Pharmacokinetic modeling of cisplatin disposition in children and adolescents with cancer

Summary A flow-limited physiologic pharmacokinetic model using volume terms, flow rates, distribution ratios, metabolic rate constants, and clearance terms restricted to physiologic or measured values was used to simulate the disposition of cisplatin in children and adolescents. Physiologic model simulations of parent cisplatin and total platinum serum concentrations were not statistically different from concentrations of these platinum species measured in 14 patients. A simplified first-order multicompartment operational model was also developed, and produced comparable simulations of parent cisplatin disposition but less accurate simulations of total platinum serum concentrations. These data provide further clarification of cisplatin disposition in humans and provide the basis for previously observed changes in the renal clearance of total platinum.Supported in part by Cancer Center Support (CORE) Grant CA 21765, Solid Tumor Program Project Grant CA 23099, Biomedical Research Support Grant RR 05584, and by ALSAC     

Thyroid cancer in children and adolescents in Denmark

From 1960 to 1985, 20 patients (12 females and eight males) with thyroid cancer, developed before the age of 20, have been registered and observed at the Radium Center, The Finsen Institute. Papillary adenocarcinoma was diagnosed in 11 cases, and mixed papillary/follicular adenocarcinoma in six cases. Three patients had medullary carcinoma. No patients had previously received cervical irradiation. On admission, lung metastases were evident in two cases. All patients underwent surgical treatment, which in 15 cases consisted of total thyroidectomy, and in nine also lymph node dissection. External irradiation was given to 10 patients, and radioiodine treatment was performed in five patients. Local and/or distant relapse of the thyroid carcinoma occurred in five cases: three were patients with medullary carcinoma, and two had papillary and mixed adenocarcinoma. The three patients with medullary carcinoma died of their disease, but the other two with recurrence recovered after surgery, external irradiation and/or radioiodine treatment. Currently, 16 patients are alive without evidence of disease. The period of follow-up ranged from 2 to 23 years.     

儿童和青少年甲状腺癌的治疗进展

儿童和青少年甲状腺癌较为罕见。本文通过分析现有数据资料,阐述儿童和青少年甲状腺癌的治疗进展。尽管发现时分期较晚,但该病总体预后较好。手术治疗是最主要的治疗方式,目前无标准的手术处理方式。大部分外科医生赞成甲状腺全切和(或)次全切。对于单侧的低危患者,也可考虑单侧腺叶切除。预防性中央区淋巴结清扫术能够降低局部复发。在特定的患者中行放射性131I治疗能降低复发风险。由于生存期较长,在长期无瘤生存后仍可能再次复发,因此患者需要长期随访。     

Distinct features of colorectal cancer in children and adolescents

BACKGROUND:

Colorectal cancer is exceedingly rare in children and adolescents. Reports from small series indicate that poor prognostic factors are more common in children than in adults, resulting in worse outcome for the pediatric population.

METHODS:

The Surveillance, Epidemiology, and End Results database was searched for records of children/adolescents with colorectal cancer, and the features and outcomes were compared with those of adults.

RESULTS:

From January 1973 through December 2005, only 159 children/adolescents (ages 4‐20 years) were reported with a diagnosis of colorectal cancer. The most common sites of involvement were the rectum (27%) and the transverse colon (26%). Adenocarcinoma was the most common histiotype in both adults and pediatric patients; however, children/adolescents had more unfavorable histiotypes (ie, mucinous adenocarcinoma [22%] and signet ring cell carcinoma [18%]) when compared with adults (10% and 1%, respectively; P < .001). Poorly differentiated and undifferentiated tumors (grades III and IV, respectively) and distant stage were more common in children/adolescents (P < .001). The 5‐year relative survival estimates in children/adolescents and adults were 40% ± 4.2% and 60% ± 0.10%, respectively, confirming a worse outcome in the pediatric age group (P < .001).

