Children's Oncology Group's 2013 blueprint for research: Soft tissue sarcomas

In the US, approximately 850–900 children are diagnosed each year with soft tissue sarcomas (STS). Key findings from recent Children's Oncology Group (COG) clinical trials include safe reduction in therapy for low risk rhabdomyosarcoma (RMS), validation of FOXO1 fusion as a prognostic factor, a modest improvement in outcome for high‐risk RMS, and a biologically designed non‐cytotoxic therapy for pediatric desmoid tumor. Planned Phase 2 trials include targeted agents for VEGF/PDGF, mTOR, and IGF‐1R for children with RMS and VEGF for children with non‐RMS STS (NRSTS). For RMS, COG Phase 3 trials potentially will explore VEGF/mTOR inhibition or chemotherapy interval compression. For NRSTS, a COG Phase 3 trial will explore VEGF inhibition. Pediatr Blood Cancer 2013; 60: 1001–1008. © 2012 Wiley Periodicals, Inc.     

Principles of chemotherapy

Combination chemotherapy is the mainstay of treatment for most childhood cancer, either alone or in combination with surgery and radiotherapy. Sequential national and international studies of combinations of mostly well established cytotoxic drugs, with careful attention paid to the maintenance of dose intensity and the optimization of supportive care to manage acute toxicity, have resulted in dramatic improvements in the outcome for childhood cancer. Increased understanding of the molecular basis of childhood cancer will lead to the introduction of more targeted anti-cancer drugs, probably in combination with existing conventional agents. This will allow the remaining stubbornly drug-resistant childhood cancers to be treated more effectively, but will also allow does reduction of conventional agents in sensitive tumour types, reducing both acute and chronic toxicity. Increasing understanding of both pharmacokinetics and pharmacogenomics offers the opportunity for more personalized anti-cancer treatment, to optimize drug dosing for an individual, and to reduce their toxicity.     

Pharmacokinetic considerations in the design of optimal chemotherapeutic regimens for the treatment of breast carcinoma: A conceptual approach

Pharmacological data are currently available for a number of antineoplastic agents which have shown clinical activity in advanced breast carcincoma. Preclinical data reveal a relationship between therapeutic response and certain pharmacokinetic parameters such as time of effective cytotoxic exposure (T_eff) and the product of concentration with time (Cxt). We have attempted to apply human pharmacologic data to get estimates of these parameters for 6 active agents in breast cancer, to relate them to response rates, and to suggest a method for estimating the role of individual drugs in a multidrug combination. The response rates for 6 single agents were obtained from literature review and related to estimates of T_eff and Cxt. The Cxt-response relations for single drugs were linear for cyclophosphamide, 5-fluorouracil, and thiotepa; exponential for vincristine; and relatively flat for methotrexate and cytosine arabinoside. Most T_eff values for the active single agents clustered about 15 hr/dose. From the graphs of response rate vs Cxt, the individual contribution of each agent in a combination study was estimated to arrive at a predicted response rate. The predicted response rates for the combination studies correlated with the actual response rates determined in the clinical study, for 6 of 6 nonrandomized studies and for 12 of 14 randomized studies analyzed. In 2 studies, deviations from the predicted response rate were attributed to differences in study design or analysis. There was no correlation between T_eff and predicted response rate. Analyses of pharmacokinetic data may be useful to simulate combination chemotherapy studies to predict the effectiveness of clinical trials in breast cancer. Since the pharmacologic data were not obtained for any of the agents in the actual clinical trials done, we can only speculate on the usefulness of this method. We would encourage the prospective collection of this data in future clinical trails.     

