Block 4 - Pediatric Cancers

ONCOL 309 - Clinical Oncology I. University of Alberta

Tumors in children tend to grow ______ and spread ____ than adult tumors

grow quicker and spread faster

Three most common types of pediatric cancers

1. Leukemia

2. Brain

3. CNS

What is the most common leukemia in children

Acute lymphoblastic leukemia (ALL)

What is the most common solid tumor in children

brain

Xeroderma Pigementosa

recessive gene unable to repair UV light damage

• ex: p53 oncogene

Ataxia telangietasia

affects the cerebellum by causing poor coordination and weakens the immune system

• ATM mutation

Bloom’s syndrome

a genetic disorder characterized by short stature, sun-sensitive skin changes, and increased cancer risk. It is caused by mutations in the BLM gene.

Fanconi’s Syndrome

a disorder in which the proximal tubule function of the kidney is impaired

Neurofibromatosis

nerve tissue grows tumor

Down’s Syndrome

extra copy of 21st chromosome

More than 2/3 of children can expect to be long term survivors of cancers due to what treatment application?

adding chemotherapy to surgery and RT

Radiation effects on pediatrics

Neuropsychological (CNS)

tissue hypoplasia

impaired growth

RT induced sarcomas

Chemotherapy effects on pediatric patients (3)

myocardial damage due to anthracyclines

nephrotoxcity due to cisplatin

secondary leukemias due to alkylating agents

how has the survival rates changed for pediatrics from the 1970s due the 2000s

1970s: 58%

2000s: 83.4%

how has the survival rate changed for ALL in pediatrics from 1975 to 2012

1975: 57%

2012: 92%

What is the prognosis for patients with glioma

poor; less than 1 year survival after diagnosis with no tumor improvemet

• brain cancer is the leading cause of death among children

what is the primary treatment modality for pediatric cancers

surgery is the preference

• RT and chemo are supplementary for surgery

what percent of children with cancer receive RT as part of their treatment

40-50%

what are the two goals of radiation therapy for pediatric patients

1. acheive tumor eradication

2. reduce treatment related toxicities

why is participation in clinical trials recommended for pediatric cancer cases

Participation in clinical trials is recommended for pediatric cancer cases because it provides access to new treatments and therapies that are not yet widely available, can lead to improvements in care, and contributes to the advancement of cancer research specifically tailored for children.

• you will get the baseline treatment no matter what

Children’s Oncology Group (COG) leads clinical trial investigations for what percent of pediatric patients

50%

within the children’s oncology group (COG), there are special treatment considerations for trials under what four categories

data guidelines, concurrent chemo, immobilization, and anesthesia

5 challenges to radiation therapy treatment for pediatric patients

1. immobilization

   • anestheic or appropriate method

2. trust

   • allow pt to manipulte equipment

3. understanding

   • comprehension of RT is limitied

4. parents

   • protective of child, nervous and scared

5. medical team

   • multidisciplinary: lots of moving parts

what RT toxicities occur from treatment of pediatric patients to the epiphysis of bones

growth alteration

what is the RT dose threshold for effecting bone growth

10 Gy

• there are some situations where 20 Gy or more are used

• there is evidence of a dose reponse effect

  • there is a greater effect seen with a dose of >33 Gy than <33 Gy

what RT toxicities occur from treatment of pediatric patients from scatter to the gonads

1. affect development of sexual organs

2. increased risk of congenital deformity

RT side effects in boys after gondal radiation

• germinal aplasia

• gynecomastia

• decreased testosterone

boys will have transient oligospermia after ____ but slow recovery can occur after _____

2 Gy, 2-5 Gy

For girls, oocytes are extremely senstive, but there has been reports of pregnancies after receiving _____ Gy

12 Gy

• most times oocytes fail after 2 Gy

what RT toxicities occur from treatment of pediatric patients to the thyroid/pituitary

1. endocrine deficiencies

   • growth hormone after pit. irradiation

2. hypothyroidism

what RT toxicities occur from treatment of pediatric patients to the kidney

nephropathy

• seens 2-3 years post RT (slow responding organ) with dose >15 Gy to both kidneys

what RT toxicities occur from treatment of pediatric patients to the lung

altered pulmonary function

what RT toxicities occur from treatment of pediatric patients to the brain

anatomic and functional abnormalities

• decrease in cognitive capabilities

what RT toxicities occur from treatment of pediatric patients to the spinal cord

paresis and transverse myelitis

• Lhermitte’s (electric shock-like sensation that travels down the spine and into the limbs upon forward flexion or movement of the neck) may result due to demyelination

what RT toxicities occur from treatment of pediatric patients to the liver

hepatomegaly, jaundice, ascites, thrombocytopenia, elevated transaminase

when are RT induced hepatopathy seen post RT?

usually occur 1-3 months post RT

Where do Ewing’s Sarcoma arise from

from primative cells in the body that form in the bone and soft tissue

What is a sarcoma

a tumor that arises out of connective tissues, most commonly found in the extremeties

