Stem cells are cells that seem to have the ability to divide perpetually, live indefinitely and, most important, possess the ability to reconstitute tissue or an entire organ.

The original stem cell is the fertilized egg, explains Aline Betancourt, PhD, research associate professor at the Tulane Center for Stem Cell Research and Regenerative Medicine in New Orleans. As it grows, internal cues cause it to “differentiate,” or to eventually become one thing or another, such as an eye or an ear. All this from one cell.

A current theory holds that cancers can develop from a rare type of cell that has the same infinite growth potential as a stem cell. Some see these not as true stem cells, but as a highly malignant and drug-resistant subpopulation of cancer cells. Others think they are, in fact, cancer stem cells, and that they are involved in metastasis as well.

Betancourt falls into the latter camp. She points to research where tumor cells that grow uncontrollably in a human don’t grow at all in a lab animal, evidence that only certain cells in a tumor can recreate that tumor.

There is a very intricate connection between cancer and our body’s immune response.

As adults, we have small pools of original stem cells remaining in specific organs. These stem cells respond to injury in that tissue. They also respond to injury signals from tumors, Betancourt says, which could make it possible to use stem cells to deliver anti-cancer agents directly to a tumor. This method could not only make treatment more effective, but also it would likely reduce side effects.

In some laboratory studies, normal stem cells have been shown to inhibit tumor growth and spread. In others, however, they seemed to encourage it. Clearly, employing these cells in treatment will require figuring out why that happens. Betancourt suspects the immune response plays a key role.

“There is a very intricate connection between cancer and our body’s immune response,” she says. “Yet the majority of studies we’re doing today are in immune-incompetent models, which miss half the picture, in my opinion. We’re working to model tumors in an immune-competent animal, so we can see if we get the same reaction as in its human counterpart.”

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Stem cells are cells that seem to have the ability to divide perpetually, but what does that mean in cancer?

Stem Cells: Helpful or Hurtful?

Diane Klenke thought she was dealing with a bout of the flu, when she finally went to see her doctor about a persistent stomachache. She was completely unprepared for the news she had stage 4 pancreatic cancer that had metastasized to her liver.

In her initial visit, she was told that she might only have three months left to live. But that was in February 2004, and today, the 54-year-old Green Bay, Wis., resident has clearly survived long past her initial prognosis and has enjoyed a high quality of life, despite living with metastatic cancer.

“I learned to be my own advocate, fighting for the care I needed and requiring doctors to answer the ‘whys’ and ‘how it works’ questions,” Klenke says. “It made me feel like I had some input, some control.”

Scientific advances and improved therapies have extended survival for many, and newer treatments are better focused with fewer side effects. However, disease symptoms and treatment side effects can still negatively impact a patient’s quality of life.

Klenke credits her success to a rigorous treatment regimen of chemotherapy, integrative therapies, a strong support system and faith. Her symptoms to date have been minimal and controllable. “As a result of the intense chemotherapy, I became a type 2 diabetic,” she says. “But a couple of prescriptions, great diet and exercise keep me in normal ranges.”

Mild swelling in her feet and lower legs that occurred during treatment was improved, she says, by increasing her protein intake.

In addition to drug-related side effects, patients with metastatic disease may also be dealing with cancer-related pain, bone weakness and fatigue, as well as treatment-related side effects, such as nerve damage and gastrointestinal issues.

Cancer-related pain may be caused by the tumor itself or by the treatment, and it remains one of the most common symptoms experienced by patients with metastatic disease, affecting more than three-fourths of all individuals at some point.

“Nearly all cancer patients [with significant pain] should be on a long-acting drug to help manage it and a short-acting drug for breakthrough pain,” says Thomas J. Smith, MD, director of palliative medicine at Johns Hopkins Sidney Kimmel Comprehensive Cancer Center in Baltimore. “And patients should see a pain or palliative care specialist if their pain is not being addressed by their regular provider.”

I learned to be my own advocate, fighting for the care I needed. It made me feel like I had some control.

Numerical rating scales of 0 (indicating no pain) to 10 (indicating the worst pain imaginable) are most commonly used in the initial and ongoing evaluation of pain. Ideally, the pain score should be kept down to 4 on that scale, as patients can function at that level, Smith says.

Regardless of its source, pain treatment usually includes the use of some type of analgesic medication. The World Health Organization’s pain ladder advocates a stepwise approach. Pain relief begins with nonopioids, such as aspirin and acetaminophen, and then progresses as needed to mild opioids, and then stronger ones, such as morphine.

Opioids are effective in controlling pain but can cause side effects—most notably constipation, which occurs in 40 to 70 percent of patients. But preventing constipation in the first place is key, Smith says. “Every good pain drug slows down the colon nerves, which causes constipation,” he says, recommending a fiber-rich diet, plenty of fluids, stool softeners or laxatives, and daily walks.

Osteolytic bone destruction occurs when cancer cells completely destroy the bone in a specific area. Another type of bone metastasis, osteoblastic lesions, occur when cancer cells lead to abnormal calcium deposition on bone tissue.

Because bone metastases can weaken bones, patients are at greater risk for bone breaks, or what is known as “pathological fractures.” In turn, these fractures and the overall weakening of the bones can force patients to be less active, which may lead to chemical imbalances in the blood, including an increase in calcium levels (hypercalcemia). Another less common complication is spinal cord compression, which can cause nerve damage or may progress to paralysis.

Treatment can be multipronged and may include surgery, chemotherapy, hormone therapy, radiation therapy and immunotherapy. Pain can be treated with opioids or other types of medication, and physical therapy and surgery may be part of the treatment plan if fractures have occurred.

Of particular importance are bisphosphonates and RANK ligand inhibitors, a new class of drugs that includes Xgeva (denosumab), that are being increasingly used to reduce the incidence of pain and other complications from bone metastases. There is also some evidence that they may improve the overall health of bones. These so-called bone modifying agents (BMAs) are able to relieve pain caused by both types of lesions, although experts believe these drugs might be more helpful for patients with osteolytic bone damage. BMAs have been associated with increased risk for osteonecrosis (bone death) in the jaws of some patients, a rare but serious side effect known as ONJ.