Total body hyperthermia in combination with etoposide and melphalan in a child with acute myelomonocytic leukemia

In vitro and clinical studies have shown antineoplastic effects of hyperthermia alone and in combination with other treatment modalities. Synergistic cytotoxic effects of chemotherapy and hyperthermia have been demonstrated on leukemic cell clones in vitro. It seems that hyperthermia is effective in overcoming chemotherapy resistance. Several groups treated solid tumors by using total body hyperthermia (TBHT). However, only a few studies have been reported investigating the clinical effects of TBHT in myeloproliferative disorders. We report the case of a 7-year-old boy with myelomonocytic leukemia treated with TBHT (2 hours, 42°) combined with etoposide (600 mg/m²), melphalan (30 mg/m²) and hyperglycemia (200-300 mg/dl). Within 24 hours after TBHT, the leukemic cells decreased after TBHT from 53,000/μl to zero. Skin leukemic infiltrates, resistant to conventional treatment, also responded well. Although our patient relapsed 34 days after TBHT, these results indicate that TBHT in combination with cytotoxic treatment may be a useful treatment modality in refractory leukemia.     

Principles of chemotherapy

Combination chemotherapy is the mainstay of treatment for most childhood cancer, either alone or in combination with surgery and radiotherapy. Sequential national and international studies of combinations of cytotoxic drugs have resulted in improvements in the outcomes for childhood cancer. These improvements have required careful attention to be paid to the maintenance of dose intensity and the optimisation of supportive care to manage acute toxicity. Increased understanding of the molecular basis of childhood cancer is now leading to the introduction of more targeted anti-cancer drugs, usually in combination with existing conventional agents. This will allow the remaining stubbornly drug–resistant childhood cancers to be treated more effectively, but will also allow does reduction of conventional agents in sensitive tumour types, reducing both acute and chronic toxicity. Increasing understanding of both pharmacokinetics and pharmacogenomics offers the opportunity for more personalized anti-cancer treatment, to optimize drug dosing for an individual, and to reduce their toxicity. This review will give an outline of the molecular basis for anticancer drug action, will look at some specific types of cytotoxic agent, and describe the principles for combining these into treatment protocols. It will describe short and long term side effects of chemotherapy, and how these often limit what can be given. The importance of pharmacokinetics, in understanding how drugs are handled by children of different ages, and increasingly these days, as a means of individualising drug dosing, will be discussed. Finally the growing importance of pharmacogenomics as a way of predicting both response and toxicity will be described.     

Diagnosis and Management of Rhabdomyosarcoma in Children and Adolescents: ICMR Consensus Document

Rhabdomyosarcoma (RMS) is a highly malignant tumor which is thought to originate from the pluripotent mesenchyme. It is the most common soft-tissue sarcoma of childhood. This review article summarizes the recent and older published literature and gives an overview of management of RMS in children. RMS can arise in a wide variety of primary sites, some of which are associated with specific patterns of local invasion, regional lymph nodal spread, therapeutic response and long term outcome, hence requiring physicians to be familiar with site-specific staging and treatment details. Most common primary sites include the head and neck region, genitourinary tract, and extremities. Prognosis for children and adolescents with RMS has recently improved substantially, especially for patients with local or locally extensive disease because of the development of multi-modal therapy incorporating surgery, dose-intensive combination chemotherapy, and radiation therapy. Despite aggressive approaches the outcome for patients who present with metastatic disease remains unsatisfactory. Clinical trials are ongoing to reduce toxicity and improve outcomes of such patients; newer agents in combination are being investigated.     

Induction of Drug Resistance in Human Rhabdomyosarcoma Cell Lines Is Associated with Increased Maturation: Possible Explanation for Differentiation in Recurrences?

