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31st December 2024

General oncology

General oncology

Ngozi Ekpemandu

The presentation, investigation and treatment of cancer depends on the type, site and stage. This section will focus on the features and investigations common to most cancers. The rest of the chapter will discuss the most common cancers in the UK.

Pathophysiology of cancer

Mutations leading to cancer may be inherited, but are most commonly acquired due to age, exposure to carcinogens and unchecked rapid cell turnover. The genes associated with the development of cancer include oncogenes and tumour suppressor genes.

Clinical presentation of cancer

Cancer can present with varied and non-specific features depending on the organ(s) affected. General features include fever, unexplained weight loss, night sweats, fatigue and anaemia.

Cancer staging

To determine the best treatment option, prognosis and role of clinical trials, staging systems are used, the most widely used being the TNM system (Table 1). It describes the extent of the tumour (T), spread to lymph nodes (N) and presence of metastases (M).

Note that staging refers to the size and spread of a cancer, while grading refers to the histological differentiation of the cancer cells.
Tx Primary tumours cannot be measured Nx Nodes cannot be assessed
T0 Primary tumour cannot be found N0 No node involvement
Tis Carcinoma in situ (abnormal cells present) N1-3 Number/location of node metastases
T1-4 Size and/or extent of primary tumour
(1 = small tumour/minimal invasion; 4= large tumour/extensive invasion)		 M0 No distant spread
M1 Distant metastases

Diagnosis of cancer

Generally speaking, most cancers are diagnosed with biopsy and histology. However, there are other investigations that may raise the suspicion or support the diagnosis of cancer, as well as those used for monitoring.

  • Routine blood tests: various abnormalities possible
  • Genetic testing, e.g. BRCA1 or BRCA2 mutations in breast cancer
  • Tumour markers: to aid diagnosis and for monitoring. Note that tumour markers generally have low specificity and sensitivity. Examples of common tumour markers include: CA15-3 (breast cancer), CA-125 (ovarian cancer), CA19-9 (pancreatic cancer), alpha-fetoprotein (AFP) (hepatocellular carcinoma), prostate-specific antigen (PSA) (prostate cancer), carcinoembryonic antigen (CEA) (colorectal cancer)
  • Imaging:
    • CT for staging and identification of primary sites if unknown
    • MRI is the imaging of choice for some tumours, e.g. for brain tumours – better contrast resolution and the ability to distinguish from differentials such as abscess
    • PET-CT using fluorodeoxyglucose (FDG), which is taken up by neoplastic cells. It can be used to establish eligibility for curative treatment in non-small cell lung cancer. It is also useful when looking for cancers of unknown primary.
  • Biopsy: tissue diagnosis is very important in cancer diagnosis. The histologic pattern of samples, such as their mitotic activity, cellular density and nuclear atypia, are used to classify, grade and identify the primary site of tumours. They are also useful in prognostication.

Cancer treatment modalities

Chemotherapy

This is one of the most common systemic treatments for cancer. The aim is to deliver enough anti-cancer drugs to cancer cells, with treatment given in cycles to allow recovery of normal tissue. To prevent resistance, it is usually given as a combination therapy (using agents from different classes).

Chemotherapy can be:

  • Neoadjuvant: to shrink tumours prior to surgery or radiotherapy
  • Adjuvant: given after an initial treatment to reduce the risk of relapse, e.g. after mastectomy
  • Palliative: given without curative aim but offers symptomatic control and may prolong survival

Hormone therapy

Hormonal therapy can slow or prevent the spread of cancers that depend on specific hormones to grow. The aim is to block the production of these particular hormones or change their receptors. Breast and prostate cancers are the two types of cancers that are most commonly treated with hormone therapy.

Immunotherapy

The goals of cancer immunotherapy are to kill or control cancer cells by activating the immune system. Examples include checkpoint inhibitors, such as ipilimumab (used in advanced melanoma), pembrolizumab and nivolumab (both used in the treatment of non-small-cell lung cancer).

Targeted therapies

Some monoclonal antibodies are referred to as targeted therapy because they have a specific target on a cancer cell that they attach to and attack. Examples include trastuzumab (breast cancer) and cetuximab (colorectal, lung, head and neck cancers).

Radiotherapy

This uses ionising radiation to cause damage to DNA, which in turn prevents cell division and ultimately leads to cell death. Radiotherapy plays an important role in oncology and forms part of the management of 40% of patients cured of their disease.

  • Radical treatment: aim is to cure. Some regimens involve several smaller fractions a day with a gap of 6-8 hours. Combine chemoradiation is used in some sites, e.g anus, to increase response rate.
  • Palliative radiotherapy: the aim is symptomatic relief. Doses are usually smaller and given in fewer fractions to offer short-term tumour control with minimal side effects.