Fatigue is the most common and pervasive symptom that patients with metastatic cancer experience, and it can stem from both the underlying illness and therapies therapies, such as chemotherapy and radiation. There is no “one-size-fits-all” solution for managing fatigue, says Jennifer S. Temel, MD, assistant professor of medicine at Harvard Medical School and clinical director of thoracic oncology at Massachusetts General Hospital in Boston. Resolving fatigue often requires a careful evaluation of the cancer and the treatment, as well as individual factors, such as anemia, poor nutrition, lack of physical activity, disrupted sleep and emotional distress that can all cause or worsen fatigue.

Stimulants, such as methylphenidate and modafinil, can help patients dealing with severe fatigue. More recently, a study found that 2,000 milligrams a day of American ginseng helped improve fatigue without any known side effects. Non-drug solutions include exercise and cognitive-behavioral therapy.

Different treatments cause different side effects, and as patients with metastatic cancer often undergo multiple treatments during the course of many months or years, it is imperative they consider their quality of life when making treatment decisions. It’s important to establish goals, says Charles Loprinzi, MD, a breast cancer specialist at the Mayo Clinic in Rochester, Minn. “Generally, the goal is to do as well as possible for as long as possible.”

We want the least toxicity and fewest side effects. We want patients to have the best quality of life, and we want them to have the longest life.

He advises patients to consider four goals of treatment: “We want the least toxicity and the fewest side effects. We want patients to have the best quality of life, and we want them to have the longest life.”

Nerve or neuropathic pain (neuropathy) is usually treatment-related and may be treated with anticonvulsants or antidepressants because of their effects on certain brain chemicals. Thus far, Cymbalta (duloxetine) is the only drug to show promising results in helping chemotherapy- induced peripheral neuropathy. The most important thing is to see a nerve specialist or pain specialist and be persistent, Smith says. “You may need to try several drugs before finding one that helps.”

Side effects related to the digestive system, including nausea, vomiting, diarrhea and oral mucositis, are also frequent side effects of treatment. A number of antinausea medicines (antiemetics) are currently available, including ondansetron, granisetron, Aloxi (palonosetron), Anzemet (dolasetron) and aprepitant. Non-drug strategies, including acupuncture and relaxation techniques, can also help relieve symptoms, as can changes in diet, such as eating before treatment begins and consuming foods that do not trigger nausea.

Diarrhea can often be treated by a change in medications or diet (eating small, frequent meals and avoiding spicy foods), or drugs to slow bowel activity

Oral mucositis, a painful inflammation and ulceration in the mouth, can make it difficult to eat and drink, or even speak. Mucositis is usually treated by relieving pain with analgesic mouth rinses that contain lidocaine plus antibiotics and anti-inflammatory drugs. Eating ice chips 30 minutes prior to and during chemotherapy may decrease the severity of oral mucositis and the resultant pain.

Klenke changed her traditional meat and potatoes diet to one rich in fresh vegetables and fruit, and some fish. She removed dairy, meat and sugar, and also used supplements prescribed by her physicians. When treatment results weren’t as good as hoped for, she used breathing exercises to help her relax and reduce stress, and visualization techniques to “picture” her tumor shrinking. She credits her dietary changes and supplements for helping enhance the effects of chemotherapy. Integrative therapy is becoming more widespread in cancer care, be it mediation, yoga, acupuncture or aromatherapy. “But with the advancement of science, we now understand exactly why and how these therapies work,” says Sarah Rausch, PhD, executive director of the Society for Integrative Oncology. “We can understand the mechanisms of action and better understand which therapies are safe and beneficial for which patients.”

We can understand the mechanisms of action and better understand which therapies are safe and beneficial for which patients.

There is scientific evidence, for example, that acupuncture is effective for relieving pain and can help manage some side effects, such as nausea and vomiting. Mind-body therapies, such as relaxation, meditation and music therapy can also be effective in managing pain, as can massage therapy when delivered by a therapist trained in oncology massage, Rausch says.

Smith’s advice to patients is to do “whatever works.” Yoga helps with stress, mood and muscle strength, and other exercise has all the same benefits. American ginseng might help with fatigue, and ginger helps with nausea, he says, and there are often good data from randomized controlled trials to support this.

However, he emphasizes that it is imperative that patients tell their doctors what they are using. “Most of these therapies are safe, but there can be [adverse] interactions with some agents,” Smith says.

 supplement, "Countering the Effect of Cancer Treatments."

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Quality Control: Even with metastatic cancer, many patients live long and well.

Living with Metastatic Illness

A diagnosis of prostate cancer in April 2010 left Tim Daugherty and his wife, Debbie, with serious concerns but a relatively positive outlook. He underwent a radical prostatectomy followed by hormone therapy, and the Florence, Ore., couple were ready to move on.

Then came the difficult news that his cancer had spread to his lymph nodes.

“We thought he would get the surgery, and it would be over, so this definitely took things in a different direction,” says Debbie Daugherty, who has been her husband’s caregiver throughout his cancer experience. “It went from a oneshot deal to 44 radiation treatments, tri-monthly injections and having to take pills for the rest of his life. It was a huge change.”

Providing care to someone with cancer is never easy, but a diagnosis of metastatic disease can be overwhelming for all concerned. As the disease progresses, relationships change, family responsibilities shift, and stress and anxiety mount.

While localized cancer often can be eliminated with surgery, radiation or chemotherapy, metastatic disease is usually an incurable, more vexing problem. “A diagnosis of metastatic disease does not automatically mean it’s a death sentence,” says Hoda Badr, PhD, assistant professor in the department of oncological sciences at Mount Sinai Medical Center in New York.

“Depending on the type and location of the cancer and the treatments that are available, many individuals with metastatic disease can expect to live a longer life and experience a better quality of life than they did in the past.”

Certain metastatic cancers, such as lymphomas and testicular cancer, are generally more treatable and curable than others. Those viewed as incurable but often manageable include metastatic breast, prostate and colon cancers.

Paul Dougherty of Norristown, Penn., is among those living with a promising prognosis. At age 29, after receiving a diagnosis of testicular cancer that had spread to his abdomen and left kidney, he underwent surgery and several months of aggressive chemotherapy. The cancer returned four months later, requiring another three months of chemotherapy, says Lynn Dougherty, his mother and primary caregiver. Today, two years out from his last chemotherapy treatment, he is doing well.

