Late Effects of Cancer Treatment: A Guide to Primary Care Management

By Asst Prof Poon Yi Ling Eileen, Consultant, SingHealth Duke-NUS Blood Cancer Centre; Division of Medical Oncology, National Cancer Centre Singapore

2/2/2024 1:10:00 PM | Defining Med

The article is contributed/written by National Cancer Centre Singapore

Systemic cancer treatments have increased tremendously in the last decade and with high survival rates general practitioners are more than likely to have cancer survivors as patients, as such knowledge of the common side late effects and management measures will help GPs optimise their care for these patients.

BASIC STATISTICS OF CANCER IN SINGAPORE

Cancer has ranked consistently as the principal cause of death in Singapore, with 26,891 deaths reported in 2022, attributing up to a 25% of total deaths. The number of cancer cases have been increasing annually and is expected to continue to increase.

Between 2017-2021, 84,002 cancer cases were reported in Singapore. Between 2018 – 2021, the National Cancer Centre Singapore (NCCS) has seen more than 6,000 young adults with cancer. Out of this, 80-85% of cancer patients, especially in the younger adults, is expected to have long-term survival. There is a difference in the types of cancers seen across the age groups, and across genders.

TYPES OF TREATMENTS AVAILABLE IN SINGAPORE FOR CANCER TREATMENT

Cancer treatment can be broadly divided into systemic treatment, surgical treatment and radiotherapy. We will focus on systemic treatment in this article. The types of systemic cancer treatment have increased tremendously in the last decade. Beyond the usual chemotherapy that is usually cancer-agnostic, there is now a whole host of different kinds of anti-cancer treatment available.

This includes immunotherapy, targeted therapy, hormone therapy, stem cell transplants, CAR-T (Chimeric Antigen Receptor T-Cell) Therapy, monoclonal antibodies, checkpoint inhibitors, cytokines, angiogenesis inhibitors and PARP (Poly ADP-ribose polymerase) therapies. There are also increasingly more clinical trial drugs that are available to our patients.

Impact on patients

With each treatment, there exists certain specific side effects and also some general toxicities. For some patients, these toxicities are slight and do not affect their overall quality of life. They will likely be able to return to regular life. However, for others, the toxicities can be debilitating and can even be permanent.

These toxicities can be divided into early, mediumterm and late effects. This article will specifically focus on late effects.

WHAT ARE LATE EFFECTS?

In general, late effects (also known as long-term or delayed effects) can occur months or years after cancer treatment has completed.

The extent of toxicities is dependent on:

Exact type of treatment received
Duration and dose of the treatment and
The patient’s co-morbidities

This can occur in almost any organ or system and can include:

Neurological and cognitive impairments
Endocrine derangements
Cardiovascular complications
Subfertility
Osteopenia and osteoporosis
Nephropathies
Gastro-intestinal and hepatotoxicities
Respiratory complications
Psychosocial
Sexuality
Psychosocial distresses

The reversibility of these toxicities is dependent on:

The extent
Timely detection and
The patient’s willingness to try methods to reverse or mitigate them

The methods to treat these symptoms may not be straightforward and may involve not medication, but also a more holistic approach that includes lifestyle changes.

WHAT IS A CANCER SURVIVOR?

Cancer survivors are defined as any cancer patient from the point of diagnosis. Broadly, this can refer to any cancer patient who is cured, in remission or has stable chronic cancer expected over a period of time.

Caring of the cancer survivors should include:

Screening and prevention of long-term side effects from a holistic standpoint
Surveillance for the original cancer to detect recurrence
Screening for secondary cancers
Care co-ordination between primary care providers and other specialists
General health management including management of risk factors and adoption of a healthy lifestyle such as regular exercise and practicing sun safety.
Concerns with reintegration into work/school/community
Psychosocial and mental health concerns

Below is a general table on some of the common late effects and the advised management.

