Mike King

Cancer patients should be on the lookout for these specific infections that can complicate treatment:

. There are more than 30 different types of 

. They are common in patients with chronic diseases, including diabetes and cancer, and most often start on the skin. Some staph infections can be caused by food poisoning. Most can be treated with antibiotics.

 One of the most dangerous of these is methicillin-resistant 

, known as MRSA. These infections, almost always acquired in a healthcare setting, are much more stubborn to treat and can be life threatening.

 A type of yeast infection on the skin and mucous membranes, 

 can sometimes occur with the use of antibiotics or as a result of a weakening of the immune system from having cancer itself or radiation and/or chemo. Generally they can be treated with antifungal agents.

A yeast-like fungal infection that settles in the lungs, sometimes as the result of immunotherapy connected to bone marrow transplants, 

 can be treated with antibiotics and, depending on the severity of damage to the lungs, corticosteroids.

 This bacterial infection can be especially problematic, playing havoc with the colon and digestive tract. It is often passed on in healthcare settings, especially to patients who have been on antibiotics and altered their normal colonic bacteria or who are hospitalized long term and are already immunosuppressed. A minimum 10-day antibiotic regimen is usually required for serious cases.

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Cancer patients should be aware of the risk of infections.

Risky Infections

When Chris Prestano learned in 2008 that she had thyroid cancer, she decided to commute between her home in New York City and Baltimore so that experts at Johns Hopkins Hospital could treat her.

Because she also has type 2 diabetes, which can lead to skin infections, Prestano knew that even a relatively simple surgery like removing her thyroid posed a risk. She and her physicians took every precaution necessary, including pre- and postoperative antibiotics, but it didn’t stop her from developing an infection. Now, more than two years later, she is battling a surgical wound infection that aggravates her recovery from cancer as well as her diabetes.

“My team of doctors is the best team I think I could assemble,” Prestano says. “We were very careful, very cautious going into this, and it still happened.”

Most cancer patients are aware of the tradeoff: Targeting cancer cells with chemotherapy agents and radiation or removing damaged organs and tissue through surgery greatly increases the chance of infection by germs that attack weakened immune systems.

The risk-versus-benefit equation is a standard topic whenever options are discussed. And both patients and their healthcare teams are getting savvier about what they can do to control infection risks before, during and after treatment.

Still, since that first thyroid operation, Prestano has been in and out of the hospital several times to treat the surgical-site infections. Among other procedures, she’s received five rounds of steroids, pulsed-dye laser treatments and surgical alterations to the scar. The loss of her thyroid and the recurrent infections has exacerbated her diabetes. Before surgery it was controlled without drugs, but now she is insulin-dependent.

“I had no idea it would take this long to heal,” says Prestano, 30, who moved to Frederick, Md., last year and now makes a much more manageable 50-mile drive to Johns Hopkins every three to five weeks so that doctors can monitor her progress. “I was more concerned about the infection and recovery from the surgery than the cancer itself.”

Prestano says she usually avoids large groups, rarely socializes with anyone who seems to be fighting a respiratory infection and has become vigilant about using hand sanitizers. “That’s the price we pay as cancer patients, I guess,” she says. While most patients won’t have the difficulties that Prestano has, it’s important to know Prestano is not alone.

I was more concerned about the infection and recovery from the surgery than the cancer itself.

Since the skin is the body’s first line of defense against infection, any break in it—through a surgical site or where a central line catheter is inserted into a vein to facilitate chemotherapy infusions&mdash;becomes a potential source for infection. Even subcutaneous central venous access devices, in which medicine is released through chest ports implanted under the skin’s surface, get infected about 5 percent of the time.

One of the most risky complications for any cancer patient is neutropenia, a hematologic disorder characterized by a lack of neutrophils—the granular white blood cells that fight micro-organisms, particularly bacteria.

Even though these treatments carry certain risks, cancer patients and care-givers can take some simple precautions to prevent infection. Wash your hands with warm, soapy water before eating or touching your face, and wash them again after blowing your nose or sneezing. Also, use hand sanitizers or disinfecting wipes after contact with items frequently touched by others, such as ATMs or grocery carts. Patients, caregivers and other family members should get annual influenza vaccines to prevent the virus’ spread. Finally, be aware of the symptoms of infection, such as fatigue, fever, redness and swelling, and contact your healthcare provider if those symptoms persist. 

Healthcare providers in most states have voluntarily started using an infection-control checklist when inserting and working with infusion ports in patients, says Peter Pronovost, MD, professor of anesthesiology and critical care at Johns Hopkins, who has spearheaded the checklist effort. Patients and family members, he adds, should be aware of them too and insist that they be followed. For example, patients should confirm that medical personnel have washed their hands with soap and water or alcohol gel before and after examining the patient, as well as when inserting, replacing, repairing or dressing a catheter; disinfected the patient’s skin before inserting a catheter and during dressing changes; maintained aseptic technique by wearing a mask, sterile gown and sterile gloves—as well as draping the patient with a sterile sheet&mdash;when inserting a catheter.

