After completing this module, students should be able to:
There are two possible goals for treatment: cure and palliation. Curative treatment is considered to engender a small degree of risk of significant side effects for the possibility of cure. On the other hand, palliative care is considered to alleviate symptoms when the risks of significant side effects outweigh the benefit of possible cure.
Curative treatment is indicated when a curative technique (usually surgery) is available, patient factors are favourable (eg. lack of comorbid illnesses), and the disease progression is localized. If a patient does not have metastases, corresponding to a lower stage tumour, curative treatment is usually possible.
Palliative care is usually the goal when there is metastatic disease, and patient factors are unfavourable (eg. presence of comorbid illnesses).
In order to make decisions about curative or palliative treatment, tumour, treatment and patient factors are considered. Tumour factors relate to tumour stage and tumour type. Treatment factors include the type of treatment being considered, availability of treatment and efficacy of treatment. Patient factors include personal choice and age, and most importantly, the patient’s status. For example, a “young 65 year old” may be a better surgical candidate than a “tired-appearing 55 year old”. When thinking about treatment for a patient, their physical condition or ability to withstand and recover from any given treatment, is of paramount importance. In order to assess a patient’s performance status and effectively communicate this in a consistent way with colleagues, physicians use a performance grade developed by the Eastern Cooperative Oncology Group, called the ECOG performance status. The ECOG performance status is graded by asking the patient a series of questions during the history-taking process. The various grades are described below.
Health care providers who may be involved in the care of cancer patients include:
Cancer treatment can be curative, if the disease has a chance of being completely eradicated by treatment. Palliative care is used to alleviate symptoms when the disease is not curative. Patient, tumour, and treatment factors guide the management of cancer patients which is provided by a multi-disciplinary team of health care professionals.
Hypercalcemia of malignancy is common in advanced stage cancers affecting over 40% of patients (9). Calcium levels require tight regulation and small variations from normal can cause significant morbidity.
The large majority of the body’s calcium is stored in bone, and a very small amount is in the blood, with about 65% of the blood calcium bound to albumin, unavailable for use (9). Low serum calcium levels stimulate the parathyroid gland to release parathyroid hormone which increases calcium levels in 3 ways: renal tubular reabsorption, vitamin D activation, and mobilization from bone (9). Vitamin D increases calcium absorption from the GI tract and decreases renal excretion (9). On the other side of regulation, calcitonin is a hormone released by parafollicular/C cells in the thyroid gland that is involved in decreasing serum calcium levels by preventing renal reabsorption and calcium mobilization from bone (9).
There are several mechanisms of hypercalcemia of malignancy including humoral hypercalcemia mediated by increased parathyroid hormone-related peptide (PTHrP), local osteolytic hypercalcemia due to breakdown of bone, excess extrarenal activation of activated vitamin D that promotes calcium reabsorption/retention, and excess ectopic or primary PTH secretion (10). The PTHrP mechanism is the most common (80%) and it’s the peptide’s structural similarity to endogenous PTH that drives increased tubular renal absorption of calcium, decreased renal excretion and stimulates osteoblasts to produce RANKL. Local osteolytic hypercalcemia accounts for roughly 20% of hypercalcemia from bone mets and is thought to be due to excessive osteoclast activation and bone resorption due to tumour cytokine secretion (10).
The classic mnemonic for symptoms of hypercalcemia is “stones, bones, abdominal moans, and psychic overtones”. In addition there are characteristic cardiovascular system features of hypercalcemia.
If hypercalcemia is suspected, measuring serum calcium and serum albumin levels (if serum albumin is abnormal, measured calcium needs to be adjusted) is the first step of investigations. Once confirmed, PTH, PTHrP and vitamin D levels will help to characterize the cause of hypercalcemia.
The first step in management is fluid resuscitation with IV normal saline. Patients presenting with hypercalcemia due to bone metastases are usually dehydrated due to hypercalcemia-induced nausea, vomiting, loss of appetite and nephrogenic diabetes insipidus. These factors all contribute to volume depletion and propagate the cycle of further increasing serum calcium (9). In addition to fluids, there are several medications used to reduce serum calcium. Exogenous calcitonin has a fast onset of action and is a good initial therapeutic option while bridging to longer term use therapies (9). It works within 4 hours, but tachyphylaxis often develops around 48 hours which is why it should only be used in the transition period for starting maintenance therapy (10). Bisphosphonates (e.g. zoledronic acid and pamidronate) are used as a longer term therapy, but their calcium lowering effect takes 2-4 days (9). In patients with high levels of PTHrP, bisphosphonates might be less effective and other options such as denosumab may be the next treatment of choice, although this use is off-label (9). Hemodialysis should be considered in patients who cannot be safely rehydrated due to cardiorenal disease.
