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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 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 treatment (eg: lymphedema, fibrosis, secondary cancers, fertility issues, neuropathy, cognition and memory deficits)  

Survivorship and Complications of Cancer Treatment

Specific cancer treatment modalities (i.e. chemotherapy, radiation therapy and/or surgery) can cause or increase the risk of long-term side effects. Identification, investigations and management of these late effects are all part of the survivorship phase after curative cancer treatment. This module is not intended to be a source of specific survivorship monitoring and follow-up guidelines, but rather a general overview of common late effects to be aware of when caring for oncology patients.

Lymphedema

The lymphatic system, comprised of lymph organs, lymph fluid and lymphatic vessels, has 3 main functions: drainage of excess interstitial fluid, immune surveillance and fat absorption (1). Lymphedema is swelling due to obstruction of lymph fluid outflow, causing build up of lymph in surrounding soft tissues (2). This occurs most commonly in the axilla, neck, groin, and pelvis with the risk of lymphedema increasing the more nodes are affected (2). It is termed secondary lymphedema when the etiology is due to removal or damage of lymph nodes from surgery or radiation (2). Chronic lymphedema can result in fibrosis, increased subcutaneous tissue deposition, and further lymphatic damage if it is left unmanaged (1).

Incidence

The risk of developing lymphedema after removal of axillary lymph nodes is 0-25%, but is lower (~3-7%) for patients who do not receive radiation, while the risk increases to an average of 12% (range 10-54%) for those who receive both full lymphatic dissection and radiation (3). In non-breast cancers for patients who have lymph node removal and radiation therapy the risk is up to 16% (3).

Presentation

It is imperative to take a thorough history including onset, areas involved, progression, past medical and surgical history should lymphedema be suspected. Lymphedema usually occurs gradually, progressing slowly over 2-4 years after lymph node dissection or radiation (4). Immediate lymphedema after lymph dissection is common and may not necessarily be permanent, whereas later presentation (months to years) will likely be permanent. As a complication of cancer treatment, lymphedema typically presents as ipsilateral swelling of the limb, often described as aching, heaviness or tightness (4). The swelling can be proximal or distal, affecting the trunk or distal limbs respectively. There is usually more pitting present in the early stages, as later stages are characterized by a hyperkeratotic state causing skin thickening, cutaneous fibrosis and adipose deposition over the affected limb (4).

To characterize the severity of lymphedema and progress through time, the difference in circumference between the affected and unaffected limb is measured. Upper limb measurements are taken at the metacarpal-phalangeal joints (if edematous), around the wrist, and 10 cm above and below the olecranon process. Lower limb measurements are also taken at metacarpal-phalangeal joints (if edematous), 2 cm above the medial malleolus, 10 cm above and below the superior pole and inferior pole of the patella respectively (4).

There are 3 stages of edema:

  • Stage 1: A difference of 2-3 cm
  • Stage 2: A difference of 3-5 cm
  • Stage 3: A difference of >5 cm
Table 1: Signs and Symptoms of Lymphedema


Table 2: Risk factors for developing lymphedema


Management

The first step in management involves staging the severity of the lymphedema. This helps determine treatment options and address any underlying contributing factors. There is no curative treatment for chronic lymphedema, and currently no drug options, so management is centered around supportive measures. Treatments aim to minimize swelling, prevent worsening, prevent infection, relieve pain and maintain or improve limb usability (2).

Taking measures to preserve the integrity of the skin will help to prevent soft tissue infections that commonly occur as a result of impaired lymphatic drainage. Avoiding scratches, tight clothes, sunburns, bug bites, and ensuring adequate moisturization can all help to improve skin condition and mitigate risk of infection (2).

Compression garments and bandages, and compression devices may help reduce swelling and encourage lymphatic fluid flow for some patients. It is also recommended that moderate, low impact exercise such as biking, swimming and walking be part of a regular routine as this type of exercise has been shown to reduce edema (2). Maintaining healthy body weight with a normal BMI is another way to minimize swelling.

Other treatments strategies include physiotherapy, manual lymph therapy massage, elevation of the affected limb, and active compression device pumps. The purpose of each of these modalities is to reduce swelling and prevent progression.

