Nicole LeBrasseur, PhD

A diagnosis of cancer usually engenders fear and uncertainty. These fears can be magnified when the diagnosis involves many unknowns, as is the case for triple-negative breast cancer (TNBC). “We don’t have a real name for what I have,” says Nancy Truesdale, who was diagnosed in 2008. “All we know is what it’s not. It’s like calling a redhead a non-blonde, non-brunette.”

Adding to the uncertainty of a so-called negative diagnosis is that TNBC does not respond to some of the most effective breast cancer treatments, such as Herceptin (trastuzumab) and tamoxifen. “It’s extremely difficult to learn that all of the progress we have made in treating breast cancer doesn’t apply to you,” says Truesdale. 

Sabrina Flath, 46, says when she put all her test results together she realized she was triple-negative. “I had an overwhelming feeling of not winning the lottery on this draw,” recalls Flath of her 2007 diagnosis.

Both Flath and Truesdale coped with the unknowns by educating themselves about their diagnosis. Flath remained positive despite what she refers to as a “mind-boggling information overload” about TNBC. “I felt I had a pretty good grasp of what triple-negative meant and what my challenges would be,” she says. “But I never felt that my diagnosis was a death sentence.”

Oncologist Mark Pegram, MD, of Sylvester Comprehensive Cancer Center in Miami, also focuses on the positive, stressing the recent progress in moving TNBC out of the realm of the unknown. “There’s a race on to hunt for new [drug] targets in this population,” he says. “And as soon as that happens, we’ll stop calling it triple-negative and start calling it something positive.” Even in the absence of newer drugs today, chemotherapy is effective in lowering the risk of recurrence for early-stage TNBC.

In the meantime, patients don’t have to stand on the sidelines waiting for better drugs to emerge. Truesdale and Flath both took an active role by participating in clinical trials of Avastin (bevacizumab), which seems to work in TNBC. (Avastin is already approved to treat HER2-negative breast cancer.) Flath is now enrolled in a phase II trial of bisphosphonate drugs to help prevent cancer from spreading to the bones, and she suggests that others do the same. “Make a difference to others by joining a clinical trial if you’re eligible,” she urges. “Who knows, you might just be making a difference for yourself too.”

TNBC patients can also draw on the support of others who share the diagnosis to relieve what Truesdale calls the “isolation of not being a part of the majority.” Truesdale and Flath have shared their experiences and advice with others through organizations such as the Triple Negative Breast Cancer Foundation (

), which was founded in 2005, and suggest newly diagnosed patients also take advantage of the information, support, and camaraderie the organization provides. 

Editor's note: In Nov. 2011, the FDA revoked the approval of Avastin for advanced breast cancer due to follow-up studies not showing a survival benefit or improved quality of life. 

Articles

Fears can be magnified when a cancer diagnosis involves many unknowns, as is the case for triple-negative breast cancer.

Positively Speaking

"I’ve basically lived my entire life knowing I was going to get cancer," says Nancy Truesdale, a 42-year-old teacher from Key Largo, Florida. “It was just a matter of when.” Having lost her mother to ovarian cancer and her grandmother to breast cancer, Truesdale knew her cancer risk was high. So she wasn’t surprised when, in July of last year, a routine breast exam revealed a lump in her right breast.  

The biopsy on Truesdale’s tumor revealed triple-negative breast cancer, or TNBC, which means the tumor cells lack expression of three proteins common to various other types of breast cancer—the receptors for the hormones estrogen and progesterone, and a growth factor receptor called HER2.

After surgery to remove the lump (the tumor was found to be stage 2), two 12-week rounds of chemotherapy, a bilateral mastectomy,  a hysterectomy because she’s at high risk for ovarian cancer, and later participation in a clinical trial for Avastin (bevacizumab), Truesdale is cancer-free. “I’ve basically done everything I can do to rid my body of cancer,” she says. “There’s really nothing else I can do but sit and wait.”

Of the roughly 190,000 new cases of breast cancer diagnosed in the U.S. each year, 10 to 20 percent are triple-negative.

The diagnosis of TNBC may be a fearful one, partly because these tumors tend to be aggressive with a high risk of metastasis, and partly because some of the most effective targeted therapies, such as Herceptin (trastuzumab) for HER2-positive breast cancer, and tamoxifen and aromatase inhibitors for hormone receptor-positive breast cancer, don’t work in these patients. As such, the current standard treatment for TNBC has been classic breast cancer chemotherapy, which is particularly effective against TNBC, perhaps because the tumor cells divide rapidly—the hallmark of chemotherapy’s target.

But that standard may soon change. Although TNBC currently lacks its own version of Herceptin, researchers have begun defining TNBC’s unique molecular features in the hope of identifying new targeted drugs. And if recent clinical trial results are any indication, targeted therapies for TNBC are just around the corner.

