Most chemotherapeutic agents exhibit a sigmoidal dose-response curve, which means that there is a threshold dose below which the drug has minimal efficacy, and beyond a certain dose, further increases do not significantly enhance the therapeutic effect. However, within the optimal dose range, there is a positive correlation between the administered dose and the antitumor response.

Dose intensity is a critical concept in chemotherapy, defined as the amount of drug delivered per unit time, typically expressed as milligrams per square meter per week (mg/m ² /week). Increasing dose intensity can be achieved through either higher individual doses or more frequent administration schedules.

The importance of dose intensity lies in the fact that even small increments in dose can lead to a substantial increase in tumor cell kill, resulting in improved treatment response and survival outcomes. Conversely, a modest reduction in dose intensity can significantly compromise the antitumor efficacy of the chemotherapeutic regimen.

Several strategies and adjuncts have been employed to allow for the delivery of higher dose-intense chemotherapy regimens while mitigating adverse effects.

Granulocyte colony-stimulating factor (G-CSF) and interleukin-11 (IL-11) can stimulate the recovery of white blood cells and platelets, respectively, facilitating faster hematologic recovery and reducing the risk of infection and bleeding complications associated with myelosuppression. Agents like dexrazoxane can help to protect the heart from the cardiotoxic effects of anthracyclines, such as doxorubicin, allowing for higher cumulative doses to be administered without compromising cardiac function. Leucovorin (folinic acid, a folate derivative) can “rescue” the effects of methotrexate, which inhibits the enzyme dihydrofolate reductase (DHFR), essential for the synthesis of purines and pyrimidines in DNA. Leucovorin provides an exogenous source of folates, allowing normal cells to bypass the DHFR block. Amifostine, a drug whose active metabolite, a free thiol compound, accumulates in higher concentrations in normal tissues compared to tumor tissues, and protects against cisplatin renal injury, neurologic and bone marrow toxicity. Mesna acts by binding to acrolein, a toxic metabolite of ifosfamide and cyclophosphamide which accumulates in the bladder, thus helping prevent hemorrhagic cystitis.

Following high-dose myeloablative chemotherapy or chemoradiotherapy regimens, infusion of autologous or allogeneic peripheral blood progenitor cells (PBPCs) can facilitate rapid hematopoietic reconstitution, reducing the duration and severity of myelosuppression. Finally, administering chemotherapy cycles at shorter intervals, known as dose-dense schedules, can increase the dose intensity while maintaining individual dose levels, potentially enhancing antitumor efficacy.

Adjuvant Chemotherapy: This type of chemotherapy is administered after the primary tumor has been treated with local therapies such as surgery or radiation therapy. The goal of adjuvant chemotherapy is to eliminate any remaining undetectable cancer cells that may have spread beyond the primary site, reducing the recurrence risk. It is crucial to initiate adjuvant chemotherapy as soon as possible after the local treatment (usually within 2 weeks of surgery), as delays can compromise the treatment’s effectiveness.

Neoadjuvant Chemotherapy: In contrast to adjuvant chemotherapy, neoadjuvant chemotherapy is given before definitive local therapy. The primary objectives of neoadjuvant chemotherapy are twofold: firstly, to treat any potential micrometastatic disease (cancer cells that have spread but are too small to be detected) as early as possible, and secondly, to shrink the primary tumor. By reducing the tumor size, neoadjuvant chemotherapy can improve the chances of successful local control and potentially make the tumor more amenable to local therapy.

Induction Chemotherapy : Induction chemotherapy is the initial treatment given for advanced or metastatic cancer, with the goal of inducing remission or achieving a cure. In acute leukemias, it is the intensive initial phase aimed at destroying leukemic cells in the bone marrow to achieve a complete remission. This type of chemotherapy is administered as the primary treatment before considering other therapies, such as surgery or radiation therapy.

Myeloablative Chemotherapy: This term refers to the use of high-dose chemotherapy regimens that are designed to destroy both cancer cells and normal bone marrow cells. Myeloablative chemotherapy is an intensive treatment that can cause severe side effects due to bone marrow depletion, and it is typically followed by a bone marrow or stem cell transplant to restore the bone marrow.

