Agents of Radiotherapy

Dr Bassi PU

University of Abuja

MBBS Lecture Series

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Introduction�

• Radiation has been an effective tool for treating cancer for more than 100 years

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• More than 60 percent of patients diagnosed with cancer will receive radiation therapy as part of their treatment

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• As underdeveloped countries gain access to therapeutic radiation procedures, these numbers will only increase.

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• Unfortunately, normal tissue toxicity still remains a major dose-limiting factor in the use of RT.

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Patient being treated with modern radiation therapy equipment.

RADIATION THERAPY

Radiation therapy: is a local modality used in the treatment of cancer.

• High energy waves such as x-rays, gamma rays or electron beams may be used to destroy or shrink tumor cells.
• Success depend in the difference in the sensitivity between the tumor and normal tissue.
• It involves the administration of ionizing radiation in the form of x-ray or gamma rays to the tumor site.
• Radiation therapy may be offered prior to or following surgery or chemotherapy.

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RADIATION THERAPY

• It can also be used for palliation to relieve symptoms of pain caused by tumor lesions that are inoperable.
• The outcome of radiation therapy is dependent on several factors such as dose, duration, mode of radiation delivered and the properties of the tumor such as its molecular properties, sensitivity to radiation, oxygenation, etc.
• As radiation does not differentiate between the normal and malignant cells, you may experience side effects depending on the area of irradiation.

RADIATION THERAPY

• A course of radiation therapy is preceded by a simulation session in which low-energy beam are used to produce radiograghic images that indicate the exact beam location.
• In order to minimize side effects and be effective, Radiation therapy is usually delivered in mall doses called fractionated doses such as as 180 to 300 cGy per day,spread across weeks ( eg five times a week of 5-8 weeks).
• Radiation therapy with curative intent is the main treatment in limited stage is Hodgkin’s disease , some NHL, limited stage CA prostate, gynecologicl tumors & CNS tumor . 
• Also can be used in palliative &.emergency setting.

Types of radiation Agents used to treat cancer

• Radiation used for cancer treatment is called ionizing radiation because it forms ions (electrically charged particles) in the cells of the tissues it passes through.
• It creates ions by removing electrons from atoms and molecules.
• This can kill cells or change genes (DNA) so the cells stop growing
• Ionizing radiation can be clasified into 2 major types:
1. Photon radiation (x-rays and gamma rays)
2. Particle radiation (such as electrons, protons, neutrons, carbon ions, alphaparticles, and beta particles)
• Some types of ionizing radiation have more energy than others.
• The more energy, the more deeply the radiation can penetrate (get into) the tissues.

Most external beam radiation treatments use photons generated by a linear accelerator.

Source: Varian Medical Systems Inc.

Types of radiation Agents used to treat cancer

• Other forms of radiation such as radio waves, microwaves, and visible light waves are called non-ionizing.
• They don’t have as much energy and are not able to form ions.
• Non-ionizing radiation does not have enough energy to remove electrons from an atom.

Photon radiation

• A high-energy photon beam is by far the most common form of radiation used for cancer treatment.
• It is the same type of radiation that is used in x-ray machines, and comes from a radioactive source such as cobalt, cesium, or a machine called a linear accelerator (linac, for short).
• Photon beams of energy affect the cells along their path as they go through the body to get to the cancer, pass through the cancer, and then exit the body.

Particle radiation

• Particle beams (or Electron beams) are also produced by a linear accelerator.
• Electrons are negatively charged parts of atoms.
• They have a low energy level and don’t penetrate deeply into the body.
• This type of radiation is used most often to treat the skin, as well as tumors and lymph nodes that are close to the surface of the body

Particle radiation

Proton beams: Proton beams are a form of particle beam radiation.

Protons are positively charged parts of atoms.

They release their energy only after traveling a certain distance and cause little damage to the tissues they pass through.

This makes them very good at killing cells at the end of their path.

Proton beams are thought to be able to deliver more radiation to the cancer while doing less damage to nearby normal tissues.

• Proton beam radiation therapy is used routinely for certain types of cancer, but still need
• more study in treating others.
• It requires highly specialized equipment and is not widely available.

Particle radiation

• Neutron beams: Neutron beams are used for some cancers of the head, neck, and prostate and for certain inoperable tumors.
• A neutron is a particle in many atoms that has no charge.
• Neutron beam radiation can sometimes help when other forms of radiation therapy don’t work.
• Because neutrons can damage DNA more than photons, effects on normal tissue can be more severe.

Particle radiation

Carbon ion radiation: Carbon ion radiation can be helpful in treating cancers that don’t usually respond well to radiation (called radioresistant cancers).

It’s also called heavy ion radiation because it uses a particle that’s heavier than a proton or neutron.

The particle is part of the carbon atom, which itself contains protons, neutrons, and electrons.

