Monika L Metzger

Prospective Medical Assessment of Adults Surviving Childhood Cancer: Study Design, Cohort Characteristics, and Feasibility of the St. Jude Lifetime Cohort Study

To facilitate prospective medical assessment of adults surviving pediatric malignancies and advance knowledge about long‐term childhood cancer survivor health, St. Jude Childrens Research Hospital (SJCRH) is establishing a lifetime cohort of survivors.

Female Reproductive Health After Childhood, Adolescent, and Young Adult Cancers: Guidelines for the Assessment and Management of Female Reproductive Complications

PURPOSE As more young female patients with cancer survive their primary disease, concerns about reproductive health related to primary therapy gain relevance. Cancer therapy can often affect reproductive organs, leading to impaired pubertal development, hormonal regulation, fertility, and sexual function, affecting quality of life. METHODS The Childrens Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancer (COG-LTFU Guidelines) are evidence-based recommendations for screening and management of late effects of therapeutic exposures. The guidelines are updated every 2 years by a multidisciplinary panel based on current literature review and expert consensus. RESULTS This review summarizes the current task force recommendations for the assessment and management of female reproductive complications after treatment for childhood, adolescent, and young adult cancers. Experimental pretreatment as well as post-treatment fertility preservation strategies, including barriers and ethical considerations, which are not included in the COG-LTFU Guidelines, are also discussed. CONCLUSION Ongoing research will continue to inform COG-LTFU Guideline recommendations for follow-up care of female survivors of childhood cancer to improve their health and quality of life.

Methotrexate-Induced Neurotoxicity and Leukoencephalopathy in Childhood Acute Lymphoblastic Leukemia

PURPOSE Methotrexate (MTX) can cause significant clinical neurotoxicity and asymptomatic leukoencephalopathy. We sought to identify clinical, pharmacokinetic, and genetic risk factors for these MTX-related toxicities during childhood acute lymphoblastic leukemia (ALL) therapy and provide data on safety of intrathecal and high-dose MTX rechallenge in patients with neurotoxicity. PATIENTS AND METHODS Prospective brain magnetic resonance imaging was performed at four time points for 369 children with ALL treated in a contemporary study that included five courses of high-dose MTX and 13 to 25 doses of triple intrathecal therapy. Logistic regression modeling was used to evaluate clinical and pharmacokinetic factors, and a genome-wide association study (GWAS) was performed to identify germline polymorphisms for their association with neurotoxicities. RESULTS Fourteen patients (3.8%) developed MTX-related clinical neurotoxicity. Of 13 patients rechallenged with intrathecal and/or high-dose MTX, 12 did not experience recurrence of neurotoxicity. Leukoencephalopathy was found in 73 (20.6%) of 355 asymptomatic patients and in all symptomatic patients and persisted in 74% of asymptomatic and 58% of symptomatic patients at the end of therapy. A high 42-hour plasma MTX to leucovorin ratio (measure of MTX exposure) was associated with increased risk of leukoencephalopathy in multivariable analysis (P = .038). GWAS revealed polymorphisms in genes enriched for neurodevelopmental pathways with plausible mechanistic roles in neurotoxicity. CONCLUSION MTX-related clinical neurotoxicity is transient, and most patients can receive subsequent MTX without recurrence of acute or subacute symptoms. All symptomatic patients and one in five asymptomatic patients develop leukoencephalopathy that can persist until the end of therapy. Polymorphisms in genes related to neurogenesis may contribute to susceptibility to MTX-related neurotoxicity.

Treatment Outcomes in Black and White Children With Cancer: Results From the SEER Database and St Jude Children's Research Hospital, 1992 Through 2007

PURPOSE Treatment outcome for black patients with cancer has been significantly worse than for their white counterparts. We determined whether recent improved treatment had narrowed the gap in outcome between black and white pediatric patients. PATIENTS AND METHODS In a parallel comparison, we analyzed survival by disease category between black and white patients with childhood cancer registered in one of the 17 cancer registries of the National Cancer Institutes Surveillance, Epidemiology, and End Results (SEER) program or treated at St Jude Childrens Research Hospital, which provides comprehensive treatment to all patients regardless of their ability to pay, from 1992 to 2000 and from 2001 to 2007. RESULTS Analysis of the SEER data indicated that in both study periods, black patients had significantly poorer rates of survival than did white patients, with the exception of a few types of cancer. Despite significantly improved treatment outcomes for patients who were treated from 2001 to 2007, the racial difference in survival has actually widened for acute myeloid leukemia and neuroblastoma. By contrast, in the cohorts treated at St Jude Childrens Research Hospital, there were no significant differences in survival between black and white patients in either study period, regardless of the cancer type. Importantly, the outcome of treatment for acute lymphoblastic leukemia, acute myeloid leukemia, and retinoblastoma has improved in parallel for both races during the most recent study period. CONCLUSION With equal access to comprehensive treatment, black and white children with cancer can achieve the same high cure rates.

