Rabiya S. Tuma, PhD

Vladimir Vukicevic was 5 years old when his family left their native Belgrade in the former Yugoslavia to come to Memorial Sloan-Kettering Cancer Center in New York, where the young boy would be treated for Ewing’s sarcoma, a bone cancer that most commonly afflicts children. After chemotherapy and a bone graft in his right femur, all looked good for a few years. But at one of his twice-yearly checkups, Vukicevic’s doctor found that he had developed leukemia, most likely a result of the chemotherapy used to treat the original cancer. Vukicevic received more chemotherapy and a bone marrow transplant, and the now 17-year-old business and management student at New York University considers himself cancer free.

For Vukicevic and other survivors of pediatric or adult cancers, surviving is only the first part of the battle. After completing therapy, survivors can continue to experience the side effects of therapy or develop new problems associated with treatment. Like most survivors, Vukicevic still sees his oncologist and endocrinologist every six months for screening and physicals. He takes a synthetic thyroid hormone pill each day because his thyroid stopped functioning normally about six months after treatment. “That is a daily reminder of what I went through,” he says. “It has become a habit, but every once in a while I realize why I am taking it.”

Long-lasting effects of cancer therapies, such as thyroid dysfunction, are not at all uncommon, says Smita Bhatia, MD, associate director of the City of Hope Comprehensive Cancer Center in California, who specializes in long-term effects of therapy for pediatric and adult survivors.

The timing of onset of such complications can vary widely. Some problems, such as fatigue, can begin during therapy and may continue indefinitely, though the duration and severity differs greatly between individuals. Conditions that start during therapy and persist for months or years, sometimes referred to as long-term effects, differ from those that start well after therapy has been completed, which are considered late effects.

Thyroid dysfunction can start during therapy, shortly after therapy or years later. Researchers know that some late effects of treatment, such as second cancers, tend to occur within a specific period of time. Leukemias and other blood cancers caused by some chemotherapeutic agents tend to develop within several years after treatment—as was the case for Vukicevic. In contrast, the risk of solid cancers, which are caused by radiation, continues to increase even beyond 10 years after therapy. Such long-lasting risk illustrates the need for new models of survivorship care and research for the growing number of cancer survivors in the United States, issues that are beginning to be addressed at the growing number of survivorship centers and clinics around the country.

While both adult and pediatric cancer survivors experience post-therapy effects, more is known about survivors of pediatric cancer because long-term survival became common in pediatric cancers earlier. Data from the Childhood Cancer Survivor Study shows that out of a group of more than 10,000 survivors, two-thirds had at least one health condition and a third had multiple problems. Moreover, pediatric cancer survivors were four times more likely to have a severe or life-threatening health condition than were their siblings.

Charles Sklar, MD, director of the pediatric Long Term Follow-Up Program at Sloan-Kettering, says the issue of research in adults is complicated by the fact that as people age normally, they develop a lot of other medical problems, or comorbidities. “So it is not completely clear which ones might be due to the treatment, which ones might be due to aging and which ones may be an interaction between the two.” Researchers are just beginning to look systematically at the physical and psychological issues of being a survivor of adult cancer.

For cancers, such as Hodgkin’s disease and brain cancer, where the disease and the treatments are similar in pediatric and adult populations, the complications also tend to be similar, though children are more sensitive to some treatments because their bodies are still developing. One of the most common effects for children who receive radiation to the brain is cognitive problems, such as learning disabilities. While researchers work on ways to minimize or even repair such damage, Dr. Sklar says early diagnosis is critical for affected children.

However, most cancers only occur in one age group or the other, and treatment-related effects are limited to that population. For instance, lymphedema occurs when the lymph nodes are damaged or removed during treatment, leading to swelling and fluid retention. Since no pediatric cancer requires routine lymph node removal, pediatric cancer survivors rarely suffer this side effect.