Surgery

Surgery, either alone or in combination with other treatment modalities, is one of the main options for cancer treatment. This depends on the type of cancer, the size and site and also the general condition of the patient. Surgery can be done with the following aim:

  • Preventive: e.g. colectomy in familial adenomatous polyposis or thyroidectomy in multiple endocrine neoplasia
  • Diagnosis and staging: tissue and lymph node biopsies, diagnosis and staging laparoscopy
  • Treatment: resection of solid tumours
  • Palliative: depending on symptoms, e.g. stenting, bypass, stoma formation

Common side effects of cancer treatment

Side effects of treatment depend on the modality, the type of cancer, the body site affected and the patient.

The most common reported side effects are: anaemia, fever (may be due to infection), diarrhoea, nausea, vomiting, fatigue and generalised body pain.

References

Breast cancer

Ava Zamani and Christie Mellor

Overview of breast cancer

Female breast cancer is the most common cancer globally. Male breast cancer is a relatively rare entity.

Risk factors include age (rare under age 30), oestrogen exposure (early menarche, late menopause, nulliparity, older maternal age at first pregnancy, not breastfeeding, use of exogenous oestrogens), previous breast disease (malignant or benign), ionising radiation exposure and obesity. There may be a genetic predisposition, more prevalent in male breast cancer (BRCA2, Klinefelter’s).

Pathology of breast cancer

Histological types of invasive breast cancer include ductal carcinoma (most common), lobular carcinoma, mixed ductal/lobular carcinoma, sarcoma (e.g. angiosarcoma), and lymphoma. Metastases in the breast most commonly arise from a breast primary. ‘In situ’ disease, as in ductal carcinoma in situ (DCIS) and lobular carcinoma in situ (LCIS), refers to a non-invasive tumour confined to the basement membrane which has the potential to become invasive.

Breast cancer metastasis is usually initially by lymphatic invasion of the axillary, supraclavicular and, less often, the internal mammary lymph node chains. Common sites of breast cancer metastasis include bone, brain, liver, lung, lymph nodes and skin.

Presentation of breast cancer

Most cases of breast cancer in the UK are detected by national screening.

The most common symptomatic presentation is with a self-detected breast lump. Other presenting symptoms include breast thickening, skin changes, nipple changes, nipple discharge, and a lump in the axilla. Breast pain is a less common presenting symptom but nevertheless warrants attention, particularly if persistent.

Paget’s disease of the breast classically presents with an eczema-like rash affecting the nipple and areola.

In inflammatory breast cancer, local invasion along lymphatic ducts gives rise to the hallmark peau d’orange appearance of the oedematous, erythematous breast.

Diagnosis of breast cancer

GP referrals for suspected breast cancer are to a specialist breast one-stop clinic at which triple assessment is performed: clinical examination, imaging and biopsy of any suspicious lesion. Imaging consists of bilateral mammograms, usually with the addition of ultrasound (US) of the breasts and axillae, particularly useful in younger patients whose breasts are typically denser. Those presenting with signs of inflammatory breast cancer require a punch biopsy of the skin.

Receptor status is determined on immunohistochemistry (IHC) ± fluorescence in situ hybridisation (FISH) if IHC is equivocal. Breast cancer receptors help determine cancer behaviour and may present targets for treatment:

  • Oestrogen receptor (ER) positive: the majority of breast cancers. Better prognosis.
  • Human epidermal growth factor receptor 2 (HER2) positive: worse prognosis but a target for therapy.
  • Triple negative: a minority of breast cancers. Negative for expression of ER, HER2 and progesterone receptors (PR). Poor prognosis.

Staging investigations are not routinely performed, but CT of the chest, abdomen and pelvis and a bone scan should be obtained if the tumour is larger than 5 cm (T3 disease), if the skin or chest wall is involved (T4, includes all cases of inflammatory breast cancer), if lymph nodes are involved, and/or if the patient presents with features suggestive of metastatic disease. If suspected metastases are identified, a confirmatory biopsy should usually be performed.

Breast cancer staging

Breast cancer may be staged using the TNM classification system or with the number staging system (I-IV). Stages I and II are considered to be early breast cancer, whereas stages III and IV are classed as advanced breast cancer. A simplified summary of the number staging system is as follows:

  • Stage I: tumour <2 cm ± lymph node(s) affected within the ipsilateral breast.
  • Stages I-II: tumour <5 cm ± involvement of up to 3 ipsilateral axillary lymph nodes OR tumour >5 cm with no nodal involvement.
  • Stage III: tumour >5 cm with nodal involvement OR tumour of any size with 4-9 axillary (or internal mammary) lymph nodes  ± local invasion of skin or chest wall.
  • Stage IV: metastatic disease, e.g. to bone, liver, lung or distant lymph nodes.