Each year, an estimated 60,000 cancer patients are hospitalized for chemotherapy-induced neutropenia. A patient dies every two hours from the complication, according to the CDC Foundation, an independent nonprofit organization. The overall mortality of cancer patients hospitalized due to febrile neutropenia, or neutropenia with fever, is estimated between 9.5 and 11 percent, the foundation reports.

While infections in healthcare settings correctly get the most attention, the risk of neutropenia also extends to other widely prescribed anticancer treatments given in a variety of settings.

In February, researchers examining 16 randomized control trials of Avastin (bevacizumab) found that patients prescribed the drug in combination with chemotherapy or biological therapy were at increased risk of death from neutropenia compared with patients who were getting conventional chemotherapy or other biologic treatments. While some cancer patients may still benefit from taking Avastin, they and their oncologists should be aware of the risk of neutropenia and other life-threatening effects, says Daniel F. Hayes, MD, a professor of internal medicine at the University of Michigan Comprehensive Cancer Center in Ann Arbor, who also serves as co-director of the Breast Care Center and clinical director of the breast cancer program.

The CDC Foundation and Amgen, a maker of anti-infective prophylactic drugs, are collaborating on a three-year effort to raise awareness of preventing infections in cancer patients. An Amgen-sponsored survey of cancer patients in 2009 showed that nearly one-fourth experienced an infection within the first year of chemotherapy. Sixty-one percent of those had more than one infection, and all of them took at least a week to recover, often interrupting their chemotherapy regimens.

Experts say cancer patients must know their infection risks as well as preventive steps they can take depending on their cancer type and treatment regimen. 

 The body’s immune function often decreases in the hours immediately following surgery and may take many months to fully recover. Using antibiotics prior to surgery is sometimes recommended for those most prone to infection.

According to the American Cancer Society (ACS), the risks for patients include how long the patient is in the hospital, the extent of the surgery, the length of the operation and the amount of bleeding. Patients who have had previous treatments for cancer, including chemotherapy and radiation, and those who are diabetic or poorly nourished going into the surgery are also at greater risk.

The surgical site itself is the most common place for infection to take hold. In addition to the complications caused by infection, including treatment delays, it can also increase medical costs. A 2008 study of women undergoing breast surgery showed that surgical-site infections raised the cost of care by more than $4,000 compared with women who came out of surgery free of infection, especially women undergoing mastectomies.

 Patients’ immune systems could be impacted by the types and dosages of chemotherapy, frequency of treatment and the cancer type and stage. Age, nutritional status and prior treatments also impact how the body’s infection-fighting ability is affected by chemotherapy.

Patients with central venous access devices should be especially vigilant. Central lines deliver chemo agents and other medications directly into the bloodstream, usually via a catheter placed in the chest, neck or groin. Because the lines stay in for days, sometimes weeks, they must be routinely handled and can become the site for infections. Even medication ports placed under the skin, usually in patients needing long-term infusion, can become infected below the surface. Patients should watch for redness, swelling and drainage from skin around the catheter or above the port site, as well as other symptoms, such as sudden fever or chills. 

 Radiation’s effect on the immune system, much like that of chemo, is exerted through changes to the bone marrow. Unlike chemo, it affects bone marrow only within the treatment field (“inside the beam”), so it has little impact when the fields are small. However, depending on the part of the body radiated and the dosage, it can also increase the risk of skin damage and infection. Patients who undergo total body irradiation should know that it is much more likely to trigger very low white blood cell counts, which can be risky. The ACS recommends patients be aware of their radiation dose, how often it is given and what parts of the body are getting the most radiation when discussing treatment options with their physicians.

 Immunotherapy boosts the immune system to recognize and attack specific cancer cells but sometimes can change the way the immune system works. Some forms of immunotherapy cause the level of all white blood cells to drop, not just neutrophils. When lymphocyte levels become too low, the risk of certain viral and fungal infections increases. But most often the neutrophil counts return to normal soon after treatment is stopped, even though lymphocyte counts stay low for months.

  Bone marrow transplants pose the most significant risk because they often involve very high doses of chemo and total body irradiation, which severely weakens the immune system. That’s why stem cells are removed from the body before treatment or taken from a donor and re-infused after the procedure so that the immune system can be rebuilt. Precautions include keeping patients in an access-controlled environment of the hospital until white blood cell counts reach normal levels—a wait that can often take weeks. During this time, exposure to people outside of the medical team is severely limited, and patients must be monitored for fever and other signs of infection.

Reducing the risk of infection for cancer patients in treatment.

Germ Warfare

For more than a century cancer was defined largely by what a pathologist observed under a microscope. The “gross morphology”—the shape, the structure and the component parts of the cancer cells taken from a biopsy&mdash;provided the only real road map for treatment.