Because risk varies depending on the therapy used, Dr. Bhatia and others have put together a comprehensive list of treatments and the long-term complications associated with them, including heart damage, bone loss and infertility. The information can be found at 

. To help survivors understand the implications of the data, her team included specific recommendations about who should undergo what type of screening and at what frequency, based on treatment history. “These guidelines are for childhood cancer survivors, but they are very applicable to adult cancer survivors also,” says Dr. Bhatia.

Dr. Sklar recommends survivors see a specialist if at all possible because the impact of cancer therapy is ongoing. Specialists can be found at survivorship clinics, which are often found at major cancer centers and at some large hospitals. As survivorship issues gain more attention, more clinics are expected to open around the country. Patients have follow-up appointments with oncologists, as well as access to family practitioners, social workers who can help with employment or education, and psychologists or psychiatrists to help with emotional issues.

“Survivor clinics help patients get access to programs they wouldn’t otherwise have,” says Michael Irwin, MD, a researcher at UCLA’s Jonsson Comprehensive Cancer Center. The clinics also provide a way to integrate treatment and research.  

That [pill] is a daily reminder of what I went through. It has become a habit, but every once in a while I realize why I am taking it. 

Dr. Irwin recently teamed up with the cancer survivorship clinic at UCLA to learn why as many as one-third of breast cancer survivors suffer from severe fatigue even years after therapy. They found that women with chronic fatigue had overly active immune systems. While it is understood that the immune system is activated to fight the disease during treatment for breast cancer, Dr. Irwin hypothesizes that it is not effectively turned off after treatment for some reason. The team is now looking for ways to treat the underlying biochemical problem using behavioral approaches like tai chi and yoga, which help slow immune system activity according to preliminary evidence. “A medical approach with drugs could work, but many survivors do not want to take more pills or shots,” says Dr. Irwin. His team is now researching possible correlations between fatigue and activated immune systems in other malignancies, such as prostate cancer.

In addition to looking for ways to treat lasting effects, researchers hope newer therapies will provoke fewer problems. Molecularly targeted therapies, such as Gleevec® (imatinib) and Herceptin® (trastuzumab), are designed to treat the disease without damaging healthy tissues—and that should mean fewer long-term and late side effects. Clinical researchers are also looking for ways to modify existing therapies to limit the problems they cause. Such changes include using narrower fields of radiation and lower doses of chemotherapy. The American Society of Clinical Oncology has even established a Survivorship Task Force that will develop a template for physicians that details possible long-term and late effects of different treatments and provides guidance on monitoring for disease recurrence.

Not everything that comes from cancer is negative. When Dr. Bhatia and colleagues looked at survivors’ quality of life they found “their spiritual well-being is amazing.”

For Grace Butler, PhD, a truer statement couldn’t be made. She was diagnosed with stage 3 colorectal cancer in 1999. During treatment, she told one of her friends, “I will not succumb to cancer.”

“That was more than a statement,” says Dr. Butler. “It was a position, an outlook, an expectation: This is not going to take me down.”

Prior to her diagnosis, Dr. Butler was a professor of education at the University of Houston, but things changed dramatically after her diagnosis. “One day I was sitting at my desk doing what I was supposed to be doing—that was a Wednesday. On Thursday I was admitted into the hospital. Tuesday I had a diagnosis. I never returned to that desk. It was a defining moment in my life.”

As she started to become more aware of cancer and how it affects people, particularly those who cannot afford health insurance or who do not have access to care, she did something about it. After completing her treatment, she started a nonprofit organization called Hope Through Grace (

) that provides prevention education workshops and other services for the community.

Though she suffers from chronic pain and fatigue, “I can see so many blessings that have come to me as a consequence of cancer. Now don’t misunderstand, I would never ask, ‘Please let me have cancer,’ but the long-term effect for me has enabled me to help others. That is what cancer has done for me. Not to me, but for me.” 

Articles

Survivors guided through territory of long-term and late effects.