Association Between Radiotherapy vs No Radiotherapy Based on Early Response to VAMP Chemotherapy and Survival Among Children With Favorable-Risk Hodgkin Lymphoma

CONTEXT More than 90% of children with favorable-risk Hodgkin lymphoma can achieve long-term survival, yet many will experience toxic effects from radiation therapy. Pediatric oncologists strive for maintaining excellent cure rates while minimizing toxic effects. OBJECTIVE To evaluate the efficacy of 4 cycles of vinblastine, Adriamycin (doxorubicin), methotrexate, and prednisone (VAMP) in patients with favorable-risk Hodgkin lymphoma who achieve a complete response after 2 cycles and do not receive radiotherapy. DESIGN, SETTING, AND PATIENTS Multi-institutional, unblinded, nonrandomized single group phase 2 clinical trial to assess the need for radiotherapy based on early response to chemotherapy. Eighty-eight eligible patients with Hodgkin lymphoma stage I and II (<3 nodal sites, no B symptoms, mediastinal bulk, or extranodal extension) enrolled between March 3, 2000, and December 9, 2008. Follow-up data are current to March 12, 2012. INTERVENTIONS The 47 patients who achieved a complete response after 2 cycles received no radiotherapy, and the 41 with less than a complete response were given 25.5 Gy-involved-field radiotherapy. MAIN OUTCOME MEASURES Two-year event-free survival was the primary outcome measure. A 2-year event-free survival of greater than 90% was desired, and 80% was considered to be unacceptably low. RESULTS Two-year event-free survival was 90.8% (95% CI, 84.7%-96.9%). For patients who did not require radiotherapy, it was 89.4% (95% CI, 80.8%-98.0%) compared with 92.5% (95% CI, 84.5%-100%) for those who did (P = .61). Most common acute adverse effects were neuropathic pain (2% of patients), nausea or vomiting (3% of patients), neutropenia (32% of cycles), and febrile neutropenia (2% of patients). Nine patients (10%) were hospitalized 11 times (3% of cycles) for febrile neutropenia or nonneutropenic infection. Long-term adverse effects after radiotherapy were asymptomatic compensated hypothyroidism in 9 patients (10%), osteonecrosis and moderate osteopenia in 2 patients each (2%), subclinical pulmonary dysfunction in 12 patients (14%), and asymptomatic left ventricular dysfunction in 4 patients (5%). No second malignant neoplasms were observed. CONCLUSIONS Among patients with favorable-risk Hodgkin lymphoma and a complete early response to chemotherapy, the use of limited radiotherapy resulted in a high rate of 2-year event-free survival. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00145600.

Thrombolytic therapy for central venous catheter occlusion

Background Long-term central venous catheters have improved the quality of care for patients with chronic illnesses, but are complicated by obstructions which can result in delay of treatment or catheter removal. Design and Methods This paper reviews thrombolytic treatment for catheter obstruction. Literature from Medline searches using the terms “central venous catheter”, “central venous access device” OR “central venous line” associated with the terms “obstruction”, “occlusion” OR “thrombolytic” was reviewed. Efficacy of thrombolytic therapy, central venous catheter clearance rates and time to clearance were assessed. Results Alteplase, one of the current therapies, clears 52% of obstructed catheters within 30 min with 86% overall clearance (after 2 doses, when necessary). However, newer medications may have higher efficacy or shorter time to clearance. Reteplase cleared 67–74% within 30–40 min and 95% of catheters overall. Occlusions were resolved in 70 and 83% of patients with one and 2 doses of tenecteplase, respectively. Recombinant urokinase cleared 60% of catheters at 30 min and 73% overall. Alfimeprase demonstrated rapid catheter clearance with resolution in 40% of subjects within 5 min, 60% within 30 min, and 80% within 2 h. Additionally, urokinase prophylaxis decreased the incidence of catheter occlusions from 16–68% in the control group to 4–23% in the treatment group; in some studies, rates of catheter infections were also decreased in the urokinase group. Conclusions Thrombolytic agents successfully clear central venous catheter occlusions in most cases. Newer agents may act more rapidly and effectively than currently utilized therapies, but randomized studies with direct comparisons of these agents are needed to determine optimal management for catheter obstruction.

