home?” asks medical ethicist Dr. Walter Robinson, a pediatric pulmonologist Boston’s Children’s Hospital.

Patients should also ask doctors to explain carefully the figures they quote from studies. Usually, such figures are averages, which means that if a drug prolongs life by five months on average, some people may get 10 months or more, some barely any.

And if you’re basing your decision on results of a few specific studies, ask exactly what those studies measured, cautions Dr. Sidney Wolfe, director of Public Citizen’s Health Research Group, an advocacy group in Washington, D.C.

“You really want to know whether the drug is effective for treating the condition you have, not some surrogate end point. Lowering blood pressure doesn’t count unless it decreases stroke,” he says. It may not be compelling for a drug “just to shrink tumor size temporarily if it’s not accompanied by increased survival.”

Ask about side effects, too, though with very new, experimental drugs, doctors may not know much. Rita Raj, a women’s health advisor to the United Nations in New York, has taken Gleevec for stomach cancer, like Gordanier. Her tumor appears to have disappeared, she says, but she has had side effects, chiefly fluid retention and kidney failure.

“Be extremely proactive,” adds Cyndie Mc Lachlan, 63, a philanthropist from Lopez Island, Wash., who was given one to three months live when she was diagnosed with advanced lung cancer nearly two years ago. She has been taking Iressa and seen the  tumors in her lungs and brain shrink dramatically.

The bottom line for patients like these is that these new drugs, imperfect as they still are, can buy time – time in which still newer, and possibly better drugs, may be found.

“I’m feeling good each day, and new drugs are in the research pipeline, but nothing is certain,” says Gordanier. “I’m still doing my best to live my life one day at a time.”

There’s a revolution brewing in the diagnosis of cancer that could dramatically change how doctors figure out which tumors are truly life-threatening – and need chemotherapy — and which are not.

In the Netherlands, the new tool – called by various names, including gene expression profiling – is expected to be available for some women with breast cancer as soon as May. In the US, it could be several years before the technique is routinely available.But if gene profiling lives up to its promise, thousands of patients a year with tumors deemed unlikely to spread might safely skip chemotherapy. At the other extreme, people with cancers deemed lethal might skip chemotherapy if it’s unlikely to work, and go straight to experimental or alternative therapies.

With early stage breast cancer, for instance, doctors currently vastly over-treat because they can’t tell which patients need chemotherapy and which don’t.  Dr. Eric Winer, director of the breast oncology center at the Dana-Farber Cancer Institute in Boston estimates that in some situations, 100 women get chemotherapy for every 20 helped and in other cases, it’s 100 to 1.

With gene profiling – also known as genetic fingerprinting, molecular signatures and molecular profiling – the idea is to determine which genes are expressed, or turned on, in a given tumor.

Once genetically analyzed, tumors can then be categorized as having a good prognosis or not, and treatment can be chosen accordingly. Gene profiling will likely be used in addition to measures doctors already use, such as tumor size and whether the cancer has spread to lymph nodes. It will also be used to determine whether a tumor is likely to respond better to drug A or drug B.

Various teams of researchers have studied gene profiling in a number of different cancers and so far, perhaps surprisingly, there is very little overlap in the genetic patterns.

Several years ago, Charles Perou, now assistant professor of genetics at the University of North Carolina, with David Botstein and Pat Brown of Stanford University, identified a set of 450 genes that can predict outcome in breast cancer.

At Dana-Farber Cancer Institute in Boston, Dr. Sridhar Ramaswamy and his team have identified a set of 17 genes that seem to be harbingers of metastasis in various cancers. And in the Netherlands, Dr. Marc J. van de Vijver, Rene Bernards and others have identified a set of 70 genes that can predict which breast tumors will metastasize, or spread to other parts of the body, and which won’t.

Researchers have also used gene expression to predict outcome in cancers of the kidney, lung, and prostate. In B-cell lymphomas, they have identified one set of 16 genes and another of 13 genes that can do likewise. In one subtype of ALL (acute lymphocytic leukemia), researchers found a set of 20 genes that can predict which patients will develop a secondary cancer called AML (acute myelogenous leukemia).

This dazzling, even frightening, ability to predict the future is possible because of commercially available “gene chips” or DNA micro-arrays.