Treatment Aftershocks

Lori Sklar was diagnosed with aggressive stage 1 breast cancer in October  2003. Her doctors recommended a mastectomy and four months of chemotherapy.  Everything looked good until April 2004. She had accompanied her husband Bill on  a business trip to New Orleans but found herself exceedingly tired, quickly  winded and bruising easily. When they returned home to Boca Raton, Florida, Lori  immediately went to see her oncologist. He confirmed her suspicion of cancer:  She had acute myeloid leukemia. 

Before she started treatment for breast cancer, Lori and Bill were told the  chemotherapy regimen of Adriamycin (doxorubicin), Taxol (paclitaxel) and  Cytoxan (cyclophosphamide)—a regimen that would best control her breast  cancer&mdash;could, in rare cases, cause leukemia by damaging the DNA of bone marrow  stem cells. But neither the doctors nor the Sklars dwelled on the risk. After  all, the statistics were in their favor since only about one-tenth of 1 percent  of breast cancer patients treated with chemotherapy and/or radiation develop  acute myeloid leukemia. But statistics don’t always count. She became that 0.1  percent.

Following her new diagnosis, Lori started back on chemotherapy—this time to  treat leukemia. After numerous rounds of chemotherapy followed by brief periods  of response and then relapses, Lori underwent a bone marrow transplant in the  fall of 2005. She is now recuperating and devoting herself to community service,  including her website designed for hereditary breast cancer survivors (

Lori’s experience of a second cancer is not unique among cancer survivors.  Indeed, survivors accounted for 16 percent of the new cancer diagnoses in 2003.  Some chemotherapy drugs and radiation used to treat a first cancer can cause DNA  damage and thus increase an individual’s risk of developing a second cancer.

While three large studies involving more than a million patients total  indicate that adult cancer survivors have almost twice the risk of having a  second cancer as healthy controls, it’s more complicated than that. The total  risk for the population is misleading, say experts, because the actual risk of a  second cancer differs among survivors and is influenced by numerous factors,  including the type of primary cancer, age at diagnosis, type of treatment  received, genetics and environmental influences. Additionally, several studies  have found that people diagnosed with their first cancer after the age of 50 are  not at greater risk for another cancer than people who have never had cancer,  says Charles Sklar, MD, director of the Long Term Follow-Up Program at Memorial  Sloan-Kettering Cancer Center in New York. (Dr. Sklar and Lori and Bill Sklar  are not related.)

The causes of second cancers also vary from one survivor to the next. Some  cases are related to treatment for their first cancer, sometimes referred to as  secondary cancers. In other cases, a survivor may have a genetic predisposition  that makes them more likely to develop malignancies than the general population. Finally, some of the cancers that survivors experience are  sporadic cancers, of which the likelihood increases as a person ages, just as it  does for people who have never had a cancer diagnosis. 

The issue of second cancers has been better characterized in pediatric cancer  survivors, in part because curative therapies for pediatric cancers have been  around longer than for adult cancers, says Smita Bhatia, MD, a second cancers  specialist and associate director of the City of Hope Comprehensive Cancer  Center in California. Additionally, pediatric oncologists are keenly aware that  their patients have a lot of growing cells and tissues that could be damaged by  anticancer therapies.

In a study of 13,581 individuals who were diagnosed with their first cancer  before age 21 and survived at least five years, about 3 percent developed a  second cancer during a 20-year follow-up period. That rate is approximately six  times higher than for the population at large, which sounds extraordinarily  high, but only leads to 1.9 extra cancers per 1,000 individuals in the study.  “The risk for the overall population of cancer survivors is not large,” says Dr.  Bhatia.

As with adult cancers, the risk for pediatric survivors is not distributed  equally. Females are at a higher risk than males, and patients diagnosed at a  younger age are at higher risk than those diagnosed later. Survivors of  pediatric soft-tissue sarcomas, Hodgkin’s disease and hereditary retinoblastoma  are most likely to experience a second cancer. Though it is not yet obvious what  predisposes sarcoma survivors to a second cancer, risk factors have been  identified for Hodgkin’s disease survivors that explain some of the secondary  cancers seen in this group.