TNBC, which is more prevalent among premenopausal and African-American women, is a fast-growing cancer that has a higher risk of early recurrence in the first three to five years after diagnosis than do cancers expressing hormone receptors.

Although it’s clear which molecular features triple-negative tumors lack, it’s trickier to define them in concrete terms. “Triple-negative is a bit of a waste-basket terminology,” explains Mark Pegram, MD, an oncologist at the Sylvester Comprehensive Cancer Center in Miami. “The majority of, but not all, triple-negatives are basal tumors,” he says. 

An estimated 65 to 90 percent of triple-negative cancers are basal-like tumors, meaning the cells express proteins typical of basal breast cells (the progenitor cells or stem cells that give rise to mature glandular breast cells), and are associated with a poorer prognosis than non-basal tumors.

Basal-like also describes most cases of inherited forms of breast cancer associated with mutations in the BRCA1 gene, which encodes a protein that helps repair damaged DNA. In fact, most BRCA1-associated breast cancers are basal-like and triple-negative. But the relationship is not one-to-one; only 5 to 15 percent of TNBC patients have a mutated BRCA1 gene.

Although hearing the word negative is usually a relief when associated with cancer—such as a negative biopsy or negative lymph node scan&mdash;it’s not quite the same when it comes to TNBC. 

Without the option of targeted drugs as first-line therapy, the mainstay of treatment for TNBC—regardless of tumor stage&mdash;is standard breast cancer chemotherapy, often with a combination called ACT, which stands for Adriamycin (doxorubicin), Cytoxan (cyclophosphamide), and Taxol (paclitaxel). In patients such as Truesdale, whose cancer had not yet spread to her lymph nodes (stage 1 or 2), treatment usually begins with surgical removal of the tumor tissue. These patients are then given chemotherapy, often followed by localized radiation therapy. 

“Chemo has gotten an undeserved bad rap,” says Lisa Carey, MD, medical director of the University of North Carolina Breast Center in Chapel Hill. “It is far more effective and less toxic than it was years ago and not necessarily worse in terms of side effects than some targeted therapies. And if the chemotherapy works well (tumor shrinkage or disappearance when chemotherapy is given prior to surgery), then the prognosis is great.”

Of course, not everyone thinks chemo’s rap is so undeserved. Chris Cooper, a 59-year-old banking executive from Atlanta, was on ACT for about four months in 2006 after being diagnosed with TNBC, and her memories are not particularly fond. 

“They call it the ‘red devil,’ ” she says, referring to the deep red color of Adriamycin. “It makes you lose your hair. You’re tired, and you just generally feel terrible.” Still, following treatment, scans found Cooper clear of cancer, and her hair eventually grew back—though it came back white instead of its previous brunette hue. 

Joyce O’Shaughnessy, MD, co-director of breast cancer research at Baylor Charles A. Sammons Cancer Center at Dallas, says many patients see a diagnosis of triple-negative as a death sentence. “But that’s not the case at all,” she says, pointing out that the majority of patients with stage 1 or 2 TNBC are cancer-free many years after treatment. Many patients with lymph node-positive disease (stage 3 or 4) also respond well to chemotherapy. 

The reason triple-negative cancer has such a bad reputation, O’Shaughnessy explains, is that the disease recurs within five years after diagnosis in about 32 percent of patients, compared with only around 15 percent of patients with other breast cancer types (a 2008 study showed the five-year recurrence rate was 13 percent for women with hormone receptor-positive disease who underwent treatment after surgery). And the average survival time for TNBC after recurrence is only nine months.

The chance of recurrence highlights the need for more effective treatments. Studies are currently examining whether certain chemotherapies are more effective than others. Showing particular promise are carboplatin and cisplatin, which are already used to treat metastatic TNBC and are undergoing more rigorous testing. Because these agents disturb cellular repair pathways that many TNBC cells rely on, “it’s not unreasonable to think they may be better than standard [ACT therapy],” says Eric Winer, MD, director of the Breast Oncology Center at Dana-Farber Cancer Institute in Boston. 

New studies of targeted drugs may add a beneficial boost to chemotherapy. “I consider clinical trials at all points in time for my patients,” says Winer. “I don’t believe that they’re only for when all else has failed.” Recent successes indicate that targeted therapies are making their way into the TNBC arsenal. 