Complications

Complications of lymphedema can occur, which is why timely recognition is important as this condition is most often permanent once it develops. In chronic lymphedema, large deposits of subcutaneous tissue can form and, along with swelling, can limit movement and poorly affect body image (4). There is a risk of soft tissue infections in the affected limb, and these can become recurrent as lymphedema worsens (1). There is a small (0.03-0.45%), but increased risk of developing angiosarcoma in patients with chronic lymphedema of more than 10 years, which is an aggressive malignancy with a 20-35% 5 year survival rate after diagnosis (5).

Fibrosis

Fibrosis can occur in any tissue exposed to radiation, with the initial presentation of symptoms typically occurring within 4 to 12 months after treatment. The degree of fibrosis varies based on several factors including the total dose, the volume of tissue treated and the fractionation schedule, as well as other important but less contributory factors like other concurrent or previous therapies, presence of comorbidities such as diabetes mellitus and genetic susceptibility (6,7).  

Pathophysiology

In radiation-induced fibrosis, the radiated tissue undergoes a process similar to any process of inflammation and wound healing (6). Increased inflammatory infiltrates, increased extracellular matrix protein and collagen deposition, and abnormal vascular changes all contribute to the fibrotic transformation that occurs gradually and continues over several months to years after the exposure.

Clinical Manifestations of Fibrosis

Table 3. Most common clinical manifestations of radiation-induced fibrosis by body site (6)


Management

Prevention is the best way to manage radiation-induced fibrosis by adjusting the dose and volume to the lowest possible. New radiation delivery techniques are limiting exposure to surrounding tissues and have become much more targeted, which has helped reduce the area of fibrosis post-treatment (7). Pentoxifylline (often in combination with vitamin E) has been shown to have some benefit for prevention as well as treatment of fibrosis (6,8).  This drug inhibits platelet aggregation, increases microvascular blood flow and may inhibit fibroblast proliferation thereby reducing production of extracellular matrix (6).  In practice, pentoxifylline is not that commonly used, but can be a potential consideration.  While there are some cell-based therapies in clinical trials that target the molecular mechanisms of the inflammatory pathway that result in fibrosis, current treatment options are generally supportive and are aimed at addressing symptoms (9). Physiotherapy, along with a regular exercise routine, can help increase range of motion, improve muscle strength and lessen progressive muscle atrophy (9). Massage therapy, including fascial techniques and myofascial relaxation, can improve blood flow, reduce lymphedema and help to loosen tense soft tissue (9).

Secondary Cancers

Secondary cancers are cancers that occur after chemotherapy or radiation therapy are completed and are thought to be caused by the treatment. After chemotherapy, the most common secondary cancers are acute leukemia, non-Hodgkin lymphoma, bladder cancer and sarcoma (2). After radiation, the most common secondary cancers are sarcomas of bone and tissue, acute myelogenous leukemia, and some solid organ tumours, but this is dependent on what tissues were exposed to radiation. Second cancers can develop at anytime after treatment completion, ranging from 2-3 years up to 20 years after (10).

Screening and Management

Screening for secondary cancers is not routine and varies based on the presence of patient risk factors for developing second malignancies. Standard risk patients are those who have undergone curative treatment for an initial primary cancer, and their only significant risk factor for developing a second malignancy was the first cancer treatment. For these patients, it is usually recommended that they follow the same screening guidelines as the general population with a thorough history and physical exam at least once annually by their family physician (11). High-risk patients have risk factors that increase their likelihood of developing a second cancer, and these include genetic predisposition, familial syndromes, residual disease after primary treatment, and some case-specific or treatment-specific features that differ between individuals. Presence of any of these may warrant more frequent screening, although there is no standard protocol for frequency and methods of screening. At minimum, an annual cancer-related physical exam should be conducted. For example, in a young patient previously treated for breast cancer, this should include examination for cancers of the thyroid, lymph nodes, and the skin in the area radiated (12). In addition to physical exam, education on preventative measures such as smoking cessation, minimizing sun exposure, diet and nutrition, safe sexual practices and avoiding harmful environmental and occupational exposures is recommended (12). Specific cancers will each have a more expansive and tailored follow-up criteria than discussed here, but this content is meant to serve as a starting point for general surveillance post-cancer treatment.

Fertility

Fertility issues can occur as a complication of all cancer treatment modalities and can be addressed pre-treatment, during treatment and post-treatment. A multidisciplinary approach can further support the patient and their family through this process.

