Principles Of Therapy In Children

Early Diagnosis And Multimodality Therapy

The quality of life and survival rate of tumors are determined by early diagnosis.  An early diagnosis is made when there is a high level of suspicion, particular exam results, and pertinent imaging information.

Multimodality therapy combines radiotherapy, chemotherapy, and surgery.  Early diagnosis improves the prognosis for stage 1 early-onset cancers.

How Childhood Cancer Presentation Is Unique?

Each set of symptoms and indicators is distinct and different. Another problem with young children is their inability to describe specific symptoms. Being irritable may indicate pain.

Children have a higher diagnosis rate of the disease than adults do.  The parenchyma of organs and deeper, visceral structures are the typical sites of childhood cancer genesis.

In adulthood, cancer mostly affects the epithelial lining. The first symptom of more than half of children malignancies is pain.

Steps Of Diagnosis

Role of History, Age, and Presentation of tumors

If the history is available, search for acute onset symptoms such as discomfort, agitation, lumps, changed sensorium, or feeding patterns.  The history of cancer in siblings in the family.  Underlying cancer or malnutrition may manifest as weight loss.

Teratomas, neuroblastomas, and hepatoblastomas are among the more prevalent germ cell tumors in fetal or newborn patients.  Leukemia, Wilm's tumor, and Rhabdomyosarcoma (occasionally) in children 1-4 years old  Hodgkin's lymphoma, non-Hodgkin's lymphoma, and brain tumors are more common in children aged 5 to 10.

The three most prevalent malignancies in adolescents are bone tumors, RMS, and lymphoma.  The beginning of aggressive tumors will be rapid; the emergence of slow-growing tumors will be more subtle and progressive.

Physical Examination

 Keep an eye out for signs of bleeding and anemia; bone marrow involvement should be suspected.
The presence of hepatosplenomegaly may indicate metastases or lymphoreticular cancer. Increased intracranial pressure (ICP) is observed in intraentorial tumors such as medulloblastoma.

Be aware of any widespread or localized lymphadenopathy.  Rubbery farm localized lymphadenopathy in the submandibular, posterior, and anterior cervical regions is a symptom of Hodgkin disease. Palpate any lumps in the abdomen.

Wilms tumors, which are tumors that originate in the spleen or liver. Keep an eye out for masses in the sacral area (teratomas) and extremities (RMS). Leukocoria, or the white pupillary reflex, increases the possibility of retinoblastoma.  Cancers such as RBS, neuroblastoma, lymphoma, Langerhans cell histiocytosis, and occasionally retinoblastoma that cause proptosis in children.

Screening for Childhood Cancers

• It is indicated only in high-risk specific groups like
  • Down’s syndrome
  • Klinefelter syndrome, 
  • WAGR syndrome, and 
  • Overgrowth syndromes like Beckwith-Weidemann syndrome, 
  • Chances of developing hepatoblastoma and WT.
• Familial cancers in the families related to genes like p53, FAP, NF-1, and 2, retinoblastoma.

Diagnosis And Staging

 Hematological and imaging studies are conducted.
Hematological examinations: Total blood count
The peripheral smear; markers in particular malignancies, such as beta-HCG, AFP, and LDH.
Imaging: - Chest X-ray: mediastinal mass present in leukemia.

When there is an acute presentation, a CT scan is required, and when there is soft tissue involvement, an MRI.  A PET scan is more helpful than staging and diagnosis in determining whether the tumor has recurred.  BM studies, bone scans, and CSF analysis for CNS involvement are examples of specific tests.

Summary of Work-up Needed

This is how HL differs from NHL in that a bone scan is not required because there is no bone metastases.

In NHL patients, a PET scan can help detect recurrences following treatment.  If there is an elevated ICP pressure in brain tumors, no CSF study is performed.  CXR is conducted during surgery because patients with Wilms tumors have obvious lung metastases.

Also Read: What's New In Paediatric Oncology

General Principles Of Therapy

 Surgery is required at some point during treatment for solid tumors; it is not required for lymphoreticular cancers. Sometimes palliation is all that is required.

Neoadjuvant therapy: Radiotherapy and chemotherapy are administered prior to surgery for large tumors.

 Adjuvant therapy is administered following surgery to prevent recurrences and eliminate any microscopic mass that may have been left behind during surgery. It is done to lower the size of the tumor mass prior to therapy.