Some of the biggest news comes from a class of drugs called PARP (poly ADP-ribose polymerase) inhibitors, which may be of particular help to patients such as Truesdale who carry a mutated BRCA1 gene. Cells that lack a normal BRCA1 gene are robbed of a major DNA repair mechanism and thus must rely on backup pathways for life-saving DNA repair. One of these backups involves repair proteins called PARPs, which mend breaks in DNA strands. PARP inhibitors are thought to kill tumor cells by crippling this important repair mechanism, while leaving healthy cells unharmed. These drugs have completed phase II testing in TNBC and in breast and ovarian cancer patients with a BRCA1 mutation. They are also being tested for the treatment of patients with melanoma and certain types of brain cancer.

View Illustration : Turning Off DNA Repair

A phase II study unveiled this summer at the American Society of Clinical Oncology’s annual meeting examined a PARP inhibitor called olaparib as a late-line therapy for patients with BRCA1 or BRCA2 mutation-related tumors. For 10 of the 27 patients receiving high-dose olaparib, the tumor shrank by at least half, and most side effects were mild. 

Early analysis of a randomized phase II trial led by O’Shaughnessy showed promising results for another PARP blocker called BSI-201. With BSI-201, overall survival times reached 9.2 months compared with 5.7 months for those treated with chemotherapy alone, and progression-free survival doubled, from 3.3 months to 6.9 months. A phase III trial of BSI-201 in TNBC is now recruiting patients.

Another success story has been Avastin, which blocks blood vessel growth to tumors by inhibiting a growth-inducing protein called vascular endothelial growth factor, or VEGF. Without VEGF, tumors are starved of the nutrients they need to survive. Avastin is approved for use in multiple cancers, including brain, lung, and colorectal, and was approved in 2008 for metastatic HER2-negative breast cancer and in 2009 for metastatic kidney cancer.

For Cooper, two different regimens of Avastin plus chemotherapy helped reduce metastatic spots that were found on her lungs in early 2008, although some of the spots have returned. 

“That’s just typical for triple-negative cancer,” says Cooper. “The darn cells always seem to figure out how to beat the drug.” She is down from six spots on her lungs to two, and is currently feeling good while taking a break from chemo.

A recent phase III clinical trial of patients with metastatic breast cancer, including some patients with TNBC, showed that adding Avastin to Taxol doubled progression-free survival &shy;to 11.8 months, compared with 5.9 months with Taxol alone. Overall survival rates, however, did not change. A study now recruiting patients will test whether adding Avastin to chemotherapy has any benefit in non-metastatic disease, but it will be years before the results are known. 

No one even talked about this cancer six or seven years ago. But many of us predicted that once pharma and academia recognized the unmet need, new therapies would follow. 

Although TNBC is still defined by its lack of distinguishing characteristics, physicians are optimistic that progress will be made in treating the disease once there is a better understanding of the biology. 

“No one even talked about this type of cancer six or seven years ago,” says Winer. “But many of us predicted that once pharma and academia recognized the unmet need, new therapies would follow.” 

While waiting for Winer’s prediction to come to fruition, the self-educating Truesdale comforts herself with numbers. Instead of focusing on the 30 percent chance that her cancer will come back, Truesdale concentrates on the 70 percent chance that it won’t. “That’s pretty darn good!” 

Winer says that, so far, nothing else has been as impressive as the PARP inhibitors, but other targeted therapies are in the works. TNBC tumor cells often have high levels of the epidermal growth factor receptor, or EGFR, which may help the tumor cells grow. Drugs such as Erbitux (cetuximab), which is used to treat some cases of metastatic colorectal cancer, block EGFR and thus may also be useful in metastatic TNBC.

Another therapy in early clinical trials is the leukemia drug Sprycel (dasatinib), which targets cellular enzymes called src kinases that transmit growth and survival signals to the tumor cell. These enzymes run amok in many types of tumor cells, including some TNBC subsets.

There's now something to take aim at in triple-negative breast cancer. 

Targeting the Triple Threat

Most patients in the midst of treatment for non-Hodgkin lymphoma, commonly referred to as NHL, would laugh at the thought of one day competing in an Ironman triathlon. But for Adam Schoener of Birmingham, Michigan, that laughable thought turned into reality last June. “I never did triathlons before I got sick,” he says. “But it’s a great way to gain back some control in your life.” Raising money along the way for The Leukemia and Lymphoma Society (LLS) was just a side benefit. 

Schoener was diagnosed in 2004 at age 35 with a fast-growing type of NHL called diffuse large B-cell lymphoma. As often occurs, Schoener’s diagnosis came without warning, just weeks after an annual physical found him in ideal health. “At first I just thought it was heartburn,” he recalls. “But soon I couldn’t catch my breath. That’s when my wife took me to the ER.” Imaging scans and biopsies revealed a Twinkie-size mass pressing on his heart and lungs.

Now, more than four years after his diagnosis, Schoener is cancer-free. His story is just one indication of the strides being made in the treatment of NHL, which affects approximately 66,000 Americans and 300,000 people worldwide each year. Treatment can be challenging, in part because NHL is a collection of nearly 60 related diseases, according to LLS, which differ in biology, treatment, and prognoses.