Chemotherapy

Gonadal dysfunction is one of the most common long-term side effects from cytotoxic chemotherapy and can be central (affecting the hypothalamic-pituitary-gonadal axis) or primary (affecting the gonads directly) in origin. Alkylating agents, such as cyclophosphamide or procarbazine, have the highest risk of gonadotoxicity, while platinum agents (e.g. cisplatin, carboplatin, oxalipatin), cytarabine and vinblastine have moderate risk (13). Possible effects of chemotherapy include disturbing sperm quality and/or count and testosterone production in men, and affecting egg quality and/or count in women (13). Should the entire ovarian reserve be depleted, the outcome is premature menopause (13). In females, chemotherapy is less toxic to oocytes than is it to follicular development, which means that while amenorrhea is common during chemotherapy and can be quite distressing for patients, menstrual function and fertility may return after cessation of therapy due to survival and preservation of the mature oocytes (14).

Radiation therapy

Radiation therapy (RT), especially at higher doses, is more toxic to oocytes and ovarian tissue than chemotherapy (14). RT, like chemotherapy, can affect fertility at several different levels. Treatment to the pelvic region can destroy both sperm and eggs, and may also result in permanent damage of the cells that produce sperm. Central hypogonadism can occur if the hypothalamus or pituitary are in the field of RT, and damage to this area can cause disturbance of GnRH, FSH and LH regulation, which will impact fertility. Radiation to the female reproductive organs can impair the ability for conception by altering the characteristics of the tissue. RT changes to the uterus can impede implantation and therefore development of an embryo, as well as reduce its capacity to stretch to accommodate a growing fetus (13).

Surgery

Surgery can affect fertility in a structural capacity. In females, treatment may require an oophorectomy (removal of an ovary) which can reduce chances of pregnancy if it’s unilateral, and cause sterilization if bilateral. Any blockage or disruption of the fallopian tubes, uterus or cervix as a complication of surgery can impair fertility and/or increase complications during pregnancy. In males with testicular cancer, surgery can result in infertility and low testosterone production. After radical prostatectomy, erectile dysfunction and reduced sperm count in ejaculate are not uncommon and can affect fertility.

Risk factors

Factors that modify the risk of infertility after cancer therapy include age at diagnosis and treatment (post-pubertal being at higher risk), pre-treatment fertility status, and treatment related factors (i.e. type and dose of chemotherapy, location and dose of radiation, surgical complications) (13).

Management

Management of potential late effects of treatment on fertility depends on the treatment modality. Management can be pre-emptive, by preserving sperm or eggs before therapy begins. It can be concurrent to therapy, such as moving ovaries out of the radiation field or administering medications to help preserve function and/or reserve of reproductive organs. Post-treatment management involves assessment of fertility status, addressing the risks and benefits of pregnancy after therapy, and often involvement of a fertility specialist. Having early discussions about the possibility of fertility issues from treatment and involving a multidisciplinary team will be beneficial in supporting patients through this challenge.

Neuropathy

All cancer treatment modalities can cause neuropathy, but it is more commonly seen from chemotherapy. Radiation and surgery at or near a nerve, nerve root, or nerve plexus can disrupt signal transmission and cause abnormal sensations and/or pain that is generally localized to that dermatone or myotome. Chemotherapy toxicity is more widespread due to the systemic distribution and can affect axons, nerve cell bodies, myelin sheath, and support cells, resulting in many different presentations of neuropathy (15).

Chemotherapy

Chemotherapy induced peripheral neuropathy (CIPN) is a late side effect of systemic anti-cancer therapy with an incidence rate as high as 30-40% (16). Since distant axons are the most vulnerable to this toxicity, presentation commonly follows the “stocking and glove” distribution, where impairment of sensory modalities starts in the toes and fingers before gradually moving more proximally (16). Both temperature and pain, and vibration and proprioception sensations can be affected, leading to dysthesias, paresthesias and discomfort, all of which can cause significant impact on quality of life. It is important to rule out diabetic neuropathy, as CIPN often presents very similarly, but is not necessarily improved with standard therapies used to treat the former (16). If motor function is affected, this tends to occur after sensory dysfunction, as the more heavily myelinated motor tracks are more protected from damage than the lightly or non-myelinated sensory nerves (15). Autonomic nerves can also be affected in which case autonomic symptoms will manifest (13). Chemotherapeutic agents known to cause peripheral neuropathies include vincristine, paclitaxel and docetaxel, carboplatin, cisplatin and oxaliplatin, and suramin (15).

