Progress in quest to reduce use of radiation in treatment of pediatric Hodgkin lymphoma

A multicenter trial showed that nearly half of young patients with early-stage Hodgkin lymphoma can be cured without undergoing either irradiation or intensive chemotherapy that would leave them at risk for second cancers, infertility, heart and other problems later.

St. Jude Children’s Research Hospital investigators led this multi-institution study, which focused on pediatric Hodgkin lymphoma patients without widespread disease or symptoms such as weight loss, fever and night sweats. The findings will likely spur efforts to identify patients with even more advanced disease whose cancer could be effectively treated with less irradiation.

“This study adds to evidence that it is possible to omit radiation even in patients treated with a less intense chemotherapy regimen and still achieve excellent long-term survival,” said Monika Metzger, M.D., an associate member of the St. Jude Department of Oncology. She is the first and corresponding author of the research, which is published in the June 27 edition of the Journal of the American Medical Association.

“These results will help push efforts to further adapt therapies based on a patient’s disease risk factors and early response to treatment with the goal of eliminating radiation for as many patients as possible,” she said. Metzger said the findings point to the possibility that elderly Hodgkin patients with similarly limited disease and who are less able to tolerate intensive chemotherapy may also be candidates for the minimal treatment approach used in this study.

For decades, radiation has been a staple of Hodgkin lymphoma treatment in children and adults. In children, radiation and chemotherapy have helped push long-term survival rates for patients with favorable-risk disease to better than 90 percent. But radiation leaves patients vulnerable to second cancers and other serious problems later. By the 1990s, work was underway in earnest to identify patients who could be cured without radiation.

Hodgkin is found in 850 to 900 children and adolescents each year and accounts for an estimated 6 percent of all childhood cancers. The disease strikes the lymph system, which includes the lymph nodes, tonsils and other immune system components.

Hodgkin disease (Hodgkin’s disease) is a highly curable malignancy. Over the past few decades, the understanding and insight into the biology of Hodgkin-Reed-Sternberg (HRS) cells as B-cell derived have led to the classification of Hodgkin disease as a lymphoma or Hodgkin lymphoma.

Hodgkin lymphoma was the first cancer to be cured with radiation therapy alone or with a combination of several chemotherapeutic agents, even before understanding of the biology of Hodgkin lymphoma improved (although its biology is still not fully understood). Since then, the cure rate for children and adolescents with Hodgkin lymphoma has steadily improved, particularly with the introduction of combined radiation and multiagent chemotherapy.

This therapeutic success has come at the price of serious long-term toxicities, such that a 30-year survivor of Hodgkin lymphoma is more likely to die of therapy-related complications than from Hodgkin lymphoma. Therefore, the therapeutic paradigm has shifted toward reducing treatment-associated toxicity while maintaining high cure rates. This new paradigm has lead to the current risk-adapted, response-based approach to the treatment of Hodgkin lymphoma.

This study involved 88 patients whose cancer had spread to less than three lymph node groups and surrounding tissue. None of the patients reported fever, weight loss or other symptoms also associated with a worse outcome. About one-third of young Hodgkin lymphoma patients fall into this favorable risk category. The patients were treated between March 2000, and December 2008, at St. Jude; Stanford University Medical Center; Dana-Farber Cancer Institute and Massachusetts General Hospital, both in Boston; and Maine Medical Center, in Portland. One patient withdrew early and was not included in the results.

The patients all received four rounds of chemotherapy with the drugs vinblastine, Adriamycin, methotrexate and prednisone, a combination known as VAMP. Unlike some other chemotherapy agents used to treat Hodgkin lymphoma, none of these drugs is linked to second cancers or infertility. One, Adriamycin, belongs to a family of drugs that can lead to heart damage, but at much higher cumulative doses.

Radiation was recommended for patients whose tumors had not shrunk at least 75 percent following two rounds of chemotherapy. Those patients received low-dose irradiation of 25.5 grays to the tumor and surrounding tissue.

Approach Considerations
Hodgkin lymphoma is one of the most curable malignancies of childhood and adolescence. Hodgkin lymphoma can be cured with radiation therapy, chemotherapy, or a combination of both. However, acute and late toxicities vary substantially according to the treatment modality used. Therefore, most modern pediatric treatment strategies focus on reducing late effects of therapy while maintaining excellent cure rates with risk-adapted chemotherapy alone or response-adjusted combined-modality regimens.

Placement of a peripheral or central venous catheter for chemotherapy and supportive care is suggested but not required. The decision to place a central venous catheter should be based on the intensity of the treatment, the level of supportive care anticipated, the state of the patient’s peripheral venous access, and the patient’s preference.

Staging laparotomy and splenectomy are no longer routinely performed in patients with Hodgkin lymphoma. In patients with suspicious lesions on imaging performed for staging, biopsy is sometimes necessary if the findings might alter the treatment regimen.

Children with Hodgkin lymphoma should be treated at a pediatric oncology center where pediatric oncologists, radiation therapists, and full ancillary services are available for children with malignancies. Initial evaluation, staging, and subsequent treatment of Hodgkin lymphoma (Hodgkin’s lymphoma) can be performed on an outpatient basis. Admission is sometimes indicated for supportive medical care. Some clinical trials that treat pediatric patients with Hodgkin lymphoma accept patient enrollments well into the third decade of patient life.

For patients with a favorable initial response to chemotherapy, omitting radiation had no impact on their survival either two years or five years after their diagnosis. Those patients fared no worse than patients who received radiation therapy after the opening rounds of chemotherapy resulted in only a partial response. All patients followed for at least five years were still alive regardless of their initial treatment.

Age and Hodgkin lymphoma

There are three different forms of Hodgkin lymphoma:

- A childhood form (in children 14 years or younger)

- A young adult form (in people 15 to 34 years old)

- An older adult form (in people 55 to 74 years old)

Hodgkin lymphoma is rare in children younger than five years old in the United States. It most often occurs in people between 15 and 40 years old and in people older than 55. In children younger than 5 years, Hodgkin lymphoma is more common in boys than in girls.

More than 88 percent of the five-year survivors were cancer-free. Patients in both treatment groups were equally likely to enjoy that status.

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