Radiotherapy

 early stage cancer usually effectively managed with either surgery or

radiation alone
 larger cancers usually managed with combination therapy
 surgery more effective in salvaging radiation therapy failures than vice
versa

Tumors that can be primarily treated with XRT

 all H+N cancers that are T1-T2 and N0-N1 necks exceptions:
1. nasopharynx
2. tumors of salivary glands and FOM generally treated primarily with
surgery

Combined Surgery and Radiation Therapy

 surgical failures usually are caused by residual microscopic disease

 radiation failures usually are caused by inability to eradicate bulky masses
 indications for adjuvant XRT:
1. T3-T4 tumours
2. extracapsular spread
3. multiple lymph node involvement
4. positive resection margins
5. recurrent disease
Energy sources:

1. Photons

2. Neutron: more destructive than photon

3. electrons

 Electrons differ from photons in that electrons travel only a certain (short)
distance within tissue.
 The absorption of the electron is directly proportional to their energy level
 The deposition of the majority of their dose is in superficial tissues, so they
are mainly used for treating superficial tumors

The most responsive tissue to radiotherapy+ higher recurrence rate:

1. Lymphoid tumor
2. Anaplastic tumor
3. Embryonal tumor

Note: sarcoma of bony origin has a very poor response

Regression Rates

 tumor regression rate is related to cycling time of tumor cells

Cell death:

 Eradicate only the cancer cells capable of unlimited division

 Cells are considered killed when they lose clonogenic survival

Factors affect the efficacy of radiotherapy:

1. Temperature:
Hyperthermia increase the efficacy

2. Oxygen content
Hypoxia protects tumor cells
This is why:
 1. we use hyperbaric Oxygen chamber
2. larger tumors are less responsive because it has hypoxic centers
3. exphotic tumor are more responsive since they are more vascularized

Cystotoxic drugs follows 1st order kinetics:

 Kills constant fraction of cells (%) regardless of the total # of cells

Fractionation and the “4 Rs” of Radiation Biology

 Conventional Fractionation: radiotherapy given in smaller interval (dosing 5

days a week for 5 weeks) rather than given all at once

 The rationale behind fractionation is to give the normal tissue time to repair
from sub lethal damage thus lower long term damage

1. Reassortment/redistribution:
 fractionation allows cells to proceed in their cycle to more
radiosensitive stages in their cell cycle
 the cell is most radioresistant in the S phase
2. Reoxygenation:
 fractionation allows for reoxygenation of previously more
hypoxic cells (more susceptible)
3. Repopulation:
 prolonged waiting between fractions results in regrowth of
tumor cells from sub lethal damage
 hypofractionation (fewer fractions) are used for tumors with
good ability to repair from sublethal injury (malignant
melanoma)
4. Repair:
 normal tissue tends to have better repair than tumor cells,
therefore it recovers more quickly from sublethal damage
  fractionation results in less total biological injury due to the
greater opportunity for repair, therefore it requires a higher
total dose than single or hypofractionated dosing

 fractionation has more acute but less log term toxicity

Methods of Fractionation

Conventiona Hyperfractionatio Accelerated Accelerated Hypofractionatio

l n Fractionatio Hyperfractionatio n

Fractionatio n n

n
5 doses/wk increases rate of Increase the Increase the rate decreases rate of
Tx (x2
for 5wk a day dosing) rate treatments
same overall Shorter Shorter duration
duration of
therapy duration
Higher dose per Increase the Increase the dose higher dose per

fraction dose fraction

Higher total dose Same total Higher total dose

dose
More acute

Less long

term

Positive biopsy result usually not reliable indicator of persistent disease until about
3 months after treatment
  lethally injured cells and surviving cells are morphologically
indistinguishable

Preoperative Radiation Therapy

Arguments in favour:

1. unrespectable lesions can be made resectable

2. extent of surgical resection can be diminished
3. before surgical intervention, treatment portals usually are smaller than
those needed postoperatively
4. microscopic disease is more radiosensitive preoperatively because it has
a better blood supply
5. viability of tumor cells disseminated through surgical manipulation is
diminished, so risk of distant metastasis decreases

Disadvantages:

1. slower wound healing

2. if there is residual disease after surgery, difficult to give more radiation

Postoperative Radiation Therapy

Arguments in favour:

 anatomic extent of tumour can be determined surgically; easier to define

treatment portals
 greater dose of irradiation can be given postoperatively than can be given
preoperatively
 total dose given can be based on residual tumour burden after surgery
 surgical resection easier and healing is better in tissue that is not irradiated

disadvantages:

 radiation may need to be postponed secondary to postoperative

complications
Intensity-Modulated Radiation Therapy (IMRT):

