Society to Fund Research Focused on Long-Term and Late Effects of Cancer Treatment

Over the past decades, cure rates for many cancers have improved dramatically. The harsh reality is, however, that too many cancer survivors suffer serious side-effects of their curative treatments. Toxic side-effects can occur months or years after the treatments are finished, sometimes as chronic conditions, sometimes life-threatening, but always unacceptably reducing a patient's quality of life.

While research continues to seek new safe and effective drugs, what patients need now is for current therapies to be made less harmful without sacrificing their effectiveness.

In a new initiative, The Leukemia & Lymphoma Society (LLS), the world's largest voluntary health agency dedicated to blood cancer founded in 1949 and headquartered in White Plains, NY, will invest in research designed to discover the biological mechanisms that cause late effects, and to develop and test measures to prevent or at least significantly reduce toxicities. LLS is seeking requests for proposals from scientists studying these issues.

The pediatric cancer story has shown us that the goal is achievable. Years of research and clinical trials enabled survival rates to reach nearly 90% for children with acute lymphocytic leukemia. But then the medical and research community recognized that the serious late effects were severely impacting quality of life. High-dose radiation treatments, once thought critical to cures, have been eliminated for most children, significantly reducing cognitive deficits and other once common side-effects.

Now The Leukemia & Lymphoma Society has set a goal of doing for all cancer patients, regardless of age, what has been achieved for many children -- survival with good quality of life.

The initiative is being led by Anna T. Meadows, M.D., medical director of the Cancer Survivorship and Living Well After Cancer Program at the Children's Hospital of Philadelphia. Dr. Meadows is an internationally recognized pioneer in late effects research; she helped quantify the serious consequences of high-dose radiation and eliminate it from curative treatments for most children with leukemia and lymphoma.

"We must find the answers and test them as soon as possible," says Dr. Meadows. "We must be determined and courageous - funders, researchers, and patients alike - because survival is just the first part of the struggle to cure cancer; the quality of that survival matters."

Dexamethasone can Eliminate One-Third of All Relapses in Childhood Acute Lymphoblastic Leukemia

The results from a study conducted by Martin Schrappe, MD, University Medical Center Schleswig-Holstein, Campus Kiel, Kiel, Germany showed that the use of dexamethasone, a corticosteroid commonly used to treat inflammation of the skin, joints, lungs and other organs, in the induction phase of combination chemotherapy led to a one-third reduction in the risk of relapse as compared with prednisone, the standard corticosteroid therapy. These results translated into a significant benefit in terms of event-free survival in children with acute lymphoblastic leukemia. Schrappe presented these results during the 50th Annual Meeting of the American Society of Hematology (ASH) in San Francisco, CA (December 6 – 9).

Dexamethasone was associated with a greater risk of severe side effects, mainly invasive infections; hence, more intensive clinical monitoring and, in particular, early antimicrobial therapy in patients should be implemented to preserve the advantage of using dexamethasone, rather than prednisone, as part of induction therapy.

Following a pre-phase treatment regimen of prednisone and intrathecal methotrexate, a total of 3,655 children (ages 1 to 17) from Germany, Italy, Austria, and Switzerland with acute lymphoblastic leukemia were randomized to receive induction therapy consisting of either prednisone (60 mg/m2/d) or dexamethasone (10 mg/m2/d) in addition to vincristine, daunorubicine, and L-asparaginase combination therapy. Post-induction therapy was also given to patients.

Six-year event-free survival reached 84.1 percent in patients who received dexamethasone as compared with 79.1 percent of those who received prednisone in the induction phase. The six-year cumulative incidence of relapse was 11 percent and 18 percent for patients randomized to dexamethasone and prednisone, respectively. The difference between the two groups was observed for bone marrow relapses (8 percent versus 12 percent), central nervous system relapses (2 percent versus 4 percent), and other relapses (2 percent versus 3 percent) in dexamethasone as compared with prednisone.

Higher toxicity was seen in those treated with dexamethasone. The cumulative incidence for death in the induction phase was 2 percent for dexamethasone compared with 0.9 percent for prednisone; however, the cumulative incidence of death during remission was similar between the two treatment groups (2 percent for dexamethasone and 1.6 for prednisone).

Although dexamethasone was associated with a greater risk of severe toxicity, the results of the study show that it leads to a marked reduction of the risk of relapse, translating this into a significant benefits. This was most evident in patients with in vivo sensitivity to the prednisone prephase, while the efficacy of dexamethasone in poor responding patients was not convincing. The researchers conclude that in the future, more intensive clinical monitoring and early anti-infective interventions could render the advantage of using dexamethasone even more evident. They also believe that other, potentially toxic, agents such as anthracyclines may be limited in induction for carefully selected subgroups of patients with the aim of limiting early or late toxicities.

For more information, read:
Schrappe M, Zimmermann M, Möricke A, Mann G, et al. Dexamethasone in Induction Can Eliminate One-Third of All Relapses in Childhood Acute Lymphoblastic Leukemia: Results of an International Randomized Trial in 3,655 Patients (Trial AIEOP-BFM ALL 2000) (Oral Session), Blood (ASH Annual Meeting Abstracts) 2008 112: Abstract #7

Also read PubMed abstracts:
Möricke A, Reiter A, Zimmermann M, Gadner H, et al. Risk-adjusted therapy of acute lymphoblastic leukemia can decrease treatment burden and improve survival: treatment results of 2169 unselected pediatric and adolescent patients enrolled in the trial ALL-BFM 95.Blood 2008 May 1;111(9):4477-89. Epub 2008 Feb 19.