Soft tissue sarcomas
Soft tissue sarcomas
Soft tissue sarcomas
Neoadjuvant chemotherapy —In this setting, chemotherapy is administered at the time of diagnosis, prior to local control, in patients in whom surgical resection is not considered feasible, or could only be completed with a radical, usually mutilating or disfiguring approach. This is a common occurrence in head and neck malignancies, where tumor location usually limits surgical options, and chemotherapy could facilitate resection and minimize side effects. Most pediatric malignancies are very chemosensitive and thus a good response is usually expected to occur and lead to better local control.
Concurrent chemotherapy —Administration of chemotherapy in conjunction with radiation therapy may result in a synergistic effect, improve local control rates, and in some cases facilitate second-look surgery. Chemoradiotherapy of the head and neck leads to significant toxicity of the oral and pharyngeal mucosas and thus patients undergoing this treatment approach need to be carefully monitored and supportive care maximized.
Adjuvant chemotherapy —In this setting, chemotherapy is given after local control (surgery, radiation, or both), and it is mostly intended for the control of the systemic disease. Adjuvant chemotherapy may result in reactivation of mucositis in patients that have recently completed radiation therapy, particularly if doxorubicin is used .
Types of Chemotherapeutic Agents
Standard chemotherapeutic agents are divided into four broad categories based on their mechanism of action: antimetabolites , alkylating agents, topoisomerase inhibitors , and tubulin-binding drugs. In addition, advances in our understanding of cancer biology have led to the development of new classes of agents such as monoclonal antibodies, differentiating agents, and tyrosine kinase inhibitors (Table 3.2) .
Anticancer drugs used in pediatric oncology
Topoisomerase I inhibitors
Topoisomerase II inhibitors
Tyrosine kinase inhibitors
The mechanism of action for most agents is through their interference with the synthesis or function of DNA and RNA at different levels:
Antimetabolites: These drugs are analogs of nucleoside precursors or folates and act by either depleting precursors or being incorporated into DNA or RNA. This class of agents is inhibitory only during the S phase of the cell cycle; for this reason, their effect is maximized when given in continuous infusion (such as methotrexate in acute leukemias and lymphomas or osteosarcoma or 5-fluorouracil in nasopharyngeal carcinoma) or in protracted schedules of daily administration (such as cytarabine or 5-mercaptopurine in acute leukemias).
Alkylating agents: This class of drugs damages DNA by forming covalent bonds to nucleobases and cross-linking between DNA strands. Different from antimetabolites, they are less dependent on the cell cycle and their effect is less schedule dependent. Most commonly used alkylating agents in pediatric head and neck cancers are the nitrogen mustards cyclophosphamide and ifosfamide, which are most commonly used in sarcomas, and the platinum agents cisplatin and carboplatin, which are more commonly used in embryonal cancers such as neuroblastoma and retinoblastoma.
Topoisomerase inhibitors : The topoisomerases are key enzymes in DNA topology; they create and religate single- (topoisomerase I) or double-stranded (topoisomerase II) breaks in the DNA that facilitate uncoiling and strand passage. Inhibitors of those enzymes result in DNA breaks. The most commonly used topoisomerase I inhibitors are topotecan and irinotecan; these agents have a maximum effect when given in protracted schedules over 5 days. Topotecan is used mostly in the frontline management of high-risk neuroblastoma, whereas irinotecan is used in high-risk or relapsed Ewing sarcoma and rhabdomyosarcoma. Topoisomerase II inhibitors are a larger category, with antitumor antibiotics such as doxorubicin, bleomycin, and dactinomycin, and epipodophyllotoxins, such as etoposide. This class of agents is used across the spectrum of pediatric malignancies .