 Computer 3D-modeled therapy based on the size and location of the primary
tumor
 Principle: each board radiation is divided into smaller beam lets which are
then added to form a dose distribution that is tailored to the shape of the
target

 delivers higher doses of therapy to the tumor bed and spares uninvolved
structures by using combination of several intensity- modulated fields from
different beam directions

 effectiveness and reduction of complications dependent on skill of planners

 the numbers of treatment sessions are the same as conventional

 but the planning duration is longer

 advantages:
a) offer sparing of vital organs, including
1. salivary glands minor salivary glands (very sensitive)
2. mandible pharyngeal musculature
3. inner and middle ears (otitis externa, serous otitis media, and
auricular chondritis)
4. temporomandibular joints
5. temporal brain lobes
6. optic pathways

b) Offers a potential for better tumor control by reducing the

constraints on the tumor dose that are due to critical organs that
occasionally limit the tumor boost doses in conventional radiation
therapy.

Acute side effects:

 Occur during radiation therapy and in the following weeks.

 They include:
1. Mucositis: indicates that limit of tissue tolerance has been reached
2. Odynophagia
3. dysphagia
4. hoarseness
5. Xerostomia
6. Dermatitis
7. weight loss.

Late toxicity:

These toxicities may become apparent many months or even years after treatment.

1. Xerostomia
2. Fibrosis
3. Thyroid dysfunction
4. carotid artery rupture
5. radiation-induced myelitis.
6. Radiation-Induced Cancer:
a. Thyroid
b. Salivary gland cancer
c. Leukemia
d. sarcoma (may have lag period of 20 years)
e. temporal bone cancer

7. Osteoradionecrosis:

 Cause:

 hypocellularity, hypovascularity, and ischemia of tissue (not

infectious)
 the bone has high absorption rate and low reflection rate
 endarteritis in blood vessels lead to bone necrosis esp of the
mandible
  osteoradionecrosis of the mandible increased with
a) doses above 50 Gy
b) dental extractions performed after radiation
c) combined chemotherapy

 radionecrosis of the larynx may clinically mimic recurrent laryngeal

carcinoma

 Treatment:

initially treat conservatively with:

1. antibiotics
2. analgesics
3. meticulous oral hygiene
4. soft diet;
5. debridement may be required
6. consider hyperbaric oxygen;

recalcitrant painful mandibular disease, orocutaneous fistula,

and/or pathologic fracture

free tissue transfer necessary

Note the commonest infection in the oral cavity is candida albican

Contra-indication to Radiotherapy:

1. pt with collagen vascular disease

2. pregnancy
3. previous radiotherapy

Chemotherapy
Works best if given to patients with well differentiated Histology

Roles of Chemotherapy in H & N CA:

 1/3 pts with SCC present with early-stage I, II:

No chemotherapy needed

 Advanced stage III and IV cancer:

May improve survival and organ preservation

 metastatic disease + locoregional recurrences

chemotherapy has a palliative role

Clinical Trials:

Phase I:

 tolerance and pharmacologic properties of newly developed compounds are

studied
 end point is determination of maximally tolerated dose+toxcicity

Phase II:

 determine therapeutic activity, or efficacy, of a new drug in a specific

disease and stage
 end point is definition of activity measured as response rate, at an
acceptable rate of toxicity

Phase III:

 new drug or combination is compared with current standard therapy

Induction (neoadjuvant chemotherapy):

Aim: improve the likelihood of organ preservation (laryngeal/Hypopharyngeal

tumor) /cure

It results in improved survival

 Advantages:

1. The blood supply is undisturbed allowing chemotherapy to reach the tumor

cells

2. Tumor may shrink allowing more:

a. Rendering of marginally resectable lesion resectable
b. Lowering the tumor burden allowing less radical radiotherapy

3. Prompt elimination of the micrometastase aid in the cure: deliver

chemotherapy at a time of lower systemic burden

4. Macroscopic response can predict the microscopic response

Disadvantage:

1. The margin of the tumor may be obscured

Chemoradiotherpy:

Rationale behind using chemoradiotherpy:

 Chemotherapy treats systemic dx(micro-metastasis), while radiation

treats local disease

 Chemotherapy cytotoxic effect making cells more sensitive to radiotherapy

 May arrest cells in a portion of the cell cycle that is more radiosensitive
 Some chemotherapy medication provides protection to normal tissue

 Affects rapidly dividing cells as radiotherapy so the acute effect is more

intense

Advantages:

 Improve disease free survival

 Improve overall survival dx

Disadvantage:
  Increased toxicity

Indication of chemoradiotherpy:

1. Organ preservation
2. Advanced tumor
3. Post operative:
a) Positive surgical margins
b) Extra-capsular extension