In rhabdomyosarcoma (RMS) of childhood and adolescence very little is known about interactions of cytotoxic drugs and tumor cells. In recurrent RMS the tumor cells are often more mature than in the primary tumor. The biological properties of these cells are still a subject of controversy. We investigated two human (RD2 and TE 671) cell lines by cultivating them with doxorubicin, cisplatinum, and etoposide. Degree of differentiation and proliferation rate were estimated morphologically and by means of immunohistochemistry and a monolayer proliferation assay. Both morphological and immunohistochemical maturation was measurable in most resistant cell lines. An increase in myosin expression was most marked in the etoposide- and doxorubicin-resistant RD cell lines. The proliferation rate was decreased in almost all resistant cell lines. Nevertheless, the resistant cell lines tolerated high-dose levels of cytotoxic drugs at a higher proliferation rate than parental cell lines cultivated under similar conditions. The maturation seen in some recurrent tumors of RMS can be simulated in vitro by cultivating cell lines with cytotoxic drugs at sublethal doses. Interestingly, the resistance-associated induced maturation was not accompanied by p170 expression. After comparing these in vitro results with the maturation seen in RMS specimens after chemotherapy, we conclude that chemotherapy-induced differentiation in vivo might be a morphological sign of chemoresistance. Received August 6, 2001; accepted December 3, 2001.     

Chromosome translocation (2;13) (q37;q14) in a disseminated alveolar rhabdomyosarcoma

Chromosome analysis of tumour cells in the bone marrow of a 13.5-year-old girl (without a primary tumour) revealed a pseudo-diploid or pseudo-tetraploid karyotype with a translocation involving the long arms of chromosomes 2 and 13: t(2;13) (q37;q14). This finding enabled the diagnosis of a disseminated alveolar rhabdomyosarcoma (RMS) to be established. The patient was treated by cytotoxic chemotherapy, went into complete remission, but died of relapse 14 months after diagnosis. As several cases with this translocation have been described recently, this additional report confirms that t(2;13) is specific for the alveolar subtype of RMS.Abbreviations RMS rhabdomyosarcoma - RPMI Roswell Park Memorial Institute - FCS foetal calf serum - nm modal number     

Treatment of myelodysplastic syndromes with low-dose oral 6-thioguanine

Several cytotoxic agents when used in vitro in very low concentrations have been shown to induce differentiation of leukemic cells. We treated 18 patients with myelodysplastic syndromes with low-dose oral 6-thioguanine (6-TG; 20 to 60 mg daily). Four patients demonstrated significant improvement in peripheral blood counts. An additional three patients had significant reductions in the percentage of leukemic myeloblasts in the marrow without a corresponding improvement in peripheral counts. With the exception of a fall in the peripheral neutrophil count in four patients requiring dose reductions, no toxicity was observed. Low-dose oral 6-TG gives a response rate in myelodysplastic syndromes similar to that of parenteral agents such as cytosine arabinoside. Given the ease of administration and lack of toxicity, oral 6-TG may be a useful treatment modality for these syndromes either alone or in combination with other differentiation-enhancing agents.     

Association of Alveolar Rhabdomyosarcoma with the Beckwith-Wiedemann Syndrome

Rhabdomyosarcoma (RMS) is a soft tissue tumor of childhood frequently diagnosed between the first and fifth year of life. Children with the Beckwith-Wiedemann syndrome (BWS), a congenital overgrowth syndrome characterized by exomphalos, macroglossia, and macrosomia, have an increased risk of developing childhood tumors including Wilms tumor, hepatoblastoma, neuroblastoma, and RMS. Although an association between RMS and the BWS is well accepted, only four cases have been reported to date, and of these, three were reported as embryonal RMS. Based on these data, an association between BWS and embryonal RMS has been proposed. We report three additional cases of BWS with RMS and review the clinical data for each patient as well as the pathology of their tumors. All three cases of BWS had histology consistent with alveolar RMS and were diagnosed at 6 weeks and 5 and 13 years of age. In two of these BWS cases, constitutional defects of 11p15 imprinting were demonstrated. Furthermore, cytogenetic analysis of the tumors did not detect the t(2;13) or t(1;13) translocations that generate the PAX3- or PAX7-FKHR fusion proteins common to alveolar RMS. These observations suggest that the development of alveolar RMS tumors in BWS may occur without the chromosomal rearrangement producing the PAX-FKHR fusion protein. In summary, we present three new cases of RMS demonstrating a new association between BWS and an uncommon subtype of alveolar RMS. The absence of the translocations commonly associated with alveolar rhabdomyosarcoma suggests a common 11p15 pathway for alveolar RMS and BWS. Received May 25, 2001; accepted July 11, 2001.     

