Wayne L. Furman

End-of-Life Care Preferences of Pediatric Patients With Cancer

PURPOSE The viewpoint of the terminally ill child at the time of an end-of-life decision has not been formally investigated. We identified the preferences of children and adolescents with advanced cancer about their end-of-life care and the factors that influenced their decisions. PATIENTS AND METHODS Pediatric patients 10 or more years of age were interviewed within 7 days of participating in one of the following three end-of-life decisions: enrollment onto a phase I trial (n = 7), adoption of a do not resuscitate order (n = 5), or initiation of terminal care (n = 8). The patient, a parent, and the primary pediatric oncologist were interviewed separately by using open-ended interview questions. RESULTS Twenty patients, aged 10 to 20 years (mean, 17 years and 4 months), with a refractory solid tumor (n = 12), brain tumor (n = 4), or leukemia (n = 4) participated. Eighteen patients (90%) accurately recalled all of their treatment options and identified their own death as a consequence of their decision. The factors that were most frequently identified included the following: for patients, caring about others (n = 19 patients); for parents, the childs preferences (n = 18 parents); and for physicians, the patients prognosis and comorbid conditions (n = 14 physicians). CONCLUSION These children and adolescents with advanced cancer realized that they were involved in an end-of-life decision, understood the consequences of their decision, and were capable of participating in a complex decision process involving risks to themselves and others. The decision factors most frequently reported by patients were relationship based; this finding is contrary to existing developmental theories.

Direct Translation of a Protracted Irinotecan Schedule From a Xenograft Model to a Phase I Trial in Children

PURPOSE In a preclinical model of neuroblastoma, administration of irinotecan daily 5 days per week for 2 consecutive weeks ([qd x 5] x 2) resulted in greater antitumor activity than did a single 5-day course with the same total dose. We evaluated this protracted schedule in children. PATIENTS AND METHODS Twenty-three children with refractory solid tumors were enrolled onto a phase I study. Cohorts received irinotecan by 1-hour intravenous infusion at 20, 24, or 29 mg/m(2) (qd x 5) x 2 every 21 days. RESULTS The 23 children (median age, 14.1 years; median prior regimens, two) received 84 courses. Predominant diagnoses were neuroblastoma (n = 5), osteosarcoma (n = 5), and rhabdomyosarcoma (n = 4). The dose-limiting toxicity was grade 3/4 diarrhea and/or abdominal cramps in six of 12 patients treated at 24 mg/m(2), despite aggressive use of loperamide. The maximum-tolerated dose (MTD) on this schedule was 20 mg/m(2)/d. Five patients had partial responses and 16 had disease stabilization. On day 1, the median systemic exposure to SN-38 (the active metabolite of irinotecan) at the MTD was 106 ng-h/mL (range, 41 to 421 ng-h/mL). CONCLUSION This protracted schedule is well tolerated in children. The absence of significant myelosuppression and encouraging clinical responses suggest compellingly that irinotecan be further evaluated in children using the (qd x 5) x 2 schedule, beginning at a dose of 20 mg/m(2). These results imply that data obtained from xenograft models can be effectively integrated into the design of clinical trials.

11q23/MLL rearrangement confers a poor prognosis in infants with acute lymphoblastic leukemia.

PURPOSE Leukemic cell characteristics were analyzed in infants less than 1 year of age with acute lymphoblastic leukemia (ALL) to determine adverse prognostic factors that might explain the poor prognosis of this group. PATIENTS AND METHODS Treatment outcomes were analyzed according to the presenting clinical and laboratory features of 30 infants treated between May 1979 and April 1993. A stepwise multivariate regression model was used to identify the most important prognostic indicator with respect to event-free survival. RESULTS Infant ALL cases were characterized by high presenting leukocyte count (median, 87 x 10(9)/L), increased frequency of CNS leukemia (50%), and blast cells with a CD10- phenotype (67%), myeloid-associated antigen expression (48%), and 11q23/MLL rearrangement (68%). The 11q23/MLL involvement was correlated with age less than 6 months, CD10- phenotype, myeloid-associated antigen expression, and high leukocyte count. Although 11q23/MLL involvement, age less than 6 months, myeloid-associated antigen expression, and female sex were each significantly associated with an inferior treatment outcome, only rearranged 11q23/MLL emerged as an independent predictor of prognosis in multivariate analysis (P = .01). Infants with this genetic abnormality had a 4.7-fold (95% confidence interval, 1.3- to 17.0-fold) increased risk in adverse events compared to other infants. CONCLUSION The 11q23/MLL involvement of blast cells identifies a major subgroup of infant ALL cases that require an innovative treatment approach. Infants who lack this genetic abnormality have an intermediate prognosis and could be treated accordingly on risk-directed protocols.

Phase I study of topotecan for pediatric patients with malignant solid tumors.