But during the worst of Dougherty’s metastatic disease, the family’s “new normal” became whatever was required to help him, including not only driving him to medical appointments, picking up his medications and making sure he took them properly, but also setting up a visiting nurse and physical therapy times. “I had to learn how to give Paul shots, clean and pack his incision, and clean and change his drainage tubes,” his mother says. “These are things I never thought I could do, but when it’s your son, you just learn to do it.”

There were also financial concerns as Dougherty’s parents pitched in to help pay for his health insurance, car insurance and medications. “My husband had been laid off from his job earlier that year, so it was not easy,” she recalls.

I had to learn how to give Paul shots, clean and pack his incision, and clean and change his drainage tubes.

The caregivers of patients with metastatic disease also face big changes in family roles and responsibilities, as well as social isolation, while they devote more time to caregiving.

“I do all the yard work, housework and any repairs that need to be done. I also manage the finances and medical bills,” says Jennifer LeBret-White of Wellpinit, Wash., whose husband, Kevin, has been dealing with metastatic colorectal cancer for eight years. “We do not attend many social events. It’s difficult to commit to anything too far in advance because often we end up canceling at the last minute.”

There are strategies that can help patients and caregivers deal with the challenging issues frequently associated with metastatic disease. Foremost is to foster a climate of communication in which all parties are honest regarding their emotions and needs. “This creates a more harmonious home environment as well as better adjustment for the patient,” Badr says.

According to Walter F. Baile, MD, professor of behavioral science and psychiatry at M.D. Anderson Cancer Center in Houston, caregivers too often try to shield their loved ones from negative thoughts and emotions in the mistaken belief that it will make their condition worse. “There will be days when patients may feel hopeless, and we just have to be there for them,” he says.

That’s why caregivers are advised to communicate a sense of availability and a willingness to discuss concerns rather than create barriers and deny that the patient may have negative emotions that they want to talk about. “It’s important for the caregiver to acknowledge all of the emotions that the patient has, not just the positive ones,” Badr says. “When you focus solely on the positive, it shuts down the patient’s ability to confide in you about a fear of the future or the negative emotions they might have.”

Caregivers should also refrain from making too many decisions for their loved ones because it robs them of their autonomy. “The one vestige we have left at the end of life is to be able to make decisions about our own health care,” Baile says. “Don’t take that away from the patient.”

When you focus solely on the positive, it shuts down the patient’s ability to confide in you about a fear of the future or the negative emotions they might have.

Decisions regarding clinical trials are also best left to the patient, Baile adds. “The family may push for clinical trials, but often they’re pushing for their own motives and don’t always have the patient’s best interest at heart,” he says. “Patients sometimes feel guilty because if they say no they are adding to the family’s suffering. But families need to be sensitive to what the patient wants, even if they don’t like it. After all, it’s the patient’s disease.”

Indeed, treatment of any kind can have a huge impact on the caregiver, Badr says. If treatment has a curative intent, she notes, the caregiver knows that at some point the patient will improve and the need for caregiving will diminish. But if there is no curative intent to treatment, the caregiver must focus on how to be an asset and help the patient manage symptoms at home. “The caregiver is another set of eyes and ears who can help the patient keep in mind what their healthcare team has recommended,” she says.

Even when metastatic disease appears curable, the stress of caregiving can be overwhelming. Baile encourages all caregivers to take advantage of local support groups to help them deal with issues, such as social isolation and economic strain. “Support is extraordinarily important,” he says. “You can’t take care of other people unless you take care of yourself.”

Tim and Debbie Daugherty know firsthand the value of a support network. Throughout his treatment they attended regional meetings of the international prostate cancer support organization Us TOO, during which patients discussed their treatments and life experiences.

Take care of yourself mentally and physically, and don’t be afraid to reach out for help. The patient is No. 1, but they can’t remain No. 1 if you’re not a high No. 2.

“I found that very helpful,” Debbie Daugherty says. “They taught me how to organize test results and financial documents, what questions to ask, what information to share, what legal documents to gather for our family It was also good just to hear other people talk. You gain strength and knowledge from that.”

Her advice to other caregivers is simple: Take care of yourself. “If we’re not OK to give care, then someone else is going to do it for us, and that’s going to make us feel even worse because we want to do it,” she says. “Take care of yourself mentally and physically, and don’t be afraid to reach out for help. The patient is No. 1, but they can’t remain No. 1 if you’re not a high No. 2.”

New Routine: Caring for those with metastatic disease calls for flexibility, commitment.

Providing Aid and Comfort

Approaching metastatic cancer is nuanced with a complex array of options and difficult decisions. This is in contrast to early-stage or highly curable cancers, where doctors tend to follow strict diagnostic and treatment protocols based on large trials that can pinpoint (or at least estimate) the optimal cure rate. This special report from 

 magazine will help patients and caregivers navigate the uncertainties they face when deciding if and how to treat metastatic disease.

The good news is that we continue to make slow yet steady progress with newer drugs that attack specific cancer-driving pathways with better ways to manage side effects of cancer and cancer treatments. The story is different for every cancer type and even within cancer subtypes. We still face important limitations—primarily, the inability to achieve a cure, even if we can improve lifespan or quality of life.

What does this all mean to patients? As readers of this issue will discover, patients can be effective partners with their care team. First, careful staging and proper tumor analysis is important in deciding the timing and type of treatments—the results and implications of these tests and resulting options represent shared decisions to be made jointly between patients and their doctors. Second, patients need to understand the balance between the expected benefits of each option and the trade-offs to be made in side effects of the proposed treatment.

What does this all mean to patients? As readers of this issue will discover, patients can be effective partners with their care team.

In many situations these are not described in “black and white” terms, but rather in probabilities (for example, one-third of patients respond for an average of eight months, with 10 percent experiencing numbness and tingling of the arms and legs, known as neuropathy). Third, patients need to know all the options, including no treatment at all, or excluding some of the treatments.

These choices should also include investigational trials, or checking for other nearby locations where patients could be offered trials, especially when there are no good standard choices for individual situations.

Finally, patients should report side effects and learn about the best ways these can be managed, and be pointed to resources to support all the needs that they and their family might encounter, such as home health care, psychological support, hospice and financial advice.

From molecular and personalized medicine to practical tips on having the best quality of life, we hope the following pages can make a difference.

