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:
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.
At a cellular level, radiation causes:
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).
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.
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.
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).
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.
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.
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.
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:
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.
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.
The most widely accepted system for colorectal cancer staging is TNM staging, as outlined by the American Joint Committee on Cancer (AJCC) (1,2). This system stages colorectal cancer according to three primary features. The first feature is the tumor size, represented by ‘T’. The second feature is the extent of spread to regional lymph nodes, represented by ‘N’, which can be determined either clinically (‘cN’) or pathologically (‘pN’). The third feature used to classify colorectal cancer is the presence of any distal metastasis, represented by ‘M’. On the basis of these features, colorectal cancer is assigned a TNM status, which correlates to a certain stage of colorectal cancer.
TX – primary tumour cannot be assessed
T0 – No evidence of primary tumour
Tis – Carcinoma in situ: intraepithelial or invasion of lamina propria.
T1 – Tumour invades submucosa
T2 – Tumour invades muscularis propria
T3 – Tumour invades through the muscularis propria into pericolorectal tissues
T4a – Tumour penetrates to the surface of the visceral peritoneum
T4b – Tumour directly invades or is adherent to other organs or structures
During surgical resection of the colon or rectum, the surgeon aims to obtain a minimum of 12 lymph nodes for staging purposes. In general, the more nodes attained, the better the prognostic accuracy. For similar reasons, the pathologist must make a note of how many nodes were actually analyzed in the determination of the pathological N-stage of the tumour.
Nx - regional lymph nodes cannot be assessed
N0 - no regional lymph node metastatis
N1 - metastasis in 1-3 regional (pericolic or perirectal) lymph nodes
N2 - metastasis in 4 or more regional (pericolic or perirectal) lymph nodes
N3 - metastasis in any node along the course of a named vascular trunk and/or metastasis to apical node
Mx - metastasis cannot be assessed
M0 – no distant metastasis
M1 – distant metastasis
The table below delineates the stage groupings for colorectal cancer based on their TNM status.
The treatment of breast cancer varies widely depending on the stage of the cancer. Similarly, the goals of treatment also vary from curative to palliative depending on tumour, patient, and treatment factors.
Surgery, radiation therapy, chemotherapy and hormone therapy are the main treatment modalities employed in breast cancer management.
As soon as a confirmed tissue diagnosis of breast cancer has been made, the patient should be referred to the appropriate treating physicians as soon as possible. The patient is usually seen first by a surgeon for consideration of resection of the malignancy, unless the disease is identified as metastatic at the time of diagnosis (1). Referral to medical and radiation oncologists is usually done by the surgeon post-operatively, unless the patient wishes to discuss his or her options with the oncologist prior to making a decision about surgery (1).
Other referrals to be considered include genetic counselling if there is suspicion for a hereditary cancer gene, and a fertility program if the patient is pre-menopausal and would like to have children in the future (1).
Surgery is a core component of breast cancer treatment and is offered for all breast malignancies with the exception of stage IV (metastatic) disease (2). For non-metastatic breast cancer, surgery is considered the primary treatment. Adjuvant systemic therapies may then be employed post-operatively to decrease cancer recurrence by eliminating micrometastic lesions that may have spread from the original primary tumour (3).
Several surgical procedures are employed in the management of breast cancer.
Breast conserving surgery (BCS), also known as a ‘lumpectomy’ or partial mastectomy, is a procedure in which the surgeon aims to remove the breast tumour along with a margin of healthy tissue, while sparing the remaining healthy breast tissue (2). When BCS is performed in patients with DCIS or early invasive breast cancer, and followed by external beam radiation therapy, it has been shown to achieve survival rates equal to those of patients treated with complete mastectomy (3). Contraindications to BCS include multicentric tumours, inflammatory breast cancer, persistent positive margins after prior surgical resections, and contraindications to radiation such as pregnancy or history of previous breast irradiation (4). BCS is also not a good option for women with large tumour size relative to breast volume, as a good cosmetic result may not be achieved under these conditions (4).
Mastectomy is a surgical procedure in which the whole breast is removed. In a simple mastectomy, only the breast tissue is removed, with the surrounding musculature and lymph nodes remaining in place. This procedure was historically performed in patients with DCIS and early invasive breast cancer (2). In a modified radical mastectomy, the breast tissue, nipple, axillary lymph nodes and pectoralis fascia are all removed. This procedure continues to be performed in patients for whom BCS is contraindicated or who prefer not to undergo radiation therapy (2).
Some women at high risk of developing further invasive breast cancer may choose to undergo prophylactic total bilateral mastectomy (2). This is not commonly performed as it is considered to be an aggressive treatment.
Surgical management also includes procedures to biopsy lymph nodes for use in cancer staging. A sentinel lymph node biopsy is usually recommended for patients with no clinically palpable lymph nodes (clinically N0) (5). In this procedure, the single axillary lymph node to which cancer is most likely to spread is removed and sent for pathology. If the sentinel lymph node is negative, the cancer is unlikely to have spread to any lymph nodes. If the sentinel lymph node is positive, the patient should undergo complete axillary lymph node dissection to remove the remaining axillary lymph nodes and allow assessment of the extent of the cancer’s lymphatic involvement (5). Patients should proceed immediately to axillary lymph node dissection if they have clinically node positive disease or inflammatory breast cancer (5).