CONCLUSIONS:

Children/adolescents represent a minority of patients with colorectal cancer and have high‐risk features and worse outcome than adults. The small number of patients in this age group was an impediment to the development of meaningful clinical trials. Thus, the principles of management for adult colorectal cancer should be used in the treatment of children and adolescents. Cancer 2010. © 2009 American Cancer Society.     

Cisplatin and gemcitabine in patients with metastatic cervical cancer

PURPOSE: To determine the therapeutic efficacy of cisplatin plus gemcitabine in the treatment of patients with metastatic cervical cancer. METHODS AND MATERIALS: A total of 51 patients were enrolled in this study. The median age was 46 years (34-67). Thirty-five patients were previously treated to the pelvis by radical radiotherapy, one patient was treated by surgery and one by surgery and postoperative radiotherapy. There were 14 patients with stage IVB cervical cancer who were previously untreated. The sites of metastases were 10 in the lungs, 5 in the supraclavicular nodes, 9 in the paraaortic nodes, 4 in the liver, 3 in the inguinal nodes, 5 in both supraclavicular nodes and lungs, 9 in both supraclavicular and paraaortic nodes, 1 in both supraclavicular and inguinal nodes, 1 in both lung and inguinal nodes, 2 in both lung and paraaortic nodes and 2 in both liver and lungs. Fine needle biopsies were done in all metastatic sites except for multiple lung and multiple liver metastases. Cisplatin was administered as an i.v. infusion on day 1 (70 mg/m2). Gemcitabine was administered as an i.v. infusion for over 30 minutes on day 1 and 8 (1,250 mg/m2) in a 21 day cycle. RESULTS: Forty patients were available for evaluation, with 3/40 (7.5%) achieving a complete response, 27/40 (67.5%) achieving a partial response (OR=30/40, 75%), 5/40 (12.5%) having a stable disease, and 5/40 (12.5%) a progressive one. Eleven patients were not assessable because of patient refusal for further treatment and loss of follow up. Myelosuppression was the major toxicity. Grade 3 or 4 anemia and granulocytopenia occurred at a frequency of 25.5% and 29.4%, respectively. Grade 3-4 thrombocytopenia was found in 3.8%. There were 3 (5.8%) patients who developed grade 4 neutropenia and fever. No other major side effects were found other than alopecia and usual gastrointestinal toxicities such as anorexia, nausea and vomiting. There were no treatment related deaths. The median time to progression was 8.3 months and the median survival was 9.6 months. With a median follow up of 7.7 months (range, 0.3 to 22.1), 30% of the patients were alive at 12 months. CONCLUSION: In this study of patients with metastatic cervical cancer, the combination of cisplatin and gemcitabine treatment induced a high response rate.     

Osteonecrosis in children and adolescents with cancer - an adverse effect of systemic therapy

Osteonecrosis (ON) is recognised increasingly as a complication of the treatment of cancer in children and adolescents. It is especially prevalent among survivors of acute lymphoblastic leukaemia and non-Hodgkin lymphoma, in whom as many as 1/3 may be affected, likely reflecting the cumulative exposure to glucocorticosteroid therapy. The pathogenesis is complex and includes suppression of bone formation, expansion of the intra-medullary lipocyte compartment and a direct effect on nutrient arteries. Children > or =10 years of age are at particular risk and the disorder is substantially more common in Whites than in Blacks. Genetic predispositions have been identified. ON is often multi-articular and bilateral, affecting weight-bearing joints predominantly. Surgical management options are of concern in young growing subjects, although injection of autologous marrow into affected sites offers promising results. Other novel approaches include the use of anti-resorptive drugs and strategies for prevention, such as with lipid-lowering agents, are being explored.     

Risk factors for central venous catheter thrombotic complications in children and adolescents with cancer

BACKGROUND:

The use of central venous catheters (CVCs) has greatly improved the quality of care in children with cancer, yet these catheters may cause serious infectious and thrombotic complications. The aim of this prospective registry study was to assess the host and CVC‐related risk factors for CVC‐created thrombotic complications.