Children are more likely than adults to receive chemotherapy because they have a greater tolerance to the drug and because their tumors are more sensitive to it. Due to the unfavorable long-term effects of radiation, such as growth disruptions and neurocognitive issues, children are less likely than adults to receive radiation treatment.

Leukemia

The cornerstone of treatment is chemotherapy.  For the purpose of treatment or to avoid CNS involvement, certain children require craniospinal irradiation.

NHL

 The cornerstone of treatment is chemotherapy.
Radiation therapy to the brain is required to treat or prevent involvement of the central nervous system.
HL  Targeted treatment using radiation, surgery, or both.
Chemotherapy is required in cases of widespread illness.

Solid Tumor -  The cornerstone of therapy is surgery.

Adjuvant therapy or palliation may involve the use of chemotherapy or radiation.

Also Read: High-Yield NEET SS Pediatric Oncology Questions

Chemotherapy In Childhood Cancers

Chemotherapy regimens with many modality combinations are employed.  Tissues that proliferate quickly and are prone to adverse effects, such as the liver, spermatogonia, oral and intestinal mucosa, and bone marrow.  The most frequent side effect is myelosuppression, or bone marrow suppression.

Other adverse effects include alopecia, The toxicity of platinum compounds, such as cisplatin, on the kidneys
Haemorrhagic cystitis treated with ifosfamide and cyclophosphamide,  Mucositis,  Vinca alkaloids-induced neuropathy.  Diarrhea, vomiting, and nausea

Radiotherapy in Childhood Cancers

 Conformational irradiation is frequently used to prevent negative side effects. The radiation volume is shaped to fit the contours of the tumor, preserving the normal tissues around it and enabling targeted, high-dose radiation to be applied exclusively to the tumor.

Intensity-modulated radiation therapy (IMRT) and proton beam therapy are two examples.  Dermatitis is the most frequent acute adverse effect.  Nausea and diarrhea are the most frequent sub-acute effects, particularly in abdominal RT.  Other typical adverse effects include baldness, somnolence, and mucositis.

Radiation Units Summarised

Radiation is of 2 kinds

• Absorbed radiation - 1J of energy is absorbed by 1kg of matter.
• Equivalent radiation is 1J of energy absorbed by 1kg of biological tissue.
• Radiation units for absorbed radiation are gray (Gy). 
• The older units are Rad.
• 1 rad = 1 centigray(cGy).
• 1 gray = 100 centigray(cGy) = 1J/kg of tissue.
• The SI unit for equivalent radiation - Sievert (Sv).

• The most radiosensitive tissue is bone marrow.
• The least radiosensitive tissue is neurons or the brain.
• The most radiosensitive blood cells are lymphocytes.
• The least radiosensitive blood cells are platelets.
• The sebaceous gland function does not recover after radiotherapy.

Biological Therapy in Childhood Cancers

 Consists of immunotherapy, biological response modifiers, or endogenous compounds that have therapeutic effects at supraphysiological dosages. • A fast-growing discipline that has a major impact on overall survival.

When treating acute promyelocytic leukemia, all trans-retinoic acid (ATRA) is the recommended treatment.
In patients with Philadelphia chromosome-containing CML and ALL, imatinib mesylate is the recommended treatment.

Rituximab is an anti-CD20 monoclonal antibody used to treat Hodgkin and CD20+ lymphomas.  Vedontin (brentuximab): an anti-CD30 monoclonal antibody used to treat CD30+ lymphomas, such as the lymphocyte-predominant Nodular form of HL. (Disc 15-, 20-, and 30+). For neuroblastoma, the FDA has approved dinuuximab.  MIBG treatment, or radioactive metaiodobenzylguanidine, for neuroblastoma.

Immunotherapy in Childhood Cancers

It utilizes the immune systems and cells, conditioned to kill tumor cells. The CAR-T cells attack the cancer cells in vivo, and the patient shows improvement in the malignancy.

• The side effects of CAR-T cells therapy include.
  • Cytokine-release syndrome (CRS):-
  • Hypotension
  • Myalgias 
  • Vascular leak
  • Seizure
  • Confusion 
  • Cerebral edema.
• Treatment - tocilizumab (MAb) directed against the interleukin-6 receptor.
  • B-cell aplasia, IVIG treatment given.

Late Adverse Effects Of Cancer Therapy

Neurocognitive Dysfunction

 Chemotherapy may interfere with a child's neuronal synapsis and maturation, perhaps irreversibly impairing their cognitive and spatial configuration abilities. • The brain continues to develop during the first ten years of life.

