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Review of Medicines for the Treatment of Common Tumours in Children

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Review of Medicines for the Treatment of Common Tumours in Children 18th Expert Committee on the Selection and Use of Essential Medicines Reviewer No. 1 checklist for: Review of medicines for the treatment of common tumours in Children In the WHO Essential Medicines List (1) Have all important studies that you are aware of been included? Yes No X (2) Is there adequate evidence of efficacy for the proposed use? Yes No X (3) Is there evidence of efficacy in diverse settings and/or populations? Yes X No (4) Are there adverse effects of concern? Yes X No (5) Are there special requirements or training needed for safe/effective use? Yes X No (6) Is this product needed to meet the majority health needs of the population? Yes No X (7) Is the proposed dosage form registered by a stringent regulatory authority? Yes X No 1 (8) What action do you propose for the Committee to take? To rename the subsections 8.2 and 8.3. To delete cytotoxic agents not mentioned for prevalent childhood cancer (subsection 8.2). To add mesna as an adjuvant medicine (subsection 8.2). To discuss retaining two anthracycline agents, two alkylating agents, and two Vinca alkaloids or choosing one of them (subsection 8.2). To delete dexamethasone oral formulation (subsection 8.3) To delete the observation “Specific use for management of bone pain.” regarding ibuprofen for palliative care (subsection 8.4). To add fluoxetine and ondansetron for palliative care (subsection 8.4). To add oral midazolam formulations for palliative care (subsection 8.4). (9) Additional comment, if any. General Comments Antineoplastic agents are used for different purposes: curative (for eradicating the disease and preventing the recurrence), palliative (for relieving tumour symptoms), adjuvant (for preventing tumour recurrence after proved exclusion of residual disease), and neo‐adjuvant (for administrating before a local definitive treatment is done). These agents are prescribed in monotherapy or in combination. Antineoplastic medicines in combination are more effective, since they act in different phases of the cell cycle, by different and synergistic mechanisms of action. The combination therapy has additional benefits relating to not sharing common mechanisms of resistance and similar profiles of major toxicities. So, it is convenient to include at least one representative of each antineoplastic class, according to his benefit in children cancer treatment. To say the least, the therapeutic response depends on the tumour histological type and localization, as well as the disease stage and other concomitant cancer strategies, such as surgery and radiotherapy. These multiple variables influence the choice of antineoplastic agents. The efficacy is usually evidenced by clinical protocols rather than by randomised clinical trials or meta‐analyses. The great variability retrains pooled‐data. Actually the literature search finds mainly book chapters, descriptive reviews, cohort studies (follow‐up studies), non‐randomised trials, and guidelines, as showed in the review offered to be analysed. The strong evidence of efficacy and safety – provided by systematic reviews, meta‐analyses and randomised controlled studies (RCTs) – is scarce in cancer pharmacology for children, especially the face‐to‐face comparisons. Even the RCTs have methodological limitations. Additionally the difficulty of choice increases because cancer is a complex disease, with variable development, severe and multiple clinical manifestations and sequelae which compromise survival, morbidity and quality of life. 2 Therefore, the decision of which medicines should be included for treatment of cancer diseases in children needs to follow a different and unusual rationality, somehow changing the criteria. The efficacy usually comes from clinical protocols (in general including medicine combinations to minimize the emergence of resistance) based on the institutional and professional experience. The inclusion also considers the ability to act in different phases of the cell cycle (subclasses with different mechanisms of action), and the degree of tumour cell resistance to certain medicines (justifying more than one representative of the same pharmacological subclass). Clinically the medicine choice is made regarding patient’s age, intensity and stage of the disease, potential treatment toxicity, and risk of relapses. Taking into account that all antineoplastic agents induce harmful, and even severe, side effects, the safety criterion has to counterbalance these risks with the rapid, and even fatal, cancer disease development. The convenience of treatment is an important issue to consider, especially in children (dosage, concentration, pharmaceutical formulation, routes of administration). The favourable comparative cost should be also considered, allowing the developing countries can afford it. Considering the essential concept that guides the List, it is worth choosing medicines used for treatment of the most common cancer diseases in children. The most common paediatric malignancies have a general incidence in the following order: leukaemias (30%), brain and other nervous system cancers (22.3%), neuroblastoma (7.3%), Wilms tumour (5.6%), non‐Hodgkin lymphoma (4.5%), rhabdomyosarcoma (3.1%), retinoblastoma (2.8%), osteosarcoma (2.4%), and Ewing sarcoma (1.4%). 