Melissa Weber

At only 5 years old, Heaven Sanchez received radiation, chemotherapy and a transplant of her own stem cells after surgery to remove a brain tumor. Now 9, she has cataracts in both eyes and an underactive thyroid, complications of the powerful treatment regimen that left her cancer-free.

“The doctors told us what the complications might be,” says Heaven’s mother, Stephanie Sanchez of San Antonio. “At the time, the only thing I was thinking was she has to get better. And we have to do whatever we can.”

Cancer survivors, young and old, confront a variety of health problems after stem cell transplantation, according to a growing number of studies. The reason: collateral damage from therapies used to kill cancer. High amounts of radiation and chemotherapy used before stem cell transplantation, and in some cases, in between multiple transplantations, can destroy the cancer with the potential consequence of bodily harm. Chemotherapy and radiation, for example, can cause congestive heart failure and new, or secondary, cancers.

Leukemia and lymphoma survivors at least 10 years out from transplantation are at higher risk for heart disease, blindness, osteoporosis, new cancers and other post-transplantation complications compared with their siblings, according to a study presented at the American Society of Hematology (ASH) annual meeting this past December.  The study also included survivors of aplastic anemia and other conditions.

After a 15-year follow-up, researchers found 74 percent of survivors had developed at least one chronic health condition compared with 29 percent of siblings. One in four survivors developed a severe or life-threatening condition compared with 8 percent of siblings.

Long-term health problems can also result from steroids used to treat graft-versus-host disease, a possible side effect of allogeneic transplantation in which the donor stem cells see the patient’s body as foreign and launch an immune system attack. Osteoporosis, for example, is a possible by-product of steroid therapy in both men and women.

Yet patients aren't being regularly told about the risk of health complications later on, says Smita Bhatia, MD, director of the Center for Cancer Survivorship and BMT (Bone Marrow Transplant) Long-Term Follow-up Program at City of Hope in Duarte, Calif. "That's because the data are just emerging on these long-term morbidities, so it will take three to four years before those discussions become incorporated into the standard practice," says Bhatia, senior author of the survivor study presented at the ASH meeting.

Long-term survivors are also at higher risk for a psychological health condition called somatic distress, according to Bhatia's study. Somatic distress occurs when there's no medical underlying cause for a particular symptom, yet a survivor experiences it. It may be in the form of abdominal pain or shortness of breath.  "There really isn't much of a clue as to why that is happening," Bhatia says.

In Heaven Sanchez’s case, doctors know what caused her eye cloudiness: radiation she received to the brain and spinal cord. Her vision started to change within two months after she finished treatment. More than three years later, her vision has worsened to the point where she can barely see a few feet in front of her.

“At home, it’s not as bad. But other times, she can’t see who she’s with or where she’s at,” Stephanie says of her daughter. “Especially when we’re in a new place, we have to walk with her and hold her hand to make sure she doesn’t trip over anything.” Heaven’s ophthalmologist wants to delay cataract surgery until it is absolutely necessary. “We may have reached that point,” Stephanie says.

Cataracts are less common today than years ago when patients often received total body irradiation in a single dose, Bhatia says. Once that link was made in the 1980s, transplantation doctors started splitting up the dose. Doctors also started shielding vital organs, such as the lungs, and, when possible, pointing the radiation beam away from the heart.

A more recent shift within the past decade involves some doctors dropping the chemotherapy drug etoposide from the list of stem cell mobilizers, drugs that stimulate the release of stem cells from the bone marrow into the bloodstream for easy collection. “We found a relationship between etoposide and the development of a highly fatal disease called therapy-related leukemia. So the use of etoposide for stem cell mobilization was greatly minimized,” Bhatia says.

But even as improvements are made, survivors need thorough and regular follow-up care. Bhatia recommends survivors get annual physicals, follow a healthy lifestyle and ask their physicians what post-transplantation health complications they’re at risk for and what symptoms to watch for. Most importantly, get screened for those complications, she says.  For example, survivors who received anthracycline drugs before transplantation should be screened for heart failure with an echocardiogram or similar test. Survivors at risk for osteoporosis should have bone density scans. And blood tests should check thyroid function and male and female hormone levels. Then, if a problem is found, treat it, Bhatia says.