Professor of Medicine, University of Southern California 

Co-Leader, Women’s Cancer Program at the USC/Norris Comprehensive Cancer Center

We are learning that the most successful way to treat cancer is to take aim at a good target. So what makes a good target? Quite simply, it should represent the driver that is inducing the cancer cell to grow and spread. The catch? There usually is not a single driver, and it may be different from one type of cancer to another, or even among individuals with seemingly identical cancers.

We are just now starting to develop ways to personalize medicine by identifying individual drivers, but at the current time, most therapies attack the consequences of the drivers, such as rapid cell division— this is how chemotherapy works. Yet major side effects result, as normal cells are also affected. Until recently, if surgery was not curative, chemotherapy represented the only therapeutic handle we had for colorectal cancer&mdash; and while these regimens have been refined, their impact is still modest.

As you will read in this issue of CURE, we have now moved to a different target for colorectal cancer—the addition of drugs that inhibit tumor blood vessel growth. In a process known as angiogenesis, the blood vessels are induced by tumor cells to grow and thereby form a delivery system of oxygen and nutrients to help cancer grow.

We still don’t know why colorectal, as well as some other cancers, appears to be preferentially affected by these therapies. The antibody Avastin (bevacizumab) continues to be an important drug to augment survival for patients with advanced colorectal cancer, even though it is usually not curative. Just this past year, two new drugs were approved that work on other targets—Zaltrap (ziv-aflibercept) and Stivarga (regorafenib). However, because angiogenesis is still not the primary driver of cancer but a consequence of several underlying genetic changes in cancer cells, there is more work to do, and we expect that more comprehensive molecular profiling will get us closer to the “drivers.”

 highlights the road of progress in colorectal cancer and the remaining challenges. Of course, we also get a word in about prevention and early detection—the first lines of defense against cancer.

Editor's Page

Becoming an effective partner in managing metastatic cancer.

Message from the Editor

People with metastatic cancer and their families often need assistance coping with the emotional and practical aspects of the disease. In addition to the resources listed here, more are available at 

Department of Pain Medicine & Palliative Care at Beth Israel Medical Center 

BenefitsCheckUp: Tool for Financial, Health and Prescription Savings 

Patient Advocate Foundation Co-Pay Relief 

National Coalition for Cancer Survivorship 

National Center for Complementary and Alternative Medicine 

Special Report

Resources

A common theme running through recent advances for metastatic cancers has been the increasing role of molecular or genomic information to identify tumors that are most likely to respond to a specific drug and to develop drugs that target specific cellular pathways.

For example, identification of the BCR-ABL mutation in chronic myeloid leukemia led to the development of effective drugs that turned a highly fatal cancer into one with survival times of 20 years and more. In colorectal cancer, the mutation status of the KRAS gene is being used to identify patients who are candidates for EGFR-targeted antibodies, while EGFR mutations may be used to select therapies in lung cancer. Overexpression of the estrogen receptor and HER2 can be used to determine treatments for patients with breast cancer. More recently, new agents have been developed for lung cancers with a rearrangement of the ALK gene and for melanomas that contain a BRAF mutation.

We use the information to assign the patients to the treatments, but we also use the tissue and material to potentially discover new things that could benefit future patients with lung cancer.

Molecular information is also beginning to drive the design of clinical trials to develop new therapies. One such trial is the BATTLE-2 lung cancer trial, a study “designed to understand how tissue biomarkers predict who will respond to targeted therapy or targeted therapy combinations,” according to Yale School of Medicine’s Roy Herbst, MD, PhD, one of the lead investigators. Patients entering the trial undergo a biopsy, the genetic status of their tumor is determined, and they are assigned to one of four different drugs or combinations. As the trial goes on and researchers learn about the predictive power of different biomarkers, this information will be used to help select the treatment that patients receive.

“We use the information to assign the patients to the treatments, but we also use the tissue and material to potentially discover new things that could benefit future patients with lung cancer,” says another lead investigator, Ignacio Wistuba, MD, of M.D. Anderson Cancer Center in Houston.

As researchers continue to mine the molecular make-up of cancers cells, patients can look forward to more effective treatments tailored specifically for them—and that’s a revolution to believe in.

Molecular and genomic information can identify tumors most likely to respond to a specific drug.

The Molecular Revolution

As researchers gain a better understanding of the toxicities associated with chemotherapy and radiation therapy, they have focused more on developing drugs and therapeutics that address the complications of cancer treatment.

One of the most important advancements in cancer treatment has been recognizing that supportive care and symptom management are key, regardless of the stage of disease or intent of treatment, says Jennifer S. Temel, MD, assistant professor of medicine at Harvard Medical School and clinical director of thoracic oncology at Massachusetts General Hospital in Boston. “More specifically, there is greater data demonstrating that the provision of supportive care, for example palliative care, can improve the experience of cancer patients.”

Another important advancement is encouraging better communication between patients and providers, says Thomas J. Smith, MD, director of palliative medicine at Johns Hopkins Sidney Kimmel Comprehensive Cancer Center in Baltimore.

Patients want to know: ‘What do I have? What’s going to happen to me? What can be done about it?’ And this is nearly universal.

“Patients want to know: ‘What do I have? What’s going to happen to me? What can be done about it?’ And this is nearly universal,” he says. “In every culture—about 90 to 95 percent of people want all the available information. The data are clear that oncologists like me don’t often give this information.”

Another major advance, according to Smith, is in the integration of palliative care and hospice into usual care. This is now recommended by the American Society of Clinical Oncology for anyone with serious cancer, he says. Research indicates that care with both an oncology and a palliative care team can lead to better symptom management, improved communication, less depression and better understanding of the illness and options.

Palliative care is focused on relieving the symptoms, pain and stress of a serious illness and is appropriate at all stages of the disease.

But many patients hear the word “palliative” and immediately think of hospice, says Charles Loprinzi, MD, a breast cancer specialist at the Mayo Clinic in Rochester, Minn. “It is important to explain the difference,” he says, “as the two are very different. And it is important to incorporate palliative care early on in treatment.”

Other advancements include the increasing use of integrative therapies and the use of bonemodifying drugs in bone metastasis.