ACR appropriateness Criteria® diffuse large b-cell lymphoma

The management of diffuse large B-cell lymphoma depends on the initial diagnosis including molecular and immunophenotypic characteristics, Ann Arbor staging, and International Prognostic Index (IPI score). Treatment approaches with different chemotherapy regimens used is discussed in detail. The role of radiation as a consolidation is discussed including: (1) the prerituximab randomized trials that challenged the role of radiation, (2) recent prospective studies (UNFOLDER/RICOVER-60), and (3) retrospective studies; the last 2 showed a potential benefit of radiation both for early and advanced stage. The document also discusses the role of positron emission tomography/computed tomography for predicting outcome and potentially guiding therapy. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every 3 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer-reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances where evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment.

Results of a prospective clinical trial for VAMP alone without irradiation for pediatric favorable, early-stage Hodgkin lymphoma patients who achieve an early complete response.

9503 Background: To evaluate the efficacy of 4 cycles of vinblastine, doxorubicin, methotrexate, and prednisone (VAMP) alone in patients with early-stage, favorable Hodgkin lymphoma (HL) who achieve a complete response after 2 cycles of VAMP. METHODS Multi-institutional phase II trial. Eighty-eight patients with clinical stages I and II, favorable risk (< 3 nodal sites, no B symptoms, no mediastinal bulk and no extranodal extension) HL were treated with four cycles of VAMP chemotherapy with or without involved field radiotherapy (IFRT). Patients who achieved a complete response (CR) (n=46) after 2 cycles of VAMP received no IFRT and those who achieved less than CR (n=42) were given 25.5 Gy IFRT, one patient progressed prior to starting IFRT and another withdrew consent to be treated elsewhere. RESULTS With a median follow-up of 5.4 years, the 5-year overall survival and event-free survival (EFS) for the whole cohort are 100% and 88% (SE=4.6%) respectively; the EFS for patients who did not get IFRT is 89% (SE=6.5%). IFRT was not a predictor of EFS (P=0.98). Ten patients relapsed and one had progressive disease. One of the irradiated patients developed recurrence as diffuse large B-cell lymphoma. All 5 non-irradiated patients who relapsed were salvaged with intense multi-agent chemotherapy and IFRT without autologous stem cell transplant. No second malignancies have been observed. Therapy was well tolerated with 8 grade 3/4 infections in 6 patients. Neither gender, histology, nor stage were significant predictors of outcome. CONCLUSIONS Risk-adapted, combined-modality therapy using only four cycles of VAMP chemotherapy without radiation for patients achieving a complete response after 2 cycles of VAMP is highly effective and without significant side effects. These results indicate that selected pediatric patients with stages I and II favorable HL can be cured with limited therapy without alkylating agent, bleomycin, etoposide, or radiation therapy. Non-irradiated relapsed patients can be easily salvaged without high dose chemotherapy.

Yield from risk-based screening in adults treated for cancer in childhood.

9010 Background: To improve health outcomes after childhood cancer, all survivors should have risk-based care that includes tailored surveillance based on the previous cancer and cancer therapy. We determined the prevalence of previously undetected cancer-related toxicities in adults surviving childhood cancer evaluated by risk-based health screening. Methods: We evaluatedadult survivors of childhood cancer (≥ 18 years old, ≥ 10 years from diagnosis) participating in the ongoing St. Jude Lifetime (SJLIFE) study. To date, 93% of contacted survivors have agreed to participate. All underwent risk-based assessments appropriate for cancer diagnosis/treatment as recommended by the Childrens Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers. To direct risk-based assessment, chemotherapy cumulative doses, radiation fields/doses, and surgical procedures were abstracted from medical records. Results: As of08/29/2009, 626 SJLIFE participants completed risk...

Neurocognitive outcomes in adult survivors of childhood Hodgkin lymphoma.

1532 Background: Adult survivors of childhood Hodgkin lymphoma (HL) are at increased risk for cardiac morbidity as a consequence of previous treatment. Cardiovascular morbidity in non-cancer populations is associated with increased rates of neurocognitive deficits. Methods: Forty-eight adult survivors of childhood HL were randomly selected from a large cohort of childhood cancer survivors (≥ 18 yrs of age and >10 yrs post-diagnosis) recruited for participation in the St. Jude Lifetime Cohort Study. Treatment included high-dose chest radiation (≥ 30 Gy) in Cohort 1 (n = 24) and anthracycline chemotherapy and chest radiation (any dose) in Cohort 2 (n = 24). All survivors completed standardized neurocognitive, cardiac, and brain magnetic resonance imaging examinations. The data were evaluated with one-sample t-tests, independent samples t-tests, and point- biserial correlations. Results: Cohorts 1 and 2 were similar in mean age and time since diagnosis (Cohort 1: age = 43.5 yrs., range 37.4- 52.4, time since...