Susan Kreimer

When she started treatment for allergies, Maureen O’Grady had no inkling that she was about to become a medical pioneer.

That journey began in 2008, when allergy treatment failed and she continued to battle congestion, cough and, especially, shortness of breath. The situation became more alarming when she coughed up blood. Soon thereafter, radiologic tests detected a large mass in her right lung.

“My first oncologist offered me no hope and told me I had 12 to 18 months to live,” says O’Grady, 62, of Milford, Conn., who was diagnosed with advanced-stage lung cancer at age 56 in January 2009. “I changed doctors. I knew I couldn’t change my diagnosis, but I could change the way I was treated.”

Despite a stage 4 diagnosis — with the metastatic cancer in her adrenal glands, liver and heart &mdash; she refused to give up. When one form of chemotherapy failed, she tried another and yet another, then enrolled in clinical trials. “I knew it was risky, but I was fighting for life,” O’Grady says.

Maureen O'Grady, who responded well to Opdivo after being diagnosed with advanced-stage lung cancer, stands with her husband, Tom O'Grady, and a banner depicting a graffiti-style wall that she and other cancer survivors painted.

Finally, she credits an early-phase immunotherapy study with her long-term survival. The drug Opdivo (nivolumab) — which works by taking the brakes off the immune system, allowing it to fight harder against cancer, and which had previously been approved for the treatment of melanoma &mdash; “has reduced and stabilized all areas of disease, with no new growths,” says O’Grady, who received the treatment from June 2010 through June 2012 at Yale Comprehensive Cancer Center in New Haven, Conn. “Physically, I’m feeling well and remain cautiously optimistic, as there is little, if any, history for this drug for lung cancer. I’m one of its pioneers.”

Based on promising results of a multi-center phase 3 trial known as CheckMate-017, the U.S. Food and Drug Administration in March approved Opdivo injection for the treatment of lung cancer, the first immunotherapy to be given the green light in this disease. Opdivo is indicated when metastatic squamous non-small cell lung cancer (NSCLC) has progressed during or after standard platinum-based chemotherapy.

Results of the trial were presented May 29 during the 2015 annual meeting of the American Society of Clinical Oncology (ASCO), a gathering of nearly 30,000 oncology professionals in Chicago.

Lung cancer can be broadly divided into two major types: NSCLC and small cell lung cancer. As one of the most common forms, NSCLC represents about 85 percent of cases. A subtype of this malignancy — squamous cell NSCLC &mdash; accounts for an estimated 25 percent to 30 percent of all lung cancers. For those with distant tumors caused by lung cancer that has spread to other organs, the five-year survival rate is only 4 percent, according to the National Institutes of Health.

While the earliest stages of lung cancer can often be treated with surgery alone with a reasonable chance of cure, they constitute only 15 percent of cases. In most instances, cancer has spread to the lymph nodes or the chest by the time it is detected. More than half of patients are diagnosed in stage 4, when the cancer has already metastasized to distant sites and surgical excision is no longer possible; these cases are not considered curable, though transient responses can be seen with chemotherapy, or when certain mutations are present in the tumor and biological therapies are given initially.

On a global scale, lung cancer claims more lives than any other type of malignancy, resulting in 1.59 million deaths each year, according to the World Health Organization’s latest statistics, released in February. Tobacco use is the most significant risk factor, causing about 70 percent of lung cancer deaths worldwide.

Hope has been offered via a number of immunotherapies recently approved, or being tested, in patients with the disease.

Like Opdivo, Keytruda (pembrolizumab) targets PD-1, an inhibitory T cell co-receptor, or PD-L1, a ligand expressed on the tumor. Interactions between PD-1 and the ligands PD-L1 or PD-L2 are believed to suppress the antitumor immune response. Immune checkpoint inhibitors are intended to impede those interactions, activating T cells — the white blood cells powerful enough to destroy cancer cells.

Keytruda is being tested in a phase 3 trial of patients with PD-L1-positive NSCLC; already approved for the treatment of melanoma, it’s being considered by the FDA under a breakthrough therapy designation, meaning the agency will expedite its review.

Yervoy (ipilimumab), too, is a checkpoint inhibitor approved for the treatment of melanoma, but it works a bit differently, by quieting the CTLA-4 checkpoint on T cells so that they can better fight cancer. It is being tested in phase 3 trials in both NSCLC and small cell lung cancer. Another CTLA-4 antibody, tremelimumab, is in phase 2 testing in patients with mesothelioma.

Immunotherapeutic vaccines include GV1001, which targets telomerase and is being tested in a phase 3 trial in patients with stage 3 NSCLC that can’t be removed surgically. Finally, adoptive T cell transfer is being considered in phase 2 lung cancer trials; this involves removing T cells from a patient, engineering them in a lab to be more active in the fight against cancer, and re-infusing them.

“Immunotherapy is a game-changer, a breakthrough that oncology desperately needs,” says Guneet Walia, director of research and medical affairs at the Bonnie J. Addario Lung Cancer Foundation in San Carlos, Calif. “For the first time, we can begin to talk about long-lasting effects and start thinking about using the ‘C word’ — for cure.”

A tumor doesn’t necessarily need to shrink for a patient to benefit from immunotherapy. “It’s a very important time for patients,” says Roy S. Herbst, a professor and chief of medical oncology at Yale Comprehensive Cancer Center. “Even if the tumor doesn’t change in size, it often stops progressing. Patients live longer because they have a slower progression of their disease.”

