Tap icon
to view sections

Objectives

The following module was designed to supplement medical students’ learning in the clinic. Please take the time to read through each module by clicking the headings below. The content of this module is mirrored to the objectives listed by the 2015 Canadian Oncology Goals and Objectives for Medical Students (by the Canadian Oncology Group).By the end of the tutorial, the following objectives should be addressed:

  1. Understand the basic physics of how radiation produces energy and its relation to the electromagnetic spectrum
  2. Describe the mechanism of how radiation damanges biological molecules and induces cell death
  3. Relate the molecular effects of cellular damage to the cell cycle
  4. Understand the concept of radiation fractionation to achieve therapeutic efficacy but also minimize side effects
  5. Summarize the effects of radiation on cancer and normal cells into the 4 R's: repair, repopulation, re-assortment, and re-oxygenation
  6. Classify the different techniques of administering radiation therapy
  7. Explain the process of receiving radiotherapy as a patient including initial assessment, planning, treatment and discharge
  8. Define the goals of radiotherapy intent and compare between curative versus palliative radiotherapy
  9. List common indications of palliative radiotherapy
  10. Explain the side effects of radiotherapy based on an anatomical and temporal classification

What is Radiation?

Radiation is what is released when an unstable, higher energy atom configuration changes into a more stable, lower energy configuration. The radiation commonly used is photon – a higher frequency electromagnetic wave. The electromagnetic spectrum contains waves such as radio and light. Cancer is treated with waves of even higher frequency and more energy, called X-rays.

Less commonly, electron and protons are used. Electrons deposit most of their energy closer to the skin and are good for treating more superficial cancer. As for protons, they tend to deposit energy with more precision with the advantage to spare more normal tissue.  Protons are increasingly being used in clinical practice but still not widely available.

Figure 1: Electromagnetic spectrum. The radiation used in treating cancer is in the x-ray range.

Mechanism of Action

At a cellular level, radiation causes:

  1. Direct Damage on DNA. Heavier particles, like protons, rely more on direct DNA damage. Overall, this is a minor cause of radiation damage.
  2. Indirect Damage occurs when the radiation hits water, and causes a series of reaction leading to free radical formation. Reacting with oxygen produces an even more toxic superoxide O2-, that in turn, damages the DNA. Most radiation damage is due to this.  

Radiation can break a single strand of the double stranded DNA, or knock out one the bases. However, this can be easily repaired. A Double Strand Break is when both strands are broken at nearly the same spot. This is harder to repair, and enough accumulation of double strand breaks will lead to cell death.

Causing a double strand break is easiest when the cell is in the M phase of the cell cycle, when chromosome divides. Therefore, if cells divide often, they are more susceptible to radiation. Poorly differentiated cells (such as cancer cells that mutated to be very different from their original form, losing many of the repair mechanism) are also more vulnerable (the law of Bergonie and Tribondeau).

Figure 2: Indirect damage causing a Double Strand Break

At a tissue level, this can be summarized into 4 factors (the 4 Rs table) that affect the killing of cancer cells and the side effects of radiation, which comes from collateral killing of normal tissue:

Repair of DNA by the cell. Normal cell does this much better than tumor cells.  So if radiation is spread out over time (fractionation), normal cell can  repair in-between fractions, the tumor cells less so.

Repopulation of the tumor cell in-between fractions. Each fraction of  radiation must cause more damage than the cell’s ability to divide and  repopulate in-between fractions.

Re-assortment – Each fraction of radiation catches the cell during different  part of the cell cycle. If radiation is given as one large dose, some of the  cells will not be in M, when it is most sensitive to radiation, and will not  be affected by the radiation. If radiation is given over many fractions,  though, there is a higher chance of catching all the cells in the M phase at  least once.

Re-oxygenation – Most of the damage from radiation is from indirect damage,  which needs oxygen to form O2-. Tumor cells further  away from blood supply (e.g., in the center of the tumor) are often hypoxic,  thus more resistant to radiation. If radiation is given in fractions, the  tumor cell that are oxygen rich dies off first, allowing the  previously-hypoxic cell to gain access to blood supply and oxygen, making  them more sensitive to radiation during the next fraction.