Breast cancer is primarily classified histopathologically in accordance with the 2003 WHO classification scheme, as seen in overview in the flowchart below. Breast cancer may also be classified by the expression of hormone receptors and genetic mutations that are impactful for treatment and prognosis (1).
Atypical ductal hyperplasia and atypical lobular hyperplasia are conditions in which there is an increase in number of abnormal cells growing in the breast ducts or lobules. While they are not malignant conditions, they are associated with a significant increased risk of future breast cancer development (2).
In-situ carcinomas are composed of malignant epithelial cells that are limited to their site of origin and have not spread or invaded past the basement membrane. These carcinomas, if left untreated, can progress into invasive carcinomas.
Lobular carcinoma in-situ (LCIS) is a pre-malignant condition arising from the cells of the breast lobules. LCIS is characterized by the presence of atypical cells that have not yet invaded nearby breast tissue (2). It often develops in multiple parts of bilateral breasts at the same time, and is an important marker for the development of future invasive breast cancer. Women with LCIS are thought to have a 10-15% risk per breast of developing breast cancer in the ten to fifteen years subsequent to diagnosis (1). As such, women with LCIS should undergo more frequent screening mammography, and may also be offered hormonal therapy to decrease their risk of future breast cancer development (2).
Ductal carcinomas in-situ (DCIS) are composed of malignant epithelial cells that arise in the breast ducts, and have not yet invaded beyond the basement membrane in their site of origin. DCIS is responsible for 20% of all abnormal mammogram findings (2). DCIS can be classified as low, intermediate or high grade on the basis of pathology, and this grading has prognostic value for the likelihood of post-operative recurrence.
Invasive breast cancers are malignant lesions in which atypical cells have spread through the basement membrane to invade surrounding breast parenchyma, lymphatic tissue or beyond. Over 95% of all invasive breast cancers are adenocarcinomas derived from epithelial tissue. Rarer forms of invasive breast cancer include stromal-derived malignancies, lymphomas and metastasis of other cancers to the breast (2,4).
Invasive ductal carcinomas (IDCs) represent 80% of all invasive breast cancers (5). IDC can be further classified into subtypes defined by characteristic histopathological features.
Invasive lobular carcinomas are the second most common form of invasive breast cancer and represent 10-15% of all invasive breast cancers (2,4). They are characterized by a single-file of infiltrating cells that invade into breast stromal tissue. On gross specimen, they have a rubbery hard consistency with irregular borders. ILC has a tendency to metastasize to atypical sites including the peritoneum, GI tract, ovaries, and uterus, as well as rarely to the lungs and pleural cavity (4).
Inflammatory breast carcinoma is a rare but highly aggressive form of breast cancer. It is more common in young women and in women of African ancestry. It usually presents as a red, warm, swollen breast. The overlying skin may appear pitted, which is known as ‘peau d’orange’ due to its resemblance to the texture of an orange peel. On histopathology, a finding of malignant cells in dermal lymphatic tissue is a characteristic feature (4). At the time of diagnosis, the cancer has often already spread to involve the lymph nodes and distant organs. Prognosis is poor, with an estimated five-year survival of 34% (2).
Paget’s disease of breast is another rare form of invasive breast cancer derived from epithelium. It is more common in women over 50 years of age. It commonly presents clinically, with signs and symptoms including crusting and scaling of skin around the nipple, burning, pruritus, nipple bleeding or discharge, and new nipple inversion. A lump may be felt near or under the nipple. Histologically, it is characterized by large dendritic neoplastic cells (Paget cells) within the epidermis. Paget’s disease of breast is often associated with an underlying DCIS or IDC component (2,4).
An example of Paget’s disease of the nipple
Additional rare breast cancers can occur, including stroma-derived malignancies (phylloides tumors and sarcomas), lymphoma, and metastases from other body sites. In combination, these malignancies represent less than 1% of all breast cancers (2).
A additional classification scheme is used an adjunct to the histopathological classification model. This scheme divides cancers based on their expression of certain hormone receptors and genes that have significance for both management and prognosis.
A malignancy can be classified according to the presence or absence of estrogen and progesterone receptors. About 75% of breast cancers are hormone receptor positive meaning that the cancer will grow in the presence of estrogen and/or progesterone. Estrogen receptors are more commonly found than progesterone receptors. The importance of determining receptor status of a cancer is that it will determine the efficacy of using hormonal therapy as a treatment. It is important to note that the receptor status of a cancer can change over time.