Table 4. Manifestations of CIPN


Management

Currently, there are no validated treatments for CIPN and one of the most important management strategies is to recognize this side effect early and minimize the dose or change agents if possible. This, however, is often not feasible as CIPN generally presents after chemotherapy is completed, in which case supportive measures become the mainstay of treatment. Physiotherapy, massage and electrical stimulation are all possible non-pharmacologic measures that patients may explore, and although the evidence for benefit has not been well studied there is minimal harm in attempting (17). Drug therapy for CIPN is similar to peripheral neuropathic pain, primarily comprising of anti-convulsants (e.g. gabapentin, pregabalin) and antidepressants (e.g. amitriptyline, venlafaxine, duloxetine) (17). Trials have failed to show a significant benefit for these therapies in CIPN, but can be considered on a case-by-case basis (17).

Cognition and Memory

Declines in cognitive areas such as memory, processing speed, attention, and executive functioning have consistently been reported in patients after cancer treatment (18). Commonly referred to as “chemobrain” or “chemofog”, patients may complain of things like difficulty multi-tasking, concentrating, and remembering small details/tasks after or during chemotherapy. Brain radiation can also impact cognition, but symptoms vary based on which area(s) of the brain was treated.

Chemotherapy

Cognitive deficits in attention, memory, planning, concentration and working memory post-chemotherapy treatment have been reported in up to 35-60% of patients and can significantly impact a patient’s quality of life (19,20). Much of the data has looked specifically at breast cancer patients, as it is thought that hormone therapy also contributes to this late side effect, but chemotherapy-related cognitive impairment has been reported in many other cancer types (20). While often subtle and noticed only by the individual themselves, patients should be encouraged to communicate these symptoms to their healthcare provider, as strategies to mitigate the impairment can then be discussed. Chemo-related cognitive impairment, or “chemo brain”, is generally mild and does not qualify as a diagnosis of mild cognitive impairment or dementia, but it may persist for months to years after completion of chemotherapy which can be very troublesome for patients (20).

Radiation therapy

Radiation therapy to the brain can cause varying degrees of cognitive effects, depending on the escalating radiation dose, fraction size, volume of brain tissue treated, concurrent chemotherapy, and age of the recipient (extremes of age being more negatively affected) (21). The impact on cognition can range from mild apathy, or slight memory difficulty to very severe cognitive decline (21). In adults, radiation induced neurocognitive decline usually follows a biphasic pattern with temporary decline followed by improvement, followed by a permanent decline (22). The first transient decline occurs around 4 months post treatment, then improves before a progressive, irreversible decline at 1 year or later (22). The degree of the impairment, however, is extremely variable and can range from being unnoticed to significantly impacting patient life.

Risk factors

General risk factors include extremes of age (very young and very old), high dose therapy, long duration therapy, use of multiple treatment modalities, and pre-existing cognitive deficits. Chemotherapy-related cognitive impairment is multifactorial with many factors contributing to its pathophysiology such as hormone changes, oxidative stress, and damage to blood-brain barrier to name a few. It has also been suggested that several genes may be associated with an increased risk (20). Endocrine therapy (for hormone positive breast cancer) and androgen deprivation therapy (for prostate cancer) may, on their own or as adjunctive treatment, be associated with negative impacts on cognition, although results have been inconclusive (20).

Management

At present, there are no drug therapies to halt or prevent cognitive decline from cancer treatment, although new techniques and modern therapy have significantly improved treatment outcomes and have thus reduced late effects on cognition (21). Having a baseline objective assessment of cognition prior to starting therapy can help determine the progression and severity of cognitive deficits a patient may be experiencing, but often this is not available. Several recommended measurement tools include the Hopkins Verbal Learning and Memory Test-Revised, the Controlled Oral Work Association, and the Trail Making Test (18). Some other non-pharmacologic strategies that may be beneficial include cognitive behavioural therapy (cognitive rehabilitation and training), physical activity, and most importantly maintaining good overall physical and mental health (18,23).

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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