Imagine a thin, roughly one inch square plate of glass containing thousands of tiny spots of DNA, each spot representing a single human gene. Researchers then take genetic material called mRNA from a tumor and spread it on the DNA. If the mRNA finds its match on a spot of DNA, it sticks, and, because it’s been pre-treated, fluoresces under a special light. This technique – at roughly $1000 a test  – tells researchers which genes are active in that particular tumor.

The idea that a tumor’s potential to metastasize may be knowable while a tumor is still very small is both encouraging and distressing.

Historically, doctors believed tumors started off benign and mutated to acquire the ability to metastasize. ”Our study shows that this notion, at least for breast cancer, is wrong,” says Bernards, the senior author of the Dutch study on 70 predictive genes and head of the division of molecular carcinogenesis at the Netherlands Cancer Institute.

In other words, ”small does not mean benign,” he continues. ”We have seen small tumors that are poor in outcome and we have seen large tumors that have a good prognosis.”

That concerns Dr. Larry Norton, head of solid tumor oncology at Memorial Sloan-Kettering Cancer Institute in New York. ”It’s a big stretch to say if a cancer is bad, you might as well give up,” he says. ”It may be that those tumors are the most curable with therapy.”

Dr. Steven Goodman, a biostatistician and epidemiologist at the Kimmel Cancer Center at Johns Hopkins University is also cautious. So far, he says, ”there is absolutely zero evidence that by deferring chemotherapy based on these predictions you are better off.”

Despite concerns by some scientists that large prospective clinical trials should be conducted before gene expression profiling hits the clinic, the technique appears be on the fast track.

Bernards, who collaborated with scientists from Rosetta Inpharmatics (a wholly-owned subsidiary of Merck & Co.) on the study of 70 predictive genes, now has his own company, Agendia, Inc. in Amsterdam that, he says, ”allows us to offer this test.”

Celera Diagnostics is also doing a study correlating gene expression in breast tumors with progression of disease, with results expected later this year, says Tom White, chief scientific officer.

At Massachusetts General Hospital, a team led by Dr. Daniel Haber, director of the Center for Cancer Risk Analysis, with colleagues from Brigham and Women’s Hospital and Dana-Farber, has started testing 500 frozen breast cancer samples, in collaboration with the Dutch group. Funded by the Avon Foundation, the team hopes to test 5,000 samples in the next few years. ”Clearly, this is at the cutting edge of oncology,” says Haber, though he warns that it should be validated in a large prospective study before patients use it to make decisions about treatment.

One development that could speed things up is an idea being tested independently at Celera Diagnostics, Genomic Health, Inc. and researchers from Duke University and the University of North Carolina.

Instead of using frozen samples of tumor tissues, as the Dutch do and others do, these scientists are testing genetic profiling on tumor tissue that has been ”fixed” in formalin (formaldehyde) and embedded in paraffin wax for long term storage.

Until recently, scientists had thought formalin-fixed tissue “was unstudy-able,” says Dr. Matthew Ellis, clinical director of Duke’s breast cancer program, because the RNA in the tumors degraded. “That turns out not to be the case,” he says. ” We can do profiling on formalin-fixed tissue, and that is incredibly powerful.”

If this strategy works, “we can analyze 10 years’ worth of information in six months,” says Ellis.

Molecular biologists aren’t a particularly grumpy lot, but they are grumbling these days that corporate interests – particularly those of the California-based Geron Corp. – may be stifling development of a promising new class of anti-cancer drugs called telomerase inhibitors.

Telomerase is a weird enzyme – part protein (called hTERT), part RNA (hTR). Its job is to restore a tiny bit of DNA at the ends of chromosomes.As normal cells divide over the course of a lifetime, these tiny bits of DNA, called telomeres (prounounced TEE-low-mears), gradually get shorter and shorter until they virtually disappear. Without telomeres, the cell can no longer divide, and therefore dies.

Unlike normal cells, cancer cells have figured out a way to keep making telomerase so that telomeres are kept intact. The obvious implication is that blocking telomerase with drugs should destroy cancer cells – and indeed it does, at least in the lab.

The grumbling – by some of molecular biology’s biggest superstars – is unusually bitter because 90 percent of human cancers show over-activity of telomerase, suggesting that they would be vulnerable to anti-telomerase drugs.