1 The offered review only analyses acute lymphoblastic leukaemia (ALL), Burkitt lymphoma (BL) and Wilms Tumour (WT). Aim of the comments: To review, through a clinical pharmacologic perspective, antineoplastic and adjuvant medicines (for correction of some antineoplastic side effects), and medicines used in palliative care during cancer treatment to rationally decided their inclusion in the WHO EMLc. Literature search: A PubMed search – performed in February 2011, using as key words the names of the common cancer diseases in children and the names of recommended antineoplastic agents, with the activated limits “Humans, Meta‐Analysis or Randomized Controlled Trial, All Children: 0‐18 years, published in the last 3 years” – found few studies regarding leukaemias (e.g. acute lymphoblastic leukaemia – ALL), non‐Hodgkinʹs lymphoma (e.g. Burkitt´s lymphoma – BL), Wilms Tumour, Ewingʹs sarcoma, rhabdomyosarcoma, and brain tumours treatment. For instance: For ALL – 7 meta‐analyses; 52 RCTs For BL – no items found (meta‐analysis); 2 RCTs For WT – 2 meta‐analyses; 7 RCTs 3 The 3‐year search period was chosen to partially cover the published information after the former committee had decided the inclusion of cancer medicines in the current EMLc. An additional search in the Cochrane Library found recent reviews about antineoplastic treatment for LLA (n=5), BL (n=5), WT (n=8), and Rhabdomyosarcoma (n=1), as well as about cytoprotective medicines (corrective effect) and medicines for palliative care. ANTINEOPLASTIC MEDICINES Cytotoxic medicines (Subsection 8.2) and Hormones and antihormones (Subsection 8.3) First of all, two suggestions: 1. Since the EMLc 8.2 subsection contains allopurinol and calcium folinate (corrective medicines instead of cytotoxic medicines) I suggest substituting its title for: 8.2 Cytotoxic medicines and adjuvant medicines (or cytoprotective medicines) 2. Since the EMLc 8.3 subsection only contains corticosteroids, antihormones are absent. So, there is no reason for the current title. I suggest its change for: 8.3 Hormones Preliminary notes: 1. The underlined medicines in the text are those already included in the 2nd EMLc (2010). 2. The reported information collected in cited RCTs and systematic reviews is only the one which concerns the members with the choice of antineoplastic medicines. Leukaemias For childhood Acute Lymphoblastic Leukaemia or Acute lymphocytic leukaemia, clofarabine with etoposide and cyclophosphamide, 2 mitoxantrone or idarubicin,3 vincristine (VCR) plus steroid pulses (prednisone/prednisolone),4 6‐mercaptopurine (6‐MP) and methotrexate (MTX),5 and anthracyclines6 were studied. A combination of daily 6‐MP, weekly MTX and VCR/DEX (dexamethasone) pulse for maintenance treatment in standard risk or high risk 201 ALL patients evidenced no differences in the event‐free survival or overall survival in comparison to the therapy stated by ALL‐96 protocol. However the first regimen induced more liver toxicity.7 In the previous review, the 17 mentioned medicines used for ALL were: asparaginase, busulphan, cyclophosphamide, cyclosporine, cytarabine (ARA‐C), daunorubicin or doxorubicin (DOX), dexamethasone (DEX), etoposide, hydrocortisone, imatinib, leucovorin, mercaptopurine (6‐MP), methotrexate (MTX), methylprednisolone, prednisone, and vincristine (VCR). The review said that “intensive use of asparaginase either IM or IV, is especially recommended in CNS prophylaxis, but at present there appears to be no reasonable alternative to the availability of all three forms of asparaginase”. The current list already includes 13 of these medicines. The exceptions are busulphan, imatinib, methylprednisolone, and prednisone. 4 Attention: Looking at the classification of antineoplastic medicines (Table 1), one can realize that there is more than one representative in the same subclass. So, it is interesting to discuss efficacy and safety among representatives. 1. A RCT8 compared two purine analogs – oral 6‐mercaptopurine (6‐MP) versus oral 6‐thioguanine (6‐TG) – in the treatment of standard‐risk ALL. The estimated 7‐year event‐free survival for subjects randomized to TG was 84.1% (+/‐ 1.8%) and to MP was 79.0% (+/‐ 2.1%); P = 0.004 log rank), although overall survival was 91.9% (+/‐ 1.4%) and 91.2% (+/‐ 1.5%), respectively
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