Radiation therapy

Delivered primarily with high-energy photons, gamma rays and x-rays, and charged particles, electrons.

More than half of all patients with cancer receive RT at some point during their treatment.

Cancer is a systemic disease and more than 90% of patients with cancer are dying of metastases while the radiotherapy is used as the local regional treatment.

The challenge for radiotherapy in cancer treatment, is that it has an effect on local regional control, but no or limited effect on overall survival.

Precision RT therapy has been advancing with use of intensity-modulated RT, volumetric therapy and stereotactic RT improving target dose conformity.

Gamma rays originate from excited and unstable nuclei and are usually produced by radioactive sources used in brachytherapy.

X-rays are produced atomic electron energy transitions or through deceleration of high-kinetic electrons and are the product of linear accelerators and used in external beam radiation.

The challenge with radiation therapy is for delineating the target, identifying the full extent of disease, tumor motion, heterogeneous affect on radiation dose distribution, and to account for the presence of multiple adjacent organs limiting ability to tolerate radiation damage.

Within a linear accelerator a narrow beam of electrons is accelerated to nearly the speed of light before striking a tungsten target resulting in deceleration of electrons and emission of x-rays.

The recognition that the connection between genotypic variation and normal tissue response there is a predictability to toxicities following RT that may help spare selected individuals from significant morbidity and mortality following therapy.

Genetic assays may help predect tumor sensitivities

A local treatment modality which can improve survival directly by reducing the risk of local tumor recurrence that can lead the death from local complications or indirectly by reducing probability of hematogenous spread from locally persistent disease.

Biologic effects result from ionization within the DNA helix.

Nearly 50% of cancer patients receive RT at some point during the course of illness.

Process kills mainly through the generation of free radicals, depositing large amounts of energy causing single and double strand breaks in cell’s DNA.

Goal of treatment is to achieve maximum toxicity in the tumor while limiting injury to surrounding normal tissues.

To be curative all clonogenic tumor cells must be inactivated to prevent recurrence.

The goal of palliative therapy is not to eradicate all tumor clones, but to induce tumor regression and regrowth for as long as possible.

Palliative treatments usually have smaller total radiation doses and shorter treatment times than curative treatments.

Risk for normal tissue late complications must be minimized and that risk that is usually accepted is referred to as tolerance.

Tolerance that is accepted is 5% or less of normal tissue complications over a 5 year period following radiation therapy.

Tolerance depends on patients preference and goal of treatment, with curative therapy less tolerance is expected and more so for palliative measures.

Fractionation refers to the total dose of radiation given to a patient and is divided into a number of daily treatments of a specific size.

The number of fractions is not considered an independent radiobiological factor, rather the effectiveness is determined by the dose per fraction and overall treatment time.

Daily treatment relies on the radiobiologic rationale that slow dividing cells of normal tissue can repair radiation induced damage between small daily fractions in a way that rapidly dividing tumor cells, characterized by deficiencies in DNA repair, cannot.

Fractionation spares late responding normal tissue relative to cancers and allows the delivery of tumoricidal doses.


Increased radiation dose to the heart is correlated with increased fatigue and dyspnea, as well as decreased physical activity, particularly in lung cancer or lymphoma.


Increasing levels of physical activity during treatment are associated with concurrent improvements in quality of life.


Increases in physical activity over time were significantly associated with concurrent improvements in fatigue and shortness of breath.

Fractionation allows for recovery of cells.

Fractionation has evolved into five daily treatments employing 1.8-2.0 Gy per fraction.

Fractionation therapy generally given for 5-8 weeks, depending upon tumor histology and clinical circumstances.

Differences exist for early and late responding normal tissues in sensitivity to changes in fractionation.

Late responding tissues have a greater ability to recover during fractionated exposure than to early responding tissues.

Decreasing fraction size has a large sparing effect on late responding normal tissues, a small effect on early responding tissues and a small or negligible effect on most types of malignant lesions.

Hyperfractionation-typically refers to a twice a day treatment schedule with a significant reduced dose per fraction compared to standard fractionation of 1.8-2.0 Gy per day.

