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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).

Symptoms depend on location of tumor. Early esophageal cancer is usually asymptomatic. Overall, dysphagia and weight loss are the most common symptoms at time of diagnosis, presenting in 74% and 57% of patients respectively [24]. 

Diagnosis

Diagnosis includes a full detailed history and physical examination. Esophageal cancer specific history questions and physical exam findings are detailed below.

Table 3. Assessment of suspected esophageal cancer

Work-Up:
Table 4. Investigative work-up for esophageal cancer

The normal thyroid gland is composed histologically of two main parenchymal cell types: follicular epithelial cells and C or parafollicular cells [7]. Most thyroid cancers are derived from the follicular cells which give rise to both well-differentiated cancers (papillary, follicular) and anaplastic thyroid cancers. In the young (under 40 years of age), thyroid cancer is usually well-differentiated and the overall prognosis is excellent. On the other hand, anaplastic carcinomas (15%), particularly in older patients, have a significantly poorer prognosis and are rarely cured. From C or parafollicular cells arise medullary thyroid carcinoma (MTC).

Papillary carcinoma

Papillary carcinoma is the most common form of thyroid cancer in Canada compromising over 80% of all diagnosed thyroid Cancers. It is a slow growing subtype and survival rates are high if diagnosed early. It is often single lobular. Metastases most commonly involve cervical lymph nodes and, less commonly, the lungs [7].

Follicular carcinoma

Follicular carcinoma is the second most common type of thyroid cancer after papillary carcinoma. It arises from follicular cells responsible for thyroid hormone production. It is slow growing and survival rates are high if diagnosed early. Follicular carcinoma is often treated with radioactive iodine since this tumor is most likely to capture radioactive iodine. When metastasized, however, follicular thyroid cancers tend to metastasize hematogenously to distant sites, in particular, to lung and bones.

Anaplastic carcinoma

Anaplastic carcinoma is the least common type of cancer (<1%) and occurs more often in middle ages and elderly patients [6]. It is the most aggressive type and is fast growing with early spread. A metastatic work-up often reveals locoregional disease and distant metastases, most commonly to the lungs followed by bones and brain. Anaplastic thyroid cancer often arises from and can coexist with differentiated thyroid cancer, but can also occur de novo. Clinicians should suspect anaplastic transformation in patients with a history of longstanding differentiated thyroid cancer if they present with symptoms such as hoarseness, dysphagia, and dyspnea. It is often too advanced to surgically resect at diagnosis and therefore treated with radiation therapy alone. The cure rate of anaplastic carcinoma is very low. 

On presentation, most patients with anaplastic thyroid cancer have a large, firm palpable mass in the thyroid with or without cervical adenopathy, and patients often develop hoarseness, dysphagia, and dyspnea. Clinicians should suspect anaplastic transformation in patients with a history of longstanding differentiated thyroid cancer if they present with the aforementioned symptoms. [6]

Medullary carcinoma

Medullary carcinoma arises from parafollicular neuroendocrine cells of the thyroid - C-cells which are responsible for the production of calcitonin. It is uncommon and constitutes 1-2% of thyroid cancers [6]. It is slow growing and survival rates are high if diagnosed early. It may spread to lymph nodes or metastasize elsewhere. It generally occurs on one side of the thyroid only. MTC is the most prominent clinical diagnosis in multiple endocrine neoplasia (MEN) 2A and MEN 2B - a quarter of medullary thyroid cancer cases occur in patients with an inherited MEN syndrome.

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

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