Evaluation of potential anticancer agents include phased studies: Phase 1 (dose-escalation studies to determine the maximally tolerated dose of a new drug); Phase 2 (efficacy of a drug to establish the spectrum of activity of the agent); and Phase 3 (prospective randomized control design to compare established effective chemotherapy combinations to new treatment regimens) trials. Combination chemotherapy is currently the mainstay of treatment (non–cross-resistant agents with nonoverlapping toxicities). The goal of chemotherapy is to maximize tumor kill while maintaining acceptable side effects.

Cancer is a genetic event. Most drugs used for children’s cancer work by interfering with DNA or RNA synthesis, transcription, or repair. They act on normal cells as well as cancer cells. Current chemotherapeutic medications can be classified by their primary mechanism of action.

The prefix “brachy” comes from the Greek word “ brachys, ” which means short or small; in this case referring to the ionizing source being a short distance away from, or in contact with, the lesion. This technique has been used since the early 1900s. Radiation safety courses are required for most surgeons, and the reader will recall that the inverse square law for radiation dose is Dose = k ∗ (1/ r ² ), where k is a constant that depends on the source strength and other factors, and r is the distance from the radiation source. Thus, brachytherapy allows a high radiation dose to be applied to the tumor, insensitive to the motion of the patient. Additionally, the quality of implantation is critical to the effectiveness of the treatment.

Brachytherapy has traditionally been used more frequently in adults than in children. However, in Europe, combined local therapy approaches- such as the AMORE protocol (Ablative surgery, Mould technique with afterloading brachytherapy, and surgical REconstruction)- have been employed in pediatric patients with relapsed or refractory rhabdomyosarcoma[Q12]. The available evidence is limited by small numbers and study quality, and most data come from patients with embryonal (fusion negative) disease.

Intraoperative radiation (IORT) is a form of brachtherapy used to improve local control while limiting late toxicity in children. It is infrequently used in pediatric oncology, with the largest series consisting of 66 patients with sarcomas whose indications for IORT included gross residual disease, suspected microscopic disease, or if deemed a high-risk site for recurrence.

Also known as radionuclide therapy, molecular radiotherapy (MR) is the use of radiopharmaceuticals systemically. A well-known application is that of radioactive iodine to treat differentiated thyroid malignancy. In pediatric oncology, Iodine-131 labeled meta-iodobenzylguanidine (mIBG) therapy has been used for many years in the treatment of advanced neuroblastoma. ^{, ,}

Other variations of EBRT include intensity-modulated RT (IMRT) and IMRT-based techniques such as volumetric-modulated arc therapy, tomotherapy, image-guided RT (IGRT), or 4D RT. In IMRT, the radiation beam is modulated or shaped to conform to the shape of the tumor, allowing for precise dose delivery to the target area while minimizing exposure to surrounding healthy tissues. This is achieved by using multiple small beamlets of varying intensities from different angles, which are optimized by specialized treatment planning software. Advances include more precise targeting and better coverage of the tumor with the ability to provide a higher dosage. These techniques may expose a larger proportion of the normal tissue, but to considerably lower doses. Nevertheless, it increases the risk of EBRT-related SPMs compared to conventional 3D conformal radiotherapy (3D-CRT, where the beams are more focused). ^{, ,}

Proton beam therapy (PBT) has the primary advantage of depositing the peak amount of energy at the end of its path (the Bragg peak), thus protecting intervening and surrounding healthy tissue from injury. When protons enter the body, they lose a relatively small amount of energy as they travel through the tissue. However, as they approach the end of their range, they undergo a rapid deceleration, resulting in a sharp peak of energy deposition. This is known as the Bragg peak. After the Bragg peak, the remaining energy of the protons is quickly absorbed, and the dose falls off rapidly beyond that point. This means that the majority of the radiation dose is delivered at the Bragg peak, while the entrance and exit regions receive relatively lower doses. This is particularly useful for very radiosensitive organs in children (“organs at risk”) such as the CNS. Medulloblastoma patients have been shown to have less neurocognitive impairment after PBT.