Genetics referrals in breast cancer

BRCA1 and BRCA2 gene mutations are germline mutations in tumour suppressor genes, which, if inherited, confer a higher lifetime risk of developing breast cancer. BRCA1 also confers a relatively high risk of ovarian cancer, whilst male carriers of BRCA2 and, to a lesser extent, BRCA1 are at an increased risk of male breast cancer and prostate cancer. Ashkenazi Jewish ancestry is a risk factor for BRCA mutation carriage.

Genetic syndromes that predispose to breast cancer include Lynch syndrome (hereditary non-polyposis colorectal cancer, HNPCC), which is most associated with colorectal (and endometrial) cancers, and Li-Fraumeni syndrome (TP53 mutation), which also causes sarcoma, brain cancer and leukaemia.

NICE guidelines outline the criteria for specialist genetics referral, which include the following:

  • Family history of breast cancer at a young age (e.g. 2 first-degree or 1 first-degree and 1 second-degree relative aged <50)
  • Family history of bilateral breast cancer (e.g. at least 1 first-degree relative aged <50)
  • Family history of ovarian cancer in combination with a family history of breast cancer at a young age
  • Family history of male breast cancer in combination with a family history of breast cancer at a young age

Furthermore, genetics referral should also be considered if there is a family history of sarcoma at a young age (<45), strong paternal family history of breast cancer or childhood glioma.

Those identified to be at an increased lifetime risk of breast cancer may be offered annual surveillance ± prophylactic mastectomy ± oophorectomy ± preventative use of hormone therapy.

Breast cancer screening

National screening programme

In the UK, people registered as female and trans men without a prior history of breast cancer are invited for three-yearly mammograms between ages 50-70, after which they may opt in to ongoing screening. In the rest of this section, we will refer to ‘women’ for simplicity, but the information also applies to trans men.

Breast cancer screening in those with previous breast cancer

According to NICE, women who have been successfully treated for breast cancer, with no known genetic risk factor, should have annual mammograms for five years following treatment.

However, women who have been successfully treated for breast cancer but are at high risk for further breast cancer (e.g. a positive family history or a known genetic mutation) should have more frequent screening:

  • Ages 30-49 (or aged 30 to 59 with a TP53 mutation): annual MRI scans
  • Ages 50-69: annual mammograms

Breast cancer screening in those who have risk factors

Women who have not had breast cancer but are at high risk due to a strong family history or known genetic mutation should have regular surveillance. In general, younger women are offered breast MRIs in preference to mammograms as breast tissue is usually denser.

NICE advises the following:

  • TP53 mutation (known, or at high risk of): annual MRI between ages 20-69. Note that TP53 mutation is the only risk factor that makes women eligible for surveillance under age 30.
  • BRCA mutation: annual MRI ± mammogram between ages 30-59, then three-yearly mammograms as part of the national screening programme.
  • High risk for another reason, e.g. family history: annual MRI ± mammogram between ages 40-59, then three-yearly mammograms as part of the national screening programme. May additionally be considered for surveillance between ages 30-39 on a case-by-case basis.

Management of breast cancer

Management of early breast cancer

Patients with early breast cancer (stages I-II) have a disease which can, by definition, be fully excised; they should be offered surgery if fit. This may be either mastectomy or breast-conserving surgery (wide local excision, WLE, or ‘lumpectomy’), depending on factors including size and position of the lesion and overall breast size. Patients simultaneously undergo axillary surgery:

  • For those with established nodal disease at diagnosis, axillary lymph node clearance is recommended. This carries the risk of lymphoedema and shoulder stiffness.
  • Patients who are node negative at diagnosis may undergo sentinel lymph node biopsy, in which the excised sentinel nodes are used to complete pathological staging and determine the need for node clearance.

Surgery for early breast cancer is usually followed by the offer of adjuvant therapy to reduce the risk of recurrence. Adjuvant radiotherapy may be offered to reduce the risk of locoregional recurrence, whilst adjuvant systemic therapies may be offered to reduce the risk of distal recurrence from occult micrometastases.