• can involve muscle and soft tissue around tumor site

EwS Epidemiology

Age range:

peak incidence:

M:F -

how many cases per 1 million

more common in what race:

childen aged 10-19

• peak incidence at 15 years of age

M:F - 1.6:1

3 cases per 1 million

6x more common in caucasians vs. African americans

EwS is the second most common bone sarcoma in children behind ____

osteosarcoma

EwS Etiology

chromosome rearrangement found between what 3 chromosomes

chromosome aberration found in 95% of cases

• rearrangement b/w chromosomes 11, 21, or 22

common locations of EwS

seen is diaphysis (shaft) of bones

• 53% in extremeties

• 47% in central axis

most common sites are femur and pelvis

2 most common metastatic sites of EwS

lungs and bones

5 best prognostic treatment factors for EwS (pre-treatment)

• distal or peripheral tumor

• volume <200 ml

• <14 years

• female

• no mets or mets in lung/bone only

5 worst prognostic treatment factors for EwS (pre-treatment)

• tumor > 8 cm

• axial tumor (spine sacrum)

• 14-20 years old

• high WBC and fever

• mets: lungs, multiple bones, bone marrow

3 post-treatment good prognostic indicators for EwS

• female

• younger age

• minimal or no residual disease after pre-surgical therapy (chemo)

post-treatment poor prognostic indictors of EwS

poor response to pre-surgical chemo

• increase risk of local recurrence

EwS natural history

occurs primarily in the bone but may also arise in soft tissue and muscle in close proximity to tumor

• thought to arise from immature reticulum cells in the marrow cavity

local spread occurs along the marrow cavity causing bone destruction

what are the main sites of clinical presentation of EwS

predominantly in the diaphyisis (shaft) of these long bones

• lower extremeties (41%)

• pelvis (26%)

• chest wall (16%)

• upper extremeities

• spine

• skull (2%)

Early clinical presentation of EwS

swelling and pain near tumor site

• 90% complain of pain and 2/3 present with mass

warm lump in arms, legs, chest, pelvis

3 late systemic symptoms of EwS

fever

unexplained fracture

intratumor hemorrhage —> anemia, necrosis —> infection

What would a CBC and liver function test show in an EwS patient

CBC —> anemia if bone filtration

liver function test —> elevated LDH = advanced disease

what would a radiograph of the tumor site of EwS show

ill defined bone margins, soft tissue involvement

• onion like appearance (lytic lesions)

• moth eaten appearance

what 4 diagnostic imaging procedures can be done for EwS

• CXR: check for mets

• CT: bone destruction, lung mets, extent of tumor

• MRI: soft tissue involvement

• PET Scan: detect mets, intramedullary or blood spread

What 4 tumors are apart of the Ewing Sarcoma Family of tumors

1. Classic EwS

2. Primative neuroectodermal tumor

3. Askin tumor (of the chest wall)

4. Extraosseous Ewings Sarcoma

all have mesenchymal bone marrow stem cell origin

Histological features of EwS

round small blue cells with scant cytoplasm, high nuclear-to-cytoplasmic ratio, and usually associated with a fibrillary background.

three routes of spread for EwS

1. Hematogenous spread

2. Lymphatic spread

3. Direct invasion of adjacent tissues

What are the two stages of EwS

1. localized

   • clinial and imaging techniques, no spread beyond primary site, maybe some spread into adjacent of soft tissues

2. metastatic

Who is part of a treatment team in an EwS patient

1. surgeon

2. Med Onc

3. Radonc

4. peds nurse

5. socail work

6. rehab specialist

7. RT

why is chemo so important for ewings sarcoma

since most patients have occult (hidden) metastatic disease and EwS is very sensitive to chemotherapy

two treatment options for localized EwS

1. Neo-adjuvent chemo + surgery

2. RT + adjuvent chemotherapy

   • remember chemo is important to have

when may RT be used over surgery in EwS

when functionable and cosmetic morbidity or surgery is deemed to high

What is the multidrug approach for nearly all EwS cases

VAdriaC-IE

• vincristine

• doxorubicin (adriamycin)

• cyclophosphamide

+ ifosamide and etoposide alternating every two weeks

duration of chemo for EwS

roughly 6 months

why is induction chemo important for EwS

Induction chemotherapy is crucial in Ewing Sarcoma (EwS) as it aims to reduce tumor size, control metastatic spread, and improve the overall response to subsequent treatments.