Advancements in Supportive Care

Stress is an inherent part of caregiving, and it can be more stressful when the patient receives a diagnosis of metastatic disease. Overwhelmed by the job, caregivers often let their own health deteriorate, which can have an adverse effect on their caregiving abilities.

Caregiving advocates offer simple solutions: Eat well, stay hydrated, get plenty of sleep, exercise regularly and don’t hesitate to enlist the help of friends and family so you can take a break when necessary. But there are additional steps caregivers can take to maintain their physical and mental well-being.

“Try to incorporate activities that give you pleasure, even when you don’t feel like it,” advises Hoda Badr, PhD, a psycho-oncology researcher. “Listen to music, work in the garden or engage in a hobby. These things help maintain a degree of normalcy in your everyday life.”

When she starts to feel down, caregiver Debbie Daugherty enjoys a bicycle ride. She also plays the piano—with her dog. “He loves it,” she says. “He sits beside me, and it’s something we do together.”

Badr also encourages caregivers to keep a journal, especially if they find themselves in a stressful situation that can’t be discussed with their ailing loved one. “If you don’t feel comfortable burdening the patient with your thoughts and feelings,” Badr observes, “writing them down may help provide perspective on your situation or an outlet for your fears and concerns.”

And don’t hesitate to seek solace and support from friends, clergy or a professional counselor, she says. “They can be beneficial at any point during the trajectory of the disease,” Badr adds. “However, making that connection early is always better, so those people will be there for you in times of need.”

Overwhelmed by the job, caregivers often let their own health deteriorate, which can have an adverse effect on their caregiving abilities.

Self-Care for Caregivers

In May 1999, Ann Pendley, then a 44-year-old speech and language therapist in Fort Collins, Colo., found a lump in her breast during a self-exam. Even though nothing had shown up on her latest mammogram and her doctor waved it off, Pendley insisted on getting a biopsy, which identified an aggressive cancer. She immediately had a lumpectomy and, when the surgeon couldn’t get clean margins, a mastectomy. After more than six months of chemotherapy, she was declared disease-free.

In 2004, after a routine scan, Pendley was told her cancer had metastasized to her lungs. The multiple spots were kept under control with chemotherapy. Then, in November 2011, tumors were found in her brain and bones. The brain tumors responded well to directed radiation therapy, but Pendley is doing research and talking to her oncologists about next steps.

“Now that it has spread past the blood-brain barrier, it’s a whole new ball game,” she says. She deals with a lot of paperwork, her insurance rates have gone up and she is using specialty pharmacies for drugs she can’t get locally. She hopes to sell her therapy practice to make life a bit easier, but that could leave her without coverage.

Such is life with metastatic disease. But for Pendley, it is life.

“I could be around for a while,” she says. “For years, I kept thinking, I don’t have to worry about that, I’ll be gone by then. But I’m not.”

Metastatic disease is cancer that has spread from the place in the body where it first started to one or more places. The resulting tumors are called metastatic tumors or metastases.

A primary tumor the size of a grape contains a billion cells, and more than a million of them may enter the circulatory system every day, says Isaiah Fidler, PhD, director of the Metastasis Research Laboratory at M.D. Anderson Cancer Center. Only a few of those cells survive and fewer still are believed capable of spreading. But a few may be all it takes.

While each cancer metastasizes in its own unique way, the most common sites for metastases to occur are the lungs, bones and liver. Some types of primary tumors seem more prone to metastasis, and certain cancers tend to spread to specific locations—breast cancer to the lungs and liver, for example, and prostate cancer to the bones and lungs. The majority of metastatic tumors land in the first capillary bed beyond the primary tumor, says Patricia Steeg, PhD, chief of the Women’s Cancers Section at the National Cancer Institute, but 30 percent don’t follow this pattern. Interaction between the tumor cell and potential host organ plays a key role; just as not all tumor cells are capable of metastasizing, not all organs can sustain one.

A cancer that spreads to another part of the body is still considered the original type of cancer—colon cancer that spreads to the liver is still colon cancer, for example, and is usually treated with drugs used for colon cancer.

Many patients have evidence at initial diagnosis that tumor cells have spread beyond the primary site, Steeg says. This may be a reflection of when certain types of cancer are caught. “For example, we’re bad at finding early-stage ovarian or pancreatic cancer, so when we find it, it has had a lot of time to metastasize,” she says. “In theory, though, in the lab there are cancers that seem prone to metastasize and those that don’t.”

Detection of metastasis varies from one type of cancer to another, says George W. Sledge Jr., MD, an oncologist in Indianapolis. A high percentage of metastases are diagnosed because an individual experienced symptoms. In the case of breast cancer, monitoring asymptomatic patients for recurrence with blood tests and scans actually does not appear to improve outcomes and is generally not recommended, but evaluations of symptoms should be pursued by appropriate scanning.

If you're having a symptom and it gradually gets worse, that is absolutely, positively a reason to contact your physician and be evaluated.

“Vigilance on the part of the patient is appropriate, and part of the discussion to have with your physician post-treatment is what you should be looking for,” he says. Two key words for symptoms are persistent and progressive. “When a cancer comes back, you tend to have the same symptoms day after day in the same place, and they tend to get worse over time.”

That was the case for Maria Wetzel, 67, a retired clinical laboratory specialist in Michigan who received a diagnosis of stage 2 invasive ductal carcinoma in 1996 and was treated for recurrence in 2004. About five years later, she noticed shortness of breath, which continued to worsen. Imaging tests confirmed metastatic disease in her lungs and liver.

“If you’re having a symptom and it gradually gets worse, that is absolutely, positively a reason to contact your physician and be evaluated,” Sledge stresses. “As a general rule of thumb, if it is enough to worry the patient, it ought to be enough to worry the doctor.”

For some cancers, the American Society of Clinical Oncology (ASCO) recommends routine follow-up testing to detect metastasis. This testing can include blood tests for high levels of carcinoembryonic antigen (ASCO recommends this for stage 2 and 3 colon cancer, for example), abnormal hormone levels or other markers; periodic imaging scans; and physical exams. Both of Pendley’s recurrences showed up in routine scans.

Although metastatic tumors maintain many of the attributes of the original tumor, there can be key differences, including different mutations and gene expression profiles, and, of course, a different environment from the primary site. While surgery can eliminate many primary tumors, and cancer treatments using medical therapies inhibit tumor growth, additional treatments may be needed to address the metastatic process.

