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.”

Articles

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. 

Susan Kreimer

Into the Future

FDA Aims to Start Regulating Custom Diagnostic Tests

Is Immunotherapy the Key to Treating Brain Cancer?

New Blood

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