In the case of hereditary retinoblastoma, the excess risk results from an  interaction between an individual’s genetic makeup and environmental  experiences, including radiation therapy. The retinoblastoma gene normally helps  suppress tumor formation throughout the body, so individuals who carry a  mutation in the gene frequently develop tumors in both eyes before age 5.  Because they lack that tumor suppressor activity, an estimated 25 percent of  these individuals will have a second cancer diagnosis within the next 50 years  of life. If they receive radiation therapy for their original retinoblastoma  tumors, that risk doubles to 50 percent. Because researchers have found this  link, Dr. Sklar says most oncologists no longer treat hereditary retinoblastoma  with radiation.

When Steven Zachary (Zach) Sochor was 29 months old, he started complaining  that his eye was “broken,” and his mother, Zoe Sochor could see him making an  effort to focus. Zach was found to have one retinoblastoma tumor in each eye,  indicating hereditary retinoblastoma. He was treated with six weeks of external  beam radiation, which stopped the cancer in the left eye, but the cancer in his  right eye continued to grow. In May of 1995, when Zach was just shy of his fifth  birthday, the doctors removed Zach’s right eye.

Since that time, he has worn a prosthesis regularly and without complaint.  But in 2004 he noticed his prosthesis no longer fit quite right. From April  through June, the family and various doctors tried to figure out what was wrong,  hoping initially that it was a bad flare-up of his springtime allergies. “An  ill-fitting prosthesis is a symptom of second cancer,” says Zoe. “But even  though you know that, it doesn’t come to the forefront of your mind right  away—even though the possibility is with you all the time.”

Finally, one of the doctors saw a lump in Zach’s eye socket that hadn’t been  there during a recent examination. The lump turned out to be a malignant fibrous  histiocytoma that was growing toward Zach’s brain, a tumor most likely induced  by the radiation used to treat Zach’s retinoblastoma 10 years earlier. After six  heavy-duty rounds of chemotherapy, six weeks of radiation and a 14-hour surgery,  Zach is in remission and doing regular ninth-grade stuff, including  snowboarding. “I always wear my helmet and my goggles,” says Zach, who is well  aware he needs to protect his one good eye. “Plus it looks cool because I have  sweet goggles.” 

 In both adult and pediatric survivors, most of the risk for treatment-related  second cancers has been associated with radiation therapy and select  chemotherapy agents. Thus far, there are two types of drugs implicated in  causing second cancers: topoisomerase II inhibitors, such as VePesid (etoposide) and anthracyclines like Adriamycin, and alkylating agents, including  Cytoxan. Each of these treatments damage DNA in the tumor cells and can cause  mutations in rapidly dividing cells in the body, leaving the patient at risk for  new malignancies.

The chemotherapies are associated with leukemias and lymphomas, which  frequently occur within one to 10 years after therapy. By contrast, radiation is  the major risk factor for solid tumors, which almost always form within the  radiation-exposed area. The delay between treatment and solid tumor development  is longer than for blood cancers, with many solid tumors arising more than 10  years beyond therapy, and the risk continues to climb 15 years after exposure.

Researchers are beginning to understand how and when these therapies cause  problems. For example, young girls and women under 30 who receive chest  radiation for Hodgkin’s disease are more likely to have breast cancer later in  life, relative to women who never had such therapy. For this reason, physicians  now avoid using radiation therapy in these patients.

One of the main questions facing researchers today is why some patients develop  treatment-related tumors, while the majority do not.

"This sort of information definitely feeds back into current treatment,” says Dr.  Sklar. “For cancers where the prognosis is very good and there are multiple  agents that can be used for treatment, avoiding the ones with serious toxicities  is clearly the way to go. Unfortunately for many malignancies, the outlook is  not very good and the available drugs or modalities are limited.” In those  cases, the risks have to be tolerated.