Hyperfractionation-reduced per dose per fraction spares late responding normal tissues which typically are dose limiting allowing for an increase in the total dose delivered resulting in greater tumor effect without and increase in late complications.

Hyperfractionation leads to a moderate treatment acceleration.

Repopulation refers to the increase in total cell number based on multiplication of proliferating stem or clonogenic cells in a tumor being radiated, and is able to compensate for radiation induced cell death during radiation treatment.

Repopulation results in decreasing radiosensitivity of the irradiated tissue.

Tissue repopulation in response the depletion of cells may be based on accelerated proliferation rate of stem cells, higher differentiation rate of stem cells or a higher division rate of transit cells.

Repopulation is accelerated when doubling time of proliferating cell pool is shorter than the tumor doubling time existed before radiation.

During radiation the doubling time of the clonogenic tumor cell fraction may be as short as 4-5 days, compared for an average doubling time of 2 months for many solid tumors.

One cannot detect the fraction of clonogens that undergo accelerated repopulation in irradiated tissue, and the presence of such proliferation may offset the regression from the initial delivered radiation dose.

It is not possible to predict which tumors have the potential for repopulation so it is advisable to keep radiation time as short as possible for lesions that have the capacity for accelerated repopulation, such as squamous cell cancer of the head and neck, lung cervix and small cell carcinoma of the lung.

It is possible that neoadjuvant chemotherapy may increase tumor cell proliferation and subsequent radiation may be less effective.

The acceleration of radiation improves tumor effect but can also increase acute side effects such as mucositis and esophagitis as such tissues will have less time the regenerate with shorter treatment times.

Hypofractionation refers to the delivery of large dose fractions greater than 2Gy which may be used for curative therapy, but is much more commonly used for palliative therapy in noncurable individuals to decrease the number of treatments.

Accelerated fractionation refers the use of standard size fractions given in a shorter overall treatment time by increasing the number of fractions per day or by treating on the weekends.

Hypofractionation utilizes daily fraction size which is larger than the size in standard fractionation, and commonly measure between 3 Gy and 8 Gy.

Hypofractionation study revealed in a randomized trial of whole breast irradiation comparing 42.5 Gy 16 fractions with 50 GY in 24 fractions reported equivalent efficacy and toxicity (Whelan TJ et al).

Most tissues are divided into early responding or late responding tissues depending upon whether they are more likely to manifest radiation damage around the time of treatment or months to years later.

Larger fractionation associated with greater damage to late responding tissues.

Early reacting normal tissues such as skin and mucous membranes are hierarchal tissues consisting of stem cells producing differentiating proliferative cells and mature cells which are functional end cells.

Proliferating normal cells are characterized by a homeostatic equilibrium between cellular production and cell loss, the latter due to differentiation or exfoliation.

Hypoxic fractions of tumors approximately 15%.

Hypoxic cells have limited response to high doses of radiation, while oxygenated cells are preferentially killed, this results in the increased fraction of hypoxic cells and increased resistance of irradiated tumor.

Reoxygenation process returns the high proportion of hypoxic cells that occur after each fraction of radiation to the level that existed before the delivery of that fraction.

If the reoxygenation process is complete during interval between fractions of treatment hypoxic cells have little influence on outcome of treatment, however short treatment times can result in incomplete reoxygenation and have a negative effect on tumor control.

Use of hyperbaric oxygen, hypoxic radiosensitizers and blood transfusions are utilized to reduce the negative effect of hypoxia on tumor control.

Tissue overlying and underlying a tumor will also be irradiated with the tumor during external beam radiation.

External beam radiation therapy utilizes a source that is a distance from the patient.

Patients who undergo CT simulation planning for thoracic radiation have a significant reduction of death, when compared to those traditionally planned.

For stage I non-small cell lung cancer overall 5-year survival 6-30%.

For stage II non-small cell lung cancer overall 5-year survival <15%.

For completely resected node positive non-small cell lung cancer patients is controversial.

External beam radiotherapy for prostate cancer-an approximate 5mm margin is typically added around the prostate to account for subclinical disease extension.

