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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. Information on how to diagnose and manage common complications of cancer and its treatment, and appropriate follow-up plans for patients after curative cancer treatment is provided. By the end of the tutorial, the following objectives should be addressed:

  1. Demonstrate an understanding of how to diagnose and manage common complications of cancer (e.g. bone metastasis pain, hypercalcemia, venous thromboembolism)

Complications of Cancer

A cancer diagnosis puts people at risk of complications such as bone metastasis pain, hypercalcemia, and venous thromboembolism. This module is intended to provide a general overview of the diagnosis and management of these common complications.

Bone Pain

Bone metastasis is a complication of cancer spreading from other sites of the body and bone is one of the most common sites of distant metastases. It causes significant morbidity and reduced quality of life with pain being the most common symptom (1). The most likely cancers to spread to the bones are breast, prostate, lung, kidney, thyroid, multiple myeloma, and lymphoma (2). In fact, 50-70% of those with advanced breast and prostate cancer will have bone involvement (3).

Figure 1. Incidence of bone metastases by cancer site (4)


Bone metastases most often distribute to the areas of red marrow such as the axial skeleton (skull, vertebrae, ribs, sternum), pelvis and proximal femurs (1,2). Bone pain attributed to metastases is the principal source of cancer-related pain and can severely impact quality of life (3).

Pathophysiology

Based on radiographic findings, bone metastases are divided into sclerotic/osteoblastic, osteolytic, or mixed lesions (4). These lesions cause complications known as skeletal-related events: bone pain, hypercalcemia, pathological fractures, and spinal cord compression (5). The exact mechanism by which bone metastases cause bone pain is poorly understood, but what is known is that malignant cells have a negative impact on the natural cycle of bone resorption and formation. Bone integrity is normally maintained by a balance of osteoclast activity (breaking down bone) and osteoblast activity (building new bone) (3). When this process is disrupted by malignant cancer cell invasion, it leads to bone destruction, instability and fractures (5).

The invasion of tumour cells into bone only plays a minor role in bone destruction. More importantly, there are factors that the cancer cells secrete that are involved in activating osteoclast activity and in stimulating the host immune system to release more activation factors. It is the up-regulation of osteoclast activity that ultimately results in bone breakdown in osteolytic lesions.

In osteoblastic lesions, typically from prostate cancer metastases, tumour cells have been shown to secrete osteoblast growth factors (TGF-beta and platelet-derived growth factor) which inhibit osteoclast activity and results in the loss of ability for normal bone remodelling (4). While the predominant mechanism of osteoblastic lesions is not bone breakdown, there is still disruption of normal regulation, resulting in formation of weak, irregular bone.

Adding to this, bone-derived growth factors and cytokines released from resorbing bone can attract and facilitate further cancer cell growth and proliferation (4). This “seed-and-soil hypothesis” describes the mechanism of bone metastasis (6).

Table 1. Bone metastases characteristics


Diagnosis

Clinical presentation

Bone pain is the most common type of cancer-associated pain and its presentation can vary greatly between individuals. It can wax and wane, or be unwavering, and is oftentimes worse at night. The quality of pain can be quite variable, ranging from dull and aching to sharp and intense, or have neurogenic features due to highly innervated periosteum, all of which can complicate management (4). The cause of the pain is due to bone destruction, bone instability and subsequent fractures.

Investigations

When a patient presents with bone pain from bony metastases, there are several important investigations to acquire in order to diagnose and to prevent other complications and morbidity associated with untreated bone metastases. Important labs include complete blood count, serum calcium and alkaline phosphatase to name a few, and the clinical context will determine what imaging is appropriate. Some examples of imaging that may be ordered are x-ray, bone scan, CT, MRI and PET scan (7).

Management

Treatment of bone pain has two components, the first one being treating the underlying cause, the cancer itself, with systemic therapies such as chemotherapy, hormone therapy, targeted therapy or immunotherapy, and/or radiation therapy. Occasionally surgical management is needed to stabilize bones or repair fractures. The second part is treating the symptomatic bone pain which involves localized and/or systemic therapy.

Localized therapy

Radiation therapy is the treatment of choice for localized bone pain when there are limited lesions that can be individually targeted. Radiation may be delivered in a single treatment or given over a longer period (e.g. 5 days).

Radiation can be highly effective for pain control. Bone fixation by orthopaedic surgery or bone cement is another form of localized treatment. Bones at risk of fracture or bones that are already fractured can be surgically stabilized to improve pain and mobility.  