These four factors are the reason why radiation are given over many smaller doses (fractions – usually 1.8-2 Gray/Fraction – Gray is the measurement of radiation dose) over time rather than one large dose. There are some exceptions, such as for palliative radiotherapy, when the goal is shrinking the tumor enough to control symptoms rather than killing all of the tumor, or SBRT, which will be discussed later.

Types of Radiation Therapy

Radiation can be given from outside the body using beams of radiation, (External Beam Radiotherapy [EBRT]), or with radioactive pellets inserted into the tumor, either temporarily (HDR) or permanently (LDR), called Brachytherapy.

Figure 3: Brachytherapy seeds and x-ray showing seeds implanted in the prostate (red arrow).

Currently, linear accelerators (LINAC) are mostly used to generate the radiation beam for EBRT. The radiation beam is shaped into the shape of the tumor by multi-leaf collimators (which are a series of metal leaves in the radiation path that can shape the radiation beam). As well, instead of one beam that deposits a large amount of radiation to the healthy tissue in its path, many lower energy beams target the tumor from different angles. This way, the healthy tissues in the beam’s path are exposed to less radiation, resulting in more tolerable side effects. This is called 3D Conformal Radiotherapy (3D CRT). One subset of 3D CRT splits each beam into many little beamlets of different intensity, tailoring the dose and shape of the radiation to the tumor even more precisely. This is called Intensity Modulated Radiotherapy (IMRT).

Figure 4: An example of IMRT treatment plan for an Head and Neck cancer. The orange and yellow areas receive a large amounts of radiation, and the blue / colourless areas receive little radiation. Note the spinal cord and a large part of the jaw receive very little radiation, leading to less side effects. Also note the orange straight lines around the head denoting the multiple beams of radiation used.

In IMRT, the head of the linear accelerator shoots one beam, stops to reposition, then shoots the second beam, repositions, and so forth. A new technique, VMAT, speeds this up by taking away the time needed to stop and reposition. Instead, the head of the linear accelerator moves in an arc around the patient, while the parameters of the radiation beam (such as size and intensity) are all automatically adjusted while the head is moving.

Previously, the radiation has been fractionated into several weeks of treatment (e.g., 20-30 fractions). Thanks to modern precision, using highly focused, higher energy beams for only a few fractions (e.g., 1-4 fractions) (called Sterotactic Body Radiotherapy, SBRT/SABR) is possible. It is gaining popularity in treating early stage lung cancer. SBRT to the brain is called Sterotactic Radio-Surgery (SRS), and it uses either a linear accelerators or a specialized machine, Gamma Knife.

Usually, for most radiation megavoltage radiation (e.g., 6 or 18 MV) is used. To treat cancer that is superficial, such as on the skin, lower energy (e.g., kV) can be used, usually generated by an orthovoltage  machine. Because it is so superficial, clinical exam (visual appearance and palpation), called a “clinical markup”, is sufficient to guide the treatment instead of a CT scan. 

Figure 5: Orthovoltage machine. This is an older model (1938), but modern models have similar designs.

Patient Walkthrough

Imagine a patient with a new diagnosis of stage III (non-small-cell) lung cancer. He has completed all the necessary staging investigations, and was referred to a Radiation Oncologist for curative concurrent chemo-radiation.

Initially, he is seen in the Radiation Oncology new-patient clinic. After a focused history, physical exam, and review of investigations, the Radiation Oncologist discusses with the patient the type of radiation treatment offered, associated side effects, logistics, and treatment benefits. After careful consideration, the patient consents to radiation therapy. Afterwards, he attends patient information classes, and meets a multidisciplinary team consisting of nurses, radiation therapists (trained in operating treatment machines) and potentially a dietician, social worker, or dentist.

He returns to the cancer centre a week later for a CT scan, performed in a position reproducible in the future (e.g., lying on his back, with his arms above his head). The Radiation Oncologist then marks out on the CT scan, with the help of prior PET scan, where the tumor is (gross tumor volume, GTV), adds a margin for microscopic cancer cells not seen on CT (clinical tumor volume, CTV), and another margin for the imprecision during treatment (planning tumor volume, PTV). Healthy organs were outlined (organs at risk, OAR) so the dose they received could be limited.

A team of planners, led by a medical physicist, calculate the details of the treatment, targeting the prescribed area at the prescribed dose, without exceeding the prescribed dose limits for the OAR. The Radiation Oncologist then reviews and approves the plan if no other changes are required.