At telomere meetings, it’s “common for people to sit around and tell Geron horror stories,” says  Elizabeth Blackburn, professor of biochemistry and biophysics at the University of California, San Francisco School of Medicine. The co-discoverer, in 1985, of telomerase, Blackburn consulted  briefly with Geron in the past but stopped that arrangement, citing potential conflict of interest. As a university employee, she is listed as a co-inventor of telomerase inhibition technology. She no longer has ties to Geron.

Carol Greider, the other co-discoverer of telomerase and a professor of molecular biology and genetics at the Johns Hopkins University School of Medicine, says that the legal agreements Geron writes to share materials with others “are often onerous,” she says, adding, “I have decided not to try to get material from them, knowing it would be difficult.”

Robert Weinberg, a professor of biology at the Massachusetts Institute of Technology and a member of the MIT-affiliated Whitehead Institute, is even more blunt. “No one in this country has had the temerity to move into this field – they didn’t want to risk the ligitation,” he says. “All this is a shame because telomerase is an extremely attractive target for anti-tumor therapy and Geron, by squatting on its patent estate, has really blocked other people from attempting to develop possible useful anti-tumor drugs.”

Not surprisingly, Geron strenuously disputes this.  “Those statements are simply not true,” says Geron’s chief scientific officer, Calvin Harley.  At a recent meeting in San Francisco and others over the last seven years, he says, “we have shown all our data. We’re highly collaborative. We have given our reagants [research materials] to hundreds of labs.”

And Nobel Laureate Tom Cech, president of the Howard Hughes Medical Institute and the co-discoverer, in 1997, of the protein portion of the telomerase enzyme, undertands that view. “I don’t see anything different in the way Geron is treating telomerase than the way any biotech company treats its intellectual property,”  he says, adding that he has “no connection” to Geron except that the company has licensed patents on discoveries made by Cech and his group at the University of Colorado.

Unlike most enzymes, which consist entirely of protein, telomerase is a combination of a protein called reverse transcriptase, which copies RNA into DNA, and a chunk of RNA, one form of genetic material that can also act as an enzyme.

Years ago, Blackburn noticed that the DNA on the ends of chromosomes “was growing and shrinking, which was not what DNA was supposed to do,” as she notes. She hypothesized that a special kind of enzyme called a polymerase must be at work. (Polymerases help create new chains of DNA.)

She and her then-graduate student Carol Greider found the enzyme and named it telomerase. It is highly active in early fetal development, when cells are rapidly dividing. But from birth through adulthood,  telomerase is made at low levels in normal cells and stored in a tiny structure called the nucleolus inside the nucleus. Just before a normal cell divides, telomerase moves to the nucleus where it restore telomeres to shrinking chromosomes.

In cancer cells, and normal cells that divide rapidly such as stem cells in the bone marrow and skin , telomerase goes back to its furious, fetal pace. As a drug target, this raises some concerns. Anti-telomerase drugs might harm some normal cells, though researchers say this is unlikely because tumor cells have shorter telomeres and therefore would be more susceptible than normal cells to anti-telomerase drugs. In addition, stem cells don’t divide often, and when they’re not dividing, they should not be impacted by the drugs.

Another concern is that, as cells “erode their telomeres, they may go into a state of genetic instability, which, ultimately, could fuel the emergence of resistance to telomerase and other anti-cancer therapies,” says Dr. Ron De Pinho, professor of medicine and genetics at the Dana-Farber Cancer Institute.

Despite such concerns and all the squabbling, telomerase research is chugging along. Studies on 20 different types of tumors in laboratory dishes and in at least 10 animal models show that blocking telomerase does indeed cause cells to die. (Internationally, Boehringer Ingelheim is also working on telomerase, though the company adds the “therapeutic benefit” from inhibitor drugs “remains an elusive target.”

Geron expects to start human trials later this year in patients with a kind of brain cancer called glioblastoma using a drug dubbed GRN163. This compound is a telomere-like bit of DNA that binds to the key region of the telomerase enzyme, blocking its action.

The GRN163 drug is not perfect, in part because it’s 10 times bigger than most drugs. (In general, the smaller the drug molecule, the more easily it gets into cells.) But so far, says Harley of Geron, GRN163 has shown “no significant toxicity.”

Geron is also conducting a clinical trial of a telomerase vaccine in 20 men with prostate cancer with researchers from Duke University.