Because it’s so heavy, it can do more damage to the target cell than other types of radiation.

As with protons, the beam of carbon ions can be adjusted to do the most damage to the cancer cells at the end of its path.

But the effects on nearby normal tissue can be more severe.

Particle radiation

• Alpha and beta particles: Alpha and beta particles are mainly produced by special radioactive substances that may be injected, swallowed, or put into the body.
• They’re most often used in imaging tests, but can be helpful in treating cancer.

Goals of radiation therapy

• To cure or shrink early stage cancer
• To stop cancer from recurring (coming back) somewhere else
• To treat symptoms caused by advanced cancer

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Goals of radiation therapy

1.To cure or shrink early stage cancer

• Some cancers are very sensitive to radiation.
• Radiation may be used by itself in these cases to make the cancer shrink or destroy the tumout completely - Achieve Cure.
• For other cancers, radiation may be used before surgery (as pre-operative or neoadjuvant therapy) to shrink the tumor, or after surgery to help prevent the cancer from coming back (this is called adjuvant therapy).
• Kill residual microscopic disease left after surgery or chemotherapy

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Goals of radiation therapy

2. To stop cancer from recurring (coming back) somewhere else

• If a type of cancer is known to spread to a certain area, doctors often assume that a few cancer cells might already have spread there, even when imaging scans (such as CT or MRI) show no tumors.
• That area may be treated to keep these cells from growing into tumors.
• For example, people with some types of lung cancer may get preventive (or prophylactic) radiation to the head because this type of cancer often spreads to the brain.
• Sometimes, radiation to prevent future cancer can be given at the same time that radiation is given to treat existing cancer, especially if the prevention area is close to the tumor itself.

Goals of radiation therapy

3.To treat symptoms caused by advanced cancer

• Sometimes cancer spreads too far to be cured.
• But even some of these tumors can still be treated to make them smaller so that the person can feel better.
• Radiation might help relieve symptoms such as pain, trouble swallowing or breathing, or bowel blockages that can be caused by advanced cancer.
• This is often called palliative (Cure) radiation.

Radiopharmaceutical Agents/drugs

• Radiopharmaceuticals are drugs that contain radioactive materials called radioisotopes.
• They may be put into a vein, taken by mouth, or placed in a body cavity.
• Depending on the drug and how it’s given, these materials travel to various parts of the body to treat cancer or relieve its symptoms.
• They put out radiation, mostly in the form of alpha and beta particles that target the affected areas.

Radiopharmaceutical Agents/drugs

Strontium-89, samarium-153, and radium-223: are used for treatment of bone pain. Tumors that have spread to the bones (bone metastases).

• These medicines are given in veins (intravenously or IV),
• The radiation they give off then kills cancer cells and eases the pain caused by bone metastases.

Radioactive iodine: Treatment of thyroid cancer: The thyroid gland absorbs nearly all of the iodine in the blood.

• Because of this, radioactive iodine (also called radioiodine or iodine-131) can be used to destroy the thyroid gland and thyroid cancer with little effect on the rest of the body.
• This treatment is often used after thyroid cancer surgery to destroy any thyroid cells left behind.

Radiopharmaceutical Agents/drugs

Phosphorus-32: This form of phosphorus (also known as P-32 or chromic phosphate P 32) are used for treatment of Brain tumors. It is inserted into brain tumors that are cystic (hollow) to kill the tumor without hurting the healthy parts of the brain.

• In the past, P-32 was used to be given as an IV, as a common treatment of polycythemia vera. And also for treatment of ovarian cancer, by inserting it inside the abdomen.

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Radio-labeled antibodies: Monoclonal antibodies immune system proteins that attack only a specific molecular target on certain cancer cells. These antibodies is paired with radioactive atoms.

• Given Parenterally, where the antibodies act as homing devices.
• They attach only to their target, bringing tiny packets of radiation directly to the cancer.
• Radio-labeled antibodies are used to treat some non-Hodgkin lymphomas, especially those that don’t respond to other treatments.

Complication of Radiation

• There are two types of toxicities

- acute and long term toxicity long term toxicity. 

• Systemic symptoms such as Fatigue , local skin reaction , GI toxicity , oropharyngeal mucositis , xerostomia & myelosuppression. 
• Long-term sequelae: may occur many months or years after radiation therapy.
• Radiation therapy is known to be mutagenic, carcinogenic ,and teratogenic, and having increased risk of developing both secondary leukemia and solid tumor.

Radioprotective agents for radiation therapy

• When RT is applied, Normal tissue side effects adversely affect
• - a patient’s quality of life both during and after RT.
• - May also bring about radiation dose reductions or treatment delays that can lead
• to poor therapeutic outcome.

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• Consequently, the protection of normal tissues from radiation injury
• continues to remain an important goal of the radiation oncology community.