Systemic therapy

Systemic therapies include systemic radiation, anti-resorptive drugs (e.g. bisphosphonates and denosumab) and pain medication such as opioid analgesics, NSAIDs and acetaminophen.

Systemic radiation therapy can be an effective treatment for diffuse or multifocal bone pain, relieving pain for several months (7). This method delivers radiation to the cancer cells through IV administered radioactive drugs that are taken up by cancer cells by way of their rapid turnover. It is most effective when the metastatic lesions are osteoblastic, but is often used for treatment of both lytic and blastic lesions (7).

Anti-resorptive medications are the preferred systemic therapy for diffuse bone pain because they address the symptoms as well as the malignant cells. In addition to their anti-resorptive effects on osteoclasts, bisphosphonates have been shown to cause osteoclast apoptosis and may have direct apoptotic effects on tumour cells (4). In both breast cancer and multiple myeloma, bisphosphonates reduced skeletal-related events (radiotherapy for bone pain or impending fracture, pathological fracture, hypercalcemia of malignancy, spinal cord compression, and need for orthopaedic surgery) (4). Denosumab, a monoclonal antibody, is another agent that may be used that has shown to reduce skeletal-related events and a mortality benefit in multiple myeloma (4). The most serious, but rare side effect from these agents is medication-related osteonecrosis of the jaw (MRONJ). The risk is <2% in the first year of treatment, and rises to 4.6% per year by year 3 and beyond (8). Risk factors for developing MRONJ include longer duration of therapy, higher dose, higher potency agents, and concurrent dental surgery, so it is recommended to complete any dental work before initiating therapy.

Table 2. Drugs used for treatment of hypercalcemia

Hypercalcemia

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.

Normal physiology of calcium homeostasis

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).

Pathophysiology of hypercalcemia of malignancy

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).

Diagnosis

Clinical presentation

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.

Table 3. Signs and symptoms of hypercalcemia

Investigations

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.

Table 4. Serum calcium level associated with degree of hypercalcemia


Management

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.

Venous Thromboembolism: Pulmonary Embolism and Deep Vein Thrombosis

Cancer associated venous thromboembolism (VTE) is the 2nd leading cause of death in cancer patients and they have a 4-7 fold increase in risk of developing a VTE compared to those without cancer (11). A VTE can be described as a deep vein thrombosis (DVT), which usually starts in the distal lower limb such as the calf, and it can move to the pulmonary system as which point it is called a pulmonary embolism (PE). These complications are common and can cause significant mortality and morbidity burden to patients, in addition to the financial and resource strain it puts on the healthcare system.

Pathophysiology

The increased incidence of VTE in cancer is due to disruptions in Virchow’s triad, which attributes blood clotting to 3 factors: venous stasis, endothelial dysfunction, and a hypercoagulable state (12). Venous stasis can occur secondary to prolonged periods of immobility, especially as morbidity from cancer increases. Additionally, tumours can compress the vasculature, impairing venous return. There are many ways hypercoagulability is caused by cancer cells. One way is malignant cells themselves becoming pro-coagulable, and they can also cause healthy cells to become hypercoagulable (12). Cancer cells undergo countless genetic mutations that can result in expression of adhesion molecules on their surface, they change the surrounding cellular environment by secreting cytokines that activate tissue factor expression on healthy cells, and they secrete procoagulant particles (13). Each of these mechanisms contribute to at least one of the 3 factors in Virchow’s triad, increasing the risk of clot formation. Recognizing patients with the following risk factors is vital to prevention and management of cancer-associated VTE. Additionally, it’s important to understand how these risk factors are dynamic and patients require re-evaluation over time.

Table 5. Risk factors for cancer patients to develop VTE


Screening and Diagnosis

Screening for risk

The Khorana Risk Model is a validated screening tool used to assess a patient’s risk of VTE (14). It helps guide decisions on whether or not a person with cancer should receive prophylactic antithrombotic therapy. The score translates to the risk of VTE at 2.5 months follow-up. Patients who score ≥3 (high risk) should be considered for VTE prophylaxis therapy (14).