Unlike conventional vaccines, this one is designed to treat, not prevent, disease. The Geron vaccine is made individually for each patient, using the patient’s own immune cells, which are removed from the bloodstream and coaxed to display tiny pieces of the telomerase molecule, like little flags, on their surfaces. These cells are then re-injected in hopes of triggering a widespread immune response to cells carrying telomerase “flags.”

Other ideas are in the pipeline, including using detection tests for telomerase to diagnose cancer from blood samples, making “toxic telomeres” to destroy cancer cells, using viruses controlled by telomerase regulators to kill tumor cells, and seeing whether newly-discovered proteins that regulate the binding of telomeres to the ends of chromosomes might also be drug targets.

All this will, of course, take time. But it may also take tinkering with the delicate balance of corporate interests and public health. 

As Tyler Jacks, director of the Center for Cancer Research at the MIT puts it, “There is a desperate need for more specific and more effective drugs for treating cancer. It would be extremely unfortunate if, due to intellectual property considerations, a very promising cancer target were not pursued as vigorously and as broadly as possible.”

Sadly enough, it often seems to take a celebrity patient to get the rest of us to sit up and take notice of certain diseases, especially diseases  in which the patient’s own behavior contributes to the risk.

This time, the celebrity is an active, young mother, Kara Kennedy , 42, the daughter of Sen. Edward M. Kennedy (D-Mass.). And the disease is lung cancer – the biggest cancer killer in the country, whose primary cause is smoking – an addiction, to be sure, but a potentially modifiable behavior as well.Kara Kennedy, a smoker, had a cancerous portion of her right lung removed 12 days ago at Brigham and Women’s Hospital in Boston and was recuperating last week before starting chemotherapy.

Though she may receive lots of emotional support, the societal prejudice against many lung cancer patients runs deep.

But this longstanding attitude is beginning to lift, thanks in part to a massive new study launched last fall by the National Cancer Institute. The $200 million, 8-year study is called the National Lung Screening Trial (NLST). It will involve 50,000 healthy smokers and former smokers at 30 medical centers across the country. So far, almost 10,000 have signed up. (For more information, visit http://cancer.gov/nlst or call, 1 800 422 6237 begin_of_the_skype_highlighting              1 800 422 6237      end_of_the_skype_highlighting.)

The trial is designed to determine which screening test, chest X-rays or a relatively new technology called spiral CT scanning, is more effective at reducing deaths by catching cancers at an earlier stage. (Currently, neither test is recommended for routine screening.) Researchers will also collect and store blood, urine and sputum samples to see which participants might be at higher genetic risk of lung cancer.

This year, 171,900 Americans will be told they have lung cancer and most will have spreading disease at the time of diagnosis. (Breast cancer, by contrast, will strike more people (212,600), but most cases will be caught before the cancer has spread.)

In a sense, there might appear to be no need for the big lung cancer trial. Everybody already knows that smoking causes lung cancer, or to be more precise, that it causes 80 to 85 percent of cases. (It’s not clear why nonsmokers also get lung cancer, why lung cancer is rising among nonsmokers, or why female nonsmokers are more likely than male nonsmokers to get the disease.)

So, if all smokers just quit, much of the lung cancer problem could disappear, which would free researchers (and funds) for cancers with less obvious causes.

But in reality, there’s an enormous need for this trial, says Dr. Denise Aberle, chief of radiology at the David Geffen School of Medicine at UCLA and one of the two co-principal investigators in the study.

Historically, lung cancer has gotten less funding than other cancers, even though it is responsible for more cancer deaths per year than cancer of the colon, breast, prostate and pancreas combined.

In 2001, the latest year for which figures are available, the National Cancer Institute spent a relatively paltry $206.5 million on lung cancer, compared to $475.2 million on breast cancer. Yet lung cancer is projected to kill 157,200 people this year, according to the American Cancer Society – nearly four times the deaths expected from breast cancer.

And the “reservoir” of people at risk is huge – 45 million current smokers and 45 million former smokers. Moreover, if the $200 million trial, as hoped, shows that early detection translates into lives saved, it could make a sizeable dent in the nearly $5 billion the country now spends annually to treat lung cancer patients, Aberle notes.