1. PERIPHERAL NEUROPATHY/PAIN

Can be in the form of numbness, paresthesias, allodynia or shooting electrical pains

Suggested relevant investigations	Severity & Management	Specialties to consider referring to
Consider X-rays or MRI scans Consider nerve conduction studies/electromyography	Non-pharmacologic treatments such as physiotherapy, heat/ice therapy, acupuncture/transcutaneous electrical nerve stimulation unit Pharmacologic treatment with nonopioids/adjuvant analgesics, topicals, vit Bs Pharmacologic treatments with opioids	Neurology Orthopaedics Pain services Interventional radiologist if there is radiculopathy Rehabilitation medicine Palliative care Consider physiotherapy

2. MYALGIAS/ARTHRALGIAS

Muscle aches
Joint aches

Suggested relevant investigations	Severity & Management	Specialties to consider referring to
X-rays of affected joints/limbs to rule out fractures/avascular necrosis DEXA scan to check bone density Bone scans if bone metastases suspected Screen for hormonal/endocrine/vitamin deficiencies Screen through medication/treatment history	Non-pharmacologic treatments such as physiotherapy, heat/ice therapy, acupuncture/ultrasonic stimulation Braces or orthoses Pharmacologic treatment from simple analgesics such as paracetamol/anarex, non-opioids/adjuvant analgesics to opioids Joint replacements may be necessary	Pain Team Physiotherapy Orthopaedics Rehabilitation medicine Refer back to oncologist should there be suspicion of recurrence

3. POOR BONE HEALTH/UNEXPECTED FRACTURES

Unexpected/multiple fractures, especially at an unexpected age
Osteopenia
Osteoporosis

Suggested relevant investigations	Severity & Management	Specialties to consider referring to
X-rays of affected joints/limbs to rule out fractures DEXA scan to check bone density annually Screen for hormonal/endocrine/vitamin deficiencies Check for calcium, vitamin D, PTH levels Check renal function Go through medication list and treatment history	Calcium supplements Replete vitamin D levels Bisphosphonates/RANK-ligand inhibitors	Endocrinologist Orthopaedics Referral to dentists before initiating bisphosphonates Should hormonal replacement therapy be considered, please refer back to primary oncologist to ensure this is acceptable

4. EARLY MENOPAUSE

Symptoms may occur regardless of ovarian function
Menopause is defined as no menses for 1 year, in the absence of prior chemotherapy or tamoxifen use OR no menses after surgical removal of all ovarian tissue

Suggested relevant investigations	Severity & Management	Specialties to consider referring to
Screen for reversible causes (e.g., anaemia, severe weight loss) Screen for menopausal symptoms Assess for contributing factors (e.g., medications, emotional distress, alcohol) Assess for endocrine/vitamin deficiencies/hormonal imbalances (e.g., FSH, LH, prolactin, estradiol levels, AMH levels for females; morning total testosterone, free testosterone in males) Review oncologic history and treatment history	Management of menopausal symptoms Consider non-hormonal pharmacologic treatment of hot flushes such as anti-depressants, anti-convulsants, neuropathic pain relievers, some anti-hypertensives Non-pharmacologic treatments include acupuncture, exercise, lifestyle modifications, weight management and cognitive behavioural therapy Limit triggers, such as alcohol Hormonal replacement therapies or pharmacologic therapies	Consider referral to gynaecologist Should hormonal replacement therapy be considered, please refer back to primary oncologist to ensure this is acceptable. Consider referral to counsellor, social worker, psychiatrist

5. SUBFERTILITY

Evaluation should be undertaken for couples who have not conceived 6-12 months of unprotected intercourse
Can be earlier should prior history be expected to affect fertility

