By Beverly A. Caley

Pamela Clark paddled into the morning surf off the Oregon coast. She had been told not to surf for a year, and, although her fatigued limbs swung heavy and her stamina was short, Clark felt no pain. "I cried with joy the whole time I was out there," says Clark, 33, who underwent a bone marrow transplant for treatment of relapsed stage 3 Hodgkin's disease in December 2003. "That was a big thing to realize that here I am just five months later, surfing."

Hodgkin’s disease, sometimes called Hodgkin’s lymphoma, develops in the lymph system, an important part of the body’s immune system found throughout the body, meaning Hodgkin’s disease can be found almost anywhere in the body.

The disease, named for Sir Thomas Hodgkin, an English physician who described it in the 1830s, is relatively uncommon, with approximately 7,880 new cases diagnosed each year.

Risk Factors

While the cause of Hodgkin’s disease remains unknown, researchers have discovered some patterns in the incidence of the disease. It is more common in young or late adulthood: most patients develop the disease between the ages of 16 and 34. People over 55 are also at greater risk, and it is more common in males and in people who have a parent, brother or sister who has had the disease.

Hodgkin’s disease is also more common in people who have been infected with the Epstein-Barr virus (EBV), but the role of the virus is unclear. According to Stephen Ansell, MD, PhD, of the Mayo Clinic in Rochester, Minnesota, the association exists between EBV and Hodgkin’s disease, but the true contribution of EBV to the development of the disease remains unknown.

Types, Stages and Subtypes

The two major subtypes of Hodgkin’s, based on the way the malignant cells look under a microscope are: classical Hodgkin’s, which has three subtypes; and lymphocyte predominant Hodgkin’s, which accounts for only 5 percent of cases. The presence of Reed-Sternberg cells (large, malformed cells with two nuclei), distinguishes Hodgkin’s disease from non-Hodgkin’s lymphoma.

The four stages of Hodgkin’s are based on factors such as whether cancer is found in more than one group of lymph nodes or on both sides of the diaphragm. In addition, each has letter designations: “A” for asymptomatic disease and “B” for patients with symptoms. The diagnosis of Hodgkin’s may also include an E, which means cancer has spread beyond the lymph system, or S, meaning cancer has been found in the spleen.

Dr. Ansell explains that from a treatment perspective, this all breaks down into two basic groups: limited-stage disease and advanced-stage disease. Patients with limited-stage disease have malignant lymph nodes on the same side of the diaphragm. In these patients, an abbreviated course of chemotherapy in combination with radiation therapy is standard. In more advanced disease, where lymph nodes are malignant on both sides of the diaphragm or the cancer has spread beyond the lymph nodes, patients typically receive combination chemotherapy for a longer course and do not receive radiation.

A Very High Cure Rate

While driving to a lunch meeting one May day, Russ Walker scratched his collarbone and noticed a small lump. Since he had been feeling a little run down, he consulted his physician, who suspected an infection and prescribed antibiotics. When blood tests showed no sign of infection, Walker’s mother, a physician, insisted that the lump be biopsied. A few weeks later, Walker got the diagnosis: Hodgkin’s disease.

"Hodgkin’s disease is very treatable and highly curable,” according to Dr. Ansell. “Patients should be treated with curative intent at every turn.”

Joseph Connors, MD, of the British Columbia Cancer Agency in Vancouver, says that several aspects of Hodgkin’s disease contribute to the high rate of cures. First, the average patient with Hodgkin’s disease is younger than the typical cancer patient, and thus better able to tolerate treatment. In addition, the malignant cells in Hodgkin’s disease cause a dramatic reaction in the body, leading to the formation of lumps in which only a low percentage of the cells are malignant. This allows the cancer to be found early in its development, before it has changed so much that it is resistant to treatment. “The reaction that it causes gives away its presence,” Dr. Connors notes.

In 1997, Alayna Kassan was a 27-year-old lawyer working in New York City. She had not been feeling well for a couple of years, but eventually her illness became so much worse that she had difficulty making herself get out of bed in the morning.

"I lost a lot of weight without trying, I had difficulty sleeping, unexplained itching, lots of little things. But overall I always felt like I had a cold or flu,” Kassan remembers.

At first her doctor suspected depression, then an eating disorder. Kassan saw various health professionals, and when it was determined that she did not have a psychological problem, her doctor ordered a chest X-ray that revealed a large mass in her chest, and Kassan was diagnosed with stage 2B nodular sclerosing Hodgkin’s disease. She received ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) chemotherapy, followed by radiation therapy, the standard treatment for someone with her diagnosis.

Vincent T. DeVita, Jr., MD, of Yale University in New Haven, Connecticut, explains that the presence of symptoms, such as unexplained weight loss and high fever, usually means the disease is potentially more aggressive.