• can also show how the tumor and patient responds to tumor

when is Stem cell support used alongside chemo for EwS

when patients have a high risk of relapse and a poor response to initial treatment

• high dose treatment with autologous stem cell transplant may improve outcome

when is surgery recommended (although never primary over chemo)

when lesion is resectable

• debulking procedure

• total in expandable bone ( take all of rib/clavicle)

• amputation

• limb-salvage surgery is possible

What two reasons would RT be recommended for EwS

1. patients with incomplete resection after surgery

2. patients who would suffer loss of function after surgery

when is adjuvent RT used after surgery

• residual microscopic disease

• inadequate surgical margins

• viable tumor in resected portion and close surgical margins

what energy is used for RT in EwS treatment

6 MV

• these are children, this is more than enough

• immobilization and position varies for age of patient and tumor site

dose / fractionation and margins for pt had pre-chemo and no Sx

50-60 Gy / 25-30 days

• 2 cm margins

EwS dose / fractionation and margins if pt had surgery (2 phases)

2 phases

1. 4500 cGy/ 25 fraction to whole bones (minus growth plate)

2. 1000 cGy / 5 fractions boost to tumor bed with generous margin

   • for high risk tumor area

what treatment technique is typically used for EwS patients

IMRT

why are the fields shaped to maintain a route for lymphatic drainage in long bones?

To prevent lymphedema and preserve function.

• decreases QoL

What should RT fields for EwS patients include

affected limb and full length of surgical scar

• want to include bolus

What is the shrinking field technique for EwS patients

the two phase boost approach previously mentioned

• tumor + margin for microscopic disease and nodes

• reduce size of field to include disease and minimize margin in second phase

  • exclude epiphyseal plate (marrow) this will effect delivery of chemo

why would electron RT make sense for cancers in the ribs

will reduce dose to lungs

what three factors does RT treatment of metastatic or recurrent EwS depend on

site of recurrence

prior treatment

individual consideration

EwS pulmonary mets RT plan

Energy

Technique

Dose

Margins

whole lung RT:

POP

6 MV

12-20 Gy to relieve cough and dyspnea

• include apex of lung and 1 cm of lateral space

• we dont treat brachial plexus and humoral head so we shield them

Acute skin side effects for EwS patients

erythema, dry and moist desquamation

Chronic skin side effects for EwS patients

telangietasia and hyperpigmentation

Side effects in muscle for EwS patients

atrophy

• hypoplasia occurs after 20 Gy

• physio required

Side effects in bone for Ews Patients

shortening and weakening

arrested bone development occurs after 20 Gy

what dose do we we see an increased risk of 2nd malignancies for EwS patients

60 Gy

Survival for localized EwS of the bone

70% at 5 years

survival for metastatic EwS of the bone

30% at 6 years

Survival for lung, bone, and both mets

lung: 40% at 4 years

bone: 28% at 4 years

Combined: 14% at 4 years

Future considerations for EwS treatment

better systemic agents

genetic therapy targeting translocations that cause malignancy

Bone and stem cell transplants

what is a wilm’s tumor

A childhood kidney cancer that usually occurs in children aged 3 to 4 years. It is characterized by the presence of a tumor on one or both kidneys and often presents with abdominal swelling or pain.

• aka nephroblastoma

Wilm’s tumor epidemiology -

Peak incidence:

more common in which gender:

most common ___ cancer in children

what ethnicities is it most common in:

rare tumor

3-5 years

more common in females

most common abdominal cancer

more common in Africans

three associated GU abnomalities in children that result in Wilms tumor screening every three months until age 8

1. hemihypertrophy

2. cryptoorchidism

3. hypospadias

4 phenotypic syndromes of Wilm’s Tumor

1. Denys-Drash syndrome

   • 90% risk

2. WAGR syndrome (wilms, anirida, genital abnormalities, retardation)

   • 50% chance

3. Beckwith-Wiedemann Syndrome

   • 10% risk

4. Mutations of WT1 gene at chromosome 11

Poor prognostic indicators of Wilm’s tumor (5)

stage of disease at diagnosis (worse than stage 1)

diffuse anaplasia

age of patient (worse >18 years old)

tumor size at presentation (large)

LN involvement

Early Clinical Presentation of Wilm’s tumor

patients typically present with an asymptomatic abdominal mass, but also may present with pain

• in addition to: hematuria, UTI, fever, anemia

Late Clinical Presentation of Wilm’s tumor

• pain at distant mets

• internal bleeding from ruptured tumor

• respiratory distress (abdominal distentions ± pulmonary mets)

How is Wilm’s tumor diagnosed

physical and history (past and family)

routine lab work: CBC, blood chemistry, liver renal function

What 3 imaging modalities can be used to diagnose Wilm’s tumor

1. abdominal U.S

2. Chest + Abdo X-Ray

3. CT - Chest/Abdo

what 4 imaging modalities can be used to stage Wilm’s

1. CT

2. X-ray

3. MRI

4. ultrasound

what are the two histologic groups for Wilm’s tumor

1. favourable

2. unfavourable (anaplastic)

Favourable Wilm’s pathology -

mimics ___ development

prognosis and chemo response

mimics normal kidney development

• 3 cell types (blastemal, epithelial, stromal)

  • blastemal = most malignant component

• better prognosis

• better chemo response