Carbon or proton beam therapy requires specialized facilities and has been primarily used in children with brain tumors. It is estimated that only about 1% of all cancer patients are treated with this modality. ^,

These drugs target the signaling, primarily via vascular endothelial growth factor (VEGF), of new blood vessel formation in normal tissue as well as in neoplasms. By inhibiting angiogenesis, these therapies can starve tumors of their blood supply and prevent further growth and metastasis. They have been more widely and successfully used in adult oncology. VEGF inhibitors like bevacizumab (anti-VEGF monoclonal antibody) have been investigated in the treatment of recurrent or refractory pediatric brain tumors, such as high-grade gliomas, medulloblastomas, and ependymomas. In neuroblastoma, antiangiogenic agents like sunitinib (a multitargeted TKI that targets VEGF receptors, PDGF receptors, and other pathways) have been studied. Bevacizumab has been studied in clinical trials in combination with chemotherapy for the treatment of relapsed or refractory Wilms tumor. Propranolol, a nonselective beta-blocker, has been found to have antiangiogenic properties and is now considered a first-line treatment for problematic infantile hemangiomas. It is believed to inhibit the VEGF and basic fibroblast growth factor (bFGF) pathways, leading to reduced angiogenesis and regression of the hemangioma. Antiangiogenic agents like sirolimus and other mTOR inhibitors have shown promising results in the management of complex venous and lymphatic malformations, particularly those classified under PIK3CA -related overgrowth spectrum (PROS). Anti-VEGF agents like bevacizumab have also been studied for the treatment of severe retinopathy of prematurity.

These therapies target specific signaling pathways that are dysregulated in cancer cells, leading to uncontrolled cell growth and survival. They interfere with the activity of proteins involved in these pathways, such as tyrosine kinases, serine/threonine kinases, or other signaling molecules. Both intracellular and extracellular signaling pathways play crucial roles, with substantial overlap. ^,

Intracellular signaling : In the context of pediatric cancers, several intracellular signaling pathways have been implicated, including:

• 1.

  RAS/RAF/MEK/ERK pathway: Mutations in genes such as RAS, BRAF, and NF1 can lead to constitutive activation of this pathway, promoting uncontrolled cell proliferation and survival. The MEK1/2 inhibitor selumetinib has shown promising efficacy in pediatric patients with neurofibromatosis type I and symptomatic, inoperable plexiform neurofibroma (NF1-PN). Selumetinib is currently the only approved treatment for children with symptomatic, inoperable NF1-PN, based on the results of a phase I/II trial. Several other MEK inhibitors (binimetinib, mirdametinib, trametinib) and the TKI cabozantinib are also being investigated as medical therapies for NF1-PN.

• 2.

  PI3K/AKT/mTOR pathway: Alterations in genes like PIK3CA, PTEN, and TSC1/2 can result in dysregulation of this pathway, which plays a crucial role in cell growth, survival, and metabolism.

• 3.

  MYC pathway: Amplification or overexpression of the MYC oncogene can drive cellular transformation and contribute to various pediatric cancers, such as neuroblastoma and medulloblastoma. It has been difficult to target the MYCN protein directly, in part because of the difficulties inherent to developing molecular-targeted therapies to transcription factors.

Extracellular signaling pathways involve communication between cells and their external environment, often mediated by growth factors, cytokines, and their corresponding receptors on the cell surface. Dysregulation of these pathways can contribute to cancer pathogenesis by promoting aberrant cell proliferation, survival, and migration.

The tropomyosin receptor kinase (TRK) pathway is perhaps the most studied and familiar example. It is activated by the binding of neurotrophins (such as nerve growth factor, brain-derived neurotrophic factor, and others) to their corresponding NTRK receptors (TRKA, TRKB, and TRKC) on the cell surface. Upon ligand binding, the TRK receptors undergo autophosphorylation, which initiates downstream signaling cascades, including the RAS/RAF/MEK/ERK and PI3K/AKT pathways.

The TRK pathway can be dysregulated through various mechanisms:

• 1.

  Gene fusions: Chromosomal rearrangements can lead to the formation of oncogenic NTRK gene fusions, such as ETV6-NTRK3 in certain cases of ALL, and NTRK1/2/3 fusions in various solid tumors like infantile fibrosarcoma and non-small cell lung cancer.

• 2.

  Overexpression: Overexpression of TRK receptors or their ligands can lead to constitutive activation of the pathway, promoting cell proliferation and survival.