What’s unprecedented is, even after the patient stops the treatment, the immune system continues to police cancer cells and mount rigorous attacks. The discovery of immunotherapy is “a quantum leap forward, a moonshot,” Walia says, “adding to our arsenal of agents that are active against even the most intractable cancers for which patients didn’t have many options, especially after their disease progressed upon treatment with the current standard-of-care therapies.” So far, only 20 to 30 percent of cancer patients seem to respond to immunotherapies, and researchers are working to find out why, and how to make the most of the treatments.

Determining which characteristics may predispose patients to derive the most positive outcomes from immunotherapy “is an area of intense investigation that could enable oncologists to deliver the treatment to more patients who could respond successfully and potentially live longer,” says Stephen V. Liu, an assistant professor of hematology/ oncology specializing in thoracic oncology at MedStar Georgetown University Hospital in Washington, D.C.

In CheckMate-017, Opdivo demonstrated markedly improved overall survival compared with chemotherapy in previously treated metastatic squamous NSCLC. Due to the promising results, the study was terminated early, with the FDA deciding to approve the drug more than three months ahead of schedule. Among the 272 participants in the randomized trial, the median overall survival (OS) was 9.2 months in the group of 135 receiving Opdivo versus six months in the group of 137 using the chemotherapy drug docetaxel. Another measure, known as the hazard ratio, calculated a 41 percent decrease in the risk of death for those in the Opdivo group.

Based on the results of a separate phase 3 study, Opdivo is also showing promise in patients with non-squamous NSCLC, and is pending FDA approval for the treatment of that disease type.

In the two trials, investigators noticed differences in the groups of patients who benefited from the drug.

In non-squamous patients, stronger OS outcomes were observed in those who were PD-L1—positive, including a 60 percent reduction in the risk of death for those with the highest PD-L1 levels. But in patients with squamous NSCLC, outcomes favored nivolumab regardless of PD-L1 expression.

Also of note in those with squamous NSCLC was that “there is a subset of patients whose benefit lasts far greater than nine months,” says Liu. “We can’t identify those patients at the beginning, and that’s something that we need to be able to do.”

In the future, with a more reliable biomarker, the response rate may reach 80 percent among patients deemed eligible for the drug, “but we’re clearly not there yet,” says Renato G. Martins, medical director of thoracic, head and neck medical oncology at the Seattle Cancer Care Alliance and a professor of oncology at the University of Washington School of Medicine.

Might PD-L1 have played a role in the response of those excellent Opdivo responders in the squamous NSCLC group? Researchers aren’t yet sure.

“PD-L1 is not a perfect biomarker,” Liu says. “There are multiple ways to detect PD-L1 and different ways to do the test. We’re still learning how to use this marker.”

There is more evidence that the marker is a predictor of successful treatment when the investigational immunotherapy atezolizumab (MPDL3280A) is used in NSCLC.

When compared with docetaxel chemotherapy in the phase 2 POPLAR study, atezolizumab doubled the likelihood of survival in people whose immune cells or advanced NSCLC tumor cells expressed the highest levels of PD-L1. People who had lower levels of PD-L1 expression also benefited from atezolizumab with an improvement in survival; those without any PD-L1 expression had a similar survival with either atezolizumab or docetaxel.

In February, atezolizumab received breakthrough therapy designation from the FDA. Approval is being sought for the treatment of those whose NSCLC, either squamous or non-squamous, expresses PD-L1, and who progressed during or after standard treatments, such as platinum-based chemotherapy and appropriate targeted therapy for EGFR mutation-positive or ALK-positive disease.

Robert “Bob” Schoenbauer, for one, has benefited greatly from the drug.

In late 2013, the now 80-year-old from Waldorf, Md. began coughing, then experiencing shortness of breath and feeling fatigued into the following year. Initial tests in Maryland weren’t definitive, and he and his wife of 60 years, Frances, suspected a winter cold as the culprit, yet were concerned that his worsening condition could be more serious. In March 2014, he was diagnosed with stage 3B NSCLC — a very aggressive form affecting the lungs and lymph nodes; long-term survival isn’t normally expected.

Robert Schoenbauer (second from the left) poses with his wife, Frances, and the bride and groom at a grandson’s wedding.

Schoenbauer entered a trial at Georgetown in which he received weekly infusions of atezolizumab in combination with two chemotherapies, carboplatin and nab-paclitaxel. After three months on this regimen, he has been receiving only atezolizumab every three weeks for about a year in the ongoing phase 1b trial. Investigators still don’t know whether his cancer expressed PD-L1, because that information was blinded as part of the trial.

Almost immediately, Schoenbauer began responding to the immunotherapy administered jointly with chemotherapy. Even his doctors couldn’t believe how quickly his tumor shrank, he says. As for side effects, there were hardly any except for hair loss on his head and body. “Once in a blue moon, I’d get a little tired, when I first started doing the chemo,” Schoenbauer recalls. For the time being, there is no evidence of cancer on his radiologic scans. “I feel absolutely great right now,” he says.

Beyond the expression of PD-L1, there are other biomarkers that indicate who might be a good candidate for immunotherapy.

While the treatment strategy works on both smokers and never-smokers with lung cancer, studies have shown that a higher presence of mutations in the genome — which is typically associated with smoking &mdash; correlates with a better response to treatment.