Insurance, however, doesn’t always cover screening for long-term survivors of stem cell transplantation, despite medical guidelines that have been in place since 2006.  If insurance will not pay for recommended screening, Bhatia suggests survivors talk to their doctor about how to find low-cost or free health resources in their community.

Catching health problems early isn’t good enough for researchers like Bhatia. The goal, she says, is to prevent them altogether. “The next step for research is to work at the genetic level to find out why certain patients get these complications and others don’t.” Then, Bhatia says, doctors can use that information to more selectively hand-pick a treatment that will save future patients from a fate of heart disease or another cancer.

For today’s survivors, researchers are testing ways to reverse or at least stop the development of transplantation-related complications. At City of Hope, Bhatia’s colleagues are testing a hormone-modulating therapy to prevent radiation-induced breast cancer and a heart medication to help prevent heart failure.

Back in San Antonio, Heaven regularly sees her pediatric oncologist, endocrinologist and ophthalmologist. They’re monitoring her current post-transplantation complications and watching for any new ones. Otherwise, she’s your average second-grader, right down to loving Justin Bieber and weekend trips to the park.

Learn more about the possible long-term complications of stem cell transplantation, and find guidelines for post-transplantation care from the 

Articles

Minimizing and preventing late effects of stem cell transplantation.

Survivors of Tranplantations Should Be Aware of Potential Late Effects

Experts predict crizotinib, a new type of targeted therapy, will be approved by year’s end for treating an infrequent subtype of non-small cell lung cancer (NSCLC). The drug’s maker submitted crizotinib for approval with the Food and Drug Administration in mid-May, and was granted fast-track status and priority review by the agency.

Crizotinib inhibits a gene mutation called ALK, which drives about 4 percent of all lung tumors’ growth. Considering that about 85 percent of the 222,000 people diagnosed with lung cancer in 2010 belong to the subcategory of NSCLC, about 5,000 to 10,000 patients stand to benefit from the drug in the U.S. alone, and it would be the first drug of its kind to get the green light from the FDA.

The drug works by turning off the cancer-causing ALK gene—and with “extraordinary” results, says Thomas Lynch, Jr., MD, one of the drug’s investigators and director of Yale Cancer Center.

The drug made an impressive debut at the annual meeting of the American Society of Clinical Oncology (ASCO) last June. Updated results reported at this year’s meeting showed that among 82 patients with ALK-positive NSCLC, 74 percent were still alive after one year and 54 percent after two years. Although the study wasn’t randomized, researchers said survival for a similar group of patients not treated with crizotinib was 44 percent after a year and 12 percent after two years.

Most patients in the crizotinib study had already received several prior therapies, as many as seven for some patients. Side effects of the drug were mild and included nausea and diarrhea.

Lynch is one of the many who expects the FDA to approve crizotinib this year. “If they don’t, it’s a crime,” he says.

It’s about finding what gene or genes are driving the cancer and then inhibiting those specific genes. That's the key.

Chemotherapy drugs used to treat lung cancer have short-term benefits and numerous side effects, Lynch says, making crizotinib “a real advance for this patient population.”

“Like [the drugs that target] EGFR mutations, this is yet another group of lung cancer patients where we have a drug that works,” he adds.

Japanese researchers discovered the errant ALK gene in lung cancer in 2007, and it appears to be more common among younger nonsmokers.

Researchers are now comparing crizotinib to standard chemotherapy in two large studies, one in untreated patients and another in patients whose tumors progressed on chemotherapy.

Lynch, who is involved in the front-line study with newly diagnosed patients, expects initial results in 2013. The second-line study should deliver results next year in 2012, he says.

As lung cancer patients and doctors await the FDA’s decision, other promising agents are making their way through the research pipeline. Topping Lynch’s list of new agents to watch: an anti-programmed death-1 antibody called MDX-1106 and Yervoy (ipilimumab). Both drugs use the body’s own immune system to fight cancer. The FDA recently approved Yervoy as a treatment for metastatic melanoma.