In general, efforts to achieve this goal have focused on two major approaches

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1.the development of technological improvements in radiation delivery and accuracy to reduce the amount of normal tissue exposed. Example includes

• advancements in intensity-modulated radiotherapy,
• image-guided radiotherapy,
• conformal radiotherapy,
• stereotactic radiotherapy and
• proton therapy are currently being used to successfully limit normal tissue toxicity in many patients

2.to reducing normal tissue toxicity, by the development of compounds, either synthetic or naturally occurring, which can be used to modulate the response of normal tissues to irradiation.

There are three categories of these compounds, depending upon the time the agent is administered with respect to the radiation.

i.Radioprophylactics (true radioprotectors): administered before radiotherapy; designed to protect against

radiation-induced injury.

• majority of the radioprophylactics function through free radicalscavenging/antioxidative mechanisms.
• Eg Amifostine: a prototype prophylactic drug cur_x0002_
• rently available in the clinic.

Ii. Radiomitigators are delivered after radiation exposure, but prior to

• the manifestation of normal tissue toxicity, in an attempt to prevent or attenuate the expression of radiation-induced side effects.
• Example.Palifermin : is a prototype mitigant.

Iii. Treatments for radiation injury: delivered following the clinical appearance of normal tissue toxicity

and function to cure or ameliorate the radiation damage

Radiation protectors in clinical use

1. Sulfhydryl compounds eg Amifostine

MOA: Free radical scavenger

Clinical indication: In clinical use for protection against xerostomia

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2.Cytokines and growth factors eg Palifermin

MOA:Stimulates proliferation and differentiation;DNA repair; Reactive oxygen species detoxification

Clinical Indications: In clinical use to prevent or reduce mucositis after

bone marrow transplantation

Radiation protectors in clinical use

3. Nitroxides eg Tempol

MOA: Detoxification of Reactive oxygen species

Clinical Uses: Radioprotection in animals. Phase I trial using topical application showed reduced radiation_x0002_induced alopecia

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4. Naturally occurring antioxidants eg Genistein

MOA: Detoxification of Reactive oxygen species ; tyrosine kinase inhibitor, hematopoietic stem cell quiescence

Clinical uses: demonstrate both radiation protection in normal tissues and radiation sensitization in tumor tissue

Radiation protectors in clinical use

5. ACE inhibitors eg Captopril

MOA: Angiotensin II inhibition; suppression of radiation-induced proliferation, NOS synthesis, TGF-β induction

Clinical Indicators: Radioprotection in animal studies. Results from clinical trials on prevention of radiation pneumonitis have not been definitive

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6. Inhibitors of apoptosis eg Entolimod

MOA: Suppression of apoptosis through activation of NF-κB

Clinical indications: Entolimod protects against lethal total body irradiation in mice and primates

Summary: Radiatherapeutic Agents

The problem

● Technological improvements in radiation therapy are currently being used to successfully limit normal tissue toxicity in many patients.

● However, the close juxtaposition between tumor and surrounding normal tissues precludes the possibility that these technological advances can completely remove normal tissue from the radiation field.

● The need for pharmacological agents that can reduce radiation-induced normal tissue toxicity, therefore, is of critical clinical importance.

● Currently, however, only two radioprotective compounds, amifostine and palifermin, have received US FDA approval for use in radiation therapy.

Summary: Radiatherapeutic Agents

Radioprotective agents in use or development

● The search for pharmacological agents that can prevent or mitigate radiation-induced damage to normal tissues is currently an intensive area of investigation.

● Historically, much of the focus on radioprotective drug development has centered on synthesizing compounds with free radical scavenger/antioxidant action that could neutralize radiation-induced radicals:

• Development of free radical scavengers/antioxidant remains an intense focus of study;
• Examples include sulfhydryl compounds, superoxide dismutase and superoxide dismutase mimetics, nitroxides and naturally occurring antioxidants.

Summary: Radiatherapeutic Agents

Radioprotective agents in use or development

• With increasing understanding of the pathways involved in the cell’s stress response, newer alternative strategies for
• radioprotector drug development have evolved, which the series of cellular insult recognition/repair cascades initiated
• following exposure to radiation:
• ū These agents act to ameliorate radiation injury by promoting repopulation of critical dose-limiting systems,
• inhibiting apoptosis or altering the balance between profibrotic and antifibrotic regulators;
• ū Examples included the cytokines and growth factors, angiotensin-converting enzyme inhibitors and modulators
• of apoptosis.

Thank You

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References

1. American Cancer Society medical information is copyrighted material.Last Medical Review: October 27, 2014.
2. Johnke RM, Sattler JA, Allison RR. Radioprotective agents for radiation therapy: future trendsFuture Oncol. (2014) 10(15), 2345–2357