“Smokers’ genomes are typically associated with higher mutational loads due to exposure to carcinogens in cigarette smoke and, therefore, may respond better than nonsmokers — an example being the promising effects of immunotherapies seen in squamous cell lung cancer and small cell lung cancer, both of which disproportionately affect smokers,” Walia says.

Lung cancer isn’t one disease; it’s a constellation of many different diseases. Comprehensive genomic profiling or a specific molecular diagnostic test may pinpoint an underlying biomarker that, even before the evolution of immunotherapy, had meaning in determining how to treat the disease.

In some cases, a mutation means a patient’s lung cancer is likely to respond to a targeted drug, such as Tarceva (erlotinib), which treats NSCLCs with certain EGFR, or epidermal growth factor receptor, mutations. In those situations, it would typically make the most sense to use targeted treatments before considering immunotherapy, oncologists say. Logically, immunotherapy would come into play after resistance to a targeted drug develops — at least, that’s the thinking at the moment.

“For now, we reserve immunotherapy for use after the standard treatment is not working. But introducing immunotherapy earlier and earlier makes sense. We want to use our best drugs first,” says Georgetown’s Liu. “Targeted drugs have changed the landscape of non-small cell lung cancer, but while they’re very effective, they do not work forever. Eventually, these cancers develop resistance, so using these immunotherapy agents before resistance sets in is really appealing and may be able to provide longer periods of control. But the optimal sequencing of how to use these drugs? We simply don’t know yet.”

Immunotherapy doesn’t work for everyone. About 70 percent to 80 percent of cancer patients don’t respond. Others gain only modest benefits, while overall survival and longterm effects are still unknown. “But this must be considered in light of the fact that these patients don’t really have many options, so any positive effect is a good effect,” says Walia.

That’s only one of the concerns about the use of immunotherapy.

The drugs can cause side effects; with Opdivo, for example, they most commonly involve shortness of breath, fatigue, musculoskeletal pain, cough, decreased appetite, constipation and nausea. The most serious side effects are immune-related and affect healthy organs, potentially including the colon, liver, lung, kidneys and hormone-producing glands, according to the FDA.

Combination regimens of more than one immunotherapy are under evaluation. Administered either concurrently or sequentially, they are more likely to cause toxicities, in some cases severe enough to warrant hospitalization. Many patients also drop out of clinical trials due to serious or lifethreatening complications, Walia cautions.

Patients and their caregivers also should be prepared for a phenomenon called “pseudoprogression.” It’s a false alarm that the disease is progressing when it isn’t. This occurs when immune cells infiltrate tumors to mount an attack, inflating the tumor’s volume before causing it to shrink. The good news is, in most instances, patients with greater pseudoprogression tend to respond better to immunotherapy, she says.

Then there are the high costs of immunotherapy, compounded by the fact that it’s not yet clear how long patients should keep taking these drugs.

As combination regimens of immunotherapy and other standard-of-care regimens continue undergoing investigation, scientific data will increase, Walia says, helping to answer the question: “Are we delivering enough value for the cost? Do four-, five- or 10-month additions in progressionfree and overall survival justify six-figure costs?”

Despite those concerns, oncologists express continued optimism about immunotherapy’s untapped potential. “We do have patients in whom the disease hasn’t returned after they’ve stopped therapy,” Martins says. “Time will tell what that means, but that is not something we used to see with other treatment.”

Herbst, of Yale Cancer Center, adds: “For lung cancer, immunotherapy is really a new paradigm. Actually, for all tumors, immunotherapy is truly revolutionizing the way we care for cancer — using the body’s own immune system to target a tumor.”

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For some with lung cancer, immunotherapies are sparking long-lasting responses.

Into the Future

Since 1976, the U.S. Food and Drug Administration (FDA) has maintained that it has the authority to regulate laboratory-developed tests (LDTs), including those that screen for genetic mutations that increase an individual’s risk of certain cancers. But the agency has taken a largely hands-off approach—until now.

Advances in genomic technologies have made possible the development of many new, more complex tests with higher-risk uses, prompting the FDA to voice concern over health care decisions based on potentially incorrect results.

In late July, the agency announced it had started a process that could allow it to initiate more vigorous monitoring of LDTs because it “is concerned that people [based on the results of these tests] could initiate unnecessary treatment or delay or forgo treatment altogether for a health condition, which could result in illness or death.” While proponents of stricter supervision contend it is long overdue, others fear it will inflate costs and curb innovation.

	“LDTs have been tremendously important in advancing medicine,” says Jan A. Nowak, medical director of the molecular diagnostics laboratory at NorthShore University HealthSystem in suburban Chicago. “If there are very burdensome oversight regulations—costly kinds of things&mdash;then it will certainly take away the availability of tests, not only in the future, but tests that we’ve relied on for years.”

	LDTs have played a significant role in cancer diagnostics. Newer LDTs, known as companion diagnostics because their use is linked to a specific drug or class of drug, fall into the evolving category of personalized medicine, which tailors therapies to individual patients. Once a test pinpoints a genetic mutation, a medicine at a specific dosage may be prescribed to target that mutation. A companion diagnostic test could help determine which patients would benefit from a particular treatment. Sometimes a companion test also can predict which patients could be harmed by a treatment.