And it wasn’t so long ago that cancer researchers kept most of their records on paper, sharing their findings with fellow researchers by sending tissue samples through the mail and transmitting notes over facsimile machines. Even after the World Wide Web was up and running, clinicians relied heavily on medical journals, scientific meetings and other methods of dissemination of research to make critical decisions about how to help patients with advanced forms of the disease. 

Modern medicine no longer relies on such outdated research protocols.

 (via computer) research, gene mapping and detailed digital pathology, scientists can now peer well beyond the biopsies of patients and predict pathways inside cells that look harmless but may provide the triggering mechanism that unleashes cancer’s spread. This, in turn, can lead to targeted treatments against some of the most difficult and lethal forms of the disease.

The programming infrastructure that enables information and analytical resources to be shared efficiently and securely among cancer researchers is called caGrid. The open-source information network that caGrid supports is called caBIG (Cancer Biomedical Informatics Grid), a major initiative of the National Cancer Institute. These developments have propelled cancer research into the molecular age and hold great promise for future clinical care.

Scientists can now peer well beyond the biopsies of patients and predict pathways inside cells that look harmless but may provide the triggering mechnism that unleashes cancer's spread.

 research is concentrating on the genetic pathology and treatment outcomes of brain tumor patients obtained through the Cancer Genome Atlas and other sources residing on the caBIG.

By utilizing rich, molecular data sets, linking them to digitized pathologic slides and annotated neurological images—as well as detailed information about patient treatments and results&mdash;brain tumor research can be conducted on a much larger scale and at a much deeper level than ever, says Daniel Brat, MD, PhD, a professor of pathology and laboratory medicine at Emory University in Atlanta. (Similar work is going on at other centers studying lung and ovarian tumors&mdash;two other forms of cancer that have proven to be stubbornly resistant to conventional therapy in patients with advanced forms of the disease.)

Patients who agree to participate in the research allow tissue samples, radiographic images, clinical notes and other details of their diagnosis and treatment to be shared with the cooperating institutions, which in turn agree to protect their identities. Names and other information that would personally identify the patient do not become a part of the record.

Researchers at Emory and elsewhere learned in the space of a few months what would have otherwise taken years to find about a range of genetic mutations in some glioblastomas, the most common malignant brain tumors in adults. 

Correlating this information may allow researchers to target specific therapies for specific tumor types to keep them from triggering the genetic “on/off” switch that spreads the cancer so rapidly and leads to death, Brat believes. Similarly, they may find that some forms of therapy cause a hypermutation of the gene and should therefore be avoided in some patients.

Modern medicine no longer relies on information just gleaned from under a microscope.

Mining Cancer Data in the Molecular Age

Over the past two decades, the FDA has changed its drug-approval process several times, with each iteration aimed at speeding the time it takes for medications to go from clinical research to routine use. 

For drugs being developed to treat serious and life-threatening diseases, such as metastatic cancers—those that seem to have a low risk of serious complications and some preliminary evidence of prolonging survival&mdash;the process can be even faster. 

The agency allows these drugs on the market on a conditional basis, but usually demands the manufacturer conduct ongoing, controlled studies to determine whether the preliminary promise holds true. The manufacturer is required to compile these studies for several years after the drug gets preliminary approval. Once confirmatory data is compiled, the drug is eligible for traditional approval from the agency.

Manufacturers can ask that drugs be assigned to one of three approval tracks.

: Moving drugs that fill unmet needs and treat serious conditions, such as cancer and Alzheimer’s, as fast as possible through the pipeline. 

: Determining whether the drugs impact survival, improve day-to-day functioning and prevent the likelihood of the disease progressing if left untreated.Preliminary studies must indicate some advantage over available treatment, an alternative to drugs with more serious side effects, improvement to diagnosing a serious disease where early diagnosis affects  outcome or decreasing the chances of toxicity of an accepted treatment.

: Conditional approval for drugs going through clinical trials that show a significant outcome prior to trial completion. 

: Efficacy must be verified in a phase 3 or 4 trial. Drugs don’t necessarily have to prove they significantly prolong lives. They can be measured on what researchers call a “surrogate endpoint,” which is a clinically meaningful outcome that can be a physical sign or laboratory measurement that is known to correlate with a more standard approvable endpoint. For example, whether patients’ tumors show significant shrinkage.

: Drugs that offer significant improvement to existing therapies or offer treatment where no adequate therapy exists can have a priority review, where the FDA agrees to a hurried-up hearing process and reduces other regulatory hurdles. 

: A drug must show the potential to significantly advance treatment, including substantially reducing a drug reaction or showing effectiveness in a new subpopulation of patients, such as children.

The FDA's drug-approval process has several tracks that help medications quickly go from clinical research to clinical use.

A Primer on How Faster Approval Works

When the Food and Drug Administration decided in 2008 to accelerate approval of Avastin for treating advanced breast cancer, it understood that the anti-cancer drug would not necessarily prolong survival. Still, the regulatory agency concluded it might slow progression of the disease when taken with conventional chemotherapy agents.