METHODS:

Patients undergoing CVC insertion for chemotherapy were followed prospectively for CVC complications. At the time of enrollment, demographic, clinical, and CVC‐related data, and family history of thrombosis were collected. Survival and Cox regression analyses were performed.

RESULTS:

A total of 423 CVCs were inserted into 262 patients for a total of 76,540 catheter days. The incidence of CVC‐related deep‐vein thrombosis (DVT) was 0.13 per 1000 catheter‐days (95% confidence interval [CI], 0.06‐0.24). Insertion of peripherally inserted central catheters (PICCs) and insertion in an angiography suite significantly increased the risk of symptomatic CVC‐related DVT. The incidence of CVC occlusion was 1.35 per 1000 catheter‐days (95% CI, 1.1‐1.63). Positive family history of thrombosis significantly increased the risk of CVC occlusion (hazard ratio [HR], 2.16; 95% CI, 1.2‐3.8). The CVC‐related risk factors were insertion of Hickman catheters, insertion in angiography suite, and proximal‐tip location. Patients developing at least 1 episode of both CVC occlusion and infection had an increased risk for developing symptomatic CVC‐related DVT (HR, 4.15; 95% CI, 1.2‐14.4).

CONCLUSIONS:

Both patient‐related and CVC‐related factors are associated with higher risk of symptomatic thrombotic complications. These risk factors could be used in the clinical setting and in developing future studies for CVC thromboprophylaxis. Cancer 2010. © 2010 American Cancer Society.     

Triiodothyronine and thyroxin binding to red blood cells in children and adolescents with thyroid cancer

A comparison of triiodothyronine and thyroxin binding to red blood cells sampled from children and adolescents with such thyroid pathologies as cancer, adenoma, nodular goiter and thyroiditis, on the one hand, and healthy children, on the other, has established significant changes in the hormone-binding activity of erythrocytes in thyroid cancer patients. The thyroiditis-related changes suggested that disturbed thyroid hormone-binding by blood cells might play a role in thyroiditis and thyroid cancer pathogenesis.     

Orphan Drug Regulation: A missed opportunity for children and adolescents with cancer

BackgroundOncology represents a major sector in the field of orphan drug development in Europe. The objective was to evaluate whether children and adolescents with cancer benefited from the Orphan Drug Regulation.MethodsData on orphan drug designations (ODDs) and registered orphan drugs from 8th August 2000 to 10th September 2016 were collected from the Community Register of medicinal products for human use. Assessment history, product information and existence of paediatric investigation plans were searched and retrieved from the European Medicine Agency website.ResultsOver 16 years, 272 of 657 oncology ODDs (41%) concerned a malignant condition occurring both in adults and children. The five most common were acute myeloid leukaemia, high-grade glioma, acute lymphoblastic leukaemia, graft-versus-host disease and soft-tissue sarcomas. 74% of 31 marketing authorisations (MAs) for an indication both in adults and children (26 medicines) had no information for paediatric use in their Summary of Product Characteristics (SmPC) at the time of the first MA. Furthermore, 68% still have no paediatric information in their most recently updated SmPC, at a median of 7 years after. Only 15 ODDs (2%) pertained to a malignancy occurring specifically in children and only two drugs received an MA: Unituxin for high-risk neuroblastoma and Votubia for sub-ependymal giant-cell astrocytoma.ConclusionThe Orphan Drug Regulation failed to promote the development of innovative therapies for malignancies occurring in children. Major delays and waivers occurred through the application of the Paediatric Medicines Regulation. The European regulatory environment needs to be improved to accelerate innovation for children and adolescents dying of cancer.     