	To date, 19 companion diagnostic tests, some of which are for the same indication, have been cleared for the selection of drugs to target various diseases and conditions. Most therapies with a companion diagnostic test are cancer treatments aimed at specific mutations.

	The premarket review process for tests regulated by the FDA is capped at 180 days, but often takes longer. If modifications are made to diagnostic tests after FDA approval, the agency can mandate new premarket submissions, says Roger D. Klein, medical director of molecular oncology at the Cleveland Clinic in Cleveland.

	“It can be a very long and costly process,” Klein adds. The shift would be an intrusive measure, he says, that would decrease innovation in the production of relatively inexpensive laboratory tests that perform well. This “would lock people into FDA-approved tests,” he says, which “are typically static—unable to adjust to rapid change in technological development and medical knowledge.”

	In the past, the FDA did not typically enforce premarket review of LDTs, because of their relative simplicity and limited availability. The agency recently stated on its website that it had found inconsistencies in several high-risk LDTs, such as claims lacking adequate evidence, insufficient controls leading to faulty results, and falsification of data.

	Clinical laboratories analyzing LDTs have been under the regulation of the Centers for Medicare & Medicaid Services (CMS), as stipulated in the Clinical Laboratory Improvement Amendments (CLIA), enacted in 1988. CLIA requires laboratories to obtain certification to report results to health care providers. The FDA and CMS, through CLIA, have different regulatory goals, according to a report from the Congressional Research Service. The FDA is primarily concerned with “the safety and effectiveness of the diagnostic tests themselves and the quality of the design and manufacture of the diagnostic tests,” whereas CLIA aims to regulate “the quality of the clinical testing process itself, mostly by assessing the quality of the clinical laboratory,” although there is some overlap.

	Alan Mertz, president of the American Clinical Laboratory Association, says his group supports strengthening CLIA rather than adding more FDA oversight, which would be duplicative and financially burdensome. CLIA-proposed enhancements would include a registry of available tests and a database for tracking adverse events.

	“Most of these LDTs will never even have that much revenue in the lifetime of that test,” Mertz says. “It is a concern with those requirements that labs will not even develop the test, because there’s no way that they could ever recoup the costs of approval.”

Advances in genomic technologies have made possible the development of many new, more complex tests, prompting the FDA to voice concern over health care decisions based on potentially incorrect results.

FDA Aims to Start Regulating Custom Diagnostic Tests

While progress in brain tumor treatment has been slow, new research has the brain cancer community buzzing. Recent work contributing to an understanding of the molecular mechanisms and gene mutations, combined with clinical trials, is leading to more promising and tailored therapeutic approaches.

Immunotherapy is a new modality showing potential in patients who receive a diagnosis of glioblastoma multiforme (GBM)—the most common and most aggressive brain cancer with a strong resistance to conventional therapies and a high relapse rate. In 2014, the American Cancer Society estimates about 23,000 new cases of brain and other nervous system tumors will be diagnosed and that there will be more than 14,000 deaths from these tumors.

Immunotherapy can include treatment with monoclonal antibodies, cancer vaccines and other therapies that stimulate an immune response to help the body recognize and attack cancer cells—all with the goal of ultimately shrinking tumors and prolonging lives.

Monoclonal antibodies are synthetic immune system proteins and are quite prolific in cancer treatment now. The monoclonal antibody Avastin (bevacizumab) has been used to treat recurrent or resistant brain cancer since it was approved by the Food and Drug Administration in 2009.

Different forms of immunotherapy already have led to major improvements in the outcomes of some cancers, including resistant HER2-positive breast cancer, lymphomas, leukemias and melanoma. However, malignancies of the brain represent more of an enigma to researchers, resulting in slower adoption of immunotherapies than in other cancers.

While many vaccines are used to prevent diseases, vaccine therapy as a cancer treatment is gaining speed. Provenge (sipuleucel-T), the first cancer therapeutic vaccine, which uses the patient’s own immune dendritic white cells that are “boosted” against a prostate cancer specific antigen, was approved in 2010 to treat advanced prostate cancer. Since then, there has been an abundance of cancer vaccine clinical trials, but no new vaccine has been approved.

“The first thing that a brain cancer has to do in order to grow and be successful to survive and thrive in its human host is to make itself invisible,” says Keith L. Black, chair of the department of neurosurgery at Cedars-Sinai Medical Center in Los Angeles. Secondly, brain cancer works to weaken or suppress the immune system. “It’s a strategy that cancers employ, particularly brain cancer.”

A diversity of cells constitutes a brain tumor, posing additional challenges. Also, “the central nervous system is cordoned by the blood-brain barrier that limits the access of common therapeutic agents,” says Nabil Ahmed, a pediatric oncologist at Texas Children’s Cancer and Hematology Centers in Houston. “Modern immunotherapy has been able to overcome this limitation with some success.” But more potent and personalized agents requiring advanced technology are needed to propel further progress.

It’s a different form of therapy. What we’re trying to do with the brain is not to replace the standard of care, but to add another category of treatment.

Typical treatment for GBM begins with surgery to extract malignant tissue from the brain, followed by radiation and chemotherapy to kill lingering cancer cells. In many cases, the cancer reappears several months later. For a select number of patients, this could lead to another operation and possibly more chemotherapy. Now, there is hope that the inclusion of immunotherapy along with this regimen can have a positive influence.