After all, Avastin (bevacizumab) had been extensively tested through the agency’s traditional approval route, and it was already being widely prescribed for patients with colon and lung cancers. A few months earlier, the drug’s manufacturer had put forth a study that seemed to show Avastin provided some potential benefit for patients with incurable forms of breast cancer.      

Indeed, that’s why 18 years ago the FDA—faced with the expanding HIV/AIDS epidemic&mdash;created the accelerated drug approval process. The goal was to significantly reduce the length of time it took to set up, implement and analyze the results of clinical trials so that patients diagnosed with life-threatening diseases and limited treatment options could get new drugs without having to wait for the traditional, time-consuming approval process to be carried out.      

And in many ways the new process accomplished just that: It cut the time the FDA took for priority review of a drug application from 10 months to six between 1992 and 2004. The success with a range of new drugs for HIV/AIDS, for instance, has clearly lengthened survival and improved the lives of those diagnosed with the disease.      

To???date, the FDA has approved more than 90 drugs to be processed faster, many of those for the treatment of cancer.  

Following its priority review and accelerated protocols in 2010 alone,?the FDA approved many new uses of existing drugs, as well as new drugs for cancer patients, including Tykerb (lapatinib) for HER2-positive metastatic breast cancer, and Tasigna (nilotinib) and Sprycel (dasatinib) for patients with chronic myeloid leukemia (CML).  

Already, about a third of the cancer drugs that have gone through the accelerated process are being made available to patients, not necessarily because they have been shown to extend life, but because they show a clinically meaningful outcome, such as delaying progression of the disease or improving symptoms. This measurement is known within the research and clinical community as a “surrogate endpoint” for determining whether a drug should be approved.

So when an FDA advisory panel recommended in July 2010 that the agency withdraw its accelerated approval of Avastin for metastatic HER2-negative breast cancer, thousands of women with the disease were, to put it mildly, disappointed. While the patients readily acknowledge that clinical trials showed Avastin may not prolong survival, some believe it can lengthen life for some patients and slow the progression of the disease in others.

Tumors release a protein called VEGF, or vascular endothelial growth factor, which signals the development of blood vessels to feed the tumor, a process known as angiogenesis. Avastin inhibits angiogenesis by binding to VEGF, slowing tumor growth in several types of cancer, most notably colon cancer. 

Ellen Jurgens, a 64-year-old Roswell, Ga., woman who has battled triple-negative breast cancer for nearly four years, was one of about 10,000 patients and their families who asked the FDA to keep Avastin available to some patients—like herself&mdash;who have no other viable alternative. She has been taking the drug since March 2008 and credits it for keeping tumors in her lymph nodes, liver and bones in check during much of that time.

“I play golf. I travel. I babysit three grandkids. I dance. I live a normal, active life,” Jurgens says. “Even if it means I only live three months longer, that’s more time to see my grandkids grow up and be with them and with my family. That has to have some value, doesn’t it?”

Despite such pleas, the FDA agreed with the advisory committee’s recommendation in December to remove the breast cancer indication from the drug’s label. However, in February the FDA granted a first-of-its-kind public hearing in late June for Genentech, the drug’s manufacturer, to appeal the FDA’s decision. 

The decision has no impact on Avastin’s use for colon, kidney, brain and lung cancers, which gained earlier approval through the conventional process.

But the effort to get Avastin approved for use in patients with breast cancer offers a glimpse into the promise and perils of fast-tracking drugs for patients with life-threatening diseases.

The preliminary evidence offered in 2007 indicated that when used in combination with Taxol (paclitaxel), Avastin delayed tumor progression an average of 5.5 months longer compared with conventional chemotherapy alone.

That finding wasn’t enough to persuade an earlier FDA advisory committee to recommend Avastin get accelerated approval for use in breast cancer patients with metastatic disease. The advisory committee voted 5-4 against—with several members expressing strong reservations about the potential risks of the drug. 

But in a rare rejection of an advisory panel’s recommendation, the FDA said a five-month delay in progression could be a significant benefit and agreed in early 2008 to put the drug on the accelerated approval track. The agency told Genentech to continue providing data as more patients started taking the drug, a standard procedure for all drugs that go through this process.

Avastin’s accelerated approval prompted cancer treatment centers across the country to start making it available to patients with advanced breast cancer. Moreover, it opened the door for Medicare and most private insurers to start paying for use of the drug by breast cancer patients—no small consideration since Avastin costs, on average, about $88,000 per year. (Genentech has capped annual spending on the drug to $57,000 per year for patients with incomes below $100,000.)

“These women often live from scan to scan, and anything that seems to lengthen their time of disease-free progression has to be given strong consideration,” says Ruth O’Regan, MD, director of translational breast cancer research at Emory University’s Winship Cancer Institute in Atlanta. In recent years, Emory has made Avastin available to certain patients, including Jurgens, and followed them closely, O’Regan says.