At this point, the patient returns to the cancer centre for daily treatment, Monday to Friday, with weekends off. He spent about an hour in the cancer centre every day and returns back home after. The treatment itself lasts less than 15 minutes, with most of the time spent positioning the patient properly on the treatment couch. He feels no different when the machine is turned on; the procedure is just as if he were having a normal CT scan. Once a week during treatment, he sees the Radiation Oncologist in the review clinic to monitor for side effects. He also receives weekly chemotherapy concurrently with his radiation.

After finishing his treatment, he sees the Radiation Oncologist regularly in follow up clinic to monitor for disease recurrence. After several years of follow up, the patient is discharged back to his family doctor for follow up.

Treatment Intent

Curative

The focus is to eradicate the cancer. Statistically, it means the goal of the treatment is prolonging life (increase overall survival outcome) or preventing disease recurrence (increased progression free survival / less local recurrence).

It can be used alone as the sole mean of treatment.

For example, low risk prostate cancer can be treated with EBRT or brachytherapy alone.

Radiation kills cancer cells locally within the treatment field, but does not affect circulating tumor cells in the blood or miniscule cancer metastases outside of the treatment field. Therefore, it can be combined with treatments that target tumor cells systemically, chemotherapy or hormonal therapy, before and/or after the radiation.  If a treatment is given prior to another definitive treatment it is termed neo-adjuvant or after therapy is it termed adjuvant.  When systemic therapy and radiation are sequenced we call this sequential therapy.

For example, high risk prostate cancer can be treated with a few month of hormonal therapy (Androgen deprivation therapy, such as Zolodex), followed by radiation (EBRT then brachytherapy), then more hormonal therapy.  This would be an example of both neoadjuvant (before) and adjuvant (after) hormonal therapy.

Chemotherapy can also be used during radiation at a lower dose, as a radio-sensitizer – it makes tumor cells more susceptible to radiation damage (concurrent chemo-radiation).

For example, inoperable stage IIIa Non-small cell lung cancer can be treated with concurrent chemotherapy (cisplatin-based) and radiation together at the same time. 

As well, radiation can be given before (neo-adjuvant) or after (adjuvant) surgery. The goal is to eradicate microscopic cancer cells around the tumor that would be impossible to excise completely. Left untreated, these cancer cells may grow into recurrent cancer in the future. If radiation is given before surgery, it can also shrink the tumor to make surgery more successful, which means that surgery has a higher chance of removing all of the tumor (negative margins).

For example, early stage breast cancer can be treated with surgery (lumpectomy) with radiation after (adjuvant) in some patients.

At times, all three (chemotherapy, radiation, and surgery) are used together.

For example, esophageal cancer can be treated with neoadjuvant chemo-radiation, then surgery.

Palliative

The focus is on symptom control rather than eradicating the cancer. At this time, the patient would not benefit from further curative treatment or has decided against it (for instance, they weighed the severity of the side effects of the curative treatment to be worse than the small possibility of cure from it, especially in an elderly patient with multiple other comorbidities limiting his/her life expectancy as well as poor performance status). Often, stage IV (metastatic) disease are treated from a palliative approach, but not always (for example, stage IVa head and neck cancer can be treated curatively with good outcome).

Radiation is a part of the tools available for symptom control in patients treated with palliative intent. The other tools include palliative chemotherapy, surgical or procedural treatments, medical, and psychosocial treatments.

For instance, for a patient with bone metastasis, who is kept bed bound because of the pain (severe symptoms limiting function), the tool box includes NSAID/ Dexamethasone, Opioids, and sometimes Bisphosphonates; palliative radiation; and for unstable bone metastasis, palliative orthopaedic surgery.

Radiation, particularly, is used for:

  • Bone Metastasis: To treat symptomatic bony pain
  • Lung mass / metastasis: To treat or prevent impending massive heomptysis from central mass eroding into bronchus. Also to treat cough and dyspnea from cancer.
  • Brain metastasis: To prevent / treat focal neurological symptoms, including seizure, headache, and change in the senses
  • Spinal Cord Compression: To restore neurological function and to treat pain
  • Superior Vena Cava Syndrome: To treat symptoms of facial swelling, pain
  • Rarer indications include: gynaecological bleeding from cancer, cancer eroding past the skin causing weeping (exudate) or bleeding, upper airway obstruction from cancer, abdominal pain from liver / upper GI mass eding

Side Effects

Side effects from radiation depends on the normal tissue near the cancer. For instance, radiation to the breast would carry the risk of side effects to the skin, lung, heart, brachial plexus, and general radiation symptoms. 