Suggested relevant investigations	Severity & Management	Specialties to consider referring to
Screen for reversible causes such as anaemia, endocrine, vitamin deficiencies, hormonal imbalances Assess for contributing factors such as medications, emotional distress, alcohol Assess for structural causes	Review oncologic history and treatment history to assess what is realistically available to patient (e.g., female with hysterectomy will not be able to physically carry a child) General recommendations is to be disease-free for 2 years before attempting to conceive, be it either naturally or via assisted reproductive technologies	Consider referral to gynaecologist or urologist Consider referral to assisted reproduction centres with fertility specialists such as CARE Should hormonal replacement therapy be considered, please refer back to primary oncologist to ensure this is acceptable

6. SEXUAL HEALTH

Important aspect of Quality of Life. Needs to be sensitively asked/broached.
This would be applicable regardless of sexual orientation

Suggested relevant investigations	Severity & Management	Specialties to consider referring to
Screen for reversible causes such as anaemia, endocrine, vitamin deficiencies/hormonal imbalances Assess for contributing factors such as medications, emotional distress, alcohol	Review oncologic history and treatment history Can screen with Sexual Health Inventory for Men/Brief Sexual Symptom Checklist for Women Assess issues concerning sexual health and see if etiology can be managed (e.g., vaginal dryness may benefit from lubricants)	Sexual health specialist Endocrinologist Gynaecologist or urologist Social worker Counsellor Marriage counsellor if appropriate

7. CHRONIC FATIGUE

Distressing, persistent and subjective sense of physical/emotional/cognitive tiredness or exhaustion that is out of proportion to activity. It affects usual functioning.
This is related to cancer or cancer treatment

Suggested relevant investigations	Severity & Management	Specialties to consider referring to
Screen for reversible causes such as anaemia, insomnia, obstructive sleep apnoea Assess for contributing factors (e.g., medications, emotional distress, alcohol) Assess for endocrine/vitamin deficiencies/hormonal imbalances Consider 2D Echo Consider sleep study	Screen for fatigue regularly Treat any reversible causes or medical causes Sleep hygiene as appropriate	Physiotherapist as appropriate Respiratory physician as appropriate Endocrinologist as appropriate

8. CHEMO BRAIN/BRAIN FOG

Cognitive dysfunction related to cancer and/or
Cancer treatments

Suggested relevant investigations	Severity & Management	Specialties to consider referring to
Screen for reversible causes (e.g., insomnia/endocrine/vitamin deficiencies/hormonal imbalances) Assess for contributing factors (e.g., medications, emotional distress, alcohol) Consider brain imaging if brain metastases suspected	Offer validation of symptom experience Treat any reversible causes or medical causes Sleep hygiene as appropriate Practical advice on coping such as taking notes, forming routines Cognitive training such as brain games	Social worker Counsellor Referral to neurologist Referral to geriatrician or early dementia clinic or equivalent as appropriate Speech therapist or occupational therapist as appropriate

9. METABOLIC SYNDROME/HYPERTENSION/HYPERLIPIDAEMIA

Co-occurrence of metabolic risk factors for T2 DM and cardiovascular disease (CVD)
CVD = Hypertension, hyperglycaemia, dyslipidaemia

Suggested relevant investigations	Severity & Management	Specialties to consider referring to
Review medical history medication/treatment history Check blood pressure, pulse rates, height and weight Screen for cardiovascular disease risk assessment and counselling Consider ECG and 2D Echo assessment Screen for diabetes and high cholesterol	Advocate for healthy range BMI 18.5 – 24.9 kg/m² Advocate for healthy lifestyle habits (e.g., physical activity, balanced diet) 2-3 sessions/week of resistance training at least 150-300 minutes of moderate-intensity activity or 75 minutes of vigorous-intensity activity; or equivalent Advocate for quitting smoking	Refer dietitian/nutritionist Refer physiotherapist Consider referral to endocrinologist/cardiologist as indicated

10. ANXIETY/PANIC/DYSTHMYIA/DEPRESSION

Anxiety

Difficult to control excessive anxiety & worry and ≥3 of following:

Restlessness/on edge, easily fatigued, difficulty concentrating, mind going blank, irritability, muscle tension, sleep disturbance