For many taking the drug, the response was encouraging and their quality of life seemed to improve. The side effects the patients had been warned about were manageable, O’Regan says. That’s why she and other breast cancer experts were surprised when two follow-up trials by Avastin’s manufacturer failed to confirm the original results that led to the drug getting accelerated approval. 

One of the studies showed the delay in tumor progression for patients was one to three months. In the other study, it was less than a month. Moreover, Avastin’s toxicity was more severe in the recent trials. Complications included high blood pressure, bleeding, perforations in the stomach and intestines, heart attack and heart failure. Together, these factors helped persuade the 2010 advisory panel to recommend by a vote of 12-1 that Avastin no longer be used for patients with advanced breast cancer. The agency affirmed that recommendation on Dec. 16 and notified Genentech it planned to withdraw marketing approval for use of the drug in breast cancer patients. 

Wyndham Wilson, MD, PhD, who headed the 2010 advisory committee and directs the lymphoma therapeutics section of the National Cancer Institute, understands the frustrations of patients and advocates who still believe the drug holds promise for prolonging progression-free survival for some breast cancer patients. But that simply wasn’t the case in the follow-up studies with Avastin, he says. 

“But we have to judge whether that is clinically meaningful from a patient’s point of view,” he says. “We didn’t have that data with Avastin.” 

Future follow-up trials of similar drugs should include patient-reported quality-of-life indicators—like improvement in symptoms, better mental health and attitude while living with cancer&mdash;to help regulators understand how patients feel, even if the drug doesn’t have a significant impact on overall survival, he says.

Still, Wilson and others do not consider the experience with Avastin a failure of the accelerated approval process. “We do not look at this as a mistake,” said Richard Pazdur, MD, director of the FDA’s Office of Oncology Drug Products in a press release at the time of the committee’s vote. “There is a risk … in approving these drugs and this is a management of that risk.”

The FDA went through a similar process when it granted AstraZeneca accelerated approval for Iressa (gefitinib) in May 2003 because preliminary studies indicated adding the drug to conventional treatment increased overall survival and tumor shrinkage in patients with non-small cell lung cancer who had failed two or more courses of chemotherapy. 

But by Dec. 17, 2004, AstraZeneca reported that a much larger clinical trial comparing patients who were taking the drug with those who were taking a placebo showed no survival benefit.The agency eventually decided that the drug should no longer be prescribed for non-small cell lung cancer patients, except in patients the drug previously benefited. Metastatic lung cancer patients had several other drugs as an alternative to Iressa, the agency said. Breast cancer patients aren’t as fortunate.

“For many of us, we have nothing else to fall back on,” says Jurgens, who wants the FDA to recommend that Avastin still be prescribed to triple-negative breast cancer patients. “That’s a small group—something like 15 percent of breast cancer patients. These patients should be able to decide with their doctors whether the drug has the benefit we seek.”

That compromise could happen as the debate continues at the late-June public hearing that the FDA has granted for Genentech. 

While the experience with Avastin and Iressa captured headlines in recent years, the faster approval process has quietly led to other anti-cancer agents being made available to more patients.

One of those, Tykerb, was approved in combination with Femara (letrozole) to treat hormone-positive and HER2-positive, postmenopausal advanced breast cancer patients for whom hormonal therapy is indicated. In randomized trials, Tykerb was shown to more than double the length of time patients lived without cancer spreading, from three months to more than eight, compared to Femara alone.

Using the speedier process, two new treatment protocols  were also made available in 2010 for patients with a rare blood cancer called Philadelphia chromosome—positive chronic phase chronic myeloid leukemia (PH+CP-CML).

In June, the agency approved a new indication for the drug Tasigna for newly diagnosed patients with this rare blood disorder after studies showed a greater percentage of patients experienced a reduction of cancer cells in those who received Tasigna compared to those who received Gleevec, a conventional anti-CML agent that had won approval from the FDA through the accelerated process in 2001. In October, the FDA approved a new indication for the anti-CML drug Sprycel for treatment of the same disorder in the same group of patients.

Len Lichtenfeld, MD, deputy chief medical officer of the American Cancer Society, understands how frustrating the process can be for patients with incurable cancers. He too would like to see the process factor quality-of-life measurements more heavily into confirmatory clinical trials.

“With cancer drugs we accept more side effects and a certain level of toxicity in hopes of achieving some improvement in survival,” he says. “If they offer a reasonable chance they can do that, we want to get them out to as many people as possible who can benefit from them.” 

But the FDA can’t simply throw open the door to any drug that seems to work in a small number of patients. The measure of success will have to be constantly refined, he says. “The judicious use of the fast-track process is worthwhile and should continue.”

Patients and the FDA battle over Avastin's breast cancer indication.

Hurdles on the Faster Track

As cancer cells go, they are the stealthiest.

They hide in tissue, unable to be detected by conventional screening. They hunker down seemingly dormant for years, and then, through some mysterious triggering process, start to grow and spread. 