"NHL is really a complex problem," says Andrew Zelenetz, MD, chief of the Lymphoma Service at Memorial Sloan-Kettering Cancer Center in New York. "It's critical to realize that this is not just one disease we are dealing with."

Lymphomas, non-Hodgkin and Hodgkin alike, originate in the lymph system, a fluid network that carries immune cells throughout the body. The uncontrolled division of normally protective white blood cells causes NHL, leading to tumors in the lymph nodes that can spread to other parts of the body.

NHL can be sneaky, sharing early signs of the flu—fever, nausea, and fatigue. For Barbara Barrow, a 65-year-old real estate agent diagnosed in 2002 with early-stage follicular lymphoma, a slow-growing variety, the only warning sign was swollen lymph nodes. Barrow’s doctor suggested a “watch and wait” approach with regular CT scans after her first few scans showed the cancer was growing very slowly.

Slow growth may be good news with some cancers, such as breast or colon, but that’s not always the case with NHL. Although somewhat counterintuitive, the fast-growing “aggressive” forms of NHL are more easily cured, if treated early, than the slow-growing “indolent” varieties.

“It’s not a paradox when you think about how [chemo] drugs work, which is to target growing, dividing cells,” says Bart Kamen, MD, PhD, chief medical officer of LLS and former director of pediatric hematology and oncology at the Cancer Institute of New Jersey. “If the disease is growing rapidly, we can kill it quickly as long as it doesn’t get the patient first.” 

NHL is really a complex problem. It’s critical to realize that this is not just one disease we are dealing with.

Schoener’s and Barrow’s cancers—diffuse large B-cell lymphoma and follicular lymphoma&mdash;are the two most common varieties of NHL, accounting for about 75 percent of adult NHL cases. Both diseases arise in a type of immune cell, called B cells, which produce antibodies that help protect the body from infection.

For decades, the standard treatment regimen for aggressive forms of NHL was intravenous infusion with a chemotherapy cocktail known as CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), which cured approximately 30 percent of patients with diffuse large B-cell lymphoma. More recently, the efficacy of CHOP dramatically improved after studies showed combining CHOP with an immunotherapy drug called Rituxan (rituximab) increased the number of patients who had complete disappearance of disease. Of patients receiving R-CHOP, 76 percent achieved a complete response compared with 64 percent on CHOP alone, according to one study. A separate study found that adding Rituxan to CHOP also boosted three-year overall survival rates from 84 percent to 93 percent.

Maintenance may be killing tumor cells we can't see. It's a way to turn cancer into a chronic disease--one that can be managed. 

Patients with indolent (slow-growing) forms of the disease still await a success story equivalent to that of R-CHOP for aggressive NHL. 

“Those (indolent) diseases are typically not curable,” says Owen O’Connor, MD, PhD, of the Herbert Irving Comprehensive Cancer Center at Columbia University, “and the goals of care are focused on chronic management with less toxicity and good disease control without significantly compromising quality of life.”

No general consensus exists about the best way to tackle indolent disease at the outset. R-CHOP, the most commonly used therapy, has proven to have some success. In one study, more than 40 percent of patients remained disease-free for nearly 10 years after treatment. But since cancer cells in these patients are not rapidly dividing, the cells often escape the regimen’s deadly effects. And because the anthracycline component of the CHOP mixture can increase the risk of heart damage, patients are typically treated with only one course of R-CHOP, and thus run the risk of losing this option down the road if their disease transforms into aggressive NHL, which occurs in 3 percent of patients each year. “I like to keep that one in my back pocket,” says Zelenetz.

Zelenetz, like many oncologists, prefers to start with the watch-and-wait&ensp;approach for indolent disease as long as symptoms are still mild. Those in favor of this approach believe treatment should begin only when disease symptoms arise or the cancer progresses, but others question whether the delay is appropriate.

“I believe observation still has a role in lymphoma,” says Zelenetz.&ensp;“Others will disagree with me. Some people say we should use rituximab because we have it, and it has low toxicity.” Again, Zelenetz says he awaits proof from clinical research before jumping on that bandwagon; an ongoing clinical trial is comparing watch-and-wait to immediate treatment with Rituxan.

Barrow’s physician initially opted for observation over immediate treatment for her slow-growing lymphoma, but then failed to recognize the flu-like symptoms and achy legs she developed two years later as symptoms of cancer progression. Barrow opted for a second opinion, and her new oncologist found her cancer had started picking up speed and had spread to her bone marrow. She was put on R-CHOP.

“I had my first treatment on a Thursday, and by &shy;Saturday, there were no visible [cancerous] lymph nodes left. They had just melted away,” says Barrow.