Panic

Sudden intense fear/discomfort with accompanying symptoms of palpitations, sweating, trembling, breathlessness, nausea, diarrhoea, vasovagal symptoms, chills or heat sensations, paresthesia, loosing sense of reality, fear of losing control/dying

Depression

Having ≥5 of the following for at least 2 weeks:

Depressed, sad, empty, hopeless mood or appearance
Loss of interest or pleasure in activities
Weight loss or gain
Sleep disturbances
Psychomotor agitation or retardation
Lack of energy
Feeling worthless or excessive guilt
Diminished concentration or indecisiveness
Thoughts of death or suicidal ideation

Suggested relevant investigations	Severity & Management	Specialties to consider referring to
Assess for suicide risk and manage accordingly Screen for depression/PTSD/mania/psychosis Screen with GAD-7/Brief Patient Health Questionnaire Assess for endocrine/hormonal imbalances Review diet, and consider reducing stimulants such as caffeine Consider brain imaging if brain metastases suspected	Non-pharmacologic stress-relieving techniques (e.g., yoga and meditation) Address root cause (e.g., pain) Encourage exercise and physical activity Cognitive behavioral therapy Pharmacologic techniques if the above cannot help Suicide precautions/managements as appropriate	Psychologist Psychiatrist Social worker If there is active suicidal ideation, there is a need to actively intervene

11. INSOMNIA

Difficulty falling asleep OR staying asleep OR waking up too early

Usually for ≥3 months
Occurs at least 3 times per week

Suggested relevant investigations	Severity & Management	Specialties to consider referring to
Assess for sleep practices and advise sleep hygiene Sleep journal Assess for medications that may affect sleep	Non-pharmacologic interventions by addressing root cause (such as pain) Sleep hygiene advice Pharmacology interventions as per guidelines antihistamines benzodiazepines Cognitive behavioral therapy	Psychologist Psychiatrist Social worker Consider referral to sleep specialist

12. NUTRITION (EITHER OVER OR UNDER) & WEIGHT MANAGEMENT

Can use BMI as a target

Suggested relevant investigations	Severity & Management	Specialties to consider referring to
Consider referral to nutritionist/dietitian	Healthy lifestyle Maintenance of adequate physical activity Healthy balanced diet	Gastrointestinologist if there is concern of dysmotility/absorption Psychiatrist/psychologist should there be a concern of body dysmorphia/eating disorder Refer back to oncologist should there be a concern with anatomy, possibly relating to cancer history

13. CARDIAC TOXICITY

Cardiac dysfunction that occurs as a result of cancer treatment (including chemotherapy, targeted therapy, radiotherapy etc)

Suggested relevant investigations	Severity & Management	Specialties to consider referring to
Screen through oncological history and treatment Screen for cardiovascular risk factors and treat accordingly ECG, 2D Echo, CK/CKMB/Troponins/BNP Chest X-ray Blood tests screening for hormonal/endocrine abnormalities	Advocate for healthy lifestyle including physical activity and balanced diet Stop smoking Maintain healthy BMI	Cardiologist Endocrinologist Dietitian/nutritionist Consider respiratory physician referral if no evidence of structural heart disease found, but patient is symptomatic Refer back to oncologist if symptoms persist

14. LYMPHOEDEMA

Occurs when fluid accumulates in the interstitial tissue, resulting in limb swelling or swelling in other areas such as neck/trunk, or genitals
Reports of feeling heavy/limb fatigue

Suggested relevant investigations	Severity & Management	Specialties to consider referring to
Screen for BMI Screen for haemodynamic circulation Regular screening via limb volume measurements	Weight control Elevation of affected limb Regular exercises that help with motion/mobility and flexibility Survivor lymphoedema education Self-care management, skin care, self-bandage Compression garments Medical procedures such as venepuncture/blood pressure measurement to avoid on affected limb if possible	Referral to physiotherapist Referral to occupational therapist Consider referral back to lymphoedema therapists at tertiary hospitals Consider referral to lymphoedema surgeon Refer back to oncologists if new lymphadenopathy