• 3.

  Mutations: Activating mutations in TRK receptors or their downstream signaling components can contribute to cancer pathogenesis.

The TRK pathway plays a particularly important role in the development and progression of certain pediatric cancers, including neuroblastoma, infantile fibrosarcoma, and ALL. Targeted therapies against TRK, such as TRK inhibitors (e.g., larotrectinib and entrectinib), have shown promising results in clinical trials for TRK fusion-positive cancers, highlighting the importance of this pathway as a therapeutic target.

The tumor suppressor protein p53, encoded by the TP53 gene, is the most commonly mutated gene identified in human cancers (15%–20% of all inherited cancers). Li–Fraumeni syndrome is one of the most recognized associations. This protein interacts with various intracellular and extracellular signaling pathways, including the TRK pathway. p53 is a transcription factor that regulates the expression of numerous genes involved in cell cycle control, apoptosis, DNA repair, and other cellular processes essential for maintaining genomic integrity and preventing uncontrolled cell proliferation. p53 is also a key mediator of cellular stress responses, such as DNA damage, oncogene activation, and hypoxia. Upon activation, p53 can induce cell cycle arrest, allowing for DNA repair or triggering apoptosis if the damage is irreparable. Mutations in either the TP53 gene or dysregulation of its upstream regulators can lead to impaired p53 function, contributing to uncontrolled cell proliferation and genomic instability. p53 can regulate the expression of genes involved in various extracellular signaling pathways, such as neurotrophin receptor TRKB (NTRK2) and its ligand BDNF (brain-derived neurotrophic factor), which are components of the TRK pathway. Dysregulation of the TRK pathway can lead to increased cell survival and proliferation, potentially overriding the tumor-suppressive effects of p53.

In cancers with mutant or deleted p53 (such as some Wilms tumors, osteosarcomas, neuroblastomas, Ewing sarcomas, and leukemias), therapeutic attempts to restore p53 functionality or inhibit the dysfunctional form have been tried. ^, MDM2 (mouse double minute 2) is a ubiquitin that is a critical regulator of TP53, controlling its stability and activity. Overexpression of MDM2 in cancers can impair TP53 function, promoting tumorigenesis. ^, Nutlin and similar MDM2 inhibitors offer a promising therapeutic strategy by blocking the MDM2-TP53 interaction, thereby stabilizing and activating TP53 to suppress tumor growth. These approaches are particularly relevant in cancers where TP53 is intact, but its activity is diminished due to elevated MDM2 levels.

Programmed cell death (apoptosis) in cancer cells can be induced or inhibited by targeting specific proteins or pathways involved in the regulation of apoptosis. Agents that induce apoptosis in cancer cells have shown promising efficacy in the treatment of various pediatric malignancies. One class of apoptosis-inducing agents includes the BH3 mimetics, such as venetoclax, which inhibit the antiapoptotic proteins of the BCL-2 family (key regulators of the mitochondrial, intrinsic pathways of apoptosis). By blocking these proteins, BH3 mimetics can activate the proapoptotic machinery, causing mitochondrial membrane permeability and cancer cell death. Venetoclax has demonstrated clinical activity in pediatric AML, particularly in patients with specific genetic alterations. Another example is bortezomib, a proteasome inhibitor that disrupts cellular homeostasis and induces apoptosis through multiple mechanisms, including activation of the unfolded protein response and inhibition of NF-κB signaling. Bortezomib has shown efficacy in the treatment of pediatric solid tumors, such as neuroblastoma and Ewing sarcoma.

Inhibitor of apoptosis (IAP) proteins (eight have been identified in humans) promote cancer cell survival and proliferation. High levels of IAPs are observed some pediatric cancers like neuroblastoma, medulloblastoma, and rhabdomyosarcoma, contributing to chemotherapy resistance and aggressive tumor behavior. Therapies designed to mimic the IAP-binding motif of second mitochondria-derived activator of caspase (SMAC), which functions as an endogenous IAP antagonist, have been utilized. However, inhibiting apoptosis in cancer cells could potentially promote tumor growth and resistance to therapy.