“This is an incredibly important trial,” agrees Dr. Phillip Boiselle, director of thoracic imaging at Beth Israel Deaconess Medical Center in Boston, one of the Massachusetts sites for the study. (The other is at Brigham and Women’s Hospital). “Even if widespread efforts at smoking cessation are successful, lung cancer will continue to be a major problem because the risk among former smokers, though less than for smokers, is still high.”

Not only does the trial address “the most lethal cancer that we face,” adds Dr. Andrew C. von Eschenbach, director of the National Cancer Institute, it should point the way to better detection at a stage of disease when therapy can do the most good. “We need a proven effective way to detect lung cancer when it is still curable.”

In recent years, studies of smokers and former smokers (including one in Japan in 1996 and one in New York in 1999) have convinced researchers of the need for a truly definitive trial.

These studies showed that spiral CT scans (an improved version of the standard computed tomography X-rays) are good at catching cancers while they are small) and in fact, are better than chest X-rays. But because these studies were small and did not randomize participants to get CT scans or chest X-rays, they could not show whether earlier detection saves lives, says Robert Smith, director of cancer screening at the American Cancer Society.

Another study, by the Mayo Clinic in 2002, also showed that spiral CT scans are better than chest X-rays at finding small tumors, but it highlighted a problem that the earlier studies also suggested: spiral CT scans are so sensitive that they often pick up tiny abnormalities that turn out not to be cancer.

Indeed, most of the abnormal nodules detected in the Mayo study turned out to be false alarms, often just tiny patches of scar tissue from bronchitis or pneumonia. But finding any suspicious nodule often sets a patient on a path of follow-up and further testing, sometimes including surgery.

The high rate of false positives “is a big drawback” to CT scans, says Aberle of UCLA. “You convert healthy participants into patients and expose them to additional tests or additional anxiety.”

Despite the risk of false positives, some worried smokers and former smokers already get spiral CT scans on their own. (The test costs $300 to $400 and is often not covered by insurance unless a doctor suspects lung cancer and orders it.)

Though it might seem obvious that CT scans constitute a better detection method, there are actually significant pros and cons to both the scans and chest X-rays.

The advantage of a spiral CT scan is that it can pick up abnormalities smaller than a dime, while chest X-rays find nodules only if they are the size of a quarter.

CT scans also give doctors a 3-D image, while chest X-rays provide only a 2-D image. On the other hand, while chest X-rays can miss up to 30 percent of suspicious nodules, they also are far less likely to yield false positives. Then again, chest X-rays expose a person to low dose radiation, while the exposure from spiral CT scans is roughly 15 times higher. (Even so, the CT scan is a lower dose of radiation than a person gets from environment radiation every year.)

The bottom line, of course, is that no knows yet which method is better. But the strong hope is that whichever one is, that earlier detection will indeed save lives.

“We Cater to Cowards,” proclaims the cheery little sign at Mount Auburn Hospital in Cambridge, where countless cowards (including this one) go for what may well be everyone’s least favorite test: colon cancer screening.It’s no secret why people stay away in droves from such things. To detect cancer, or the small growths called polyps that might someday turn cancerous, a doctor must pass a tube containing a tiny video camera up through the patient’s rectum into the large intestine, or colon – not exactly most people’s idea of a good time.

If the doctor looks at only the lower third of the colon, the procedure is called a flexible sigmoidoscopy, though this test is so limited that some doctors are abandoning it, arguing it’s like doing a mammogram on only one breast. If the doctor inspects the whole colon up to the small intestine, that’s a full colonoscopy  – psychologically, a bit more daunting, perhaps, though the patient does get sedation, and the whole day off from work.

With either a colonoscopy or “flex sig,” the bowel must be pumped full of air to keep the walls from closing together and obscuring the view. And with either test, the patient must “prep,” that is, spend a few lovely hours cleaning out the colon, either by drinking a gallon of a  nonabsorbable liquid such as Golytely, taking strong laxatives like Fleet phosphosoda  that flush stool from the entire system, or (for flexible sigmoidoscopies) by using enemas such as Fleet.

At the moment, only 20 percent of people who should get regular colon cancer screening – in other words, everybody over age 50 –  actually do so, even though such screening can save lives.  But take heart, fellow cowards.

A number of new techniques now being tested, including a noninvasive test called “virtual colonoscopy,” should make screening more appealing. And if these new tests can be refined to match the accuracy of current colonoscopy, the death rate from colorectal cancer, which has been declining for the last 20 years, could decline further.