Barrow only briefly suffered from some of the typical side effects of R-CHOP—fever, chills, and nausea&mdash;and her cancer disappeared after three rounds of treatment.

A newly approved option is Treanda (bendamustine). Although the agent has been used for decades in        Europe to treat solid tumors and lymphomas, it was just approved by the Food and Drug Administration in late 2008 for indolent B-cell NHL. (The FDA approved Treanda for chronic lymphocytic leukemia in early 2008.)

The approval was based on a single-arm study of 100 patients, 17 of whom had a complete response to the drug, meaning no signs or symptoms of the disease were present. Side effects of Treanda may include nausea, vomiting, anemia, and fatigue. 

Based on the success of Rituxan, researchers have designed related antibody-based drugs, some of which have been approved for treating relapsed indolent lymphomas or those that did not respond to prior treatments.

One twist is to combine these drugs with the deadly effects of radiation therapy by attaching a radioactive molecule directly to the drug. The modified drug can then deliver a lethal dose of DNA-damaging radiation directly to the tumor cells. Radioactive antibody-based therapies approved for the treatment of low-grade NHL include Bexxar (tositumomab) and Zevalin (ibritumomab tiuxetan).

In a recent study of 51 patients with refractory B-cell lymphoma, 37 patients responded to Zevalin, with nine of those 37 having a long-lasting response of more than three years. Other research showed that a third of patients with Rituxan-resistant disease went into complete remission after treatment with Bexxar.

Certain drawbacks, however, make radioactive therapies less popular than some might hope. Part of the problem is their high price. And giving patients radioactive drugs is risky and requires the close supervision of a radiologist.

For patients who have exhausted other options, many clinical trials are available. “Right now, we’re living in the most exciting time ever in the history of cancer care,” says O’Connor. “There are enormous numbers of new drugs that are beginning to emerge that offer you a chance to reduce the non-specific effects of chemotherapy and, theoretically, gain better efficacy.”

One promising option for NHL is Revlimid (lenalidomide), an agent approved to treat multiple myeloma and myelodysplastic syndromes. Scientists are still investigating how the drug works against lymphoma, but one effect is to ramp up the activity of immune cells that attack and kill tumor cells.

Another drug undergoing clinical testing is pralatrexate, which O’Connor helped develop. The agent shuts down multiple metabolic pathways that cells need to survive, but the trick with pralatrexate, explains O’Connor, is in its specificity.

“Pralatrexate is uniquely designed to be selectively transported into cancer cells over normal cells.” It is proving particularly successful in less common forms of NHL that stem from T cells rather than B cells, and O’Connor hopes it will be approved for peripheral T-cell lymphoma in the coming year.

Another treatment showing potential is a class of drugs known as histone deacetylase inhibitors. The first of this class was Zolinza (vorinostat), approved in 2006 for T-cell lymphoma. Zolinza and related therapies work by reactivating genes that may have been inappropriately shut down by cancer. The re-ignition of these genes helps control normal cell growth and development. (Read more about these agents in 

“Medicine’s New Epicenter? Epigenetics”

With a plethora of drugs working their way through clinical trials, choosing the best trial for each patient can be challenging. “With 60 different kinds of lymphomas, wouldn’t it be great to say that we have one drug that kills all lymphomas?” says O’Connor. “But it’s not going to emerge that there is one drug that is the panacea for all forms of NHL.” Instead, he hopes a better understanding of the biology of each type of NHL will eventually allow physicians to use tailored, or individualized, combinations of targeted drugs along with conventional chemo&shy;therapy to most effectively treat each patient’s disease.  

To help prevent relapse, some oncologists recommend continued treatment with Rituxan—known as maintenance therapy&mdash;after initial success with R-CHOP. “Maintenance may be killing tumor cells we can’t see,” says proponent Kamen. “It’s a way to turn cancer into a chronic disease&mdash;one that can be managed.”

Because it’s still unclear whether maintenance improves overall survival, other physicians are holding off on recommending maintenance. However, a new report, published in the February 18 issue of the 

, examined data from five randomized trials looking at maintenance Rituxan therapy compared with observation or treatment at relapse in follicular lymphoma. The analysis, which contained nearly 1,000 patients, found a 40 percent improvement in overall survival in patients who received maintenance Rituxan. Although studies indicate that patients can be safely treated with Rituxan for up to two years, longer follow-up is needed to determine whether continual treatment carries health risks.

“I’m willing to wait to see what the data show,” says skeptic Zelenetz. Results of the eagerly awaited PRIMA trial, which examined the effects of Rituxan maintenance in more than 1,200 follicular lymphoma patients, are expected within a year or two.