Acute myeloid leukemia

Acute myeloid leukemia (AML) is a heterogeneous group of leukemias that result from clonal transformation of hematopoietic precursors through the acquisition of chromosomal rearrangements and multiple gene mutations. As a result of highly collaborative clinical research by pediatric cooperative cancer groups worldwide, disease-free survival has improved significantly during the past 3 decades. Further improvements in outcomes of children who have AML probably will reflect continued progress in understanding the biology of AML and the concomitant development of new molecularly targeted agents for use in combination with conventional chemotherapy drugs.     

Antifungal agents for the treatment of systemic fungal infections in children

Traditionally, the mainstay of systemic antifungal therapy has been amphotericin B deoxycholate (conventional amphotericin B). Newer agents have been developed to fulfill special niches and to compete with conventional amphotericin B by virtue of having more favourable toxicity profiles. Some agents have displaced conventional amphotericin B for the treatment of specific fungal diseases. For example, voriconazole has emerged as the preferred treatment for invasive pulmonary aspergillosis. This notwithstanding, conventional amphotericin B remains a useful agent for the treatment of paediatric fungal infections. Knowledge of the characteristics of the newer agents is important, given the increasing numbers of patients who are being treated with these drugs. Efforts need to be directed at research aimed at generating paediatric data where these are lacking. The antifungal agents herein described are most often used as monotherapy regimens because there is no uniform consensus on the value of combination therapy, except for specific scenarios.     

Rapid diagnosis in pediatric infectious diseases: the past,the present and the future

The focus of rapid diagnosis of infectious diseases of children in the last decade has shifted from variations of the conventional laboratory techniques of antigen detection, microscopy and culture to that of molecular diagnosis of infectious agents. Pediatricians will need to be able to interpret the use, limitations and results of molecular diagnostic techniques as they are increasingly integrated into routine clinical microbiology laboratory protocols. PCR is the best known and most successfully implemented diagnostic molecular technology to date. It can detect specific infectious agents and determine their virulence and antimicrobial genotypes with greater speed, sensitivity and specificity than conventional microbiology methods. Inherent technical limitations of PCR are present, although they are reduced in laboratories that follow suitable validation and quality control procedures. Variations of PCR together with advances in nucleic acid amplification technology have broadened its diagnostic capabilities in clinical infectious disease to now rival and even surpass traditional methods in some situations. Automation of all components of PCR is now possible. The completion of the genome sequencing projects for significant microbial pathogens, in combination with PCR and DNA chip technology, will revolutionize the diagnosis and management of infectious diseases.     

O6-methylguanine-DNA methyltransferase activity and promoter methylation status in pediatric rhabdomyosarcoma

OBJECTIVES: To determine the activity of the DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) and MGMT promoter methylation status of pediatric rhabdomyosarcoma (RMS) and examine MGMT in RMS tumors from different prognostic groups. METHODS: Fifteen samples each of the alveolar (ARMS) and embryonal (ERMS) subtypes were obtained for analysis of MGMT activity and promoter methylation status. MGMT activity was assayed by measuring the removal of O6-[3H] methylguanine from [3H]-methylated substrate by a tumor extract containing the enzyme. Promoter methylation status was examined using methylation-specific polymerase chain reaction (PCR). RESULTS: MGMT activity was successfully assayed from 25 samples, 10 ERMS and 15 ARMS. All ERMS and 11 of the 15 ARMS samples displayed high activity levels. There was significant intertumor variability among both subtypes but no significant difference in mean activity between the two histologic groups. There were trends toward increased activity in ERMS tumors and tumors from anatomically unfavorable locations. Only one tumor was hypermethylated at the MGMT promoter region. CONCLUSIONS: This analysis suggests that a low percentage of RMS samples are hypermethylated at the MGMT promoter and that most have significant MGMT activity, implying that clinical trials with MGMT-modulating agents may have a role in the treatment of these tumors. This analysis does not support MGMT activity as an explanation of the differential response to chemotherapy demonstrated by ARMS and ERMS, but does suggest that MGMT may be involved in RMS treatment failure regardless of subtype and in the poorer response shown by tumors from unfavorable locations.     