Figure 6: Side effect of radiation for breast cancer depends on which organs are near the cancer.

Side effects can also be acute - starting during or immediately after treatment; subacute - within 3 month of treatment; or late. There is no need to memorize them all – below is a table for reference.

Table 1. Acute, subacute, and late anatomical side effects of radiation

The American Joint Committee on Cancer (AJCC) uses different tumor-node-metastasis (TNM) classification for differentiated and anaplastic thyroid cancer, and for medullary thyroid cancer. For the purposes and level of this module we will provide the staging for only the differentiated and anaplastic thyroid cancers below in Figure 2. For specific staging guidelines, see AJCC 8th edition TNM classification [10]:

Figure 2. AJCC 8th edition updated TNM staging for differentiated and anaplastic thyroid carcinoma. Please note that there are specific and separate TNM staging for medullary thyroid cancer discussed in detail in the AJCC 8th edition manual and not covered in this module.

There are additionally separate stage groupings based on AJCC 8th edition staging guidelines for differentiated, medullary, and anaplastic carcinomas seen in Table 2.


Table 2. AJCC 8th edition specific stage groupings for differentiated, anaplastic, and medullary carcinoma

Management of thyroid cancer can be highly individualized and treatment may differ depending on patient, center, or physician factors. The details of management decision is beyond the scope of this module, however, general approaches and treatment options will be briefly reviewed.

The pathological assessment of the thyroid tumor is of paramount importance as it will not only give the degree of differentiation of the tumor but will assess multicentricity, the extent and site of nodal involvement and the completeness of the surgical resection. Overall, surgery is the mainstay of the majority of thyroid subtype treatments. 

Surgery

Surgery is the primary mode of therapy for patients with differentiated thyroid cancer and should be performed by an experienced thyroid surgeon to minimize the risk of hypoparathyroidism and recurrent laryngeal nerve (RLN) injury.

Operative management can include either a thyroid lobectomy or a total thyroidectomy. The choice to pursue either depends on extent of disease, patient factors, and presence of comorbid conditions:

  • For tumors < 1cm without extrathyroidal extension and no lymph node involvement: thyroid lobectomy is preferred unless there are clear indications to remove the contralateral lobe (i.e. clinically evidence thyroid cancer in the contralateral lobe, previous history of head and neck radiation, strong family history of thyroid cancer)
  • For tumors 1 - 4 cm in size without extrathyroidal extension and no lymph nodes: either total thyroidectomy or thyroid lobectomy can be performed and would be chosen either based on patient preference, ultrasound abnormalities in contalateral lobe, or on a decision that radioiodine therapy may be beneficial adjuvantly.
  • Any tumors greater or equal to 4 cm, extrathyroidal extension, or metastases deem a total thyroidectomy is recommended.
  • Additionally, total thyroidectomy should also be performed in all patients with any history of childhood head and neck radiation, and in multifocal papillary microcarcinoma (> 5 foci) [8].

Post-operative thyroid hormone is generally not started for patients who received a lobectomy, however, is started for patients who received a total thyroidectomy.

Intra-operatively, careful search for lymph nodes in the area must be made and all obvious nodes removed. More extensive resection is required for different types and sizes of tumors and its spread to surrounding lymph nodes [5]. 

Radioactive Iodine Therapy

131-Iodine ablation may be used adjuvantly after surgery to target remaining thyroid tissue where recurrence may occur, or to treat already recurring or metastasized disease. In studies showing a benefit with 131-I ablation, patients with larger tumors, multifocality, residual disease, and nodal metastasis seem to benefit from treatment [7]. Therefore, the recent treatment guidelines recommend consideration of adjuvant 131-Iodine ablation in postoperative findings of [6]:

  • Large tumor sizes (>= 4cm)
  • FTC with extensive vascular invasion
  • Microscopic or gross extrathyroid extension
  • Central or lateral compartment neck lymph node metastases
  • Distant metastases

Only papillary and follicular cancers will take up iodine, and only 50% of less of these tumors are able to take up enough iodine for it to be therapeutic.