Rituxan, which received its first approval for lymphoma from the Food and Drug Administration more than a decade ago, works by targeting the CD20 protein that is found at high levels on cancerous B cells. R-CHOP has been successful in treating aggressive forms of NHL and is now the standard first-line therapy for these diseases.

Patients typically receive six to eight cycles of R-CHOP at three-week intervals, although some oncologists advocate a more accelerated two-week regimen. Schoener’s schedule fell in between—he received eight rounds of R-CHOP at two-and-a-half-week intervals followed by radiation therapy. The optimal dose and schedule of R-CHOP remains a matter of debate and is currently being tested in clinical trials.

Despite the success of R-CHOP, approximately 40 to 50 percent of patients with aggressive NHL relapse after the initial treatment, pointing to a need for new options. High-dose chemotherapy followed by autologous stem cell transplantation is only appropriate for select patients, as many are too frail for this grueling treatment.

“I personally think that they’re underused,” says Kamen. Bruce Cheson, MD, head of hematology and director of hematology research at Lombardi Comprehensive Cancer Center at Georgetown University, agrees. “They’re the most effective but least used drugs for lymphoma,” says Cheson.

Another relative of Rituxan called ofatumumab (the proposed trade name is Arzerra) may be just as effective as Rituxan with less toxicity. Not yet approved for treating NHL, the increased benefit of ofatumumab is thought to be due in part to its ability to bind to the protein CD20 with increased affinity.

Yet other antibody-based drugs hone in on different proteins on the cancer cell. Campath (alemtuzumab), for instance, targets a protein called CD52 instead of CD20 and is now in early-phase trials for NHL. Already approved for a type of leukemia, Campath may also work in NHL since CD52 is found on a wide variety of immune cells. Campath, however, is so adept at destroying its target cells that the immune system can be dangerously dampened, leaving the patient susceptible to sometimes life-threatening infections.

The gold standard in treating non-Hodgkin lymphoma gets new backup. 

Trying Something New

It started with an odd mix of symptoms: headaches, tunnel vision, a whooshing sound in his ears. But when Chris Funk started having mini-seizures, he headed for the hospital. At 28 years old, Funk was diagnosed with a malignant brain tumor in his left frontal lobe and given a dismal prognosis.

That was 2001. Still alive years later to tell the tale, Funk, of Madison, Wisconsin, credits the talents and persistence of his oncologist for his path to recovery. He points out, however, that the path can be uncertain, for patients and doctors alike. “Even the experts don’t have all the answers.”

Uncertainty is engrained in most studies of the brain, with its intricate wiring and hazy biology. Because the brain is the command center for the entire body, treating cancer in this sensitive organ is tricky. Removing a tumor surgically can damage essential neuronal connections that control mobility, speech, even mood.

Additionally, the biology of the brain is problematic. Between the brain and its blood supply sits a physical barricade called the blood-brain barrier, which restricts the ability of traditional chemotherapy agents to make their way to the tumor. For decades, researchers have sought better ways to fight primary brain tumors without much success. But recent advances have improved prognoses for patients and revitalized research in the area.

“The environment is the most positive I’ve seen in a long time,” says Funk’s oncologist Minesh Mehta, MD, of the University of Wisconsin.

Compared to lung, breast, or prostate cancer, brain tumors are relatively uncommon and occur in a wide range of age groups. This year, more than 21,000 American adults will be diagnosed with a primary malignant brain tumor, according to the American Cancer Society. (Benign brain tumors make up about 22,000 additional diagnoses.) Due in part to their rarity, funding for research into the area has been kept comparatively low, and investigators face plenty of additional challenges.

Brain tumors are actually a collection of different tumor types. From benign meningiomas that might never require surgery to malignant glioblastomas, each has its own unique properties and ideal treatment strategies.

As in Funk’s case, brain tumors often present as seizures or unrelenting, progressive headaches, though the symptoms and effects vary depending on the tumor location. If it lies within a functional area of the brain, problems in speech, vision, or mobility might occur.

Brain tumors are most often identified with an MRI (magnetic resonance imaging) scan, which picks up on masses, swelling, increased cell density, and leaks in the blood-brain barrier. Biopsy and additional MRI tests determine the type and location of the tumor.

For benign brain tumors, surgery is often successful at fully removing the tumor. Surgery is also used whenever possible for malignant tumors. Although rarely curative in these cases, surgery can improve a patient’s quality of life by relieving symptoms, such as headaches and seizures. But the surgery itself poses significant risks, as brain function may be damaged in the process.

“In the brain, nothing is redundant,” says Dr. Mehta. “So removing a chunk of it risks causing a deficit.”