One of the main questions facing researchers today is why some patients  develop treatment-related tumors, while the majority do not. If scientists can  determine what makes one person sensitive to the negative effects of therapy,  they can avoid using that treatment for those individuals. In some cases, it  seems risk is associated with genetic factors, while other cases point to  environmental factors. The environmental ones can be controlled and already  allow survivors to take steps toward prevention. For example, some researchers  think that pediatric cancer survivors who smoke increase their risk of a second  cancer, and survivors who received radiation therapy are at increased risk of  skin cancer and sun exposure exacerbates the problem.

As researchers learn more about what causes second cancers, they are working  to find ways to intervene. In the case of genetic syndromes they are looking for  ways to preempt the problem, like using prophylactic mastectomies to reduce the  risk of breast cancer in BRCA mutation carriers. And in the case of  treatment-related disease, they are working to modify or reduce an individual’s  exposure. A good example of this has been the effort to narrow the radiation  field and reduce radiation doses, which damage a smaller area of tissue and  thereby reduce the risk of a new cancer.

The important thing for survivors, Dr. Bhatia says, is to know his or her  risks based on what therapies they had and have regular follow-ups with a  qualified physician and undergo recommended screenings, so if something does  develop, it can be dealt with quickly. While it’s important to use therapies  that do not increase the risk of second cancers, doctors and patients agree that  the bottom line is to cure the first cancer.

Editor’s Note: Lori Sklar passed away on December 30,  2006. 

Certain aggressive treatments may increase the risk of late effects, including secondary cancers.

Future Risk for Survivors

The goal of radiation therapy is to irradiate as many  cancer cells as possible while sparing normal, healthy cells. Improvements in  radiation therapy include targeting specific tumor sites and counteracting  involuntary movements, such as breathing, that make it difficult to zero in on a  specific location, such as lung tumors. 

Intensity-modulated radiation therapy (IMRT) uses multiple beams of radiation instead of a single high-dose beam, which can damage healthy tissue surrounding the tumor. While many IMRT devices use three-dimensional images, such as in computed tomography, newer devices include the aspect of time (4D IMRT). This form of image-guided radiation therapy localizes the target during each treatment to account for real-time organ motion. Because the location of the tumor can change with the patient’s breathing or other small movements, taking several images over time can help the radiologist pinpoint when and where the tumor is located during treatment.

In stereotactic radiosurgery, several weak beams of radiation originating from different angles intersect to produce a concentrated high dose of radiation at the tumor site. The procedure involves no surgery and little radiation to the surrounding tissue. CyberKnife® and Gamma Knife® use stereotactic radiosurgery to treat brain tumors (see page 39).

For breast cancer, partial breast irradiation employs radiation therapy within the lumpectomy cavity. It reduces side effects and cuts treatment time from six weeks to one week. With MammoSite®, a balloon filled with saline is placed inside the breast and a radioactive “seed” is delivered to the lumpectomy site. Other forms of brachytherapy, or radiation given internally, allow radiation to be given near or at the tumor site and radiated outward via radioactive seeds, wires or needles. Internal radiation techniques are used to treat breast, head and neck, gynecological and prostate cancers, among others.

Targeted therapies disrupt the inner workings of cancer.

v4n4 - Cancer's Molecular Machinery

Esophageal cancer is an aggressive form of cancer, and one that often remains  asymptomatic until relatively late in the disease process. “Before I was  diagnosed with this, I had never heard of it,” says Bart Frazzitta, from  Manalapan, New Jersey. “I didn’t even think you could get esophageal cancer.” In  fact, there were approximately 14,250 new cases of esophageal cancer diagnosed  in 2004 in the United States and 13,300 deaths from the disease. Additionally,  of all the solid tumors, esophageal cancer is the one that has been increasing  most rapidly in recent years. The reasons for the increase may be related to an  increase in gastroesophageal reflux disease and other lifestyle factors.

