Janet Gammon

A pilot pharmacokinetic and antiangiogenic biomarker study of celecoxib and low-dose metronomic vinblastine or cyclophosphamide in pediatric recurrent solid tumors.

Tumor vasculature is a reasonable target for cancer therapy and lower more frequent doses of traditional chemotherapeutics [low-dose metronomic (LDM) chemotherapy] has been shown to have antiangiogenic efficacy. This study evaluated the safety and pharmacokinetics of celecoxib and LDM vinblastine or cyclophosphamide in children with recurrent, refractory solid tumors. We also investigated whether a subset of circulating plasma proteins are surrogate markers of angiogenic activity. Thirty-three children were enrolled in this pilot study and received celecoxib (250 mg/m2 PO b.i.d.) and either vinblastine (1 mg/m2 IV 3×/wk) or cyclophosphamide (30 mg/m2 PO daily) continually. Celecoxib alone and with LDM chemotherapy was well tolerated and plasma concentrations were consistent with those shown to have antiangiogenic activity. Four patients (13%) had durable stable disease (28 to 78 wk) although no complete or partial responses were observed. The surrogate markers measured (vascular endothelial growth factor, basic fibroblast growth factor, soluble vascular cell adhesion molecule, soluble intercellular cell adhesion molecule, endostatin, and thrombospondin-1) were highly variable and no statistically significant relationship between them and disease progression or maintenance of stable disease was observed. We concluded that this regimen is well tolerated hence supporting the use of this form of therapy in pediatric patients. However, future studies should include more homogenous patient populations and focus on validating surrogate markers to monitor treatment activity.

Single-dose and steady-state pharmacokinetics of celecoxib in children

Celecoxib is a member of a novel group of agents that selectively inhibit cyclooxygenase 2 (COX‐2). COX‐2 inhibitors have emerged as an important class of drugs because of the lower incidence of side effects when compared with traditional nonsteroidal anti‐inflammatory drugs, which inhibit both cyclooxygenase 1 and COX‐2. Because children often differ from adults with respect to drug disposition, the objective of this study was to determine the single‐dose and steady‐state pharmacokinetics of celecoxib in pediatric patients.

Chemotherapy versus supportive care alone in pediatric palliative care for cancer: comparing the preferences of parents and health care professionals

Background: The choice between palliative chemotherapy (defined as the use of cytotoxic medications delivered intravenously for the purpose of our study) and supportive care alone is one of the most difficult decisions in pediatric oncology, yet little is known about the preferences of parents and health care professionals. We compared the strength of these preferences by considering children’s quality of life and survival time as key attributes. In addition, we identified factors associated with the reported preferences. Methods: We included parents of children whose cancer had no reasonable chance of being cured and health care professionals in pediatric oncology as participants in our study. We administered separate interviews to parents and to health care professionals. Visual analogue scales were shown to respondents to illustrate the anticipated level of the child’s quality of life, the expected duration of survival and the probability of cure (shown only to health care professionals). Respondents were then asked which treatment option they would favour given these baseline attributes. In addition, respondents reported what factors might affect such a decision and ranked all factors identified in order of importance. The primary measure was the desirability score for supportive care alone relative to palliative chemotherapy, as obtained using the threshold technique. Results: A total of 77 parents and 128 health care professionals participated in our study. Important factors influencing the decision between therapeutic options were child quality-of-life and survival time among both parents and health care professionals. Hope was particularly important to parents. Parents significantly favoured chemotherapy (42/77, 54.5%) compared with health care professionals (20/128, 15.6%; p < 0.0001). The opinions of the physician and child significantly influenced the parents’ desire for supportive care; for health care professionals, the opinions of parents and children were significant factors influencing this decision. Interpretation: Compared with health care professionals, parents more strongly favour aggressive treatment in the palliative phase and rank hope as a more important factor for making decisions about treatment. Understanding the differences between parents and health care professionals in the relative desirability of supportive care alone may aid in communication and improve end-of-life care for children with cancer.