Hormonal Treatment

Treatment with thyroxine is important in management of patients with thyroid carcinoma. The aim of such treatment is to suppress TSH stimulation of the thyroid which can be achieved by maintaining the serum T4 at the upper limit of normal. The starting dose of thyroxine is 1 mcg/lb/day. The level will equilibrate in one month and then the T4 and TSH can be checked. The dosage can then be altered to achieve the desired level.

External Irradiation

External irradiation has a definite role as an adjuvant to surgery or as treatment in the following circumstances:

  1. As an adjuvant treatment following surgery and radioactive iodine ablation when the surgical resection has been incomplete and residual microscopic or macroscopic disease is left behind which does not take up the radioisotope
  2. As a palliative treatment for inoperate unresected tumors or anaplastic carcinomas
  3. As a palliative treatment for symptomatic metastasis.

Chemotherapy

The role of chemotherapy in thyroid cancer is limited. The single chemotherapeutic agent most commonly used for thyroid cancer is doxorubicin (Adriamycin) with partial response rates of 30% and up to 45% in some series. For surgically unresectable local disease that has not responded to radioiodine, the best treatment may be a combination of hyperfractionated radiation treatments plus Adriamycin. Response rates of more than 80% have been reported using this regimen, but even in this situation, complete responses are rare and limited in duration.

Initial follow-up is generally undertaken by an endocrinologist, surgeon, or at a cancer centre. Thereafter, most patients are referred back to the care of their family physician [5].

The follow-up is variable from centre to centre and from patient to patient, however, generally it is recommended a visit every 3 to 4 months for the first two years. If there is no evidence of recurrence after 2 years then visits should be every 6 months for the next two years, with annual visits thereafter.

Initial investigations may include neck ultrasonography (every 6 - 12 months), TSH levels, and serum thyroglobulin (Tg) levels on thyroid hormone suppression (every 3 to 6 months for the first year). Iodine scanning is typically continued until there is no evidence of uptake in the neck or elsewhere and only repeated if the thyroglobulin starts to rise of recurrence or metastasis is clinically detected.

If a patient is high risk and demonstrate either a biochemical or structural incomplete response to therapy, additional imaging can be considered, including MRI, CT, and FDG-PET. Gross residual disease in cervical lymph nodes identified by physical examination or ultrasonography should be confirmed by FNA and surgical resection considered. Diagnostic whole-body radioiodine scanning may have a role in the follow-up of patients with high or intermediate risk.

Most recurrences of differentiated thyroid cancer occur within the first five years after initial treatment, however, recurrences may occur many years or even decades later, particularly in patients with papillary cancer. Therefore, ongoing follow-up after one year post-treatment is guided by individual assessment of the patient’s response to therapy during the first year of follow-up [5].

References

  1. Cox, J.D., Stetz, J., and Pajak, T.F. Toxicity criteria of the Radiation Therapy Oncology Group (RTOG) and the European Organization for Research and Treatment of Cancer (EORTC). Int J Radiat Oncol Biol Phys., 1995, 31 (5):1341-6.
  2. Hansen, E. K., and Roach, M. Handbook of Evidence-Based Radiation Oncology, 2nd Ed. New York, NY: Springer; 2010: 691-710.
  3. Rodrigues, G., Velker, V., and Best, L. Radiation Oncology primer and review: Essential concepts and protocols. New York, NY: Demos medical; 2013: 47-62.
  4. Figure 1 adopted from NASA, 2007, http://mynasadata.larc.nasa.gov/images/EM_Spectrum3-new.jpg
  5. Figure 3 adopted from Heilman, J., Brachytherapybeads.png by Dr. James Heilman, 2016, https://upload.wikimedia.org/wikipedia/commons/6/62/Brachytherapy.jpeg; And from US Government, 2006, https://upload.wikimedia.org/wikipedia/commons/7/77/Brachytherapybeads.png
  6. Figure 4 adopted from Morelmorel, 2013, https://upload.wikimedia.org/wikipedia/commons/7/75/Przekr%C3%B3j_cia%C5%82a_Pacjenta_z_rozk%C5%82adem_dawki_promieniowania_z_nowotworem_G%C5%82owy_i_Szyji_leczonego_technik%C4%85_IMRT..jpg
  7. Figure 6 adopted from Haggstrom, M., 2010, https://en.wikipedia.org/wiki/File:Surface_projections_of_the_organs_of_the_trunk.png.

Whiteboard Videos