Finally, surgery may be considered for palliative intent. Mastectomies may be considered for patients with large, painful, or fungating breast lesions. Surgery for isolated brain or spinal cord metastases, isolated lung metastases, and/or isolated liver metastases may be considered to help control pain and other symptoms of metastatic disease (2,3).
External beam radiation therapy is an important component of breast cancer management. Radiation therapy is offered to breast cancer patients following breast-conserving surgery in order to reduce the risk of cancer recurrence (5). For early invasive breast cancer, the use of external beam radiation therapy results in a 20% absolute reduction in risk of recurrence at 10 years post-diagnosis, which in turn results in a 5% reduction in breast cancer mortality (5).
Radiation treatment is usually not performed in patients who have undergone modified radical mastectomy for early invasive breast cancer. However, radiation therapy may be offered to these patients if certain high-risk features are present, including lymph-node positive disease (2).
External beam radiation may also target the lymph nodes if they are found to be positive, as well as the chest wall if certain high-risk features are present (2).
The schedule for radiation therapy typically involves treatments being given five days per week for a duration of five to seven weeks (6). Patients may experience side effects from radiation therapy, including (2,5):
External beam radiation may also be considered for palliation. It may be used to control pain and other symptoms arising from localized metastases, such as bone metastases, spinal cord metastases, metastases causing bronchial obstruction, and large or painful chest wall metastases (2).
Hormonal therapies are offered as adjuvant therapies to patients with hormone-receptor positive DCIS or invasive breast cancer of any stage. The duration of recommended use ranges from five years for DCIS to ten years for more advanced breast cancers (2,5). Options for hormonal therapy include selective-estrogen receptor modulators (SERMs), aromatase inhibitors (AIs), ovarian suppression with luteinizing hormone-releasing hormone (LHRH) agonists, and surgical removal of the ovaries.
SERMs are competitive partial agonists for the estrogen-receptor (ER) and have variable agonist and antagonist action on ERs throughout the body. AIs inhibit the enzyme aromatase, which functions to convert androgen precursor molecules to estrogen in the body’s peripheral tissues. AIs are ineffective in pre-menopausal women, as the main source of estrogen in these women is the ovaries (not the peripheral tissues) (2).
In pre-menopausal women, SERMs are the first-line hormonal therapy for estrogen or progesterone-receptor positive breast cancers (2). Tamoxifen is the most commonly used SERM, and has been shown to reduce the risk of breast cancer recurrence by 30-50% in premenopausal women (7). Tamoxifen is also the most commonly used agent in post-menopausal women, in whom it reduces the risk of breast cancer recurrence by 40-50% (7). However, in post-menopausal women with stage 4 breast cancer, AIs are considered first-line due to their greater efficacy in this population (2). The most commonly used AI is letrozole (2).
Tamoxifen is associated with an increased risk of endometrial cancer, DVT/PE and stroke (2,5). It is therefore relatively contraindicated in women with a personal history of venous thromboembolism or endometrial cancer (5). AIs are associated with an increased risk of osteoporosis and dyslipidemia, and caution should be therefore be used when prescribing AIs to women with a history of these conditions (2,5).
Side effects of hormonal therapy may include the following (2):
Chemotherapy is most often used as an adjuvant therapy for breast cancers that are stage II or greater. It is particularly important for breast cancers that are ER and PR negative, as these malignancies do not qualify for hormonal therapy (2). The age, medical comorbidities, and values of the patient should be considered prior to starting any chemotherapy regimen (3).
Chemotherapy may also be used as a neoadjuvant therapy to reduce the size of the tumor prior to surgery. This may render previously non-operable tumors operable or allow breast-conserving surgery in a patient for whom this was not previously feasible goal (2,3).
Multiagent chemotherapy regimens are usually employed due to their greater efficacy (2). Herceptin (trastuzumab) is a monoclonal antibody against the HER2 receptor that is used in the treatment of HER2 positive breast cancers (5).
Information in the table above was derived from the Canadian Cancer Society and the American Cancer Society (2,8,9).
As demonstrated in the table below, the prognosis of breast cancer is determinedly largely by the stage of disease. Stage 0 and Stage 1 disease has a 5-year survival of 98-100%, while Stage 4 disease has a median survival of 18-24 months (2,3,5). Within staging, the presence or absence of spread to lymph nodes is the most important prognostic factor (2). Higher numbers of positive lymph nodes are associated with a worse prognosis (2). The second most important prognostic factor within staging is the size of the tumour, with larger tumours having a worse prognosis (2).
Information in the table above was derived from the Canadian Cancer Society (2).
Additional factors also have an influence on prognosis and may guide treatment decisions. Positive hormone-receptor status is associated with a better prognosis, as these tumours are usually less aggressive and respond well to hormonal therapies (2). HER2 positive status is associated with a worse prognosis, as these tumours are usually more aggressive and more likely to metastasize (2). Younger age at diagnosis (age < 35 years) is also associated with more aggressive, higher-grade tumours, and thus a worse prognosis (2).