These therapies target hormone receptors or hormone signaling pathways that are involved in the development and progression of certain types of cancer, such as breast and prostate cancers. Examples include tamoxifen, which blocks the estrogen receptor in breast cancer, and leuprolide, which suppresses testosterone production in prostate cancer. These agents are not widely used in pediatric oncology.

Many biologic-targeted therapies have multiple mechanisms of action and span more than one category.

Immunotherapy (harnessing the power of the body’s immune system to recognize and eliminate cancer cells) has emerged as a promising approach in the treatment of pediatric tumors, and it often overlaps with other biologic-targeted therapies. It includes monoclonal antibodies, immune checkpoint inhibitors, adoptive cell therapies, and oncolytic vaccines.

Adoptive immunotherapy is a form of cancer treatment that harnesses the power of the immune system to recognize and eliminate malignant cells. ^, This approach involves manipulating and enhancing the patient’s own immune cells or introducing exogenous immune cells to target and destroy cancer cells. Adoptive immunotherapy can be broadly categorized into active and passive modalities.

Active immunotherapy aims to stimulate and augment the patient’s endogenous immune response against tumor cells via agents that can activate or enhance the function of the patient’s immune cells.

Cancer vaccines : inactivated or genetically modified tumor cells are administered to stimulate an immune response against tumor-associated antigens (TAAs) and are being investigated in pediatric cancers. For example, the Wilms tumor 1 (WT1) antigen has been explored as a potential target for vaccine-based immunotherapy in various pediatric solid tumors. Antigen-based vaccines use specific TAAs or peptides to elicit an immune response against tumor cells antigens.

Immune checkpoint inhibitors (ICIs) can block certain proteins (checkpoints) that normally prevent the adaptive innate immune system from attacking cancer cells, allowing immune response against the tumor (disrupting inhibition between tumor and both phagocytes and natural killer [NK] cells). Alternatively, the ICI can provide a stimulatory signal for phagocytosis, cytotoxicity, and antibody response against the tumor. ICIs have been very successful in melanoma and other adult carcinomas. In contrast, the majority of childhood solid cancers have seen few clinical successes from immunotherapy, with especially disappointing response rates to checkpoint inhibitors, often due to low tumor mutational burden. While their application in pediatric cancers is still limited, ongoing clinical trials are evaluating their potential, particularly in combination with other therapies.

Cytokines are signaling proteins produced by helper T lymphocytes and monocytes that help recruit other effector cells (e.g., granulocytes, monocytes, macrophages, eosinophils, dendritic cells), including antigen presenting cells. They also regulate antibody production. These include the interleukins (Interleukin-2 [IL-2] stimulates the growth and activity of T and NK cells, and has been used in the treatment of certain cancers, such as ALL and neuroblastoma); the interferons (these have antiviral, antiproliferative, and immune-modulating properties; interferon-alpha [IFN-α] has been used to treat pediatric cancers like malignant melanoma and certain types of leukemia); and TNF or tumor necrosis factor, which induces apoptosis.

Other cytokines such as granulocyte-colony stimulating factor (G-CSF) are used to mitigate the effects of chemotherapy by stimulating the bone marrow to produce and release more neutrophils, with guidelines for their use available. ^,

Passive immunotherapy involves the transfer of preformed immune components, such as antibodies or immune cells, to directly target and eliminate cancer cells. This modality does not rely on the patient’s immune system to generate an antitumor response. Passive immunotherapy strategies in pediatric oncology include the following.

Monoclonal antibodies , such as dinutuximab and naxitamab, have shown promising results in the treatment of high-risk neuroblastoma. ^, These antibodies target the GD2 antigen, which is highly expressed on neuroblastoma cells, and can induce antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC), leading to tumor cell death. Monoclonal antibody therapy has been one of the most important advances in medical oncology.

Adoptive cell transfer (ACT) may involve autologous or allogeneic immune cells, such as T cells or NK cells, which are isolated, expanded, and activated ex vivo before being reinfused into the patient to target and eliminate cancer cells.