Table 6. Khorana Risk Model for assessing risk of VTE (14)

Interpretation of Khorana scores:

  • Low risk = 0 (0.3% VTE rate at 2.5 month follow-up)
  • Moderate risk = 1-2 (2.0% VTE rate at 2.5 month follow-up)
  • High risk ≥ 3 (6.7% VTE rate at 2.5 month follow-up)

Screening for diagnosis and treatment

The Wells score is a set of criteria used to determine a pre-test probability of either a DVT or PE when there is clinical suspicion. It is not diagnostic, but helps to guide what further investigations are needed and those that will be most beneficial.

Table 7. Wells criteria for assessing likelihood of a PE (15)

Interpretation of Wells score for pre-test probability of PE

  • PE likely >4 (37.1%)
  • PE unlikely ≤ 4 (12.1%)
Table 7. Wells criteria for assessing likelihood of a DVT (16)

Interpretation of Wells score for pre-test probability of DVT

  • DVT likely >1 (28%)
  • DVT unlikely ≤ (6%)

Diagnosis

Pulmonary embolism usually presents with shortness of breath and tachycardia, but other variable features such as pleuritic chest pain, cough, and symptoms of a DVT can also be present. In the context of clinical suspicion and a likely pre-test probability, the next steps in investigation and diagnosis are D-dimer and imaging (e.g. VQ scan, CT Scan) (17). As a general rule, a D-dimer > 500 ng/mL is considered positive, however the cut off increases with increasing age and it is recommended to use an age-adjusted D-dimer (age x 10) after 50 years old (12).

A DVT often presents with swelling or edema, pain, redness and warmth that is unilateral. The extent of the extremity affected depends on the location of the DVT. The entire leg could be affected if it is more proximal, whereas only the lower leg will be affected if it is located more distally (18). If a DVT is suspected, a Doppler Ultrasound is the imaging modality of choice.

Management

Prophylaxis

Primary prophylaxis is indicated in some outpatient cases where the type of malignancy and chemotherapy combination call for this, but it is not routine. One example where prophylaxis is recommended is for patients with multiple myeloma receiving thalidomide, lenalidomide or pomalidomide with chemotherapy and/or dexamethasone as their risk of VTE is high. Prophylactic options include aspirin, unfractionated heparin (though this cannot be administered in an outpatient setting), low molecular weight heparins (LMWH) (e.g. dalteparin, enoxaparin and fondaparinux). All of these agents are given at lower doses than the doses given for therapeutic treatment of an established VTE.

Treatment

The mainstay of VTE treatment in cancer patients is LMWH. Head to head trials have shown that it is more effective than warfarin at preventing recurrent cancer-associated thromboembolisms (CAT), and has a lower incidence of major bleeding. Some appropriate LMWHs include dalteparin, enoxaparin and tinzaparin. Some of the direct oral anticoagulants (DOAC) have shown to be non-inferior to LMWH for treating CAT, and may be implemented into practice in the near future as more data becomes available on the efficacy and safety of these agents (19,20). Standard duration of treatment is 6 months, but this should be re-evaluated at least every 3 months and a discussion for extension of treatment in certain clinical situations where people are high risk of recurrence is warranted (e.g. patients who continue to live with incurable cancer).

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):

  • Bowel habit changes (diarrhea, constipation, ‘pencil-thin’ stools)
  • Sensation of incomplete emptiness following bowel movements (tenesmus)
  • Blood in the stool (bright or dark red)
  • Fatigue
  • Abdominal pain or discomfort
  • Nausea or vomiting
  • Loss of appetite
  • Weight loss
  • Palpable mass in the abdomen
  • Anemia
  • Lymphadenopathy
  • Bowel obstruction
  • Bowel perforation

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:

  • Hepatomegaly
  • Jaundice
  • Ascites
  • Shortness of breath

A more detailed description of the signs and symptoms associated with colon cancer, including their pathogenesis, is included in Table 1 below.

Table 1. Signs and Symptoms of Colorectal Cancer

TNM

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 [8]. The 2017 AJCC guidelines are as follows [8]:

Tumour Staging
Nodal Stage


ENE = extranodal extension

Metastases Stage
Prognostic Stage
In the aforementioned TNM system, imaging is necessary to establish the “N” and “M” stages. However, imaging is not performed on the majority of patients with BCCs or cSCCs because only 1-5% of cSCCs and <0.1% of BCCs metastasize [2,3]. That being said, it is important to note that despite the low rate of mortality incurred by these cancers, there can be significant morbidity. BCCs can be extremely locally destructive to tissues and bones despite being low grade [4].There is no definitive consensus as to how to determine which patients should be imaged. Experts agree that the TNM system is inadequate, as the vast majority of patients have T1 or T2 N0M0 disease and they do not all have the same prognosis [2,5,6]. As such, most guidelines suggest that tumours should be classified as either “high risk” or “low risk” according to their potential for metastasis [2,5,6]. These defining features are not standardized, however, the high-risk features typically increase the 5-year recurrence rate and/or metastatic rate over 15% [3].