To limit the potential for problems, doctors are now relying on a high-quality map of the brain and enhanced views of the tumor within it. “Instead of just hoping for patients to come out intact, with fancy imaging studies, we can see critical structure and functional areas of the brain and plan the surgery accordingly,” says Dr. Mehta.

“Preoperative tests let us estimate the risk of surgery, to tell if it’s feasible to do a gross total resection,” says neurosurgeon Michael Vogelbaum, MD, PhD, associate director of the Brain Tumor and Neuro-Oncology Center at the Cleveland Clinic. When important brain structures lie near the tumor, surgeons remove only what they can without damaging key neurons.

The biggest change in the last 20 years has been in the marriage of radiology and imaging into the operating room.

Susan Chang, MD, says that in her neurosurgery department at the University of California, San Francisco, attempts are being made to design MRI machines that use stronger magnets, which afford greater detail. An advanced version, called functional MRI, associates certain areas of the brain with particular activities.

At age 23, Jonathan Woodruff, of Miller Place, New York, underwent such a procedure just before his high-grade tumor was removed in 2003. “It was like a regular MRI,” Woodruff recalls, “except they told me to move different fingers, wiggle my toes, and speak, while they mapped out my brain.”

“The areas involved light up on the [functional] MRI,” says Dr. Vogelbaum, “and then we can look at the relationship of those spots to the location of the tumor.” Language deficits can also be avoided if the surgeon wakes the patient during surgery to speak while the tumor is removed. If problems surface, the surgeon changes tactics to prevent long-term speech defects.

Imaging can also be done during the resection surgery, using a fully integrated operating room plus MRI combination, such as BrainSUITE, to help navigate the brain and determine how much of the tumor remains.

“The biggest change in the last 20 years has been in the marriage of radiology and imaging into the operating room,” says Henry Brem, MD, director of neurosurgery at Johns Hopkins Hospital in Baltimore. “We have made tremendous advances in imaging and computer navigation systems that allow us to localize tumors by fusing the imaging data to the procedure we’re doing. Therefore, the ability to remove the tumors safely has radically improved.”

In the future, the goal will be to perform surgery without even opening the skull, says Keith Black, MD, director of the Maxine Dunitz Neurosurgical Institute at Cedars-Sinai Medical Center in Los Angeles. “We’re looking towards a new paradigm of surgery now—noninvasive ways to eliminate these tumors, like focused microwave imaging, where we put in a small microwave probe into the tumor without doing a big operation.”

Computer assistance is also improving radiation therapy, most often used to treat patients with highgrade tumors. Because of radiation’s side effects, including fatigue, hair loss, and memory loss, and the lack of a clear survival advantage, there is some debate over whether radiation should be used to treat less aggressive brain tumors.

Radiation can be effective following surgery, and even later should the tumor recur, as happened to Funk. Four years after the bulk of his tumor was removed, Funk again experienced seizures. The tumor now spanned both hemispheres of his brain, making surgery implausible.

Funk was referred to Dr. Mehta, who suggested six weeks of traditional whole-brain radiation. Two years later, Funk is doing well, taking anti-seizure medications and practicing yoga, although he says his memory isn’t what it used to be. “Books I’ve read and movies I’ve seen aren’t as easily recalled,” says Funk, who formed the nonprofit 

 with his wife in 2004. Proceeds from its annual brain tumor awareness event fund the HEADRUSH Brain Tumor Research Professorship at the University of Wisconsin Comprehensive Cancer Center.

To limit side effects, radiation oncologists are trying to skillfully focus the radiation beam so that it avoids normal tissue. Improved accuracy is provided by a process called image-guided radiation therapy, which uses a computer to reproducibly position the patient—and the tumor&mdash;from one day to the next. A smaller, more focused radiation beam can then be used. Intensity-modulated radiation therapy, an advanced type of conformal (precise) radiation therapy, uses multiple beams with varying intensity to treat the tumor.

Radiation is also being used with stereotactic radiosurgery. Gamma Knife, for example, uses a computer to simultaneously focus about 200 small beams onto a tumor. The treatment is usually done once, and the patient’s skull must be anchored to a specialized helmet to maintain positioning during the procedure. Not only uncomfortable, the helmet attachment can cause complications, such as infection.

A similar technique, known as CyberKnife, bypasses the need for the helmet by instead using real-time imaging to make adjustments. Gamma Knife is used for small- to medium-sized tumors, while CyberKnife is typically employed for large lesions.

In addition to surgery and radiation, chemotherapy is now often used to treat aggressive tumors and has resulted in improved survival and quality of life for some patients. The Food and Drug Administration has so far approved two chemotherapies for treating brain tumors—Temodar (temozolomide) and Gliadel wafer.