Esophageal cancer initially develops in the esophagus, which is the smooth  muscular tube that carries food and liquids from the throat to the stomach.  There are two types of esophageal cancer: squamous cell carcinoma and  adenocarcinoma. Squamous cell carcinoma occurs when the cells that normally line  the inside of the esophagus begin to proliferate abnormally. Adenocarcinoma  develops from abnormal glandular cells that line the walls of the esophagus that  has been damaged by gastroesophageal reflux disease (GERD).

Previously, squamous cell carcinoma was the predominant form of the disease.  In recent decades, however, adenocarcinoma has become more prevalent and now  accounts for more than half of all cases of esophageal cancer in the United  States, says Stuart Spechler, MD, from the University of Texas Southwestern  Medical Center in Dallas.

Unfortunately, the disease does not produce many symptoms in its early stages  and thus goes undetected. Large, advanced tumors may cause weight loss,  difficulty swallowing, or evidence of blood in stool or vomit.

With no early warning symptoms, individuals often don’t realize something  serious is going on until they have advanced cancer. Frazzitta’s only symptom  was chronic heartburn a couple of times a week for about a year. Yet when he was  diagnosed in December 1999, he had stage 3 cancer, which means the disease had  already spread from the esophagus to surrounding tissues or lymph nodes.

“A lot of people will go and get an antacid and feel better and think they  have cured the problem,” says Frazzitta, who subsequently has become a patient  advocate and co-founder of the Esophageal Cancer Education Foundation (

). In truth, the antacid just masked a symptom  of a serious disease, which is why experts recommend that if heartburn or  indigestion persists, people should see a doctor.

The two types of esophageal cancer occur with different frequencies in  different ethnic groups. Squamous cell carcinoma is more common in blacks and  Asians, while white men are at highest risk for adenocarcinoma.

Some of the risk factors for the two subtypes are the  same, but not all of them. For example, obesity is a risk factor for  adenocarcinoma, while malnutrition puts individuals at increased risk for  squamous cell carcinoma. However, heavy smoking and age over 50 are associated  with an increased risk of both types of disease.

Sometimes, however, even those risk factors don’t apply. Vickie Powell, a  resident of Radcliff, Kentucky, was just 38 when she developed a case of the  hiccups that she couldn’t keep at bay. Initially her doctor put her on an  antacid, which she took for a week and a half.

"You know your own body," says Powell. “I went back to the doctor and said  something just is not right.” After more tests, she was told that she had a golf  ball-sized tumor in her lower esophagus and upper stomach. She wasn’t  overweight, she didn’t drink or smoke, and she doesn’t ever remember having  heartburn.

A major risk factor for adenocarcinoma of the  esophagus is Barrett’s esophagus, which occurs when the valve that lies between  the stomach and the esophagus doesn’t function properly. Normally, it acts like  a one-way gate, letting food and liquid move from the esophagus into the  stomach, but keeping the acid and digestive enzymes of the stomach in the  stomach. If the valve weakens, then acid will escape into the esophagus, which  is called acid reflux. Repeated exposure to the acid damages the esophageal  cells, causing them to die.

When new cells arise to take their place, a strange thing happens, says Dr.  Spechler, who is an expert on Barrett’s esophagus. Instead of regenerating new  esophageal cells that would continue to be damaged by the acid escaping from the  stomach, the esophagus begins to produce cells that resemble those that line the  intestinal tract. Such cells are ready for an acid bath and aren’t damaged as  easily by acid reflux.

Unfortunately, these cells are predisposed to form cancers when they arise in  the esophagus. Thus, patients with chronic GERD and who develop Barrett’s  esophagus are at significantly higher risk for esophageal cancer and should  undergo regular cancer surveillance. One common form of surveillance is called  endoscopy, in which a physician runs a thin tube with a camera and a light at  the end into the esophagus, allowing for a visual of what the tissue looks  like.

 Screening all GERD patients with endoscopy to look for Barrett’s  esophagus is neither feasible nor practical, however. Approximately 60 million  adults in the United States have regular heartburn, but only a tiny fraction of  those will develop esophageal cancer. Researchers are trying to identify better  ways to diagnose esophageal cancer earlier.