High-Risk Features of Basal Cell Carcinoma [2,3,4,9]

Clinical features
  • >6mm for mask area, >1cm for cheek, forehead, scalp and neck, and >2 cm in size other areas
  • High risk locations: nose, eyelid, temple, preauricular, postauricular, lower legs
  • Inadequate margins for excision
  • Poorly circumscribed
  • Recurrent tumour
  • Incomplete excision
  • Lesions in sites of previous radiation therapy
Histologic features
  • Morpheaform,sclerosing, infiltrating, desmoplastic, micronodular, basosquamous, keratotic metatypical subtypes
  • Perineural spread

High-Risk Features of Cutaneous Squamous Cell Carcinoma [2,3,5,6,7,10,11]

Clinical features
  • >2 cm in size
  • High risk locations: ear, lip, genitals
  • Rapid growth
  • Immunosupressed patient
  • Arisen from within a trauma site (chronic wound or irradiation site)
  • Recurrent disease
  • Incomplete excision
  • Multiple tumours
Histologic features
  • Depth beyond subcutaneous tissue (increasing risk with increasing depth beyond 2mm)
  • Close margins (<2mm)
  • Primary mucosal SCC
  • Poorly differentiated
  • Perineural spread
  • Intravascular invasion

The Brigham and Women’s Hospital Tumour Staging system has been designed to improve prognostic value in assessment of tumours [12]. 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).

Imaging

Basal Cell Carcinoma

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 [3].

Cutaneous Squamous Cell Carcinoma

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 [3].

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 [10]. 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 [3].

Prognosis

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 [2]. However, this prognosis changes considerably for high-risk lesions with rates dropping down below 50% for T4 lesions [3]. 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.

Tumor (T) (1)

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

Regional Lymph Nodes (N) (1)

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

  • N1a - metastasis in 1 regional lymph node
  • N1b - metastasis in 2-3 regional lymph nodes
  • N1c - tumor deposit(s) in the subserosa, mesentery, or non-peritonealized pericolic or perirectal tissues without regional nodal metastasis

N2 - metastasis in 4 or more regional (pericolic or perirectal) lymph nodes

  • N2a - metastasis in 4-6 regional lymph nodes
  • N2b - metastasis in 7 or more regional lymph nodes

N3 - metastasis in any node along the course of a named vascular trunk and/or metastasis to apical node

Distant Metastasis (M) (1)

Mx - metastasis cannot be assessed

M0 – no distant metastasis

M1 – distant metastasis

  • M1a – metastasis confined to one organ or site (e.g., liver, lung, ovary, nonregional node)
  • M1b – metastasis in more than one organ/site or the peritoneum
  • M1c - metastasis to the peritoneum with or without other organ involvement

Stage Groupings

The table below delineates the stage groupings for colorectal cancer based on their TNM status.

Table 2. TNM staging for colorectal cancer (1)

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.

Initial Considerations

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).

Treatment Modalities

Surgery

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).

Radiation

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):

  • Fatigue
  • Skin changes: radiation dermatitis (clinically akin to a sunburn), moist desquamation of the axilla or inframammary fold, post-inflammatory pigmentation changes, skin fibrosis
  • Breast pain
  • Lymphedema
  • Esophagitis
  • Respiratory effects: radiation pneumonitis, radiation fibrosis (late effect)

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

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):

  • Hot flashes and other symptoms of treatment-induced menopause
  • Sexual dysfunction
  • Weight gain
  • Constipation
  • Diarrhea
  • Nausea
  • Fatigue
  • Hair thinning
  • Change in vaginal discharge
  • Osteoporosis (with AIs)
  • Dyslipidemia (with AIs)

Chemotherapy

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).

Treatment of Breast Cancer by Stage

Table 3. Treatment of breast cancer by stage of disease

Information in the table above was derived from the Canadian Cancer Society and the American Cancer Society (2,8,9).

Prognosis

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).

Table 4. Prognosis of breast cancer by stage

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).

References

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