Although still in the early stage of testing, the immune-targeting agents “look very exciting,” Lynch says.

In Portland, Alan Sandler, MD, is keeping an eye on two experimental agents that target the MET pathway, a master switch that turns on cancer growth. MetMAb and tivantinib

ARQ 197) block signals from MET, which is to blame for one out of five NSCLCs developing a resistance to drugs that inhibit the epidermal growth factor receptor (EGFR)—a gene sometimes mutated in lung cancer cells. Dual inhibition of MET and EGFR could offer a one-two punch to shut down both pathways.

Adding MetMAb to the EGFR inhibitor Tarceva (erlotinib) resulted in patients with high MET expression living nearly twice as long without their advanced disease getting worse compared with those receiving Tarceva alone: 2.9 months versus 1.5 months. Plus, the combination tripled overall survival, reaching 12.6 months compared with 3.8 months for Tarceva alone. A phase 3 study is scheduled to start later this year.

In a study testing Tarceva with or without tivantinib, patients with advanced nonsquamous cell lung cancer lived about 14 weeks longer if they received the combination—43.1 weeks versus 29.4 weeks for Tarceva alone. Combining the drugs also delayed disease progression: 18.9 weeks versus 9.7 weeks.

In both studies, the side effects were similar between the two arms and included rash, diarrhea and fatigue.

Tivantinib is now in the final stage of testing in combination with Tarceva. “Hopefully [MET] will be the next pathway that leads to drug approval in non-small cell lung cancer,” says Sandler, chief of the hematology and medical oncology division at Oregon Health & Science University and one of the study’s researchers.

As cancer researchers better understand what makes a tumor tick, better drugs can be designed to outsmart the cancer. “It’s about finding what gene or genes are driving the cancer and then inhibiting those specific genes,” Lynch says. “That’s the key.”

For more on lung cancer advances, read “

” from the Spring 2010 issue. You can also read more news, articles and patient stories at 

Lung cancer treatment continues to make strides.

What’s Next in Lung Cancer Treatment

There’s nothing like a good night’s sleep—unless cancer is what’s making you tired.

About nine of every 10 patients struggle with fatigue during treatment, and unlike everyday fatigue, cancer-related fatigue is a debilitating exhaustion that can’t be cured with a soft bed or cup of coffee. Sleep offers no relief against the persistent tiredness. And the side effect can drain some patient to the point where they can’t stand in the shower or muster the energy to dress.

The exact reason for cancer-related fatigue remains unknown. Treatment may be the culprit, though the cancer itself may be to blame.

So what’s an exhausted cancer patient to do? Experts offer these tips:

• Conserve energy. Prioritize so you have enough energy to do what’s most important. And don’t rush—take your time, even if it feels like you’re moving at a snail’s pace. Spread chores throughout the week and make rest part of your daily routine&mdash;but limit naps to no more than 30 minutes.

Most importantly: Ask for help. If mowing the lawn, doing laundry or running errands are too tiring, enlist friends and family to help. If a trip to the grocery store is necessary, most stores offer motorized carts for customers.

• Get moving. It may sound contradictory, but regular physical activity can lessen fatigue. Patients can increase their energy by exercising several times a week, says Wendy Crabbe, RN, an oncology nurse practitioner at University of Texas Health Science Center at San Antonio. But she cautions them to start slow and increase slowly.

A half-hour walk is a good place to start for patients battling severe fatigue. You can even split it up—15 minutes in the morning and 15 minutes in the afternoon. Patients with the energy to do more can try a combination of exercises. There’s aerobic (walking, swimming or bicycling), resistance/strength (light weights and resistance bands) and simple stretches to improve flexibility.

•	Rearrange your environment. Simply picking up or putting away the things you use most can add up to sap your energy. So place things you use often within easy reach, whether it’s your favorite cooking pot or the shampoo in the shower.