PURPOSE To determine the dose-limiting toxicity and potential efficacy of topotecan in pediatric patients with refractory malignant solid tumors. PATIENTS AND METHODS In this phase I clinical trial, 27 patients received topotecan 0.75-1.9 mg/m2 by continuous intravenous infusion daily for 3 days. Fifty-three treatment courses were given to these patients. RESULTS Myelosuppression was the dose-limiting toxicity at levels of 1.3 to 1.9 mg/m2 for 3 days, requiring significant support with transfused packed RBCs and platelets. Myelosuppression was variable in severity at the 1.0-mg/m2 dosage level; thus, additional patients were treated with this dosage, followed by human recombinant granulocyte-colony stimulating factor (G-CSF). Other toxicities were not significant. One patient with neuroblastoma had a complete response that lasted for 8 months. Stable disease activity was recorded for other patients with neuroblastoma, rhabdomyosarcoma, and islet cell carcinoma. Pharmacokinetic studies showed that topotecan plasma concentrations ranged from 1.6 to 7.5 ng/mL during infusions of 1.0 mg/m2/d, and that there was a biphasic plasma distribution with a mean terminal half-life of 2.9 +2- 1.0 hours. CONCLUSION Topotecan is a promising anticancer agent that deserves phase II testing in pediatric solid tumors. We recommend that pediatric phase II topotecan trials use 1.0 mg/m2/d for 3 days as a constant intravenous infusion, followed by G-CSF for 14 days, and that these treatment courses be repeated every 21 days.

Phase I Study of Everolimus in Pediatric Patients With Refractory Solid Tumors

PURPOSE To determine the maximum-tolerated dose (MTD), dose-limiting toxicities (DLTs), and pharmacokinetic and pharmacodynamic properties of the mammalian target of rapamycin (mTOR) inhibitor, everolimus, in children with refractory or recurrent solid tumors. PATIENTS AND METHODS Everolimus was administered orally at a daily dose of 2.1, 3, 5, or 6.5 mg/m2 in cohorts of three to six patients per dosage level. Pharmacokinetic and pharmacodynamic studies were performed during the first course. The phosphorylation status of various components of the mTOR signal pathway was assessed in peripheral-blood mononuclear cells (PBMCs) isolated from treated patients. RESULTS There were 26 patients enrolled; 18 were assessable. DLTs included diarrhea (n = 1), mucositis (n = 1), and elevation of ALT (n = 1) at 6.5 mg/m2. At the MTD of 5 mg/m2, the median everolimus clearance was 15.2 L/h/m2, with a plasma everolimus concentration-time area under the curve (AUC) from 0 to infinity of 239.6 ng/mL x h. Significant inhibition of mTOR pathway signaling was observed in PBMCs from patients achieving AUCs 200 ng/mL x h, equivalent to dosages of 3 to 5 mg/m2 of everolimus. No objective tumor responses were observed. CONCLUSION Continuous, orally administered everolimus is well tolerated in children with recurrent or refractory solid tumors and demonstrates similar pharmacokinetic properties to those observed in adults. Everolimus significantly inhibits the mTOR signaling pathway in children at the MTD. The recommended phase II dose in children with solid tumors is 5 mg/m2.

End-of-life decision making by adolescents, parents, and healthcare providers in pediatric oncology: research to evidence-based practice guidelines.

Participating in end-of-life decisions is life altering for adolescents with incurable cancer, their families, and their healthcare providers. However, no empirically developed and validated guidelines to assist patients, parents, and healthcare providers in making these decisions exist. The purpose of the work reported here was to use three sources (the findings of three studies on decision making in pediatric oncology, published literature, and recommendations from professional associations) to develop guidelines for end-of-life decision making in pediatric oncology. The study designs include a retrospective, descriptive design (Study 1); a prospective, descriptive design (Study 2); and a cross-sectional, descriptive design (Study 3). Settings for the pediatric oncology studies included a pediatric catastrophic illness research hospital located in the Midsouth (Studies 1 and 2); and that setting plus a children’s hospital in Australia and one in Hong Kong (Study 3). Study samples included 39 guardians and 21 healthcare providers (Study 1); 52 parents, 10 adolescents, and 22 physicians (Study 2); and 43 parents (Study 3). All participants in the studies responded to six open-ended questions. A semantic content analysis technique was used to analyze all interview data. Four nurses independently coded each interview; interrater reliability per code ranged from 68% to 100% across studies. The most frequently reported influencing factors were “information on the health and disease status of the patient,” “all curative options having been attempted,” “trusting the healthcare team,” and “feeling support from the healthcare provider.” The agreement across studies regarding influencing factors provides the basis for the research-based guidelines for end-of-life decision making in pediatric oncology. The guidelines offer assistance with end-of-life decision making in a structured manner that can be formally evaluated and individualized to meet patient and family needs.