In theory, it would be easier to prevent metastasis than to treat it. “To shrink an already established metastatic tumor, you have to kill billions of tumor cells,” Steeg says, “but to prevent the outgrowth, you only have to get a few cells.” This is the principle underlying the use of adjuvant therapy—that is to treat the individual who has had complete removal of the primary tumor, but in whom there is a high risk of cancer recurrence and spreading. Even with full adjuvant therapy, unfortunately, the risk of metastasis is lowered, but cancer can still spread. Moreover, the effectiveness of adjuvant therapy, as well as the best drugs to use, varies from cancer types and subtypes.

We have to take care of the seed, learn about the soil that it likes and target both. Something that does that will probably be our best therapeutic.

Effectively preventing or treating metastatic cancer requires understanding the relationship between cancer cells and their environment. The seed and soil hypothesis, first proposed in 1889 by Stephen Paget and later verified through modern research, theorizes that metastatic tumor cells (the “seeds”) need to find favorable microenvironments (the “soil”) in order to thrive.

“We have to take care of the seed, learn about the soil that it likes and target both,” says Aline Betancourt, PhD, research associate professor at the Tulane Center for Stem Cell Research and Regenerative Medicine in New Orleans. “Something that does that will probably be our best therapeutic.”

Regardless of the therapy, though, given the variety of types of cells in a tumor, and the vast quantity of them, some of those cells inevitably prove resistant to it, Fidler says. Over time, the cells that are resistant to treatment replace those that aren’t.

This resistance can be very disease-dependent, Sledge says. Cancer of the prostate, and leukemias and lymphomas, for example, have high survival rates, he says. “With most solid cancers, however, we’re not very good at curing metastatic disease. Our goals shift from the primary goal of cure to the goal of prolonging life, managing symptoms and maintaining quality of life.” The approach becomes long-term management and fortunately, for the most part, as one treatment stops working, something different is available.

“As we get better at identifying those mechanisms of resistance, we’ll become better at overcoming them,” Sledge adds. “It’s like a criminal trying to escape town. The cops throw up a roadblock, and if all the criminal has to do is turn around and leave by a different route, it won’t take him long to get out of town. It’s a matter of throwing up a sufficient number of roadblocks in strategic places.”

Creating those roadblocks and identifying strategic places to put them are huge challenges. Meanwhile, those with metastatic disease wonder where the bad guys will show up next.

Living with this uncertainty becomes the new normal. “With metastatic disease, you really don’t know,” Pendley says. “I didn’t think I’d still be here now. But you just keep showing up.”

In August, Pendley joined a phase 2 trial for GRN1005, a chemotherapy drug that uses the LRP-1 pathway to cross the blood-brain barrier and target tumors in the brain. So far, it seems to be working.

“I may not die of cancer,” she says. “I may die of running off the road on my mountain bike.”

Guessing Game: Patients with metastatic cancer live with uncertainty.

What is Metastatic Cancer?

Not too many years ago, when a patient received a diagnosis of cancer that had spread beyond the primary site, doctors had little to offer. Now, they have an increasing number of therapies, emotional and financial support and an improved quality of life. Years of research are yielding dividends in the form of more active drugs and more effective treatments to deal with metastatic disease. Many metastatic cancers are moving toward becoming manageable chronic diseases, and for a few types of cancer, cures are even possible.

At age 30 and having never smoked, Anne Marie Cerato received a diagnosis of stage 3 lung cancer in April 2009. The Toronto resident underwent chemotherapy and radiation together, followed by surgery, but the cancer came back in May 2011. Cancer cells had also spread to her other lung. Radiation and surgery were no longer options—doctors told her to wait until she was symptomatic, at which point they would treat her with chemotherapy.

But for Cerato, “going home and sitting and waiting and watching was not good enough,” she says. She began investigating her options and found a clinical trial for an investigational drug, now known as Xalkori (crizotinib). She spoke with her oncologist, who referred her to a nearby center participating in the trial. Analysis of her tumor cells revealed that they carried an uncommon mutation in the ALK gene, which produces a protein leading to growth and spreading of cancer cells that is blocked by Xalkori. She enrolled in a phase 3 trial where she received the experimental treatment. Cerato has been taking the drug for a year. “My scans are clear, everything is stable, and so far there is no evidence of disease in my lungs, which is great,” she says.

Cerato says that while receiving a diagnosis of metastatic (stage 4) disease was devastating, in some ways it was also liberating.

“It gave me permission to realize that my life would never really be normal,” Cerato says, “and allowed me to choose to live my life for myself and not for anyone else.”

One action she found therapeutic was getting tattoos, which was “a way of exerting control over my own body,” she says. While Cerato says she knows Xalkori isn’t a cure, “It has given me a completely clean slate and lots and lots of hope because I’m responding so positively and others are too.”

[My diagnosis] gave me permission to realize that my life would never really be normal and allowed me to choose to live my life for myself and not for anyone else.

The goal of treatment for late-stage cancer varies, depending on the type of cancer. In some cases, a cure may be possible with current therapies, even when the cancer has spread beyond the primary site. In other cases, although a cure may not be attainable, newer and better therapies are extending the time patients can live with their disease while maintaining a good quality of life. A few cancers are even becoming chronic diseases that can be stabilized and managed with a succession of different treatments.

Testicular cancer is a model of success, with one of the highest cure rates of any solid tumor. Over the past four decades, the cure rate has risen from 25 percent to about 80 percent for patients with metastatic disease. This dramatic improvement was the result of discovering that testicular cancers were particularly sensitive to the chemotherapy drug cisplatin, and regimens containing this drug have become a mainstay of treatment. For patients who relapse, a cure may still be possible with other therapies.

Some forms of lymphoma may be curable at advanced stages, too. Overall, Hodgkin lymphoma has an 80 percent cure rate, while approximately two-thirds of patients with diffuse large B-cell lymphoma can currently be cured. For patients with lymphoma whose disease returns after a remission, one potential option is more aggressive treatment with highdose chemotherapy followed by a stem cell transplantation to replenish essential blood cells that are wiped out during the treatment. However, it has risks of its own and is only appropriate for patients in good overall health, but may be curative for relapsed lymphoma, as well as certain other blood cancers. New drugs are also being investigated for resistant lymphomas, and the FDA recently approved the anti-CD30 antibody drug conjugate Adcetris (brentuximab vedotin) for relapsed Hodgkin lymphoma.