•	Optimize sleep quality. Go to bed and get up at about the same time every day, including weekends. Don’t exercise in the evening and avoid caffeinated drinks and foods. You may also consider creating a relaxing bedtime ritual that starts one hour before bedtime—and that means turning off the television. Listen to calming music or take a bath instead. Do not drink alcohol or eat immediately before going to bed.

•	Screen for and treat the possible underlying cause. Sometimes fatigue serves as a clue to another medical problem. If cancer treatment depletes a patient’s red blood cell count, for instance, the body’s tissues don’t get enough oxygen and fatigue sets in. Treat the anemia, and you’ll start to get your energy back. Other side effects of treatment that can lead to fatigue include pain, depression, anxiety and nausea.

Patients expect to be fatigued during treatment. “The issue is how much of a fuss they’ll make about it,” says Charles Cleeland, PhD, chair of the department of symptom research at M.D. Anderson Cancer Center in Houston. Too often, he says, patients don’t bring it up, and physicians don’t ask.

It’s helpful for patients to know they’re not losing their marbles. Fatigue is a natural consequence of treatment...

So M.D. Anderson came up with a kind of safeguard: a one-page questionnaire given to patients that’s called the Brief Fatigue Inventory. The assessment, developed by Cleeland and his colleagues, instructs patients to rate their fatigue on a scale of zero to 10. It also asks patients to rate how fatigue has interfered with their quality of life—how active they are, what their mood is like, how far they can walk before exhaustion kicks in.

Other places are creating websites so patients can report fatigue and other symptoms to their physicians in real time. Researchers at Memorial Sloan-Kettering Cancer Center have developed the Symptom Tracking and Reporting for Patients, or STAR, website. Patients don’t have to wait days or weeks until their next office visit if the symptoms are affecting their quality of life. They can simply go online and alert their physician to a new or worsening symptom. The study testing the web-based approach should be complete early next year.

As for treating cancer-related fatigue, what works for one patient may not work for another. But a number of strategies are gaining traction. Yoga, acupuncture and massage may be effective at fighting off fatigue, according to some studies. The stimulant Ritalin (methylphenidate), a drug typically prescribed for attention deficit hyperactivity disorder (ADHD), is being used with some success to treat fatigue in cancer patients. The narcolepsy drug Provigil (modafinil) may also offer relief.

Fatigue typically subsides after treatment ends, Cleeland says. Until then, a support group may offer a platform for patients to share how fatigue has impacted their lives—and even swap tips and tricks for managing it. Chronic fatigue after treatment is a different type of fatigue, but strategies for managing the long-term effect may be similar, such as introducing an exercise regimen (see “

“It’s helpful for patients to know they’re not losing their marbles,” says Cleeland. “Fatigue is a natural consequence of treatment, and that often comes out in support groups.”

Learn tips on figuring out what causes cancer-related fatigue and how to manage it.

Figuring Out Fatigue

Erica Griffin had entered the home stretch. She’d made it to her sixth and final week of radiation therapy for stage 3 breast cancer without any side effects. “I thought I was going to skate right on through with nothing,” says Griffin, 33, of Van Buren, Mo.

With only a handful of radiation treatments left, what Griffin describes as “a really bad sunburn” appeared under her arm and breast. Everyday routines of wearing a bra and shirt became difficult.

Although not inevitable, many cancer patients receiving radiation therapy will experience skin toxicities during treatment, says Peter B. Schiff, MD, PhD, vice chairman of the department of radiation oncology at NYU Clinical Cancer Center. Redness, swelling, dryness and itching of the skin are the most common problems, although some patients may experience more serious reactions, such as moist desquamation, which is wet, peeling skin that may be prone to wounds and infection.

Radiation therapy causes skin problems by creating “free radicals” that alter the cells and tissues, causing changes in the top (epidermal) and middle (dermal) layers of the skin. When the skin becomes damaged by radiation or any type of trauma, naturally occurring proteins called cytokines help heal and repair the damage. But this process often breaks down while a patient receives radiation, says Tracy Gosselin, RN, associate chief nursing officer of oncology services at Duke University Hospital.

