​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

  1. ​Consider X-rays or MRI scans

  2. Consider nerve conduction studies/electromyography

  1. ​Non-pharmacologic treatments such as physiotherapy, heat/ice therapy, acupuncture/transcutaneous electrical nerve stimulation unit

  2. Pharmacologic treatment with nonopioids/adjuvant analgesics, topicals, vit Bs

  3. Pharmacologic treatments with opioids

  1. ​Neurology

  2. Orthopaedics

  3. Pain services

  4. Interventional radiologist if there is radiculopathy

  5. Rehabilitation medicine

  6. Palliative care

  7. Consider physiotherapy

​

2. ​MYALGIAS/ARTHRALGIAS

  • Muscle aches

  • Joint aches

​​Suggested relevant investigations
​Severity & Management
​​Specialties to consider referring to

  1. ​X-rays of affected joints/limbs to rule out fractures/avascular necrosis

  2. DEXA scan to check bone density

  3. Bone scans if bone metastases suspected

  4. Screen for hormonal/endocrine/vitamin deficiencies

  5. Screen through medication/treatment history

  1. ​​Non-pharmacologic treatments such as physiotherapy, heat/ice therapy, acupuncture/ultrasonic stimulation

  2. Braces or orthoses

  3. Pharmacologic treatment from simple analgesics such as paracetamol/anarex, non-opioids/adjuvant analgesics to opioids

  4. Joint replacements may be necessary

  1. Pain Team

  2. Physiotherapy

  3. Orthopaedics

  4. Rehabilitation medicine

  5. 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

  1. X-rays of affected joints/limbs to rule out fractures

  2. DEXA scan to check bone density annually

  3. Screen for hormonal/endocrine/vitamin deficiencies

  4. Check for calcium, vitamin D, PTH levels

  5. Check renal function

  6. Go through medication list and treatment history

  1. ​​Calcium supplements

  2. Replete vitamin D levels

  3. Bisphosphonates/RANK-ligand inhibitors

  1. ​Endocrinologist

  2. Orthopaedics

  3. Referral to dentists before initiating bisphosphonates

  4. 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

  1. Screen for reversible causes (e.g., anaemia, severe weight loss)

  2. Screen for menopausal symptoms

  3. Assess for contributing factors (e.g., medications, emotional distress, alcohol)

  4. 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)

  5. Review oncologic history and treatment history

  1. Management of menopausal symptoms

  2. Consider non-hormonal pharmacologic treatment of hot flushes such as anti-depressants, anti-convulsants, neuropathic pain relievers, some anti-hypertensives

  3. Non-pharmacologic treatments include acupuncture, exercise, lifestyle modifications, weight management and cognitive behavioural therapy

  4. Limit triggers, such as alcohol

  5. Hormonal replacement therapies or pharmacologic therapies

  1. ​Consider referral to gynaecologist

  2. Should hormonal replacement therapy be considered, please refer back to primary oncologist to ensure this is acceptable.

  3. 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

  1. ​​Screen for reversible causes such as anaemia, endocrine, vitamin deficiencies, hormonal imbalances

  2. Assess for contributing factors such as medications, emotional distress, alcohol

  3. Assess for structural causes

  1. ​​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)

  2. General recommendations is to be disease-free for 2 years before attempting to conceive, be it either naturally or via assisted reproductive technologies

  1. Consider referral to gynaecologist or urologist

  2. Consider referral to assisted reproduction centres with fertility specialists such as CARE

  3. 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

  1. ​​Screen for reversible causes such as anaemia, endocrine, vitamin deficiencies/hormonal imbalances

  2. Assess for contributing factors such as medications, emotional distress, alcohol

  1. ​Review oncologic history and treatment history

  2. Can screen with Sexual Health Inventory for Men/Brief Sexual Symptom Checklist for Women

  3. Assess issues concerning sexual health and see if etiology can be managed (e.g., vaginal dryness may benefit from lubricants)

  1. ​​Sexual health specialist

  2. Endocrinologist

  3. Gynaecologist or urologist

  4. Social worker

  5. Counsellor

  6. 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

  1. ​Screen for reversible causes such as anaemia, insomnia, obstructive sleep apnoea

