HC22: Chemoradiation

Enhancement of sensitivity

The therapeutic window can be increased by:

• Fractionation of the total dose
• Decreasing the toxicity → lower the dose to normal tissue
• Increasing the tumor control → enhancing the sensitivity

The sensitivity can be enhanced via:

• Chemoradiotherapy
  • Radiotherapy + chemotherapy
• Biological agents
  • Cetuximab in head and neck cancer
• Oxygen to tumor tissue
  • Increases the oxygen which reaches the tumor → high response rate
  • Doesn’t really work
• Hyperthermia
  • Exposing tumor tissue to high temperatures
  • In patients with cervical cancer and relapses of breast cancer

Concomitant and sequential

Chemoradiation is a combination between radiotherapy and chemotherapy. This can be:

• Concomitant: in the same time period
• Sequential: behind each other

Mechanism of action

If chemoradiation is used, DNA damage to tumor cells is more often fatal than with irradiation alone. Normal cells have a greater variety of escape mechanisms and repair the damage, which causes them to be more able to repair DNA than tumor cells → have a higher tolerance to the therapy. There are different modes of action for radiation and chemotherapy. Chemotherapy is used as a radiosensitizer which enhances the effect of radiotherapy.

Synergy:

Chemo- and radiotherapy can be used to create synergy:

1. Cisplatin adducts to DNA → causes single strand breaks
2. Radiotherapy will create more breaks which are more difficult to repair
3. Post-irradiation repair is inhibited

Chemotherapy inhibits nucleotide metabolism, while radiation is effective in a different phase of the cell. Chemotherapy treats hypoxic cells, which are less radiosensitive for radiotherapy. Chemoradiation is seen as local treatment to increase local control and thereby cure.

Uses of chemoradiation

Chemoradiation is only used in curative treatment:

• As a primary treatment modality
  • Organ saving treatment
  • Curative resection is not possible
• As adjuvant treatment
  • Increases local control after resection
• As neoadjuvant treatment
  • Increases local control after resection

Primary treatment:

As primary treatment, chemoradiation can be used as an organ saving treatment. This can be useful when curative resection causes a large loss of function and therefore isn’t possible or when the patient isn’t operative anymore. Examples are:

• Anal cancer
  • When surgery is done, the patient will most likely lose his anus and need a stoma
• Head and neck tumors
  • E.g. in case of larynx cancer: if a patient loses their voice, the quality of life decreases significantly
• Cervical carcinoma
• Vulvar cancer
• Esophageal cancer
  • Not operable
• Stage III lung cancer

Adjuvant treatment:

Chemoradiation as adjuvant treatment increases the local control after resection, for example in case of stomach cancer. It can prevent recurrence.

Neoadjuvant treatment:

Chemoradiation as neoadjuvant treatment:

• Increases the local control after resection
• Downstages resectable cancer

Examples are operable esophageal cancer and advanced stage rectal cancer.

Side effects

Chemoradiation has much more acute side effects in contrast to surgery:

• Acute side effects
  • Skin
  • Mucosa
  • Pain
  • Infections
• Late side effects
  • Function loss
    • Incontinence
    • Swallowing
  • Fibrosis/stenosis
    • Especially in the neck region
  • Edema
    • Especially in the neck region
  • Infertility

Acute toxicity can be healed with analgetics, ointments and by encouraging patients.

Stereotactic radiotherapy

Stereotactic radiotherapy is a precisely targeted radiation at much higher doses, in only a single or few treatments, as compared to traditional radiation therapy. This treatment is only possible due to the development of highly advanced radiation technologies that permit maximum dose delivery within the target while minimizing the dose to the surrounding healthy tissue. The goal is to deliver doses which will destroy the tumor and achieve permanent local control.

Stereotactic radiotherapy has a high tumor control and results in more direct cell death.

Practice:

Stereotactic radiotherapy works as follows:

1. Radiotherapy is given from many different angles around the body
2. The beams meet at the tumor
3. The tumor receives a high dose of radiation, while the tissues around it receive a much lower dose → lowers the risk of side effects
   • A high dose is given to the tumor in 1-8 fractions

This leads to a more direct cell death compared to a normal fractionation scheme. There is a steep dose fall → the dose in normal tissue is low.

Indications:

Stereotactic radiotherapy is used in the following cases:

• Brain cancer
  • 1-3 brain metastasis
  • Small benign tumors
• Stage I lung cancer
  • Ideal for patients who cannot undergo lobectomy
  • Results of stereotactic radiotherapy and lobectomy are the same
• Oligo metastasis
  • The immune system is activated due to high amounts of cell death → amplifies the effect of immunotherapy

Proton therapy

Proton therapy is a type of particle therapy that uses a beam of protons to irradiate tumors. The advantage of proton therapy over other types of external beam radiotherapy is that the dose of protons is deposited over a narrow range of depth. This results in:

• Minimal entry
• Minimal exit
• A scattered radiation dose to healthy nearby tissues

Bragg peaks:

The difference between proton and photon therapy is that proton therapy gives a large amount of its energy later in its path, while photons lose energy as they travel further into the patient. The whole patient can be covered by giving many little Bragg peaks, while keeping the dose in the surrounding tissues lower. This can be done with the pencil beam technique.

Pros and cons:

Proton therapy has both advantages and disadvantages:

• Advantages
  • Increases the dose to the tumor → improves local control
  • Spares normal tissue → less side effects
• Disadvantages
  • Expensive
  • Restricted in radiation possibilities
  • Range uncertainties
    • Small day to day chances

Standard proton indication:

Proton therapy is mainly applied in:

• Children
• Tumors from the skull base and spine
  • Chordomas or chondrosarcomas
  • Need very high doses to be cured
  • Are in difficult positions
    • Vital parts of the memory system and the carotis arteries are located behind the eyes
      • These tissues are more sensitive to radiation than the tumor is → destruction of these parts is not an option

There also are model based indications. These are based on comparison of photon/proton treatment plans. If the proton treatment plan is better at sparing normal tissue, a reference to the proton center is made. This is mainly based on grade 2-3 toxicity:

• Proton therapy results in >10% decrease in grade 2
• Proton therapy results in >5% decrease in grade 3

This can happen in case of the following cancers:

• Head/neck cancer
• Breast cancer
  • Using proton therapy can spare the heart
• Brain tumors
  • Proton therapy can irradiate a much smaller part of the brain than photons
    • Photons will irradiate the contralateral side → cause problems in cortical functioning
• Lung cancer
• Esophageal cancer
• Mediastinal lymphoma

Photon versus proton treatment:

In short, both photon and proton treatments have advantages and disadvantages:

• Photons
  • Advantage
    • Steep dose decline
    • No problems between tissue transitions
  • Disadvantage
    • More dose behind the tumor
    • More chance on the acute and late side
• Protons
  • Advantage
    • Less dose in normal tissue behind the tumor
  • Disadvantage
    • Less steep dose decline
    • More problems with tissue transitions
    • More skin toxicity
    • Costs