Health-related quality of life and enrollment in phase 1 trials in children with incurable cancer.

OBJECTIVES To investigate health-related quality of life (HRQOL) in children eligible for Phase 1 trials and the reasons why families consider participating in these trials. METHODS Individual, semistructured interviews were conducted with parents (seven mothers, two fathers) and three children, after a child was invited to participate in a clinical trial. Information regarding disease and treatment progression, daily life, and decision making about experimental treatments was elicited. Interviews were recorded, transcribed, and coded for themes. RESULTS HRQOL themes were grouped into four main domains: physical, psychological, social, and spiritual. Minimal physical restrictions, maintaining normalcy and control, information sharing, and having hope for life seemed to be critical HRQOL components. Hope for a cure and prolonging the childs life were the main reasons for enrolling in Phase 1 trials. CONCLUSIONS Normalcy and control are key end-of-life HRQOL components, and hope for life is a main reason for participating in Phase 1 trials.

Hospital and home chemotherapy for children with leukemia: a randomized cross-over study.

The study objective was to compare a hospital‐based and a home‐based chemotherapy program for children with acute lymphoblastic leukemia (ALL) in relation to Quality of Life (QOL), safety, caregiver burden, and costs.

A multi-centre Canadian pilot study of metronomic temozolomide combined with radiotherapy for newly diagnosed paediatric brainstem glioma.

PURPOSE Survival rates for paediatric diffuse intrinsic brainstem glioma (DIBSG) are dismal. Metronomic dosing of temozolomide (TMZ) combined with standard radiotherapy may improve survival by increasing the therapeutic index and anti-angiogenic effect of TMZ. This study aimed to evaluate the safety and efficacy of this regimen in paediatric DIBSG patients. METHODS Children aged 18 years or younger with newly diagnosed DIBSG were treated with standard radiotherapy and concomitant metronomic TMZ at 85 mg/m(2)/day for 6 weeks, followed by metronomic TMZ monotherapy at the same dose. Treatment was continued until tumour progression or unacceptable toxicity occurred. Primary endpoints included overall survival and toxicities. For patients who consented, plasma and urine samples were collected at diagnosis, post-induction and prior to each course of maintenance therapy for the quantification of angiogenesis markers. RESULTS Fifteen eligible patients were enrolled, with a median age of 6.4 years. The most common toxicities were myelosuppression, most notably prolonged lymphopaenia and thrombocytopaenia. The only dose-limiting toxicity was thrombocytopaenia. Intratumoural haemorrhage was confirmed in one patient. Median time to progression was 5.13 months (95% CI = 6.4, 10.8) and median overall survival (OS) was 9.8 months (95% CI = 6.4, 10.8). Six-months OS was 80% ± 10.3%, with a 1-year OS of 20% ± 10.3%. Serum levels of both VEGF and endoglin tended to decrease during the first two cycles of therapy. CONCLUSION Chemoradiotherapy with metronomic dosing of TMZ showed similar toxicity to previous TMZ regimens, and does not appear to improve survival in paediatric DIBSG.

A Canadian paediatric brain tumour consortium (CPBTC) phase II molecularly targeted study of imatinib in recurrent and refractory paediatric central nervous system tumours