15. CHRONIC PAIN

Pain can be related or unrelated to underlying cancer (e.g., Pain can be due to previous zoster infection as a result of poor immunity while on chemotherapy)

Suggested relevant investigations	Severity & Management	Specialties to consider referring to
Comprehensive pain assessments to evaluate if this is new or old Consider specific pain syndromes Consider multi-modality approach to pain management If pain is acute, rule out oncologic emergency or other acute non-cancer emergencies such as appendicitis	Treat etiology of pain Non-opioid adjuvant analgesics Non-pharmacologic interventions such as heat/cold massage, acupuncture, physical/occupational therapies Opioid treatment if necessary	Consider chronic pain team Consider rehabilitation medicine Consider interventional radiologist if necessary (such as for nerve blocks) Consider palliative care referral Consider other referrals as appropriate, depending on site and etiology of pain

16. SECONDARY CANCERS

A development of a new cancer

Suggested relevant investigations	Severity & Management	Specialties to consider referring to
Consider a repeat of CT scans and basic end-organ blood tests if suspicion is low However, if suspicion is high it would be better to get these investigations done with the oncologist	Review through cancer history and also treatment history	Should there be a suspicion of cancer relapse or a development of a new cancer, it is always best to refer back to the primary oncologist for an evaluation within 2 weeks

*Definitions as adapted/taken from NCCN Guidelines Version 1.2023: Survivorship*

WHEN SHOULD A REFERRAL BACK TO THE ONCOLOGIST BE NECESSARY?

Ideally, when a patient is discharged from a cancer centre, this should be accompanied with an individualised care plan. This care plan should include details of the cancer and treatment, including what needs to be monitored at what intervals. There should also be clear guidelines on when to refer back, with clear points of contact to reduce the difficulties in referring back to the oncologist.

Should there be no such care plans given, it would be a good idea to get in touch with the primary oncologist for a full report. This will definitely help in the long-term holistic management of the patient, and aid to keep the patient in primary care. It would also be helpful to consider referring young adults cancer survivors to cancer survivorship clinic dedicated for young adult cancer survivors.

FINAL NOTES

A patient’s cancer journey does not start and stop with a cancer diagnosis and treatment. Once a person has been diagnosed with cancer, it will likely result in a lifelong change. It will inevitably lead to a lifetime heightened risk of anxiety and fear, with the need to be more prudent/cautious with health. Inevitably, survivors are also at heightened risks of long-term toxicities and secondary malignancies.

We would want to be able to return our survivors back into community well and be able to function. This need to be able to right-site them is imperative, helping the country to move towards its goal of HealthierSG.

REFERENCES

NCCN Guidelines Version1.2023 Survivorship
NCCN Guidelines for Adolescent and Young Adult (AYA) Oncology
Cancer Statistics article from NCCS website (https://www.nccs.com.sg/patient-care/cancer-types/cancer-statistics)
UpToDate – Metabolic Syndrome (insulin resistance syndrome or syndrome X)

Asst Prof Eileen Poon is a consultant with Medical Oncology at NCCS. She sees lymphoma, sarcoma and melanoma patients. Her passion is in working with Adolescents and Young Adults (AYAs) with cancer. This is a field in its infancy, especially in Asia and combines both the science and art of Oncology and Medicine. Dr Eileen is looking to revolutionise the care that AYAs receive to empower them to live well through a cancer diagnosis.

GPs can call the SingHealth Duke-NUS Blood Cancer Centre for appointments at the following hotlines, or click here to visit the website:

Singapore General Hospital: 6326 6060

Sengkang General Hospital: 6930 6000

KK Women's and Children's Hospital: 6692 2984

National Cancer Centre Singapore: 6436 8288