Currently, colorectal cancer is the second leading cause of cancer deaths, according to the American Cancer Society. Last year, more than 135,000 people were expected to be diagnosed with it, and nearly 57,000 to die.

Yet it is “one of the most preventable of cancers,” says Dr. J. Randolph Hecht, a gastroenterologist and oncologist at the UCLA Jonsson Comprehensive Cancer Center in Los Angeles. The average person – someone with no family history of the disease –  has 1-in-20 lifetime chance of getting colon cancer. Early detection, by eliminating the polyps and early cancers, can reduce this risk even further.

“Some people say they’d rather die than have a colonoscopy,” says Hecht.  “But I have lots of people who are dying because they didn’t have a colonoscopy.”

That’s a shame, because standard colonoscopy, which at $1000 or more is relatively expensive, is still the best way to find polyps and cancers in the colon. Medicare and many other insurers now pay for routine colonoscopy, though if  all the millions of people who should get a colonoscopy did, the financial squeeze would be enormous.

The big advantage of colonoscopy is its accuracy. It has a “miss rate” of only 2 percent, says Dr. Douglas Pleskow, director of the colon cancer center at Beth Israel Deaconess Medical Center in Boston.

And if the doctor finds a polyp, he or she can take it right away. If the patient does have polyps, the recommendation is for a repeat colonoscopy in three years. If no polyps are found, you don’t need another for 10 years because polyps turn into cancer do so slowly.  

“The procedure is not entirely risk free. There’s the risk of perforation of the intestine, which leads to infection or bleeding in one of every 500 to 1000 procedures”, says Dr. Seth Glick, clinical professor of radiology at the University of Pennsylvania.

With flexible sigmoidoscopy, a big advantage is that no sedation is required. But it’s being phased out in many hospitals, including Beth Israel Deaconess and Massachusetts General Hospital in Boston, because it does not catch enough potential cancers. In a major study published in August in the New England Journal of Medicine, researchers found that “flex sig,” even when combined with a low-tech test called FOBT, failed to detect cancer and high risk polyps in 24 percent of patients.

(FOBT stands for fecal occult blood test. Doctors analyze a tiny stool specimen for traces of blood. The test is not very reliable, because many cancers or polyps bleed only intermittently and some things that bleed do not indicate cancer.)

Of the emerging alternatives, virtual colonoscopy is the furthest along. In fact, it’s already used for patients who cannot tolerate colonoscopy – either because they have intestinal obstructions or because they refuse to have the invasive test.

In virtual colonoscopy, which insurers do not yet pay for, the patient still has to clean out the bowel beforehand, and the bowel must still be pumped full of air. But instead of having a video camera inserted through the rectum, the patient gets a CT scan – a series of X-rays – that are reconstructed by a computer into a two- or three-dimensional image.

The downside is that this involves considerable radiation – much more “than a mammogram because you expose the entire abdomen,” says Dr. William Brugge, director of gastrointestinal endoscopy at Massachusetts General Hospital in Boston. And if the doctor discovers polyps, the patient has to go on to have a full colonoscopy anyway, so the doctor can take them out. 

On the other hand, virtual colonoscopy carries no risk of perforation. Because the X-rays scan the whole lower abdomen, doctors can also pick up cancers in the liver, spleen, kidneys and stomach that might otherwise be missed. Moreover, virtual colonoscopy requires no sedation and it takes under one minute of the patient’s time, though it can take an hour to analyze the results, says Dr. Judy Yee, chief of CT and gastrointestinal radiology at the San Francisco Veterans Affairs Medical Center and a pioneer in the technique.

In a study of 300 patients published in Radiology in June, 2001, Yee’s team found that virtual colonoscopy was great at picking up polyps that measure 10 millimeters or more, the ones that are most likely to turn into cancers. But because the quality of the CT images are not as good as in standard colonoscopy, the virtual technique didn’t catch many smaller polyps.  A 1999 study at the Boston University School of Medicine came to similar conclusions.

For that reason, among others, no one is – yet- recommending that virtual colonoscopy replace standard colonoscopy for routine screening.

But virtual colonoscopy could take off in the next year or two if scientists succeed at making it “prep-less,” that is, if patients don’t have to clean out the colon beforehand. One idea is to have patients swallow a substance such as barium that would act as a positive contrast agent to “tag” residual fluid and stool in the colon so that it shows up as a different color or density in the computerized image. Doctors could then “electronically subtract” this part of the image and, “see” any true polyps or cancers lying underneath.  