A phase II trial of thalidomide and cyclophosphamide in patients with recurrent or refractory pediatric malignancies

BACKGROUND: Previous clinical and pre-clinical research has demonstrated synergy between anti-angiogenic agents and cytotoxic chemotherapy. This trial was undertaken to investigate whether the combination of cyclophosphamide and thalidomide would be active against pediatric tumors. PROCEDURE: Patients with pediatric malignancies who had no remaining conventional therapeutic options were recruited from January 1999 to May 2001. They received thalidomide (6-12 mg/kg po every day; maximum daily dose 800 mg) and cyclophosphamide (1,200 mg/m2 IV every 28 days). RESULTS: Twenty-seven patients were enrolled on the study. Seventeen were male and 10 were female. Median age at the time of registration was 15 years (range 1-54 years). The median number of prior treatment regimens was four. Twenty-one patients were evaluable for response; 1 had a partial response (Hodgkin disease), 1 demonstrated stable disease (neuroendocrine tumor), and 19 had progressive disease. The most common toxicities were hematological (leukocytopenia and neutropenia) and gastrointestinal. One patient experienced a grade 3 rash. Fatigue and daytime somnolence were variable. No peripheral neuropathy was observed. CONCLUSION: The combination of thalidomide and cyclophosphamide as described herein has a modest and tolerable toxicity profile but little evidence of efficacy.     

Consensus and controversies regarding the treatment of rhabdomyosarcoma

Optimal treatment of rhabdomyosarcoma (RMS) requires multidisciplinary approach, incorporating chemotherapy with local control. Although current therapies are built on cooperative group trials, a comprehensive standard of care to guide clinical decision making has been lacking, especially for relapsed patients. Therefore, we assembled a panel of pediatric and adolescent and young adult sarcoma experts to develop treatment guidelines for managing RMS and to identify areas in which further research is needed. We created algorithms incorporating evidence‐based care for patients with RMS, emphasizing the importance of clinical trials and close integration of all specialties involved in the care of these patients.     

Paratesticular rhabdomyosarcoma presenting as thickening of the tunica vaginalis

Pediatric paratesticular primary malignant tumors are rare, and most of them correspond to rhabdomyosarcomas (RMS). Paratesticular RMS has a better prognosis than RMS originating in other locations, because of its favorable histology and possible early diagnosis. The diagnosis relies upon the US findings of a paratesticular hypervascular mass in an adequate clinical setting. We report the unusual appearance of an infiltrating RMS tumor in a 3-year-old boy. The tumor presented as thickening of the tunica vaginalis. Atypical US appearance and discordance with clinical features caused suspicion of a tumoral process, allowing early diagnosis and treatment.     

Central nervous system pharmacology of antileukemic drugs

The blood-brain barrier provides a pharmacologic sanctuary for leukemic cells within the central nervous system (CNS), protecting them from the cytotoxic effects of systemic antileukemic therapy. Attempts to overcome this problem have included specific CNS-directed treatment in the form of direct intrathecal drug injection, cranial irradiation, and alteration in the dose and schedule of systemic agents to enhance their CNS penetration. Use of these treatments and strategies has led to the effective prevention and control of meningeal leukemia. Intrathecal therapy, primarily with methotrexate or cytosine arabinoside, is a form of regional chemotherapy that can achieve very high drug concentrations at the target site [i.e., in the meninges and cerebrospinal fluid (CSF)] with a low total dose. Therefore, there is minimal systemic toxicity. The dose and schedules, clinical pharmacology, and toxicities of the commonly used intrathecal agents are discussed in detail in this article. Another approach to overcoming the limited penetration of antileukemic drugs into the CNS has been the use of high-dose systemic therapy. Methotrexate and cytosine arabinoside in high doses have produced favorable clinical responses in patients with overt meningeal disease, and pharmacokinetic studies have documented cytotoxic concentrations of these drugs within the cerebrospinal fluid. A clear understanding of the CNS pharmacology of the antileukemic drugs is required in order to use these agents in the safest and most efficacious manner for the treatment of meningeal leukemia.     