In radiotherapy, it happens when craniospinal, ear, or total body irradiation is administered. It is more common in children under three years old, in females, in families with a history of learning disabilities, in doses greater than 24 gray, in supratentorial tumors, and in whole-body irradiation.

Sensory Neuron Hearing Loss

Common side effects of radiotherapy such as cranial, infratemporal, or nasopharyngeal irradiation; Associated with platinum-based chemotherapy drugs such as carboplatin and cisplatin.  Risk is frequently dose-dependent and has an additive effect when radiation and cisplatin are used together.

Peripheral Neuropathy

Common with medicinal substances such as vinca alkaloids.  Vinblastine, vincristine, cisplatin, and carboplatin for sensory neuropathy.  Vincristine and vinblastine-induced neuropathy, often known as glove and stocking neuropathy.  Vinblastine and vincristine for motor neuropathy.

Endocrine Dysfunction

More common with radiotherapy.Includes: -

Obesity, hyperphagia, diabetes insipidus, precocious, or delayed puberty, and growth failure. High doses of RT in the head and neck region up to 10 years of age have a high chance of developing thyroid malignancies in children.

Gonadal Dysfunction

Common with radiation therapy and chemotherapeutic agents such as alkylating agents; frequently dose-dependent, observed with RT doses ≥15 Gy in prepubertal girls and ≥10 Gy in pubertal girls; gonad radiation ≥ 20-30 Gy in boys for androgen insufficiency; reversible azoospermia seen at doses of 1-3 Gy, irreversible at doses >3 Gy; irreversible ovarian failure seen at doses >20 Gy; ovarian recovery superior to testis recovery.

Cardiac Toxicity

This condition manifests as cardiomyopathy or myocarditis and is brought on by anthracyclines such as daunorubicin and doxorubicin.The negative consequences are worse in the long run than they are in the short term.

Pulmonary Fibrosis and ILD

 Common with radiation therapy to the lungs or mediastinum;  Associated with chemotherapeutic drugs such as bleomycin, busulfan, lomustine, and carmustine.
If CT and RT are administered together, the risks are increased.

GI obstruction, strictures, and hepatic fibrosis

It occurs if radiotherapy ≥ 40-45 Gy is given.

Renal Insufficiency 

Common with platinum compounds and RT.

Osteoporosis/ Osteopenia/ Osteonecrosis

Common with corticosteroids.Methotrexate produces osteoporosis, and radiation >40 Gy causes osteonecrosis.

Risk of second malignancy

 The risk rises by 0.5% every year, meaning that 25 years after treatment, the incidence will be about 12%.

Commonly occurring second malignancies include.

Alkylating agents and topoisomerase II inhibitors-induced AML. Solid tumors, such as breast cancer, RMS, thyroid, and bone tumors.

Among childhood cancer survivors, breast cancer is the most commonly reported subsequent solid tumor, with an incidence ranging from 10–20% after 20 years from radiation.

Late Adverse Effects Of Cancer Therapy

 Risk-stratified shared care models establish classifications to identify patients at high risk of recurrent cancer.  Everything listed below poses a low risk.  Medication combined with alkylating drugs such as bleomycin, anthracyclines, or epipodophyllotoxins, or just surgery.  Radiation-free.  Minimal chance of return .  Moderate to nonexistent therapy-related toxicity.

The following are all at a moderate risk:  Low-to-moderate concentrations of alkylating substances such as bleomycin, epipodophyllotoxins, or anthracyclines.

Radiation doses that are low to moderate.  Autologous stem cell transplant.  Moderate persistent toxicity of medication or moderate chance of recurrence.

The risky scenario: Any of the subsequent  High concentrations of alkylating drugs such as bleomycin, epipodophyllotoxins, or anthracyclines.  Radiation at high doses.  SCT that is allogeneic.  High potential for therapy-induced recurrence or prolonged multiorgan damage. Patients must have ongoing follow-ups on a regular basis.

Important Points

 Leukoencephalopathy linked to high methotrexate dosage.  Damage to the heart caused by anthracyclines (Daunorubicin or Doxorubicin) in combination with trastuzumab or RT.  Bleomycin toxicity linked to pulmonary fibrosis.  Renal dysfunction linked to nitrosourea, ifosfamide, and platinum drugs.

Hearing loss brought on by the dose-dependent toxicity of cisplatin.

Hope you found this blog helpful for your NEET SS Pediatrics Oncology preparation. For more informative and interesting posts like these, keep reading PrepLadder’s blogs.