Researchers are also pursuing a different kind of fecal tagging to help diagnose colon cancer. First, the patient supplies a whole stool specimen. (This involves a special “bucket” that fits onto the toilet seat; the patient defecates into the bucket.) The sample is then tested for human DNA mutations known to be involved in colon cancer.

In this non-invasive approach, reported in late January in the New England Journal of Medicine, researchers at Johns Hopkins University, M. D. Anderson Cancer Center, a team in Sweden, and the Lahey Clinic and Exact Sciences Corp. in Massachusetts, reported they were able to find fragments of human DNA in stool (which contains mostly bacterial DNA). They were then able to isolate the colon cancer-causing APC gene in about 60 percent of early-stage cancer patients tested. The test could become a noninvasive method of detecting colon cancer

The bottom line, fellow cowards?

• If a radiologist touts the plusses of virtual colonosopy (which radiologists do), ask for an opinion from a gastroenterologist, who does colonoscopies. These two groups of specialists will be competing ever more aggressively for the privilege of looking inside your guts. Don’t assume that if you get a fancy “total body scan” for $1000 or so that you’ve taken care of colon cancer screening. You haven’t. since those scans involve no “prep” beforehand, the intestine is too full of stool for the scan to detect anything else.

• So, be a savvy consumer. But one way or another, get screened for colon cancer at regular intervals after age 50. 

  For more information, you may contact:

  The American Cancer Society, 1 800 ACS-2345 begin_of_the_skype_highlighting              1 800 ACS-2345      end_of_the_skype_highlighting (1 800 227 2345 begin_of_the_skype_highlighting              1 800 227 2345      end_of_the_skype_highlighting) or www.cancer.org.

  The National Cancer Institute’s information line, 1-800-4-CANCER begin_of_the_skype_highlighting              1-800-4-CANCER      end_of_the_skype_highlighting; also, www.cancernet.nci.nih.gov

Several years ago, Dr. Michael J. Glantz, a brain cancer specialist, was struck by what appeared to be an extraordinary number of divorces and separations among his patients, many of whom had primary brain tumors that were expected to kill them in 15 months.Not only did there seem to be lots of breakups, but most of them seemed to occur when the women got sick. So, Glantz, who was then at Brown University and is moving this summer to the University of Arizona, began keeping track.

To the surprise of his male but not his female colleagues, Glantz found that 17 out of 183 married brain cancer patients had endured a divorce or separation within about a year of their diagnosis – an overall divorce rate of 9 percent. More importantly, he said, 14 of the 17 divorced or separated patients – 82 percent – were women.

To see whether this was tied to something particularly stressful about brain cancer, which can alter personality and cognitive function, Glantz also studied two other groups: 107 married patients with multiple sclerosis, a chronic disease that is not usually fatal, and 172 married patients with cancers that neither arose in nor had spread to the brain.

Divorces in those cases, too, he found, disproportionately occurred when it was the wife who was sick – 96 percent of the cases with MS, 78 percent of the cases of systemic cancer.

One rather unappealing interpretation is obvious: That women hang in there with sick husbands while men bail out on sick wives. But stay with this a bit longer, guys. And, ladies, don’t despair. This is not heading to the all-men-are-cads conclusion you may be expecting.

For years, when researchers probed the emotional impact of cancer and other serious illnesses, they usually focused on the patient. Today, there’s a growing realization that, at least in the emotional sense, it’s the couple or the whole family that “has” the disease.

In fact, the well spouse sometimes feels more distress than the sick one, who at least can throw his or her efforts into survival. And, while some men do have trouble taking on the nurturing role, researchers say, many do it quite well. In fact, many couples get closer when one member has cancer, especially if the marriage was strong to start with. Beth and David Savard of Methuen can vouch for that, though things got very shaky while she was in the midst of chemotherapy for breast cancer six years ago. Both 35 now, they were 29 and the parents of a 2-year-old when Beth was diagnosed. David could deal with the factual issues about cancer, she said, but he shut down emotionally.

“He was not talking about his feelings. I was trying to talk about mine, but I couldn’t talk to him because I was not getting a response.”