External beam radiotherapy for prostate cancer-most severe acute effects are an increase in bowel problems.

External beam radiotherapy for prostate cancer associated with erectile dysfunction in 2-34% of cases.

Concurrent administration of chemotherapy and radiation in rectal cancer, non-small cell lung cancer, small cell lung cancer, breast cancer and cervical cancer have improved outcomes.

For breast cancer usually consists of whole breast radiation with additional boost to the tumor bed for patients receiving breast-conserving surgery.

For breast cancer alters the skin and it remains drier than other areas, with variable hyperpigmentation, with some degree of peau d’orange.

For breast cancer-peau d’orange is most commonly seen in patients

withlarge and pendulous breasts.

For breast cancer may leave the breast firmer and have a lift compared to the untreated breast.

Older patients have a lower rate of ipsilateral recurrence of breast cancer, with or without radiation, especially with small hormone receptor positive tumors (Merchant TE, Hughes, KS).

In a large randomized trial of older females with small hormone receptor positive tumors treated with lumpectomy and radiation revealed that the addition of breast radiation did not improve survival and 94% of deaths in both groups were from non-breast cancer causes. (Hughes KS).

Meta-analysis-the addition of breast radiation to lumpectomy did not improve 15 year survival rates in patients with breast cancer in patients with breast cancer at low risk for local or regional recurrence (Clarke M).

Cisplatinum enhances the effects of radiation when given concurrently.

Increases the risk of breast cancer in patients treated for Hodgkin’s disease.

Modern radiotherapy with moderate doses to the brain does not lead to significant cognitive impairment within a median of 3 years.

Patients with systemic lupus or scleroderma have exaggerated acute and late side effects from radiation therapy.

Secondary sarcomas are located in or at the edge of the radiation beam suggesting that high doses are required for initiation of the second malignancy.

Late complications of radiation therapy for Hodgkin’s disease include secondary malignancies, particularly breast cancer, valvular heart disease, and premature coronary artery disease.

Late cardiac toxicity in breast cancer patients is associated with radiation to the internal mammary node field.

Incidental irradiation of the sinoatrial node during chemo, radiotherapy, may be associated with development of  atrial fibrillation and increased mortality.

One-third of patients with solid tumors treated for cure suffer local recurrences.

Interruption of 1 day may reduce disease-control rates by 1.4% and a treatment break of 1 week reduces control rates by more than 10%.

Historically radiation fields were large to include potential microscopic disease, regional nodal drainage and visible tumor, but with the use of chemotherapy during radiation treatment the portals now encompass the visible tumor and a limited surrounding margin.

Planning treatment begins with defining the target volumes, typically outlined by CT and can be complemented by MRI, MRI spectroscopy and PET/CT.

Imaging establishes gross tumor volume, and clinical target volume which covers potential microscopic involvement.

The planning target volume is an expansion of the gross tumor volume and clinical target volume to account for patient variations in position, movement and organ movement.

No salivary gland function recovery with radiation above 24-26 Gy.

When the volume of parotid radiation for a given dose increases from 50-90% the probability of dysfunction increases fro 5% to 95%.

In the absence of oxygen cells that are irradiated are more resistant than cells that are well oxygenated.

Oral complications affects 100% of patients who receive radiation fields to the oral cavity.

Acute mucositis can lead to dose reductions and treatment interruptions and compromise efficacy of the treatment.

Combined with chemotherapy may increase oral complications.

Complications of oral radiation can include mucositis, xerostomia, dental caries, trismus and osteonecrosis.

Pelvic radiation associated with diarrhea as a major form of toxicity.

Pelvic radiation as adjuvant treatment in patients with concurrent pelvic radiation and fluorouracil 53% had diarrhea in a North Central Cancer Treatment Group trial (Miller).

Palliative radiation therapy for bone metastatic lesions is 30 gray in 10 fractions as standard treatment.

Similar outcomes for radiation therapy for bone metastases is 30 grays 8 Gy in 1 fraction and 20 Gy in 5 fractions.

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