The skin’s reaction to radiation can depend on the part of the body being treated. Problems are more common in moist, friction-prone skin folds, such as the armpit, groin and under the breast. Breast cancer patients, particularly those with large breasts, should minimize moisture under the breast by avoiding friction and keeping the area clean and dry, says Gosselin.

Plus, the type of cancer matters. A radiation beam aimed at a prostate tumor deep within the pelvis does little damage to the skin, whereas radiation targeted at a melanoma tumor on the skin itself or at a tumor near the skin’s surface isn’t merely a passerby. “The skin may be getting a different dose depending on what site is being treated,” says Schiff.

Skin changes can occur as early as one to two weeks after starting radiation therapy, says Gosselin. When Griffin’s skin reaction developed near the end of treatment, the mother of three used the ointment Aquaphor for about two weeks until it healed.

Other treatments include Biafine cream, RadiaPlex gel and plant-based options such as aloe vera, calendula cream and shea butter. The Food and Drug Administration also just approved Epicyn HydroGel to relieve the itching and pain associated with skin reactions caused by radiation.

For the more severe moist reactions that can cause sores and infections, Schiff suggests Aquaphor with an anesthetic, Silvadene cream or special wound dressings, such as Vigilon, that protect the skin and create a moist environment for the skin to heal. A break in treatment may be recommended if the moist area is large enough, Schiff says.

But serious skin reactions occur less often today, he points out. “Over the last decade, as the targeting of radiation has become more precise and we use image guidance more and more, we are treating less normal tissue, including less skin,” he says.

The skin typically heals within a few weeks after completing radiation, although in some cases the treated skin will be darker than it was before. Radiation may also leave some patients with fibrosis, or thickening of the skin, which makes the skin less elastic. Once researchers pin down how fibrosis occurs and the best way to measure skin elasticity, Schiff says therapies can be developed to prevent and treat the late effect.

Another possible, though relatively uncommon, late effect of radiation known as telangiectasia results in the permanent growth and dilation of small blood vessels that appear through the skin. These harmless “spider veins” may appear within six months of completing radiation. In some cases, they may take years to develop. Rarely, damage to the bone and, even more rarely, secondary cancers like angiosarcoma can develop in radiated areas.

To manage radiation’s collateral damage to the skin, Gosselin and Schiff offer the following dos and don’ts:

•	Avoid extreme temperatures on the area being treated. Don’t use a heating pad or ice pack, and wear protective clothing during the winter months.

•	Do not wear clothes that are tight or made from abrasive fabrics such as wool. A breast cancer patient, for example, can wear a cotton tank top instead of a bra. A loose-fitting sports bra could offer more support if needed.

•	Avoid tanning beds and protect the treated area from direct sunlight with clothing or a hat. The skin will remain sensitive to sunlight following treatment, so it’s important to use sunscreen with an SPF of at least 30 both during and after radiation therapy, preferably lifelong.

•	Do not scrub the skin with a washcloth or loofah. Gently clean the area using warm water and a mild soap, and pat dry.

•	Use only an electric razor if shaving the treated area is necessary.

•	Tell your radiation oncologist which chemotherapy drugs you’ve received. Chemotherapy sensitizes the cancer cells to the effects of radiation, but certain drugs also sensitize normal, healthy tissues within the radiation beam area. Examples include 5-FU (fluorouracil), Xeloda (capecitabine), Adriamycin (doxorubicin) and taxanes (Taxotere [docetaxel] and Taxol [paclitaxel]).

•	Do not use perfumes, cosmetics or deodorants on the skin in the treatment area. Use only skin products recommended or prescribed by the doctor or nurse.

•	Do not put adhesive bandages on the treated area of the skin. Use only non-stick pads, such as telfa.

•	Alert the doctor or nurse of any skin changes you notice.

Calming the effects of radiation on the skin.

Melissa Weber

Survivors of Tranplantations Should Be Aware of Potential Late Effects

What’s Next in Lung Cancer Treatment

Figuring Out Fatigue

Afterburn

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