  2. Assess for contributing factors (e.g., medications, emotional distress, alcohol)

  3. Assess for endocrine/vitamin deficiencies/hormonal imbalances

  4. Consider 2D Echo

  5. Consider sleep study

  1. ​Screen for fatigue regularly

  2. Treat any reversible causes or medical causes

  3. Sleep hygiene as appropriate

  1. ​Physiotherapist as appropriate

  2. Respiratory physician as appropriate

  3. 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

  1. Screen for reversible causes (e.g., insomnia/endocrine/vitamin deficiencies/hormonal imbalances)

  2. Assess for contributing factors (e.g., medications, emotional distress, alcohol)

  3. Consider brain imaging if brain metastases suspected

  1. Offer validation of symptom experience

  2. Treat any reversible causes or medical causes

  3. Sleep hygiene as appropriate

  4. Practical advice on coping such as taking notes, forming routines

  5. Cognitive training such as brain games

  1. Social worker

  2. Counsellor

  3. Referral to neurologist

  4. Referral to geriatrician or early dementia clinic or equivalent as appropriate

  5. 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

  1. Review medical history medication/treatment history

  2. Check blood pressure, pulse rates, height and weight

  3. Screen for cardiovascular disease risk assessment and counselling

  4. Consider ECG and 2D Echo assessment

  5. Screen for diabetes and high cholesterol

  1. Advocate for healthy range BMI 18.5 – 24.9 kg/m2

  2. 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

  3. Advocate for quitting smoking

  1. Refer dietitian/nutritionist

  2. Refer physiotherapist

  3. 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

  1. ​​Assess for suicide risk and manage accordingly

  2. Screen for depression/PTSD/mania/psychosis

  3. Screen with GAD-7/Brief Patient Health Questionnaire

  4. Assess for endocrine/hormonal imbalances

  5. Review diet, and consider reducing stimulants such as caffeine

  6. Consider brain imaging if brain metastases suspected

  1. Non-pharmacologic stress-relieving techniques (e.g., yoga and meditation)

  2. Address root cause (e.g., pain)

  3. Encourage exercise and physical activity

  4. Cognitive behavioral therapy

  5. Pharmacologic techniques if the above cannot help

  6. Suicide precautions/managements as appropriate

  1. ​Psychologist

  2. Psychiatrist

  3. Social worker

  4. 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

  1. ​​Assess for sleep practices and advise sleep hygiene

  2. Sleep journal

  3. Assess for medications that may affect sleep

  1. ​​Non-pharmacologic interventions by addressing root cause (such as pain)

  2. Sleep hygiene advice

  3. Pharmacology interventions as per guidelines

    • antihistamines

    • benzodiazepines

  4. Cognitive behavioral therapy

  1. ​Psychologist

  2. Psychiatrist

  3. Social worker

  4. 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

  1. ​​Healthy lifestyle

  2. Maintenance of adequate physical activity

  3. Healthy balanced diet

  1. Gastrointestinologist if there is concern of dysmotility/absorption

  2. Psychiatrist/psychologist should there be a concern of body dysmorphia/eating disorder

  3. 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

  1. Screen through oncological history and treatment

  2. Screen for cardiovascular risk factors and treat accordingly

  3. ECG, 2D Echo, CK/CKMB/Troponins/BNP

  4. Chest X-ray

  5. Blood tests screening for hormonal/endocrine abnormalities

  1. ​Advocate for healthy lifestyle including physical activity and balanced diet

  2. Stop smoking

  3. Maintain healthy BMI

  1. Cardiologist

  2. Endocrinologist

  3. Dietitian/nutritionist

  4. Consider respiratory physician referral if no evidence of structural heart disease found, but patient is symptomatic

  5. 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

  1. ​​Screen for BMI

  2. Screen for haemodynamic circulation

  3. Regular screening via limb volume measurements

  1. Weight control

  2. Elevation of affected limb

  3. Regular exercises that help with motion/mobility and flexibility

  4. Survivor lymphoedema education

  5. Self-care management, skin care, self-bandage

  6. Compression garments

  7. Medical procedures such as venepuncture/blood pressure measurement to avoid on affected limb if possible

  1. ​Referral to physiotherapist

  2. Referral to occupational therapist

  3. Consider referral back to lymphoedema therapists at tertiary hospitals

  4. Consider referral to lymphoedema surgeon

  5. 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

  1. ​​Comprehensive pain assessments to evaluate if this is new or old

  2. Consider specific pain syndromes

  3. Consider multi-modality approach to pain management

  4. If pain is acute, rule out oncologic emergency or other acute non-cancer emergencies such as appendicitis

  1. ​​Treat etiology of pain

  2. Non-opioid adjuvant analgesics

  3. Non-pharmacologic interventions such as heat/cold massage, acupuncture, physical/occupational therapies

  4. Opioid treatment if necessary

  1. ​​Consider chronic pain team

  2. Consider rehabilitation medicine

  3. Consider interventional radiologist if necessary (such as for nerve blocks)

  4. Consider palliative care referral

  5. 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

  1. ​Consider a repeat of CT scans and basic end-organ blood tests if suspicion is low

  2. 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

  1. NCCN Guidelines Version1.2023 Survivorship

  2. NCCN Guidelines for Adolescent and Young Adult (AYA) Oncology

  3. Cancer Statistics article from NCCS website (https://www.nccs.com.sg/patient-care/cancer-types/cancer-statistics)

  4. 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