“It takes time to develop that immune response,” says Donald M. O’Rourke, an associate professor of neurosurgery at the University of Pennsylvania’s Abramson Cancer Center and the Perelman School of Medicine in Philadelphia. “The more rational goal of immunotherapy is to prevent a recurrence rather than reduce what’s already there. It’s a different form of therapy. What we’re trying to do with the brain is not to replace the standard of care, but to add another category of treatment.”

Because there is significant variation among GBMs and the patients that have them, one-size-fits-all treatments cannot address their needs. A number of personalized immunotherapy treatments in brain cancer are currently being tested. Among them, the DCVax-L vaccine for newly diagnosed GBM, which is created by combining dendritic cells (the patient’s own immune cells) and the patient’s own tumor tissue in the laboratory. Now that the dendritic cells can “identify” the patient’s cancer cells, they are injected back into the patient and alert the immune system to attack those specific cells.

“In our previous clinical trials of immunotherapy for GBM, there appears to be an interesting tail end of survivors—10 years or more,” says Linda M. Liau, principal investigator of the DCVax-L trials and director of the Brain Tumor Program at the Ronald Reagan University of California, Los Angeles Medical Center. In a phase 1/2 study, a third of patients have lived a median of at least four years or more. Traditionally, fewer than 10 percent of GBM patients receiving standard care survive five years or more. The vaccine is currently being tested in a phase 3 study. Patients must enter screening at a participating site before surgery to treat the tumor.

Another phase 3 study is investigating the efficacy and safety of a combination of  the chemotherapy Temodar (temozolomide) and the investigational drug rindopepimut—a cancer vaccine that could promote anti-tumor effects in newly diagnosed patients whose GBM tumors express the EGFRvIII protein, a byproduct of a mutation seen in about a third of GBM cases.

Also factoring in the individuality of patients’ tumors, the Prophage Series vaccines, including the Prophage G-200 series, which is undergoing phase 2 clinical trials—are tailored uniquely to each person’s cancer. Like DCVax-L, every vaccine is manufactured using the surgically removed tumor. However, instead of using the patient’s own dendritic cells, the Prophage vaccines contain the heat shock protein gp96. This protein is used in the vaccine because it carries around tumor-specific peptides extracted from the tumor tissue. Once injected, the patient’s immune system would be able to identify the heat shock protein gp96 and peptides complex, giving the immune system a way to identify the cancer cells and attack them.

Results of the phase 2 study have shown it improves survival in patients with recurrent GBM. The results, published in 

 earlier this year, showed that patients who received the vaccine after surgery had a median survival of more than 10 months. Comparatively, patients who have a recurrence of their brain tumor historically have a median survival of about 3 to 6 months. The vaccine had few side effects, but mostly included fatigue and skin sensitivity to the injection.

Because the phase 2 study did not include a control group, scientists are unable to confirm if the vaccine is better than Avastin, often used for recurrent GBM. Another phase 2 study is underway to compare the vaccine with Avastin. The trial will look at how the vaccine, given either in combination with Avastin or followed by Avastin at disease progression, compares to the regimen of Avastin alone.

ICT-107 is another approach that uses a patient’s dendritic cells to harness the immune response.   “The goal is for the ICT-107 vaccine to stimulate the patient’s immune response to kill the remaining brain tumor cells after surgery and chemotherapy,” says Texas Children’s Ahmed.

The vaccine is being studied after surgery in patients with newly diagnosed GBM in combination with standard treatment of radiation and chemotherapy. Disappointing data showed no improvement in survival, but it did delay progression of the disease. Further results may be available this summer at the annual meeting of the American Society of Clinical Oncology.

Unlike traditional chemotherapy and radiation, all of these brain cancer vaccines theoretically target only malignant cells and do not harm healthy cells. This means that these vaccines are particularly gentle, with limited toxicities.

As the scientific community gains a better understanding of the diversity of brain tumor cells and the ways in which they evade the host immune system, immune-based therapies will likely become part of the antitumor options used to treat these deadly cancers.

Advances in immunotherapy are showing progress in treating brain cancer, especially glioblastoma.

Is Immunotherapy the Key to Treating Brain Cancer?

Anemia is one of the most common side effects of cancer treatment, with roughly 90 percent of chemotherapy patients developing anemia. Untreated anemia can impair quality of life and survival, with symptoms including fatigue, dizziness, inability to concentrate, shortness of breath, chest pain, and elevated heart rate. Severe anemia can delay chemo&shy;therapy or require the dose to be lowered. 

Red blood cells (RBCs) are made in the bone marrow and carry oxygen to the body’s tissues using hemoglobin molecules. Anemia results when the body has too few RBCs, and getting at the root of anemia is essential before treating it.

Although the causes of anemia can vary, cancer therapies are a primary culprit. Chemotherapy can damage healthy cells, including cells in the bone marrow that produce RBCs; radiation therapy can also damage bone marrow.

Sometimes the cancer itself causes anemia. Patients with leukemia, lymphoma, or myeloma have a higher risk of developing anemia because in addition to treatment-induced decreases in RBCs, these three types of cancer can grow in the bone marrow and suppress the production of RBCs.

Certain tumors, such as stomach and colon, may cause significant blood loss, resulting in iron deficiency. Other causes of anemia include nutritional deficiencies, tumor-related blood loss, major organ problems, sickle cell disease, or a combination of these factors. 