Tubulin binders : Tubulin is the precursor of microtubules, high-dynamic proteins that are key in the formation of the mitotic spindle. They are also involved in the movement of organelles within the cell and have effects on cell support and shape. The vinca alkaloids (vincristine, vinblastine, vinorelbine) inhibit tubulin by blocking microtubule polymerization; this class of agents is commonly used in pediatric cancers, usually in combination with alkylators . The taxanes (paclitaxel, docetaxel) inhibit depolymerization of the microtubules. Taxanes are less commonly used in pediatric cancer, although paclitaxel and docetaxel are used in second-line regimens for germ cell tumors and nasopharyngeal carcinoma, respectively.
Monoclonal Antibodies : This new class of agents is acquiring an increasingly important role in the treatment of some childhood malignancies. The rationale for the development of this approach is the identification of selective antigens in the surface of malignant cells that could be targets for antibody therapy. Three monoclonal antibodies may be of relevance in head and neck malignancies in children: anti-GD2, anti-IGF1R, and anti-CTLA4. Monoclonal antibodies against the tumor-associated disialoganglioside GD2, which is expressed in neuroblastoma, have been shown to increase survival in patients with high-risk neuroblastoma and are now incorporated in the frontline treatment for this group of patients . Anti-IGF1R monoclonal antibodies have shown efficacy in relapsed Ewing sarcoma and their use in combination with standard chemotherapeutic agents in the frontline of patients with high-risk Ewing sarcoma and rhabdomyosarcoma is currently being evaluated . Ipilimumab, an antibody against cytotoxic, T-lymphocyte-associated antigen 4 (CTLA4), has shown to prolong survival in patients with advanced melanoma , and it is currently being investigated in children with this malignancy.
Molecularly targeted agents: Advances in our understanding of cancer biology have resulted in the development of more selective agents designed to inhibit or activate specific pathways. Relevant agents with documented efficacy in pediatric head and neck cancer include kinase inhibitors such as crizotinib (anaplastic large cell lymphoma, neuroblastoma, and inflammatory myofibroblastic tumor) , sorafenib (thyroid carcinoma) , and vemurafenib (malignant melanoma and thyroid carcinoma) , and differentiating agents such as cis-retinoic acid (neuroblastoma) .
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Pharmacokinetics of Chemotherapeutic Agents
The dose, schedule, and route of administration of antineoplastic agents are dependent on the unique pharmacokinetics of each drug, including drug absorption, distribution, metabolism, and excretion .
Absorption: Very few antineoplastic agents are administered orally to children; however, oral treatment is a key component in the management of acute lymphoblastic leukemia (ALL), where oral methotrexate and 6-MP form the backbone of maintenance therapy. Limitations to absorption include degradation in the gastrointestinal lumen, inability be transported across the mucosa, and metabolism in the intestinal epithelium or liver.
Distribution: Once the drug enters the systemic circulation by absorption of intravenous administration, it is transferred and distributed into the interstitial and intracellular fluids, including tumors. Each organ and tissue receives different amounts of drug; this distribution is dependent on vascular permeability, regional and systemic blood flow, rate of binding to plasma proteins, ability of the drug to bind tissue, and lipid solubility.
Metabolism: Drug metabolism entails the biochemical modification of the antineoplastic agents through specialized enzymatic systems. Metabolism is the most important determinant of variability in the pharmacokinetics of anticancer drugs; it is susceptible to constitutional variations in the levels and activity of drug-metabolizing enzymes as well as interactions with other agents. Drug-metabolizing enzymes are divided into two major groups. Phase I reactions introduce or expose a functional group on the drug, usually by oxidation, hydrolysis, reduction, or demethylation; this usually diminishes the drug’s activity, although for some agents such as cyclophosphamide and ifosfamide, phase I reactions activate the drug. The CYP (cytochrome P450) superfamily of enzymes catalyze oxidation and demethylation for a large number of drugs. They have very broad and overlapping substrate specificity; CYP genes are genetically polymorphic and this may result in significant patient variability in drug metabolism. CYP enzymes are also susceptible to inhibition or induction by other drugs, thus resulting in risk of interactions that could potentially alter the effect of the anticancer agent . Phase II conjugation reactions covalently link a conjugate such as glucuronic acid or glutathione to the drug; the conjugated drugs are very polar and are excreted very rapidly.
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