Both estrogen and progesterone receptor positive cancers are associated with a more favorable prognosis, including higher disease-free survival and reduced mortality. Estrogen-receptor positive cancers can be treated using anti-estrogen therapy (2,6). Estrogen-receptor positive cancers are more common in post-menopausal women (6).
Human epidermal growth factor receptor 2 (HER2) is a proto-oncogene for a transmembrane growth factor receptor. HER2 is present in normal breast epithelial cells, but is overexpressed in 20-25% of all breast cancers. Cancers that overexpress HER2 are considered to be HER2 positive, and are associated with a higher grade and more aggressive rate of spread (2).
Targeted therapies are available for HER2 positive cancers, including Herceptin (transtuzumab), a monoclonal antibody against HER2 protein (2).
Colorectal cancer is often asymptomatic, which is why screening is critical to detect pre-malignant and malignant lesions as early as possible (1).
Colorectal cancer may present with a number of symptoms, signs, or complications, including (1):
Patients who are symptomatic due to obstruction or perforation at the time of diagnosis carry a worse prognosis than patients who are asymptomatic.
20% of patients with colorectal cancer have metastatic disease at the time of presentation. The most common sites of metastatic spread in colorectal cancer are the regional lymph nodes, liver, lungs and peritoneum; the liver is often the first distant site involved. Colorectal cancer may therefore also present with signs and symptoms concerning for metastatic disease, including:
A more detailed description of the signs and symptoms associated with colon cancer, including their pathogenesis, is included in Table 1 below.
The current standard for staging non-melanoma skin cancers is the TNM classification system. This classification is only applicable to malignant disease and cannot be applied to precursor lesions. The American Joint Committee on Cancer (AJCC) staging system lacks prognostic accuracy for NMSCs and as a result the use of high risk features is often preferred. There have also been efforts to develop alternative staging systems with better prognostic value. The 8th edition staging system was published in 2017 and was designed for use only with NMSC of the head and neck . The 2017 AJCC guidelines are as follows :
ENE = extranodal extension
The Brigham and Women’s Hospital Tumour Staging system has been designed to improve prognostic value in assessment of tumours . In this staging system tumours are risk stratified based on the presence of risk factors: T1 tumours have zero high risk factors, T2a tumours have one high risk factor, T2b tumours have two to three high risk factors and T3 tumours have over four high risk factors or bone invasion. Risk factors are defined as the following: tumour diameter >/= 2cm, poorly differentiated histology, perineural invasion >/= 0.1mm, or tumour invasion beyond fat (excluding bone).
As it is exceedingly rare for BCCs to metastasize, there is no standardized approach for imaging high risk BCCs. BCCs that do metastasize most commonly spread to the local lymph nodes, lung and bone .
The protocol for imaging cSCCs is much more established than that for BCCs because of their higher rate of nodal spread and metastasis. cSCCs most commonly spread to regional lymph nodes, however they can also metastasize to the lung, liver, bone and brain .
A suggested approach for investigating invasive cSCC is depicted in the image below [modified from reference 3]:
All cSCC patients should have a regional lymph node examination to detect clinical lymphadenopathy . Patients with palpable lymphadenopathy must undergo a lymph node biopsy to establish whether there is evidence of disease in the palpable node. The biopsy is typically conducted using a fine needle aspiration technique. If the cytology confirms that the node is positive for disease, the patient should undergo imaging tests to characterize the extent of nodal involvement along with complete nodal dissection. If the cytology does not indicate that there is disease in the palpable lymph node, the physician should consider whether the tumour is “high-risk”. Physicians may decide to send patients with sufficient high-risk features, with or without palpable lymphadenopathy, for imaging of the regional lymph nodes. Ultrasound of lymph nodes may also be considered for high risk cSCCs. In large infiltrating tumours with signs of involvement of underlying structures imaging such as CT or MRI may be required to assess the extent or tumour spread. The most common imaging modality used for staging nodal involvement is CT. Other imaging techniques that may be considered are MRI, PET and ultrasound [2,3].
Patients with confirmed nodal involvement and/or extremely high-risk disease may undergo full-body imaging for distant metastases. The options for full-body imaging include CT, PET and PET-CT. The gold standard is currently unknown .
The prognosis for NMSCs is extremely good in most cases with a greater than 95% disease free survival at 5 years for low stage disease . However, this prognosis changes considerably for high-risk lesions with rates dropping down below 50% for T4 lesions . This underscores the importance of properly staging NMSCs.
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).