The hormone erythropoietin, or EPO, is produced in the kidneys and tells the body when it needs to produce more RBCs. Genetically engineered EPO, which compensates for the shortage of natural EPO in the body, has been used widely since the 1990s for chemotherapy-induced anemia.

EPO drugs, such as Procrit (epoetin alfa) and Aranesp (darbepoetin alfa), were attractive alternatives to repeated blood transfusions in patients burdened with chemotherapy infusions. (Iron supplementation is usually recommended with EPO use.)

In the past few years, however, research revealed greater evidence of complications arising from the overuse of EPO drugs. Studies have shown that these drugs may lead to increased harm, particularly blood clots, and decreased survival in certain groups of cancer patients, including those with cancers of the head and neck, breast, lung, and cervix.

These drugs were given a “black box” warning, signifying serious side effects, in early 2007. And as of August 2008, the Food and Drug Administration placed stronger restrictions on EPO agents.

The FDA advises that they only be used to avoid transfusions or severe anemia instead of trying to raise red blood cell counts to a normal level. The agency does not recommend these drugs for anemic cancer patients who are not receiving chemotherapy, nor does it recommend them for patients receiving chemotherapy as curative treatment (such as adjuvant chemotherapy for early-stage cancers).

Since the FDA noted blood transfusions as the preferred method for correcting anemia, more patients have been receiving transfusions and fewer EPO drugs are being prescribed. 

Nutrient-rich foods might help fight fatigue and other symptoms of anemia. Because dietary needs vary among patients, a registered dietitian can develop a customized plan.

In general, prevention can be as simple as eating a well-balanced diet that includes green leafy and cruciferous vegetables, fresh and dried fruits, iron-fortified cereals and breads, lean red meats, eggs, and dried beans.

Iron and folic acid supplements may minimize dietary deficiencies, but patients who are anemic should not take them without a physician’s approval.

Patients also should report any bleeding to their physician so it can be resolved before anemia develops. Routine blood tests can detect anemia in an earlier stage. The goal is to treat the underlying cause of anemia so that symptoms subside or go away.

—Heather Lindsey contributed to this article. 

FDA decision changes the routine for treating cancer-related anemia. 

New Blood

Although early detection of lung cancer has mostly eluded modern medicine, computed tomography and other diagnostic tools may eventually lead to better outcomes.

The vast majority of lung cancers are diagnosed at an advanced stage, making this malignancy 

most prevalent cause of cancer death worldwide. Only about 15 percent of patients in the United States survive five years or longer. 

CT scans of current and former smokers may pinpoint lung cancer at an early stage, raising the rate of diagnosis and treatment. The latest findings, however, caution that such screening may not lower the risk of advanced disease or death from lung cancer.

Journal of the American Medical Association 

“Until more conclusive data are available, asymptomatic individuals should not be screened outside of clinical research studies that have a reasonable likelihood of further clarifying the potential benefits and risks,” investigators wrote in the 

in 2007. The study assessed the value of annual CT scans in more than 3,200 participants.

 is still under way. Sponsored by the National Cancer Institute, this trial was launched in 2002 as a 

—the “gold standard” in medical research.

The large number of participants—almost 50,000 current or former smokers ages 55 to 74 enrolled at more than 30 U.S. sites by February 2004&mdash;will help investigators accurately measure if there is a decrease in lung cancer mortality from screening with spiral CT compared with standard chest X-ray.

Until now, neither chest X-rays nor spiral CT scans has been proven to reduce deaths from lung cancer even though early studies have shown that tumors detected by screening CT scans are of lower stage than those detected because of symptoms. The NCI study, designed to collect and analyze data for eight years, is evaluating whether either method is more effective in lowering mortality.

“The point of doing screening CTs, even in the best situation, is to detect patients that could be cured if detected early, but who would perhaps not present with symptoms until they’re incurable,” says David P. Carbone, MD, PhD, professor of medicine and cancer biology at Vanderbilt-Ingram Cancer Center in Nashville. So far, research hasn’t shown that CT scans of everyone in a risk category would be beneficial.

Other types of lung cancer screening tools are in development. Researchers hope to devise sensitive tests that can detect small changes in the lungs. Proteomics—the large-scale study of 

—uses specific biomarkers in the breath, blood, urine, and sputum to diagnose disease swiftly.

“We’ve come up with some tests that are fairly good, but probably not good enough to test in very big populations,” Carbone says. “The hope is that we could have something in the next five years.”

Mass spectrometry is emerging as a promising method to identify the proteins expressed in cancer cells but not healthy cells. This could lead to the development of drugs targeting specific proteins.

The National Lung Screening Trial is gathering blood, urine, and sputum specimens from 10,000 of the 50,000 participants. “We would have loved to have collected on all of them, but the cost was prohibitive,” says John D. Minna, MD, director of the Hamon Center for Therapeutic Oncology at University of Texas Southwestern Medical Center in Dallas. He serves on the trial’s advisory committee for biologic specimens.

Pursuing CT scans for lung cancer on a widespread basis raises concerns about potentially causing more harm than benefit. The screening would detect a large number of nodules that require

follow-up, subjecting many patients to invasive procedures such as biopsies and lung resections for benign disease.

Those with an abnormal nodule may have to return every three to six months for re-screening, which compounds the risk and worry for the patient and burdens the health care system, Minna says.