Osteopenia and cancer in children and adolescents: the fragility of success

The attainment of a satisfactory peak bone mass, which is accomplished largely by the end of adolescence, is the best protection against excessive bone mineral loss in late adulthood. Factors that influence this process include age, race, sex, body size, pubertal status, diet, physical activity, and other lifestyle elements. Cancer and its treatment in children and teenagers adversely impact bone mineralization. In particular, chemotherapy (especially glucocorticosteroids and methotrexate) and cranial irradiation (apparently by reducing growth hormone secretion and by causing hypogonadotropic hypogonadism) interfere with normal bone turnover. Resorption often exceeds formation, resulting in net bone mineral loss and providing a rational basis for the use of antiresorptive drugs. Such osteopenia may be symptomatic, with pain and abnormal gait, and increases the risk of fractures several fold. The disorder is compounded by reduced physical activity, so programs to reduce this deficit are of measurable benefit. All of those engaged in the care of children and adolescents with cancer have an opportunity to improve the bone health of these young people and to limit their risk of developing osteoporosis and fragility fractures in adult life.     

Teniposide (VM26) disposition in children with leukemia

The clinical pharmacokinetics of teniposide (VM-26, NSC 122819) has been studied in 21 children (median age, 4.7 years) with acute lymphocytic leukemia. Teniposide was administered at a dosage of 165 mg/sq m as a 30- to 60-min i.v. infusion. Patients were studied either on the first or second dosage of the drug. Plasma samples were assayed for teniposide and metabolites by high-performance liquid chromatography with electro-chemical detection. Both compartmental and noncompartmental pharmacokinetic analyses were performed. Systemic clearance and apparent volume of distribution of steady state averaged 13.82 +/- 6.0 ml/min/sq m (S.D.) and 7.9 +/- 4.0 liter/sq m, respectively. Univariate and multivariate stepwise regression analyses were used to construct mathematical models to describe the relationships between certain patient-specific demographic and laboratory values and the pharmacokinetic parameters, systemic clearance, elimination rate constant, and area under the concentration-time curve. A significant relationship between serum alkaline phosphatase and systemic clearance, elimination rate constant, and area under the concentration-time curve was found, suggesting that liver function influences the disposition of this anticancer drug in humans.     

重组人促甲状腺激素辅助131I在儿童和青少年分化型甲状腺癌的临床研究

目的 评估重组人促甲状腺激素(rhTSH)辅助¹³¹I对治疗儿童和青少年分化型甲状腺癌的安全性和有效性。方法 本研究共纳入87例分化型甲状腺癌患者,¹³¹I疗前注射重组人促甲状腺激素的46例患者为实验组,¹³¹I疗前停用甲状腺素药物的41例患者为对照组,对其进行回顾性调查研究。结果 实验组患者在注射重组人促甲状腺激素后第1天、第3天和第6天血清中促甲状腺激素浓度间存在统计学差异,第三天的浓度最高。¹³¹I疗前两组患者的促甲状腺激素浓度存在统计学差异(t=2.362,P=0.023)。对于甲状腺球蛋白抗体阴性患者,对照组患者的血清甲状腺球蛋白浓度显著高于实验组rhTSH注射第3天浓度(1.5±1.2 vs. 0.7±1.4,P=0.034)。¹³¹I清甲3~8个月后全身显像结果显示,实验组34例(84%)患者无放射性物,对照组例40例(87%)患者无放射性物,实验组与对照组患者间不存在统计学差异(χ²=0.277,P=0.599)。实验组和对照组患者¹³¹I再次清甲的原因分析结果显示不存在统计学差异(P=0.875)。结论 在短期内重组人促甲状腺激素和停用促甲状腺激素对于¹³¹I清甲治疗在甲状腺清除、生化缓解、短期复发等结局不存在统计学差异。重组人促甲状腺激素介导¹³¹I清甲治疗对于儿童和青少年分化型甲状腺癌是一个更好的方法。     

Psychosocial issues in adolescents with cancer

Cancer in adolescents is uncommon and when it occurs raises a number of unique challenges for both the patient and their families. Adolescence is a period of time of significant physical and emotional changes and a diagnosis of cancer during this time has a major impact on their psychological and physical development. In this review we will look at the psychosocial issues facing adolescents who have cancer. We will address adolescent development, issues related to informed consent and assent, initial responses to the diagnosis of cancer, quality of life and the experience of the adolescent with cancer, psychological adjustment, support systems, body image issues, sexuality, education, hope, and treatment compliance.