Like many cancers, the timing of diagnosis is critical in esophageal cancer.  “If we can catch it early, we can cure it,” says Dr. Spechler. With that in  mind, physicians like to closely follow patients who have Barrett’s esophagus or  other high-risk factors for the disease.

If the cells in the esophagus begin to look abnormal but are not yet  cancerous, a stage called dysplasia, Dr. Spechler and others will often  recommend surgical treatment to prevent full-blown cancer from developing. If  left untreated, 31 to 59 percent of patients with high-grade dysplasia will  develop cancer within five years.

Currently, the standard surgery for high-grade dysplasia is an esophagectomy,  in which the surgeon removes the unhealthy portion of the esophagus and possibly  some of the neighboring stomach, and then reconnects the remaining regions of  the tube together. Although this surgery is effective at preventing the disease  and treating some stages of the cancer itself, it is a difficult surgery and  between 3 and 12 percent of patients may die as a result of the surgery itself.

Researchers are testing less drastic surgical methods, but these are still in  clinical trials, and it is not yet clear how effective they are at preventing  the development of cancer, although early results look promising. One method  involves using an endoscope with a small blade attached to the end to cut away  the unhealthy cells. Another method being tested is to use a laser to burn away  the dysplastic cells.

For those patients who are diagnosed with esophageal cancer, esophagectomy is  the standard therapy, unless the cancer has spread beyond the esophagus and  adjacent tissue. The proportion of esophageal cancer patients alive five years  after diagnosis is between 5 and 30 percent, depending on the stage of cancer  they have at diagnosis and how well they respond to treatment.

Most patients  with localized esophageal cancer (stage 1 or 2 disease) used to be treated with  surgery alone. In recent years, a combination of chemotherapy and radiation or  chemotherapy and radiation followed by surgery is being used more often to treat  esophageal cancer, says David Ilson, MD, from Memorial Sloan-Kettering Cancer  Center in New York. The addition of chemotherapy to a radiation treatment  protocol can enhance the effectiveness of radiation and increase the proportion  of patients who achieve a complete remission or a good partial remission with  radiation. Subsequent surgery, done after chemotherapy and radiation, can then  be used to remove any residual cancer. Combining chemotherapy, radiation therapy  and surgery (called combined modality approaches) are increasing the cure rate  of this cancer.

The current standard chemotherapy given with  radiation therapy is a combination of 5-FU plus cisplatin, but this can lead to  significant side effects of mouth sores and esophagitis. “We are trying to  identify more effective chemotherapy regimens that have fewer side effects,”  says Dr. Ilson.

Regimens currently being tested use cisplatin in combination  with newer chemotherapy drugs like Camptosar® (irinotecan), Taxotere®  (docetaxel), Taxol® (paclitaxel) and Gemzar® (gemcitabine). Since cisplatin  causes a number of side effects, including nausea, vomiting, kidney damage and  hearing loss, a better-tolerated analogue of platinum oxaliplatin (Eloxatin™) is  being studied in esophageal cancer.

For patients with metastatic (stage 4) disease, surgery is not recommended.  Rather, physicians treat such advanced disease with chemotherapy, which is not  likely to cure the cancer but may slow its progress and make the patient more  comfortable.

Chemotherapy drugs that are used include 5-FU, cisplatin, Taxol, Taxotere,  Camptosar and Eloxatin. Additionally, a phase III randomized trial in the United  Kingdom is testing the efficacy of a Xeloda® (capecitabine) combination in  esophageal cancer. But Dr. Ilson says Xeloda is not yet used frequently in the  United States for this disease.

In addition to traditional chemotherapy agents, physicians are testing the  use of newer, less toxic targeted drugs in esophageal cancer. Unlike standard  chemotherapy drugs, which kill all dividing cells, targeted therapies block  specific steps in the cancer cell growth pathway and leave most healthy cells  undamaged.