“Exactly the same issues came up for mammography screening for breast cancer 25 years ago,” he adds. “The randomized trial showed the benefit, so that led to adoption of this as a standard policy for breast cancer screening.”

Results from the National Lung Screening Trial are expected to shed light on the CT scan versus chest X-ray controversy. “The trial is still on track for reporting initial results sometime in late 2009 or thereafter,” says Michael J. Miller, a spokesman for the National Cancer Institute.

Meanwhile, Minna says, individuals with a strong family history of lung cancer may wish to ask their doctor about devising a personalized detection plan. 

Controversy surrounds lung cancer screening.  

To Screen or Not to Screen

When Mikio Yamashiro* needed a stem cell transplant, he wanted to be at the optimal place. “For any given condition, there is a best hospital. I believe very strongly that it’s worthwhile to find that hospital and to go there,” says Yamashiro, 38, whose acute lymphoblastic leukemia, diagnosed in January 2007, is now in remission.

“On top of that, there is the cost of living in a new place,” says Debbie Fraley, housing coordinator at the Seattle Cancer Care Alliance, which is linked with Fred Hutchinson. “Our mission as staff is to try to help patients piece together any and all financial assistance they might qualify for.” Fraley says rent, transportation, food, deductibles, copayments, and other uncovered medical bills “can be daunting and devastating.”

Traveling for treatment posed financial challenges for Yamashiro, who had to cover living expenses in two locations—a New Jersey condo and a temporary apartment in Seattle&mdash;on disability payments, which were 60 percent of his prior earnings. Luckily, most of their lodging costs were covered by the hospital and the Leukemia & Lymphoma Society through the nonprofit’s Patient Financial Aid program. 

It is becoming more common for patients to travel to other states, says Lakshmi Naik, clinical social work supervisor at M.D. Anderson Cancer Center in Houston. “When they are faced with the prospect of a life-threatening disease such as cancer, these patients now get into a survival mode,” she says. “Scared and desperate, they are willing to go to any lengths, even beg or borrow if needed, to find the best treatment or a cure for their disease.” 

Some cancer centers may have designated “hospitality houses” that offer discounted or free housing.

M.D. Anderson’s department of social work has negotiated rates with nearby lodging facilities, many of which offer a free shuttle to the hospital. For instance, a basic room renting for $70 per night may cost $50 plus tax with the discount. Because resources are very limited, M.D. Anderson patients must meet eligibility criteria based on disease, income, region of residence, and other factors.

Limited resources may pose hardships for patients being treated at the Seattle Cancer Care Alliance, where there can be a waiting list for the Pete Gross House, a 70-unit fully furnished apartment building. Monthly rates for the Pete Gross House start at $43 a night, and treatment can necessitate stays of several weeks to several months.

To address the growing demand, the Pete Gross House will soon be joined by the SCCA House, an 80-room facility expected to open in fall 2009 that is designed to target the needs of those with shorter stays averaging about six weeks. The Alliance offers other housing options to patients, including a nearby residential building with furnished apartments where Yamashiro and his family stayed.

Among the few free places to stay across the nation are the 26 Hope Lodges that the American Cancer Society operates for patients and caregivers traveling for treatment. Last November, its newest and most expansive Hope Lodge opened near Penn Station in New York City.

In addition to 60 guest suites on 11 floors, the 77,000-square-foot building features communal kitchens, activity rooms, and free laundry facilities. Support services, such as special shared meals and yoga classes, are offered at no cost.

The Manhattan facility functions at more than 90 percent capacity, says Lindsay Edgar, manager of guest and volunteer programs. The ACS works with medical centers to identify nonlocal patients with the greatest need on a first-come, first-served basis. To be considered, prospective guests must submit a special form signed by their social worker or doctor.

When the lodge is full, staff and volunteers refer patients to other options in Manhattan such as Miracle House. Established in 1990 to address the AIDS crisis, Miracle House now accepts patients with cancer and other critical conditions for its five, three-bedroom apartments in a modern high rise that has a sports club and Olympic-size indoor pool.

Each unit is equipped with a kitchen, dining room, living room, free high-speed Internet access, television, air conditioning, and 24-hour security. More than 150 volunteers assist with apartment renovations, food drives, and fundraising events.

For $50 per night including tax, the patient and caregiver get one bedroom and share common areas in the apartment with other clients. (A second bedroom costs an additional $50 per night.) Patients are required to have a caregiver at least 18 years of age. Miracle House covers breakfast Monday through Friday, dinner Tuesday through Thursday, and brunch on Saturday at a nearby diner. Meals for Miracle House residents are at set times, encouraging families to socialize.

Support becomes more critical for patients spending weeks or months away from familiar turf. Cheerful staff and volunteers at Miracle House go a long way to make their guests feel comfortable and upbeat.

“I want them to think about coming to New York for the treatment—that’s the main reason&mdash;but they also need to go and have fun,” says Majo Prazenec, client services coordinator, who suggests activities for residents. Miracle House has been able to obtain free passes to venues such as the Guggenheim Museum and the Museum of Modern Art, as well as discounts to Broadway shows. 

Susie Wade, 75, of Lancaster, South Carolina, was diagnosed with mesothelioma in July 2006, a decade after retiring from 26 years at a textile plant that manufactured bed linens. Wade began treatment near her home in the Atlanta area, where three of four daughters live. Doctors originally estimated she would live “six weeks to six months.”