They were about to see a divorce lawyer when they went to a We Can Weekend, an annual family retreat sponsored by the American Cancer Society. During that weekend, David began to talk and cry with other men whose wives had cancer. He began to tell Beth how helpless he felt, she recalled. He even voiced the most frightening feeling of all – that she would die and he would have to raise their child alone.

Many couples say that “when cancer came in, communication went out,” Beth Savard said. But it needn’t be that way. Today, Beth said, she and David are “very, very talkative. We share a lot.”

Having cancer or a spouse with cancer, particularly brain cancer, has”got to be the most stressful thing in the world,” said Dr. John Henson, executive director of the brain tumor center at Massachusetts General Hospital. And generally, he has found, couples are extremely supportive of each other.

But often, he said, the spouse with cancer often has some level of denial, “which is probably a healthy coping mechanism.” The healthy spouse even may be more emotionally affected, something that Henson said has nothing to do with gender.

Frank McCaffrey, a clinical social worker who runs support groups at Beth Israel Deaconess Medical Center for men whose wives have advanced cancer, agreed. If the spouse who gets cancer has historically been the one who has provided most of the emotional caretaking, he said, the well spouse, regardless  of gender, “has to evolve and be able to understand that the patient, the ill spouse, can’t provide the same emotional caring and support that they have been.”

Not surprisingly, this is easier if the marriage is good to start with. “If the marriage was teetering before, it gets harder. They are the ones at most risk,” said Dr. Jimmie Holland, chief of psychiatry and behavioral science at Memorial  Sloan-Kettering Cancer Center in New York.

Even Glantz’s data, alarming as it seems at first blush, does not actually prove that the divorce rate is higher than normal among couples in which one spouse has cancer or MS.

If anything, the opposite may be true.

According to data released in May by the National Center for Health Statistics, 43 percent of first marriages end in separation or divorce within 15 years; 20 percent end within five years.

It’s statistically risky to compare national divorce rates, which include many young couples, with divorce rates in couples in which one spouse gets a serious disease, in part because the latter couples are often older, and possibly more mature. But Glantz’s study suggests that couples dealing with at least one serious illness, MS, have a lower than average divorce rate, just 24 percent after a median of 14 years of followup.

That doesn’t surprise Steven Marcus, 58, a free-lance editor in Brookline who has been married for 25 years to Kit Crowe, 51, a librarian who was diagnosed  with MS just after their marriage. In recent years, he said, Kit has not been able to work full time, and “it’s been scary for me to be the primary  wage-earner – that freaks me out sometimes.”

But splitting up has never crossed is mind.

“You do the best you can,” he said. “It’s a question of love. Even if you’re freaked out, that’s not enough to make you run.”

And even when a couple divorces soon after the woman gets cancer, that doesn’t prove that her husband abandoned her.

Laurel Northouse, a nurse with a doctorate in research who studies the impact of cancer on couples at the University of Michigan School of Nursing, has studied couples in which the wife has breast cancer. She has found not only that the  divorce rate within the first 12 months of diagnosis is a fairly low 3 to 4 percent, but that sometimes it’s the woman who decides not to spend whatever time she has left with a man she no longer loves.

A divorce soon after cancer may look “like the husband is leaving her, but she may be saying, `Enough already,’ ” Northouse said.

In a study of colon cancer published last year, she said, female care givers of men with cancer actually reported more distress than their husbands. One reason for that, Northouse said, is that when husbands become care givers, they are often seen as heroes doing more than society expects.

“Nobody brings casseroles to women when their husbands are sick because people assume a woman can do the caretaking, that she’s a natural care giver. But women need help, too.”

On the other hand, when men become care givers, they often don’t ask for the support they need because they may be too stoic, said Betty Ferrell, a nurse-researcher at City of Hope National Medical Center in Duarte, Calif. Men “really do feel the financial burden. They feel they must try to keep things normal, to keep going to work.”

The bottom line is that when life-threatening disease strikes, the marriage needs attention as well as the disease itself, said psychologist David Cella of Northwestern University Medical School. “It’s very easy for people to put all the attention on the treatment. But some attention should be spared to focus on the couple.”The American Cancer Society is enrolling volunteers in a new study of quality  of life among cancer survivors and their families. Call 1-800-ACS-2345 begin_of_the_skype_highlighting              1-800-ACS-2345      end_of_the_skype_highlighting.