PURPOSE To evaluate the safety, efficacy and pharmacokinetics of imatinib in children with recurrent or refractory central nervous system (CNS) tumours expressing KIT and/or PDGFRA. METHODS Nineteen patients aged 2-18 years, with recurrent or refractory CNS tumours expressing either of the target receptors KIT and/or PDGFRA (by immunohistochemistry) were eligible. Participants received imatinib orally at a dose of 440 mg/m(2)/day and toxicities and tumour responses were monitored. Serial blood and cerebrospinal fluid samples for pharmacokinetics were obtained in a subset of consenting patients. Frozen tumour samples were analysed retrospectively for KIT and PDGFRA gene amplification in a subset of patients for whom samples were available. RESULTS Common toxicities were lymphopaenia, neutropaenia, leucopaenia, elevated serum transaminases and vomiting. No intratumoural haemorrhages were observed. Although there were no objective responses to imatinib, four patients had long-term stable disease (SD) (38-104 weeks). Our results suggest a possible relationship between KIT expression and maintenance of SD with imatinib treatment; KIT immunopositivity was seen in only 58% (11/19) of study participants overall, but in 100% of patients with SD at 38 weeks. All patient tumours showed PDGFRA expression. Pharmacokinetic data showed a high interpatient variability, but corresponded with previously reported values. CONCLUSIONS Imatinib at 440 mg/m(2)/day is relatively safe in children with recurrent CNS tumours, but induced no objective responses. Demonstration of SD in previously progressing patients (KIT-expressing) suggests cytostatic activity of imatinib.

Children receiving chemotherapy at home: perceptions of children and parents.

The aim of this descriptive exploratory study was to determine the perspectives of parents and children with cancer on a home chemotherapy program. Qualitative analyses were used to organize data from 24 parents and 14 children into emerging themes. Themes included (1) financial and time costs, (2) disruption to daily routines, (3) psychological and physical effects, (4) recommendations and caveats, and (5) preference for home chemotherapy. When home chemotherapy was compared with hospital clinic-based chemotherapy, parents reported fewer financial and time costs and less disruption to their work and family schedules, and children reported more time to play/study, improved school attendance, and engagement in normal activities. Although some parents felt more secure with hospital chemotherapy, most found it more exhausting and stressful. At home, children selected places for their treatment and some experienced fewer side effects. Although some coordination/communication problems existed, the majority of parents and children preferred home chemo-therapy. Home chemotherapy treatment is a viable, acceptable, and positive health care delivery alternative from the perspective of parents and children with cancer.

Phase 2 study of safety and efficacy of nimotuzumab in pediatric patients with progressive diffuse intrinsic pontine glioma

BACKGROUND The prognosis of diffuse intrinsic pontine glioma (DIPG) remains poor, with no drug proven to be effective. METHODS Patients with clinically and radiologically confirmed, centrally reviewed DIPG, who had failed standard first-line therapy were eligible for this multicenter phase II trial. The anti-epidermal growth factor receptor (EGFR) antibody, nimotuzumab (150 mg/m(2)), was administered intravenously once weekly from weeks 1 to 7 and once every 2 weeks from weeks 8 to 18. Response evaluation was based on clinical and MRI assessments. Patients with partial response (PR) or stable disease (SD) were allowed to continue nimotuzumab. RESULTS Forty-four patients received at least one dose of nimotuzumab (male/female, 20/24; median age, 6.0 years; range, 3.0-17.0 years). All had received prior radiotherapy. Treatment was well tolerated. Eighteen children experienced serious adverse events (SAEs). The majority of SAEs were associated with disease progression. Nineteen patients completed 8 weeks (W8) of treatment: There were 2 PRs, 6 SDs, and 11 progressions. Five patients completed 18 weeks (W18) of treatment: 1 of 2 patients with PR at W8 remained in PR at W18, and 3 of 6 children with SD at W8 maintained SD at W18. Time to progression following initiation of nimotuzumab for the 4 patients with SD or better at W18 was 119, 157, 182 and 335 days, respectively. Median survival time was 3.2 months. Two patients lived 663 and 481 days from the start of nimotuzumab. CONCLUSIONS Modest activity of nimotuzumab in DIPG, which has been shown previously, was confirmed: A small subset of DIPG patients appeared to benefit from anti-EGFR antibody treatment.

Phase I Study of Vinblastine and Sirolimus in Pediatric Patients With Recurrent or Refractory Solid Tumors

The combination of vinblastine and mammalian target of rapamycin (mTOR) inhibitor sirolimus inhibits the growth of neuroblastoma xenografts through pro‐apoptotic and anti‐angiogenic mechanisms. This phase I study aimed to explore the safety and toxicity of this combination in pediatric patients with advanced solid tumors.