The search for a second opinion led Wade’s youngest daughter, Teresa Wade, to an oncologist in New York City. The prognosis—and Susie Wade’s spirits&mdash;brightened in March 2007 when she consulted with the oncologist and decided to become his patient. Teresa has covered nearly all the travel and housing costs.

The path to extending her life hasn’t been easy. She endured 24 rounds of chemotherapy, three surgeries, and one radiation treatment, as well as various scans, fluid taps, blood drawings, and medications too numerous to count. Sometimes it’s hard to tell what exhausts her more—the treatment or flying back and forth, she says.

During each visit, one of Wade’s four daughters stays with her at Miracle House. “The vital care she receives from her doctor and the home-away-from-home atmosphere that Miracle House provides are the reasons we keep returning to NYC,” says daughter Deloris Wade Ball of Decatur, Georgia, her caregiver on a recent trip.

Helen Domenico, 76, of Cheyenne, Wyoming, received chemotherapy treatments near her home, but her oncologist conferred with her second oncologist at M.D. Anderson, where she underwent surgery for peritoneal cancer in 2001. She flies back to Houston for checkups, and in May and June, she returned for six weeks of radiation after a recurrence because she preferred to continue her care at M.D. Anderson.

Employees at Jesse H. Jones Rotary House International—connected to M.D. Anderson via an enclosed skywalk&mdash;welcomed her back with a smile. Domenico’s two-bedroom suite at the Marriott-operated, M.D. Anderson-owned full-service hotel, which caters exclusively to M.D. Anderson patients and their families, cost her $225 per night not counting tax (room rates vary from $98 to $315 per night).

“I feel it’s worth it, and my family feels that it’s worth it,” says Domenico, a widow with four stepchildren and one biological child. “I get excellent care here. They know the latest in cancer care. I’m able to take advantage of anything new that’s coming out.”

As for Mikio Yamashiro*, he returned home after the stem cell transplant and is having his health monitored by a local physician. He and his wife, Kazuko, believe the trip to a leading transplant hospital was well worth it.

(*notes that name has been changed to protect interview subject's privacy)

Our mission as staff is to try to help patients piece together any and all financial assistance they might qualify for.

Patients who travel for treatment now have more places to stay.

Far From Home

Interview both your local oncologist and social worker and an  oncologist or social worker at the facility where you plan to go to see if it  will provide something substantially different from treatment near home. 

An alternative for patients who are physically, logistically, or  mentally unable to travel for treatment is telemedicine—using the telephone and  computer to consult with health professionals outside your area. These experts  can validate the treatment planned by your local team, offer a second opinion,  or recommend a different protocol that your team is willing to follow. In many  cases, oncologists are willing to work together for your care.

If you feel well enough to travel and have determined that the  best care necessitates it, the National Cancer Institute offers suggestions on  selecting the right facility at 

www.cancer.gov/cancertopics/factsheet/Therapy/doctor-facility

Also, consider a destination based on where your extended family  or friends live. They may be a valuable support network, and in some cases,  provide housing, meals, and transportation to the hospital.

Finding affordable housing or financial support for distant care  becomes an essential part of the equation. Here are some resources to explore:

 pay for temporary lodging if a patient has to travel for  treatment. Private insurers also may include travel and lodging benefits. Check  your state’s requirements and review your health insurance coverage.

The National Association of Hospital  Hospitality Houses

) helps patients and their families locate  housing around the country. Make sure you understand all the conditions and  policies before leaving home.

> The American Cancer Society’s Hope Lodges

  offer free housing to patients and caregivers in 26 areas with an average length  of stay of six to eight weeks. Accommodations and eligibility requirements vary  by location and include the patient having a caregiver at least 18 years old  with them at all times. To find a Hope Lodge, call 800-ACS-2345 or visit 

 provides  housing for families of seriously ill children receiving treatment at nearby  hospitals. Visit 

) is a  lodging guide for cancer patients and caregivers. “We now have over 1,230 places  to stay listed on the site in 46 states and over 80 cities,” says Ann W.  Calahan, who launched the online resource with her second husband, Don Calahan,  in 2003. Her first husband, Joe Warnecke, died in 1997 of liposarcoma. While Joe  battled the disease for six years, he and Ann had difficulty finding appropriate  accommodations in unfamiliar cities.

 is a Boston-area program  whose volunteers open their living quarters to patients in need of lodging. A  personal reference is required, and patients must be accompanied by a friend or  family member. Call 888-595-4678 or visit 

> The Mesothelioma Applied Research Foundation

  has established the Mary and Bob Cosentino Travel Grant Program to help newly  diagnosed patients afford the travel and lodging costs to consult with an expert  on the asbestos-related cancer. To apply, call 805-563-8400 or visit 

 offers  supplementary financial assistance for transportation and other costs to  patients in significant financial need through its Patient Financial Aid program  (a Co-Pay Assistance program is also available). Visit 

While some patients are intent on traveling wherever their best  hope lies within the United States, anyone considering travel should do  preliminary research since treatment for many cancers is standard and does not  necessitate specialty care, and traveling can add many stressors.

Anyone considering traveling for cancer treatment should thoroughly research the treatment facility services, specialties and pysicians and plan ahead for a place to stay and living expenses.  