When their presence becomes painfully known, they often have already wreaked havoc on the surrounding tissue. And the final, most lethal straw: They possess unique molecular skills that can render useless the treatments that can be so effective on other forms of cancer.

Over the past 40 years, science has made remarkable progress in the detection and treatment of most major cancers, resulting in dramatically increased cure rates and long-term survival for patients diagnosed with well-known and widespread cancers, such as childhood leukemia, breast and prostate cancers. 

But for some cancers—like the tumors that develop in the pancreas, liver and ovaries, or glioblastomas in the brain and melanomas that have burrowed beneath the skin&mdash;achieving that same kind of treatment success has remained largely out of reach. Because the prognosis of patients diagnosed with early-stage disease, such as those with breast cancer, is so encouraging, it is hard for those who have hard-to-treat cancers to understand why theirs is not.

For years the widely accepted reason these cancers seem so difficult to treat has been rather simple—we don’t catch them at an early enough stage to stop them. That remains the case today, although we are now uncovering other biological reasons for the more recalcitrant cancers. But there are new, hopeful treatments&mdash;especially in the area of targeted gene therapy&mdash;that could begin to swing long-term treatment success over to the side of the patient.

Unlike mammograms for breast cancer and colonoscopies for colorectal cancer, most of these cancers lack an effective screening tool to detect them early. For many patients, the first symptoms they experience are after the cancer has spread to other organs. 

Ovarian cancer patients, for instance, usually don’t know they are sick until the disease has spread throughout the abdomen, resulting in pain from a bowel obstruction. Pancreatic cancer’s symptoms also tend to present in later stages. And by the time most glioblastomas in the brain are detected, the tumor is growing so rapidly it has already infiltrated regions of the organ that are vital to many of the body’s functions. Internal organs such as the lungs, pancreas and brain keep their secrets not only because of a lack of screening tests but also because the tumors are difficult to touch.

For years the widely accepted reason these cancers seem so difficult to treat has been rather simple—we don’t catch them at an early enough stage to stop them.

While the mortality rate for these cancers remains unacceptably high, in raw numbers the death toll from them is comparatively small. For instance, there are about 14,000 deaths a year in the U.S. from ovarian cancer compared with 40,000 for breast cancer; or 8,700 melanoma deaths to colorectal cancer’s 51,000. The incidence rate of these cancers is correspondingly low compared with the more common forms. Right or wrong, this lower incidence rate may have dampened research into screening tools and treatment methods for them.

A National Cancer Institute breakdown for how it spent $4.8 billion on research in 2007 shows that prostate cancer got nearly $300 million while pancreatic cancer received $73 million. Similarly, breast cancer received $572 million in funding that year compared to $97 million for ovarian cancer. The NCI stresses that there are funding overlaps in some cases and the figures do not represent its total research budget for specific cancers. Still, the disparities are obvious.

Pharmaceutical company-funded research into hard-to-treat cancers faces similar challenges. The process is made all the more complicated because of the time it takes to find enough patients and accumulate sufficient data on them to get through the rigorous testing demanded before new drugs are approved for use.

Otis W. Brawley, MD, chief medical officer of the American Cancer Society, worries at times about the “Disease Olympics”—the competition for funding that research generates. “You don’t get promoted at the university for trying and failing to find successful treatments for hard-to-treat diseases.”

We would try one drug, and it would fail. Then we would try another, and then we’d try a combination of drugs, and the results were not what we had hoped for. It was very frustrating.

But at the same time, he says, such comparisons can be overstated. It makes sense to aim research funding where it will have the most impact in preventing death and disability in large numbers of patients, he says. And it’s important to remember that unsuccessful treatments for one disease may one day be found to work wonders on another. (AZT, azidothymidine, was originally studied as a cancer treatment in the 1960s, Brawley points out. It is now a standard therapy for HIV.)

Jeffrey Sosman, MD, professor of medicine at Vanderbilt University and director of the melanoma and tumor immunotherapy program at Vanderbilt-Ingram Cancer Center, describes the discouraging path of treatment for many of his advanced-stage patients the way many clinicians working with hard-to-treat cancers have for years: 

“We would try one drug, and it would fail. Then we would try another, and then we’d try a combination of drugs, and the results were not what we had hoped for. It was very frustrating.” 

While reduction in mortality rates against these hard-to-treat cancers have not kept pace with other forms, that doesn’t mean there hasn’t been any progress. 

Even with advanced-stage lung cancer, which kills more Americans than any other form, new developments in molecular science have opened the door to creating personalized treatment plans that attack some of the same specific targets in cancer cells that make other hard-to-treat forms of cancer so lethal. These targeted therapies remain mostly in the clinical trial stage—and it is much too early to draw conclusions about their long-term success&mdash;but the preliminary results have been encouraging and will help guide new areas of research.

With the discovery of genetic mutations in certain cancer cells, “we are seeing signs of progress” with targeted agents, Sosman says. The goal is to learn as much about the pathways melanoma cells use to replicate and target therapies to shut that process down.