Follicular lymphoma (FL) is a good example of a cancer that cannot be cured with current drugs, but because of its slow disease course and the effectiveness of available treatments, such as chemotherapy plus the anti-CD20 antibody Rituxan (rituximab), it can be managed for long periods of time. In fact, the median survival time is 14 years, with some patients living even longer. Since many patients are older and will likely die of other causes before succumbing to their cancer, the primary goal of treatment in many cases has shifted to maintaining quality of life and managing symptoms while living with FL.

Prostate cancer is similar in some ways to FL. Often, advanced disease can be controlled for years with currently available hormone therapies. The primary concern is managing disease symptoms as well as side effects of therapy. For patients whose disease has developed resistance after treatment with either hormone therapies or standard chemotherapy, a number of drugs have recently been shown to further extend survival, including Provenge (sipuleucel-T), an active cellular vaccine that takes immune cells from the patient and teaches them to recognize and destroy the cancer cells; Zytiga (abiraterone), a drug that blocks the production of androgens, the hormones that fuel prostate cancer cells; and Jevtana (cabazitaxel), a new taxane chemotherapy. Finally, another new drug that inhibits androgen receptor signaling in the cancer cells, Xtandi (enzalutamide), improved survival in men with castration-resistant prostate cancer and was approved by the FDA in late August.

Stage 4 breast cancer is another increasingly manageable cancer (see sidebar, page 19). For patients with estrogen receptor-positive cancer, there are a variety of hormone therapies that can be used, and patients often cycle through several of these before starting more toxic chemotherapy regimens. New targeted agents continue to be tested in combination with hormone therapies to to be tested in combination with hormone therapies to overcome tumor resistance. This approach has recently proven successful. Adding Afinitor (everolimus), a drug that inhibits mTOR (a protein that helps regulate cell growth) to exemestane (an aromatase inhibitor) more than doubled the time until their disease progressed. This combination was approved by the FDA in July.

For women whose breast cancers overexpress the HER2 receptor or exhibit HER2 gene amplification, the introduction of Herceptin (trastuzumab) marked a turning point in treatment and led to an explosion of research into additional HER2-targeted therapies. Perjeta (pertuzumab), an antibody that targets the HER2 receptor in a slightly different way than Herceptin, was recently added to the arsenal for metastatic HER2- positive breast cancer. Another new therapy, T-DM1, uses the Herceptin antibody to deliver a potent chemotherapy drug (emtansine) directly to tumor cells. This drug also extends the progression-free survival, as well as overall survival, and is currently being reviewed by the FDA.

Although colorectal cancer has traditionally had a poor outlook, advances in surgical techniques and systemic therapies have actually made it possible to cure some patients with metastatic disease, particularly if it has only spread to the liver. The use of chemotherapy before surgery may be able to shrink some tumors and make them operable, further expanding the subset of patients who can be treated with curative intent. For patients with more widespread metastases, the outlook has also improved significantly in the last decade. The introduction of targeted agents, such as Avastin (bevacizumab), Erbitux (cetuximab) and Vectibix (panitumumab), as well as refinements in standard chemotherapy regimens, led to an increase in median survival, from eight months to more than two years. More new therapies are poised to enter the clinic, including two new drugs that, like Avastin, block the formation of blood vessels in tumors. Zaltrap (ziv-aflibercept) was approved by the FDA in August, while Stivarga (regorafenib) was approved in September.

Years of patience and basic research is finally beginning to pay off even for those cancers that have traditionally been associated with a very poor prognosis and lack of treatment options. For example, the discovery that lung cancers with mutations in the epidermal growth factor receptor were more sensitive to drugs targeting this receptor triggered the start of individualized, molecularly targeted therapy for non-small cell lung cancer. More recently, about 2 to 7 percent of lung cancers were found to contain a rearrangement of the ALK (anaplastic lymphoma kinase) gene, leading to the rapid testing and approval of Xalkori (crizotinib), an ALKtargeted drug, as mentioned above in Cerato’s story.

David Gandara, MD, director of the thoracic oncology program at the University of California—Davis Comprehensive Cancer Center in Sacramento, Calif., says the biggest change has been the recognition that lung cancer is not just one disease, but multiple subtypes that originated in the lung. “To a certain extent, each patient represents their own subset,” Gandara says, “and we know that because we can distinguish the molecular biology of that cancer—it’s like a fingerprint, and that molecular fingerprint is almost different for every single patient. That’s what has changed therapy, thinking of the patients as individuals.

“I think what patients can look forward to in the future is coming into their oncologist’s office with their own genetic resume—here’s my molecular fingerprint&mdash; and working with their physician as a partner to decide what forks down the road they should take,” Gandara says.

There are collaborative efforts under way to study the genome of the two most common subtypes of lung cancer (adenocarcinoma and squamous cell carcinoma).

Some cancers, such as ovarian, are just beginning to enter the era of molecularly targeted therapy. There has been little progress in improving survival outcomes for patients with stage 4 ovarian cancer since the introduction of platinum-based therapy more than 30 years ago, but research efforts are now focusing on targeting therapies toward selected subsets of cancers. For example, inhibitors of PARP (poly [ADP-ribose] polymerase), an enzyme involved in DNA damage repair, are being investigated for patients with ovarian, breast and other cancers that are driven by inherited mutations in the BRCA1 or BRCA2 DNA repair genes. In a randomized phase 2, the PARP inhibitor olaparib extended the remission of ovarian cancer after platinum-based chemotherapy.

Niki Quasney of Munster, Ind., received a diagnosis of stage 4 ovarian cancer when she was 33 years old. The diagnosis didn’t come as a shock—when an older sister developed breast cancer at a young age, Quasney was tested for the BRCA mutations. After she had discovered she was positive for a mutation that increases the risk for breast and ovarian cancers she underwent a prophylactic mastectomy but delayed having her ovaries removed. She had always been told by her doctors that she could wait until she was 35 to 40 years old to remove her ovaries, and she thought she had time. But then a biannual blood test indicated increased levels of CA-125, a biomarker that is elevated in ovarian cancer as well as other conditions. Additional tests revealed ovarian cancer that had spread throughout her abdomen. The hardest part of the diagnosis was telling her family, particularly because her father was in the last stages of pancreatic cancer.