For Clark, the Portland surfer, her signal was a coughing fit that stretched out for six months before she finally saw a doctor. When her chest X-ray came back, the film was dotted with tumors.

Evolution of a Cure

"Right now there is ongoing debate as to which is the best chemotherapy
regimen to use,” says Dr. Ansell, explaining that ABVD has become the standard treatment in the United States because it is the easiest to give, well tolerated and very effective.

For more than 100 years, radiation has been used to treat Hodgkin’s disease, with today’s trend toward applying radiation to smaller areas rather than to an extended field. However, the extent of radiation varies by the stage and location of the disease. In mantle-field radiation, the neck, chest and lymph nodes in the armpit are radiated. Alternatively, radiation can be targeted specifically to an area of known cancer, which is called limited-field or involved-field radiation treatment.

Currently, in very limited stage 1 disease, radiation therapy alone might be used, but the vast majority of patients now receive some kind of chemotherapy. In 1970 Dr. DeVita and colleagues reported an 80 percent complete remission rate in previously untreated patients who received a drug combination called MOPP (mechlorethamine [nitrogen mustard], vincristine, procarbazine, prednisone). This was an important advance, but long-term studies showed that 20 to 30 percent of patients who initially achieved a complete remission eventually relapsed.

During the 1970s numerous new chemotherapy drugs were developed. Creation of the ABVD regimen was based on attributes of certain drugs that were thought to make them effective in treating lymphomas, which in turn made them suitable for patients who did not respond to MOPP therapy. In 1975, a study of ABVD for advanced Hodgkin’s disease showed that the new combination was at least as effective as MOPP. In this study, the toxic effects of treatment in combination with radiation therapy showed different patterns. With MOPP, development of acute leukemias was a problem, while with ABVD, radiation caused toxicity to the heart and lungs.

In 1992, a study on patients with advanced disease was published that compared MOPP, ABVD and alternating MOPP/ABVD, with no radiation therapy for any group. Overall survival rates were equivalent with ABVD, MOPP and MOPP/ABVD, but ABVD and MOPP/ABVD were superior to MOPP in terms of a lower relapse rate. In 2002, after 15 years of follow-up in this study, the overall survival rate was 65 percent with ABVD and MOPP/ABVD, which is considered very encouraging.

At present, ABVD is the regimen most commonly used for initial treatment of Hodgkin’s in the United States. Other chemotherapy regimens currently in use or being investigated include BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone), COPP/ABVD, MOPP/ABV hybrid and Stanford V (doxorubicin, vinblastine, mechlorethamine, etoposide, vincristine, bleomycin, prednisone).

A group of physicians known as the German Hodgkin’s Lymphoma Study Group has developed a treatment program called dose-escalated BEACOPP. In a study of 1,200 patients, they found that 96 percent of patients treated with dose-escalated BEACOPP had complete remission and 91 percent were alive five years later. BEACOPP is more toxic than ABVD, but Dr. DeVita believes that its beneficial effects outweigh its side effects, especially for younger patients and patients with more aggressive disease. “If I were a patient and had advanced Hodgkin’s, I would ask my doctor why I’m not being treated with dose-escalated BEACOPP,” he says. However, Dr. Connors cautions that the risks and benefits of using a dose-escalated regimen must be weighed carefully.

Treatment of Relapsed Disease

Even with such a high cure rate, some patients relapse. In 1987, Dan Shapiro, PhD, was diagnosed with Hodgkin’s and, as he puts it, “essentially spent the next five years in treatment.” He was originally treated with MOPP and radiation therapy, but in just a little over a year, he relapsed. He was then treated with high-dose chemotherapy and a bone marrow transplant, followed by more radiation therapy.

The principle underlying high-dose chemotherapy is that “more is better.” Hodgkin’s is a chemotherapy-sensitive disease, and high-dose chemotherapy kills cancer cells more efficiently. The most common high-dose regimen for Hodgkin’s is BEAM (carmustine, etoposide, cytarabine, melphalan). Bone marrow (the tissue inside large bones where blood cells are produced) or peripheral blood stem cells (stem cells obtained by passing a large quantity of blood from a vein through a special cell-separating machine) are removed prior to high-dose chemotherapy and then replaced afterward to help the patient replace destroyed blood cells.

Despite the aggressive treatment, Shapiro had a second relapse. According to the book he has written about his experience, Mom’s Marijuana: Life, Love, and Beating the Odds, the doctors told him he had one last chance. This time he was successfully treated with the Stanford V regimen, followed by additional radiation.

Though most patients are cured with modern therapy, the outlook for any individual depends on several important factors, including the presence of systemic symptoms, such as unexplained weight loss, the disease stage, the size of the masses and whether appropriate treatment is given.