Dr. Ilson’s research group is setting up trials to  test the monoclonal antibody Erbitux™ (cetuximab), which targets the epidermal  growth factor receptor (EGFR), in combination with standard chemotherapy in  patients with locally advanced esophageal cancer. They will also test Avastin®  (bevacizumab), another monoclonal antibody that blocks blood vessel formation,  in combination with chemotherapy and radiation in adenocarcinoma-type esophageal cancer.

Patients with advanced esophageal cancer may experience difficulty swallowing  and an inability to take solid food, which can cause malnourishment and an  inability to tolerate chemotherapy. In patients who are not candidates for  curative surgery or radiation-based treatment, the relief of swallowing  difficulties is a primary goal of palliative or symptom-relieving management.  Chemotherapy alone in advanced disease may relieve swallowing problems.

Additionally, there are several  options for local therapy, and esophageal stenting is one of the most common.  During the procedure, a physician uses endoscopy to place a stent in the  esophagus, and, because the stent is a semi-rigid tube, it prevents the tumor  from blocking or narrowing the esophagus.

Another option that is sometimes  used is called photodynamic therapy. In photodynamic therapy, the patient  receives an injection of a drug called Photofrin® (porfimer sodium) that causes  cells to be sensitive to light. The gastroenterologist uses an endoscope to then  shine laser light on the tumor, killing the cancer cells. One problem with this  approach is that the patient has to avoid light for several weeks after  treatment, which can significantly lower his or her quality of life. Also, the  results of this treatment are relatively short-lived.

If a patient has failed chemotherapy or they have a  stent in place but the tumor is overgrowing the stent, physicians may use  radiation to locally control the tumor. In some cases, the doctor may opt to use  laser therapy in which a laser is attached to an endoscope to kill off parts of  the tumor that are causing swallowing difficulties. In this situation, however,  radiation is used more frequently than lasers, says Dr. Ilson.

For patients who are malnourished and not able to take in adequate amounts of  calories, a feeding tube is placed in the stomach. This tube (usually called a  PEG tube) allows food to be administered directly into the stomach, thus  ensuring the patient receives adequate nutrition.

Until less toxic treatments are available, the emotional and physical cost of  therapy can be high. For example, Powell had an esophagogastrectomy in which the  surgeons removed one-fifth of her stomach, 8 inches of her esophagus, the  surrounding lymph nodes and the sphincter muscle that controls flow between the  esophagus and the stomach. Additionally, because she was so young, her doctor  wanted to use a particularly aggressive therapy to prevent recurrence. Thus,  after surgery, she received two rounds of chemotherapy, with each round  consisting of five days of continuous intravenous drip of 5-FU and cisplatin.  She also had 30 radiation treatments.

Now, as she has just had her  seventh-year CT scan, she remains cancer-free, though she suffers from surgery  complications. Without a sphincter muscle, she still has trouble keeping food  down and has to eat small meals every couple of hours rather than three  normal-sized ones. And even the small ones make her nauseous.  “For a while I was really depressed about it, but I have learned to deal with  it. This is what I have left. But I am cancer-free and I try to move on every  day,” she says. “Sometimes I don’t realize how lucky I am until I go to the  doctor and I tell my story. Now, I’m just at a point where I want to help as  many people as I can.”

Frazzitta, who participants can meet at the  

 Patient & Survivor Forum in Washington, D.C., this July, had  six weeks of Taxol and cisplatin chemotherapy plus radiation to treat his stage  3 disease. After recovering from this therapy for two months, he underwent an  esophagogastrectomy in which the surgeon removed two-thirds of his esophagus and  one-third of his stomach. He left the hospital 10 days later.

That was May 2000. Now, nearly five years later he  won’t say he’s cancer-free, but his last CT scan six months ago was clear—and he  hopes the next one will be clear as well.

Fighting esophageal cancer starts by addressing the reasons behind it. 

Rabiya S. Tuma, PhD

Treatment Aftershocks

Future Risk for Survivors

v4n4 - Cancer's Molecular Machinery

Esophageal Cancer: A Disease on the Rise

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