“Trying to Be a Good Parent” As Defined By Interviews With Parents Who Made Phase I, Terminal Care, and Resuscitation Decisions for Their Children

PURPOSE When a childs cancer progresses beyond current treatment capability, the parents are likely to participate in noncurative treatment decision making. One factor that helps parents to make these decisions and remain satisfied with them afterward is deciding as they believe a good parent would decide. Because being a good parent to a child with incurable cancer has not been formally defined, we conducted a descriptive study to develop such a definition. METHODS In face-to-face interviews, 62 parents who had made one of three decisions (enrollment on a phase I study, do not resuscitate status, or terminal care) for 58 patients responded to two open-ended questions about the definition of a good parent and about how clinicians could help them fulfill this role. For semantic content analysis of the interviews, a rater panel trained in this method independently coded all responses. Inter-rater reliability was excellent. RESULTS Among the aspects of the definition qualitatively identified were making informed, unselfish decisions in the childs best interest, remaining at the childs side, showing the child that he is cherished, teaching the child to make good decisions, advocating for the child with the staff, and promoting the childs health. We also identified 15 clinician strategies that help parents be a part of making these decisions on behalf of a child with advanced cancer. CONCLUSION The definition and the strategies may be used to guide clinicians in helping parents fulfill the good parent role and take comfort afterward in having acted as a good parent.

123I-MIBG Scintigraphy and 18F-FDG PET in Neuroblastoma

The purpose of this study was to compare the diagnostic utility of 123I-metaiodobenzylguanidine (123I-MIBG) scintigraphy and 18F-FDG PET in neuroblastoma. Methods: A total of 113 paired 123I-MIBG and 18F-FDG PET scans in 60 patients with neuroblastoma were retrospectively reviewed. Paired scans were acquired within 14 days of each other. Results: For stage 1 and 2 neuroblastoma (13 scans, 10 patients), 18F-FDG depicted more extensive primary or residual neuroblastoma in 9 of 13 scans. 123I-MIBG and 18F-FDG showed equal numbers of lesions in 1 of 13 scans, and 3 of 13 scan results were normal. For stage 3 neuroblastoma (15 scans, 10 patients), 123I-MIBG depicted more extensive primary neuroblastoma or local or regional metastases in 5 of 15 scans. 18F-FDG depicted more extensive primary neuroblastoma or local or regional metastases in 4 of 15 scans. 123I-MIBG and 18F-FDG were equal in 2 of 15 scans, and 4 of 15 scan results were normal. For stage 4 neuroblastoma (85 scans, 40 patients), 123I-MIBG depicted more neuroblastoma sites in 44 of 85 scans. 18F-FDG depicted more neuroblastoma sites in 11 of 85 scans. 123I-MIBG and 18F-FDG were equivalent or complementary in 13 of 85 scans, and 17 of 85 scan results were normal. Conclusion: 18F-FDG is superior in depicting stage 1 and 2 neuroblastoma, although 123I-MIBG may be needed to exclude higher-stage disease. 18F-FDG also provides important information for patients with tumors that weakly accumulate 123I-MIBG and at major decision points during therapy (i.e., before stem cell transplantation or before surgery). 18F-FDG can also better delineate disease extent in the chest, abdomen, and pelvis. 123I-MIBG is overall superior in the evaluation of stage 4 neuroblastoma, especially during initial chemotherapy, primarily because of the better detection of bone or marrow metastases.

Combination of gemcitabine and docetaxel in the treatment of children and young adults with refractory bone sarcoma

The combination of gemcitabine and docetaxel has demonstrated promise in sarcomas diagnosed in adults. In the current study, the toxicity and efficacy of this combination were evaluated in pediatric sarcomas.

Cancer-Related Symptoms Most Concerning to Parents During the Last Week and Last Day of Their Child's Life

OBJECTIVE. Studies of symptoms in children dying a cancer-related death typically rely on medical chart reviews or parental responses to symptom checklists. However, the mere presence of a symptom does not necessarily correspond with the distress it can cause the childs parents. The purpose of this study was to identify the cancer-related symptoms that most concerned parents during the last days of their childs life and the strategies parents identified as helpful with their childs care. METHODS. Sixty-five parents of 52 children who had died a cancer-related death within the previous 6 to 10 months participated in telephone interviews. Eligibility criteria included being the parent or guardian of a child aged 0 to 21 years who had died within the previous 6 to 10 months after being treated at a pediatric cancer center, having been with their child during the last week of the childs life, speaking English, being willing to participate, and having access to a telephone. RESULTS. Eighteen symptoms of concern were identified as occurring during their childs final week and final day of life. The most frequently reported symptoms at both times included changes in behavior, changes in appearance, pain, weakness and fatigue, and breathing changes. The proportion of reported symptoms did not differ according to patient gender, disease, or location of death (intensive care, elsewhere in the hospital, or home). The most helpful strategies used by health care professionals to assist the child or parents included giving pain and anxiety medications, spending time with the child or family, providing competent care, and giving advice. CONCLUSIONS. This knowledge can guide professionals in preparing parents for the symptoms that a child imminently dying of cancer is likely to experience and in providing care that will be helpful to parents.