Treatment aimed at BRAF mutant cells seen in a subset of melanoma tumors, for instance, is showing “pretty astonishing results,” he says. Every month brings more scientific results and more optimism.

“I would not have had much good to say to my patients a few years ago,” Sosman says. “I try not to give patients false hope, but there are some positive developments that we are watching closely.”

But he quickly adds, “We still can’t get around the fact that this is not a cure. At least we have gotten to first base on some of these particularly difficult forms of cancer.”

Glenn Mitchell of Kennesaw, Ga., has been battling lung cancer since it showed up on an X-ray in his left lung just before he underwent heart bypass surgery at the age of 53. Mitchell went through surgical resection of his lung shortly after his heart surgery nine years ago. For more than five years he showed no signs of recurrence.

But two years ago, a CT scan showed that the cancer was back. His oncologist referred him to Emory University’s Winship Cancer Institute in Atlanta, where Suresh S. Ramalingam, MD, was starting to enroll patients in a clinical trial to test crizotinib, an anaplastic lymphoma kinase inhibitor targeted to treat the ELM4-ALK translocation, a genetic mutation seen in a small fraction of non-small cell lung cancers.

We learn something from every patient we treat, and what we learn will help us do a better job of taking care of future patients.

During a clinic visit in late August, Ramalingam told Mitchell, 62, that the latest CT scan did not detect the tumor that was on his lung when he started taking the drug in April.

“We typically expect reduction in the tumors in the first few months of the trial,” Ramalingam says. “But I was surprised by the disappearance of the tumor altogether in this case.”

Still, physician and patient both know that cancer— especially lung cancer&mdash;can find ways to thwart many forms of therapy. Even with the newest agents the cancer often begins to develop resistance to the therapy within 10 to 12 months, Ramalingam says.

Finding agents that can interrupt the signals for replication sent out by the mutation of the KRAS gene, for instance, could lead to better outcomes for the 20 to 25 percent of lung cancer patients who have the defect, says Ramalingam, who describes such research as the “holy grail” for lung cancer success. 

“We learn something from every patient we treat,” Ramalingam says. “And what we learn will help us do a better job of taking care of future patients.”  

Hampered by lack of screening tools, science is taking aim at the most lethal forms of the disease.  

Hitting Hard-to-Treat Cancers

Cecil Pharr thinks he was about 16 when he smoked his first cigarette. He’s not sure about that; he could have been a little younger. But what he is sure of is that it didn’t take long to develop a nasty smoking habit. By the time he was an adult, he was up to two packs a day.

The Tucker, Georgia, man smoked heavily for about 50 years, quitting often, but always going back. He stopped for good about 15 years ago.

Even though he had shown no signs of lung cancer during his life, Pharr’s worries about the damage smoking may have done to his lungs persisted. He was being treated for emphysema in 2003 when his pulmonologist suggested he volunteer to be one of the 53,000 Americans who were eventually enrolled in the National Lung Screening Trial (NLST), one of the largest trials for cancer screening ever conducted by the National Cancer Institute (NCI). 

Pharr was randomly assigned to get an annual CT scan at Emory University School of Medicine in Atlanta to test whether the three-dimensional screening method was better at detecting hidden lung cancers among smokers over the age of 55 than conventional chest X-rays.

“I’m here now, when I could have been just another statistic.”

On Nov. 4, the NCI released details of the lung screening trial showing, for the first time, that routine CT screening—like the kind Pharr received&mdash;reduces the risk of death from lung cancer among current and former heavy smokers by one fifth. After five years of follow-up study, 442 patients who were getting routine chest X-rays had died of lung cancer, compared to 354 cancer deaths among those getting CT scans. Even more startling was the finding that routine CT scans also seemed to reduce the risk of death from cardiovascular and other diseases.  

News of the trial continues to produce great enthusiasm among cancer researchers and clinicians, who have long sought a screening tool to test patients at high risk for lung cancer even though they show no signs of it. 

At least for people over the age of 55 who have a history of heavy smoking, the trial produced a “statistically convincing answer” that screening with CT “has the potential to spare very significant numbers of people from the ravages of this disease,” says NCI director Harold Varmus, MD. 

The NCI is stressing, however, that it is premature to recommend CT scans as a way to screen for lung cancer. “At this time, NCI is not releasing recommendations for the use of lung screening CT for any population. Once the final data have been fully analyzed and published, recommendations will be made by any of several bodies commonly called upon to make medical service recommendations, including the United States Preventive Services Task Force and the American Cancer Society,” says Varmus in a press release. 

The trial is also likely to prompt difficult public policy decisions in the months and years to come about who will pay for the tests and how often they should be administered—exactly the same contentious issues connected to other, now routine forms of cancer screening like mammography and PSA testing. 

More problematic, the results also showed that about 25 percent of patients who had CT scans indicating a possible cancerous lesion were found on follow-up to be cancer-free after a biopsy or surgery, a false-positive rate that makes many clinicians uneasy.  