Quasney underwent surgery and intensive chemotherapy, and her cancer went into remission for two years before she experienced a relapse. After surgery and another round of chemotherapy put her cancer back into remission, Quasney enrolled in a clinical trial designed to test whether another investigational PARP inhibitor, veliparib, could help to maintain her remission. So far, it appears to be working, although there are not enough data on this drug yet to know whether it will extend her remission.

Despite the uncertainty, Quasney is putting this remission to good use and living life to the fullest—raising her daughter with her partner, biking and participating in sprint triathlons, fundraising for ovarian cancer research and pursuing social justice issues about which she is passionate. She gets a CA-125 test every three weeks to monitor for signs of the cancer’s return. Quasney compares getting good results to American Idol, “I feel like I’m safe for another three weeks. I haven’t been voted off yet.” If the cancer does return, Quasney says, “I don’t know what the next step is, but I know there are a lot of other drugs out there.”

It's very encouraging to know that these people [researchers] are devoting their jobs and their lives to finding cures for ovarian cancer and new drugs.”

Another cancer that has been traditionally hard to treat is pancreatic cancer, but even there, new treatments are finally beginning to show promising results. A new combination of chemotherapy drugs, FOLFIRINOX (5-FU [fluorouracil], leucovorin, irinotecan and oxaliplatin), was recently shown to improve overall survival in a phase 3 trial.

“Median survival is now over 10 months, close to a year, which is very encouraging, and we’re starting to see patients survive for two years, which we never saw before,” says Ramesh Ramanathan, MD, clinical professor at the Translational Genomics Research Institute and medical director of the clinical trials program at the Virginia G. Piper Cancer Center in Scottsdale, Ariz. Researchers are also investigating targeted agents, searching for biomarkers to identify patients who can benefit most from the already-approved Tarceva (erlotinib), a drug that targets EGFR (epidermal growth factor receptor), and evaluating new therapies that target overexpressed or mutated genes, such as the PI3 kinase inhibitors, c-Met inhibitors, IGF-1R inhibitors and agents targeting the stroma, the supporting nonmalignant tissue that tumor cells op-opt (or recruit) to help support them.

“I think in pancreatic cancer we are moving from standard cytotoxics [chemotherapy] to looking at the molecular profiles of patients,” Ramanathan says. “I think that’s a big advance for pancreatic cancer.”

Ramanathan encourages patients to ask about new approaches and clinical trials related to their individual care.

Cerato says if her cancer stops responding to Xalkori, she is open to trying one of the many new treatments currently under investigation.

“It is interesting what is coming down the line, and it is an exciting time,” she says.

“Clinical trials are where they are going to find things that are going to make a difference,” Quasney says. “It’s very encouraging to know that these people [researchers] are devoting their jobs and their lives to finding cures for ovarian cancer and new drugs.”

Reasons for Hope: Options are available to keep disease at bay.

Treating and Managing Metastatic Disease

On Sept. 27, the Food and Drug Administration announced that it had approved Stivarga (regorafenib) for patients with metastatic colorectal cancer (mCRC) who have progressed after trying other therapies. The FDA had granted the drug a priority review in late June, which guarantees a drug will be reviewed within six months.

Stivarga works as a multikinase inhibitor, which means it targets several different pathways that can promote tumor growth, including the vascular endothelial growth factor (VEGF) receptor, which signals tumor blood vessel growth, and c-KIT, an oncogene that also helps cancer growth. Patients take the drug orally, once daily in four-week cycles (three weeks on, one week off, before starting the therapy again).

The approval is based on the phase 3 CORRECT trial, which randomly assigned 760 patients with mCRC who had prior treatment to receive either Stivarga or a placebo. All patients in the trial received best supportive care. Stivarga was shown to extend median overall survival to 6.4 months compared with the five months for those in the placebo arm. The drug also delayed tumor growth by two months compared with the 1.7 months for those on placebo.

Common side effects include fatigue, hand-foot syndrome and diarrhea. The drug also carries a warning that severe and fatal liver toxicity can sometimes occur.

Stivarga has already been made available to some patients through an extended access program. For additional information, visit 

On Aug. 31, the FDA approved Xtandi (enzalutamide, formerly known as MDV3100) for patients with metastatic castration-resistant prostate cancer that has spread or recurred after surgery or hormone therapy. Patients also must have been previously treated with docetaxel. The approval comes three months ahead of schedule after the FDA granted the drug a priority review, which guarantees a six-month evaluation for promising treatments.

A targeted therapy, Xtandi works by preventing testosterone, a hormone that drives prostate cancer cells’ growth, from binding to the cell’s androgen receptor as well as helping to induce self-destruction of the tumor cell.

The drug’s effectiveness was proven in the AFFIRM trial, which randomized 1,199 patients with the experimental treatment versus placebo. Xtandi was shown to improve median overall survival by 4.8 months compared with a placebo. Results presented at this year’s American Society of Clinical Oncology Genitourinary Cancer Symposium showed the drug also promoted tumor shrinkage, caused a significant decline in PSA levels and delayed cancer growth by five months.

Common side effects include fatigue, diarrhea, musculoskeletal pain, hot flashes and headaches, among others. About 1 percent of patients taking Xtandi had seizures. For more details, visit 

On Aug. 3, the FDA approved Zaltrap (zivaflibercept) for treating patients with mCRC and tumors that have progressed or are resistant to oxaliplatin-containing therapies. The drug is used in combination with the standard colorectal cancer chemo regimen FOLFIRI (leucovorin, 5-FU [fluorouracil] and irinotecan).

The approval is based on the phase 3 VELOUR trial, in which 1,226 patients who had previously received an oxaliplatin treatment combination were randomized to receive FOLFIRI plus either Zaltrap or a placebo. Those in the Zaltrap arm had a median overall survival of 13.5 months compared with 12 months in the placebo arm. Zaltrap also extended progressionfree survival to 6.9 months compared with the 4.7 months for FOLFIRI plus placebo.

Recent drug approvals for metastatic cancers.

Winter Supplement 2012 | CURE