Another form of ACT is chimeric antigen receptor (CAR) T-cell therapy, which has shown remarkable success in treating certain pediatric hematological malignancies, including ALL and NHL. CAR T-cell therapy involves genetically engineering a patient’s T cells to express synthetic receptors (CARs) that recognize and target specific antigens on cancer cells. Once the CAR-T cell is bound to the cancer cell, intracellular signals trigger T-cell proliferation and cytokine release, resulting in the death of the malignant cell. This is a highly specific and potent therapy (minimizing collateral damage to healthy cells, avoiding immunosuppression), and the effects are long lasting and persistent. Perhaps a less well-known advantage of CAR-T cell therapies is their relatively short treatment duration compared to other cancer treatments: a single infusion over a few hours, with most patients requiring inpatient monitoring for less[Q14] than 2 weeks after the procedure, provided they are well enough to be discharged. Limitations include lack of efficacy due to downregulation of the targeted antigen on the cancer cells, tumor heterogeneity, and other factors. ^, Additionally, toxic side effects like cytokine release syndrome (CRS) and neurotoxicity can occur.

Immunotherapies often overlap and synergize with other biologic-targeted therapies, such as signal transduction inhibitors. For instance, certain signal transduction inhibitors, like the MEK inhibitor trametinib, have been shown to modulate the tumor microenvironment and enhance the efficacy of immunotherapies by increasing antigen presentation and promoting T-cell infiltration into tumors.

Additionally, combinations of immunotherapies and targeted therapies, like TKIs or angiogenesis inhibitors, are being explored in clinical trials. These combinations aim to simultaneously target multiple pathways involved in tumor growth and immune evasion, potentially leading to improved treatment outcomes.

Immunotherapies can also lead to unique immune-related adverse events, such as autoimmune reactions and cytokine release syndrome.

Cryoablation works by freezing and destroying cancer cells through a process called cryonecrosis. During the procedure, a cryoprobe is inserted into the tumor, and liquid nitrogen or argon gas is circulated through the probe, creating extremely low temperatures (typically around −180°C). The freezing process causes the formation of ice crystals within the cancer cells, leading to dehydration, protein denaturation, and disruption of cell membranes, ultimately resulting in cell death. It has been used for benign and malignant processes, including osteoid osteomas, desmoid tumors, hepatic tumors, pheochromocytomas (particularly in those associated with von Hippel Lindau mutations, with a lower risk of malignancy and a higher chance of bilaterality), and others.

Potential complications include incomplete tumor ablation, injury to local tissues, unknown risks of recurrence, and other complications. Overall, there is very limited experience with this modality in pediatric oncology.

Radiofrequency ablation involves image-guided application of a probe. The device generates heat with subsequent coagulation necrosis of cells. It has been used for osteoid osteomas, and fetal sacrococcygeal teratomas with hydrops (with poor outcomes). ^, Potential complications are similar to those with cryoablation.

Chemoembolization has primarily been used in adults with hepatic tumors, and pediatric use has been minimal.

It is important to identify lymph node involvement in pediatric tumors for accurate staging and treatment. Imaging studies, even MRI and CT scans, often have false-positive and false-negative rates that make them unreliable for accurately identifying tumor within lymph nodes. Lymph node mapping (sentinel lymph node biopsy, SLNB) aims to identify the first lymph node(s) that receive drainage from the primary tumor site, known as the sentinel lymph node(s). If the sentinel node is negative for metastasis, it is highly unlikely that other nodes are involved, potentially avoiding the need for more extensive lymph node dissection and associated morbidity.

The technique involves preoperative lymphoscintigraphy: a radioactive tracer (e.g., technetium-99m) is injected around the tumor site and imaging with a handheld gamma camera is performed to identify the sentinel lymph node(s), and then intraoperatively, blue dye, or more recently fluorescent green dyes such as indocyanine green (with better visualization and increased detection rates), is injected around the tumor site. The dye travels through the lymphatic vessels, staining the sentinel lymph node(s).

The identified sentinel nodes are removed and sent for pathological examination, via frozen section analysis or imprint cytology. If the sentinel node(s) are positive for metastasis, a more extensive lymph node dissection may be performed. The technique requires an experienced surgeon and a reliable pathologist.

The primary uses of SLNB in pediatric oncology have been for melanoma and rhabdomyosarcoma, ^, and the topic is discussed at some length in their respective chapters.

Complications include allergic reactions to the dye or radioactive tracer, seroma or hematoma formation at the injection or biopsy site, neurovascular injury at the injection site (rare), and lymphedema (rare).