The study found that, for every 300 people screened, one person lived who would have otherwise died during the study, according to the NCI. 

Still, while virtually every researcher interviewed cautions that details of the huge trial need more study before CT screening becomes routine among smokers, they agreed that the findings represent an enormous advance in detecting lung cancer, which claims more lives every year than breast, pancreatic, colorectal and prostate cancers combined. 

“Many of us believe that routine CT screens for heavy smokers is a good idea, but this is the first empirical data we have on it,” said Fadlo R. Khuri, MD, deputy director of the Winship Cancer Institute at Emory, which enrolled about 1,400 patients in the NLST.

 “This is robust science we have to work with,” Khuri says. “Trying to determine who benefits the most and how routine the screening should be is the next step. But, clearly there is reason for optimism now in screening for this form of cancer that has defied effective screening mechanisms in the past.”

Finding a way to screen for lung cancer when it is in a localized state—before it has spread to other parts of the lung or migrated to other organs&mdash;has been a goal for cancer clinicians for decades. Mammography has become standard practice in screening for breast cancer, and colonoscopies are now routinely used to look for colorectal cancer, but there has been no effective screening method for lung cancer in patients without symptoms of the disease. 

Over the next few months radiologists and bioinformatics experts will pore over specific details about the cancer patients who lived and died. They’ll be correlating how old patients were when diagnosed, what their pathology reports showed and how fast their cancers progressed. They’ll also be looking at smoking history, gender, ethnicity and dozens of other variables, all in an effort to create a consensus on the cost, risks and benefits of routine CT screening.  

This effort is important because of the estimated 46 million Americans who currently smoke and the additional 48 million who have smoked heavily in the past. Potentially, every one of those—with the exception of those who haven’t smoked in 15 years&mdash;may benefit from routine CT screening which could detect lung cancer at its earliest stage. 

Even though the form of CT used in the trial, known as helical (or spiral) scanning, is relatively inexpensive (about $300 according to most reports) and it exposes the patient to about one-tenth the radiation of a conventional, whole-body scan, routine use of CT for screening is not without controversy.

Medicare and most private insurance carriers do not pay for the scans in patients who show no signs of lung cancer. (CT use is usually covered only as a diagnostic tool.) But as more information on the benefits of the technology as a screening tool are uncovered, this could change. 

On a per-patient basis, spending $300 for a yearly CT scan  doesn’t seem like much considering the number of lives that may be saved. But because of the enormous size of the at-risk population, routine use of CT scans would significantly increase overall health care spending—and push up the cost of insurance, if they are going to be covered&mdash;when doctors are being urged to rein in the high cost of technology by ordering fewer tests. 

Then there is the issue of false-positives. 

The helical scan offers radiologists three-dimensional looks that slice through the lungs at multiple angles, allowing it to pick up very slight abnormalities in the tissue. This is both the bane and benefit of CT scanning. Even the healthiest of non-smokers are likely to have some abnormalities inside the lungs as they age. The vast majority of them are not cancer.

Finding a suspicious nodule usually prompts another series of scans—and more exposure to radiation&mdash;over three to six months to see if there is any discernable growth. It could also lead to a lung biopsy, which carries its own risks. 

These findings should in no way distract us from continued efforts to curtail the use of tobacco. No one should come away from this believing it is now safe to continue to smoke.

In the NLST, 25 percent of the abnormalities in patients who needed follow-up scans and other tests turned out to be benign. That’s a rate that causes some concern among radiologists, not to mention anxiety among patients who think they may be facing a cancer diagnosis.

But as more information is gleaned from the study, radiologists hope to develop better protocols that will help determine which patients need to be re-tested and aggressively followed, says Kay Vydareny, MD, associate executive director for diagnostic radiology and subspecialties of the American Board of Radiology, and principal investigator for the Emory portion of the NLST. That will be one of the many challenges awaiting experts over the next months and years, she says.

From a lung cancer prevention standpoint, clinicians and advocates alike worry, too, that if a relatively inexpensive screening tool becomes available to smokers to reduce their risks of dying, they may lose their motivation to quit. 

“These findings should in no way distract us from continued efforts to curtail the use of tobacco. No one should come away from this believing it is now safe to continue to smoke,”  Varmus emphasized when the study was released. “Tobacco remains the major causative factor for lung cancer and several other diseases.”

And indeed, one of his first scans showed a suspicious nodule in the upper lobe of his left lung. Follow-up scans showed it was not growing, but by February 2005, at the time of his last scheduled screening, a tumor was clearly present. Three months later, it was surgically removed. 

Instead of being among the 157,000 Americans who die every year from lung cancer, Cecil Pharr’s life was changed by a $300 screening test that gave his physicians the time they needed to get ahead of the nation’s number one cancer killer.

“No doubt in my mind, that test saved my life,” says Pharr, now 78.

Trial shows CT scans may save lives of heavy smokers. 