Approved in 1999 for refractory anaplastic astrocytoma and in 2005 in combination with radiation for new diagnosed glioblastoma multiforme, Temodar damages DNA and is thereby toxic to rapidly dividing tumor cells. Common side effects include nausea, fatigue, and headaches. Funk received Temodar, administered as an oral pill, after his surgery in 2001.

Gliadel wafer, on the other hand, is a challenge to administer and requires an expert surgeon. Immediately following tumor resection, the surgeon places wafers made of a biodegradable polymer inside the resulting cavity in the brain. The wafers contain a cytotoxic agent called BCNU (carmustine) and over the following weeks, the agent leaks out into the nearby brain tissue, killing tumor cells that escaped surgical removal. The FDA first approved Gliadel wafers in 1996 for recurrent glioblastoma multiforme and in 2003 for newly diagnosed high-grade malignant gliomas.

For Woodruff, the drug was part of a program that saved his life. Doctors implanted wafers after removing three-quarters of his right frontal lobe to resect the tumor. The wafer can cause infection, seizures, or vomiting, but the side effect Woodruff recalls most is disorientation. “But you know what, I’m still alive. So whatever they did worked.” He’s had no indications of recurrence.

Neurologists continue to search for more chemotherapy options. “The biggest difficulty in treating malignancies is in the delivery,” says Dr. Vogelbaum. In other organs, blood vessels that feed the area are leaky and allow systemic drugs to seep out passively into the surrounding tissue. The brain, however, has a more stringent border patrol—the blood-brain barrier.

“The brain blood vessels essentially form a wall,” says Dr. Black. “They do not allow anything to get out. So most chemotherapeutic agents do not get to the brain.” To pass the barrier, therapeutic compounds must either dissolve through the lipid cell membrane, as Temodar does, or be selectively carried across or placed, as with the Gliadel wafer.

A technique in clinical trials, known as convection-enhanced delivery, aims to bypass the barrier mechanically. In this method, catheters are inserted into the brain during surgery. Chemotherapeutics are then slowly pumped in to treat the tumor locally. Not all surgeons are a fan of this approach, however. “It’s a bit crude,” says Dr. Black. “It’s certainly not the most ideal way of doing things.”

If we have the tissue of the tumor, we can say this pathway or that is affected, and then we can pick the ideal drugs for that patient.

A number of cancers have been successfully treated with a class of drugs called angiogenesis inhibitors, which may offer hope for brain tumor patients as well. Avastin, already approved for colorectal, lung, and breast cancers, as well as a new experimental agent called cilengitide do not need to pass through the blood-brain barrier to reach the tumor. Rather, because the agents work by blocking the growth of blood vessels to the tumor, the subsequent cutoff of oxygen and nutrients to the tumor causes it to shrink.

Both agents had some success in phase II trials, but serious side effects, such as internal bleeding, can occur. Common side effects of angiogenesis inhibitors include fatigue, nausea, and diarrhea. Avastin can also cause high blood pressure, which can be managed with medication. Genentech, the maker of Avastin, plans to submit the drug for approval later this year for relapsed glioblastoma multiforme.

In the future, a genetically altered virus called Delta-24-RGD may kill off brain tumor cells that are most resistant to radiation and chemotherapy. The virus is modified so that it infects and kills only tumor cells, leaving normal brain tissue unharmed. Although not yet in clinical testing for brain tumors, Delta-24-RGD was recently shown to nearly double survival times in mice that were grafted with highly malignant human glioblastoma cells.

These and many other agents hold promise, but the best strategy may lie in mixing and matching. “In the future, combinations of drugs are going to be very powerful,” says Dr. Brem. “Every other cancer is treated with multiple agents, and we’re finding that certain drugs work best in combination with each other.”

For this approach to be most fruitful, each patient’s tumor should be considered a unique case, says Dr. Chang. “If we have the tissue of the tumor, we can say this pathway or that is affected, and then we can pick the ideal drugs for that patient.”

Considering the complexities of the brain, patients should seek out centers that have the best equipment and staff to handle the charge.

“There are 3,000 neurosurgeons in the country,” says Dr. Black, “but really only a couple hundred specialize in brain tumors. More than technology, experience will ensure a much better operation. The idea is to be like a thief in the night—sneak in, get the tumor, and sneak out without the brain ever realizing that we’ve been there.”

Dr. Brem says that given the range of new options, “it’s vital that patients be treated in centers that have access to experimental trials and the newest treatments, and that it’s individualized to the patients. It’s not a standard one-size-fits-all therapy.”

Dr. Vogelbaum agrees. “Our attitude here [at the Cleveland Clinic], and at other places like this, is that we consider investigational therapies in this disease to be part of our standard regimen, because there is no cure. At some point, these patients will need something more.”

New technology and smart drugs take a direct approach to targeting brain tumors.

Nicole LeBrasseur, PhD

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