Late Side Effects

Long-term effects of treatment are important concerns for people treated for Hodgkin’s disease. These can include secondary cancers (mostly solid tumors, acute leukemias and non-Hodgkin’s lymphoma), thyroid disease, heart damage and infertility. In fact, after 10 to 15 years have passed since the original diagnosis, more people die from the long-term effects of Hodgkin’s disease treatment than from progressive disease.

The risk of developing other cancers is more than five times higher for survivors of Hodgkin’s disease than for the general population. The major risk factor for developing solid tumors is previous radiation therapy. According to Dr. DeVita, radiation damages DNA, and if the cell survives that damage, there is a risk that it will become malignant. The risk of acute leukemia is associated with certain chemotherapy regimens, such as MOPP, that include a class of drugs known as alkylating agents. The risk of developing non-Hodgkin’s lymphoma is the same in patients treated with chemotherapy, radiation therapy or a combination of both.

Treatment for Hodgkin’s disease can also damage the heart. A recent study found that 88 of 2,232 patients died from heart disease. The risk of heart problems is higher in people who are over 40 at the time they are treated.
The use of MOPP is also associated with high rates of infertility. In 1987, when Shapiro began his five-year battle with cancer, he banked sperm and now has two children. Kassan discussed fertility with her doctor and was assured that it would not be an issue with ABVD and radiation to her chest. In general, treatment with ABVD does not result in sterility, but aggressive new regimens such as BEACOPP do carry a risk of infertility. Anyone undergoing treatment for Hodgkin’s disease should talk with his or her doctor about the risk of infertility and explore options for preserving fertility.

One strategy being explored to reduce the long-term effects of Hodgkin’s disease therapy is to treat early-stage disease with chemotherapy only, without using radiation. Early data indicates, however, that while chemotherapy alone produces excellent chances of survival, the combined approach results in better five-year progression-free survival rates. Further follow-up is needed to determine whether a reduction in late side effects with chemotherapy alone will be associated with an improvement in overall survival.

The Latest Research

According to Dr. Ansell, the current goal of treatment is to suppress Hodgkin’s disease as much as possible with combination chemotherapy in hopes that the immune system will regain control. Researchers are exploring better and more targeted ways of accomplishing this.

Two monoclonal antibodies are under investigation for their ability to treat Hodgkin’s disease: SGN-30 and MDX-060. (A monoclonal antibody is a drug that is more likely to spare healthy cells because it is targeted to a particular protein on cancer cells.) Both SGN-30 and MDX-060 target a protein called CD30, which is found on the Reed-Sternberg cell. In early clinical trials, both of these monoclonal antibodies have produced partial responses and have been well tolerated. Dr. Ansell believes that because they have few side effects, these drugs may eventually be used in combination with chemotherapy regimens such as ABVD.

Dr. DeVita observes that it is very hard to introduce a new therapy for Hodgkin’s disease, because the high rate of cure seen with current therapies creates ethical concerns. If a new drug is administered only to patients who have failed all other therapies and are very sick, there is little chance of proving it can work. On the other hand, if the drug is given as initial therapy, the possibility exists that it could somehow interfere with the cure. Resolving this dilemma is important, Dr. DeVita says. “We have to find some way to get these drugs into patients to find out if they work, because if they work, they are likely to be a lot easier to use.”

Kassan also emphasizes the importance of research. She was motivated by her experience with Hodgkin’s disease to found Presents for Purpose, a website that sells fashionable items, such as clothing, accessories and jewelry, and donates 25 percent of proceeds to charity, including the Lymphoma Research Foundation and CancerCare. “Someone did fundraising 20 years ago that funded the research for the treatment that cured me,” Kassan explains. “I want to do something to help the person 20 days, 20 months, 20 years from now.”

Make No Compromises in Treatment

Shapiro, a keynote speaker at the CURE Patient & Survivor Forum in Washington, D.C., has remained well since he received treatment for his second relapse. In fact, his doctor told him that he now has a better chance of being hit by a bus than of dying from Hodgkin’s disease. The outlook for Walker is also positive. He was diagnosed with stage 2A disease, has completed chemotherapy and is scheduled to begin radiation therapy.

"Patients today ought to ask a lot of questions,” Dr. DeVita advises. “When you have a disease that is curable 90 percent of the time, you don’t want to go to someone who is half-hearted about it. Be treated by someone who understands it is highly curable and make no compromises.”

Clark hasn’t compromised her goals. Determined not to let her disease stunt her budding hopes of being a professional surfer, she now competes at a higher level than she was prior to the transplant. That didn’t seem likely during her treatment when Clark—who stays busy with volunteer projects and being profiled in a yet-untitled surfing documentary slated for release in 2005—struggled to find Hodgkin’s survivors who emerged from their treatment in better physical shape.

But now that she’s proven it is possible, Clark is eager to tell others. “You’re going through all this pain, and to have to go through all this work in the first place, I wondered what my body was going to be like on the other side,” she says. “But in my case, I’m surfing better than I was before the transplant.”