p53 and mdm-2 Expression in Rhabdomyosarcoma of Childhood and Adolescence: Clinicopathologic Study by the Kiel Pediatric Tumor Registry and the German Cooperative Soft Tissue Sarcoma Study

Rhabdomyosarcomas (RMS) are the most common malignant soft tissue sarcomas in childhood and adolescence. Despite a large number of publications about this heterogeneous group of tumors, little is known about proliferation, p53 and mdm-2 in relation to histological subtype, clinical parameter, and prognosis of patients. We studied 150 cases of RMS treated in the German Cooperative Soft Tissue Sarcoma Study (CWS) by immunohistochemistry on paraffin-embedded tissue, using antibodies against p53, mdm-2, and Ki-67. The results were correlated with histological subtype, mitotic count, and various clinical parameters. Both p53 and mdm-2 were expressed at low levels and did not show differences between embryonal and alveolar RMS. Tumors of patients with metastatic embryonal RMS showed significantly higher levels of p53 protein than nonmetastatic tumors. This might be a clue to an important role of p53 in metastatic embryonal RMS. Nevertheless, neither p53 nor mdm-2 showed any correlation to prognosis. Proliferation measured by Ki-67 immunostaining (KiS5 antibody) or mitotic count did not show significant differences between embryonal and alveolar RMS. In addition, these parameters did not correlate with response to therapy or prognosis. In conclusion, we could not demonstrate that any of the investigated parameters had an influence on prognosis of RMS. p53 protein overexpression might be a crucial step in metastatic disease for patients with embryonal RMS.     

Primary angiitis of the central nervous system: neurologic deterioration despite treatment

Primary angiitis of the central nervous system (PACNS) is an idiopathic vasculitis confined to the central nervous system. In children with PACNS, small-vessel (SV) involvement is characterized clinically by progressive neurologic symptoms, multifocal lesions on brain imaging, occasional pseudo-tumor presentation, and normal angiogram results in most patients. Small case series of patients with SV PACNS with short follow-up usually reveal favorable outcomes in children treated with immunosuppressive therapy. We report here the cases of 3 children with biopsy-confirmed SV PACNS and long-term follow-up who developed different patterns of neurologic deterioration despite immunosuppressive therapy. One patient had transient ischemic attacks shortly after initiation of corticosteroid treatment. Early ischemic events probably result from residual thrombogenicity or residual inflammation of recently affected vessels, which supports the use of antiplatelet agents and suggests potential benefits of stronger immunosuppressive therapy. In contrast, the other 2 patients had later neurologic deterioration after corticosteroid withdrawal, which suggests failure of initial immunosuppressant treatment and the need for stronger agents, longer treatment duration, or both. All patients responded to long-term treatment with corticosteroids combined with cytotoxic agents. This particular combination is probably indicated in many cases of SV PACNS, including those with neurologic deterioration that occurs during maintenance corticotherapy or after corticosteroid withdrawal. In 1 case, SV PACNS recurred several years after discontinuation of combination therapy. Long-term relapses may reflect intrinsic predispositions to SV PACNS rather than treatment failure. These cases highlight different chronological patterns of neurologic deterioration despite immunosuppressive therapy, which supports the relevance of monitoring clinical, laboratory, and radiologic responses to treatment and of long-term follow-up of patients with SV PACNS.