Adjuvant systemic therapies include chemotherapy, hormonal therapy and targeted therapy:

  • Hormonal therapy is offered to patients with ER-positive breast cancer. Tamoxifen is first line in pre- and peri-menopausal women; aromatase inhibitors such as letrozole are first line in post-menopausal women. Tamoxifen increases the risk of venous thromboembolism and endometrial cancer, whilst arthralgia syndrome (isolated joint pain and swelling) is the most common reason for discontinuation of aromatase inhibitors. This is secondary to reduced oestrogen levels causing reduced bone mineral density.
  • Targeted anti-HER2 therapy is offered to patients with HER2-positive breast cancer and is usually in the form of recombinant monoclonal antibodies trastuzumab (Herceptin) and/or pertuzumab. The main associated adverse effect is of cardiotoxicity and patients are surveyed with regular echocardiograms.
  • Targeted therapy with abemaciclib (a CDK4/6 inhibitor) is authorised for use alongside aromatase inhibitors in cases of hormone receptor-positive, HER2-negative, node-positive early breast cancer where there is estimated to be a high risk of recurrence. Abemaciclib can cause diarrhoea, which can be explosive.

Neoadjuvant systemic therapy (given prior to surgery) aims to reduce tumour size and, therefore, make breast-conserving surgery more feasible, as well as reduce the risk of recurrence. Neoadjuvant therapy is indicated in a number of settings, one example being HER2-positive early breast cancer where there is a high risk of recurrence, in which case neoadjuvant therapy combining taxane-containing chemotherapy with targeted anti-HER2 therapy (pertuzumab plus trastuzumab) is usually offered.

Management of advanced breast cancer

Patients with advanced breast cancer may have locally advanced disease and/or distal metastases, meaning their disease is not, at least initially, completely resectable. In patients with locally advanced disease, achieving local control to prevent tumour fungation is a priority. Patients are usually treated with a combination of radiotherapy and systemic therapies. If there is a good response, surgery may become feasible. Metastatic breast cancer is incurable and any treatment is with palliative intent. A full description of treatment options is beyond the scope of this chapter. However, it is important to appreciate that, as with early breast cancer, decisions are guided by performance status, hormone receptor status and, increasingly, immune-related biomarkers. Several examples follow.

ER-positive, HER2-negative advanced breast cancer: first-line management is usually endocrine therapy, which, as in the adjuvant setting, may be combined with targeted therapy (e.g. letrozole ± a CDK4/6 inhibitor such as abemaciclib). Chemotherapy is usually reserved for hormone-refractory disease further down the line.

PD-L1-positive advanced triple negative breast cancer: patients whose tumours express specific immune-related biomarkers may be offered targeted treatment with immune checkpoint inhibitors. These work to ‘activate’ the immune system against tumour cells by preventing tumour cells from binding to and de-activating T-cells. First-line treatment options for advanced triple-negative breast cancers include:

  • Pembrolizumab (anti-PD-1) + nab-paclitaxel (paclitaxel bound by albumin nanoparticles, also known as Abraxane)
  • Atezolizumab (anti-PD-L1) + nab-paclitaxel

Management of carcinoma in situ

Patients with DCIS are offered resection (usually wide local excision, unless very large), and adjuvant radiotherapy should be considered. LCIS may be observed unless features are non-classical (usually pleomorphic LCIS), in which case patients may be offered resection.

References

Prostate cancer

Ava Zamani and Christie Mellor

Overview of prostate cancer

Prostate cancer is the most common cancer in men in the UK, and the second most common cancer in men globally. It represents a spectrum of disease from small well-differentiated tumours which may never become clinically significant to rarer high-grade tumours which are more aggressive and carry high morbidity and mortality.

Risk factors include age (rare in those aged less than 50), ethnicity (more common in Black men, uncommon in Asian men) and family history. There are no well-established links to any modifiable risk factors.

Pathology of prostate cancer

The majority of prostate cancers are adenocarcinomas and arise in the outer zone of the prostate gland, where they are unlikely to produce urinary symptoms. Low-grade (Gleason 6) tumours are less likely to invade through the prostate capsule; high-grade (Gleason 8-10) tumours are more aggressive and more likely to invade through and metastasise. Spread is by direct invasion of the adjacent organs (seminal vesicles, bladder and rectum), infiltration of pelvic lymph nodes, and haematogenous spread to sites of distal metastasis. The most common site of metastasis is bone, where the classical picture is of osteoblastic or sclerotic metastases, although liver and lung may also be affected.

Presentation of prostate cancer

Patients may present symptomatically with lower urinary tract symptoms (LUTS) such as urgency, frequency, hesitancy, nocturia and retention, although LUTS usually indicate coincident benign prostatic hyperplasia. They also may present with systemic symptoms such as weight loss, poor appetite, and fatigue. However, the majority of new diagnoses are entirely asymptomatic, with referral made on the basis of an elevated age-adjusted prostate-specific antigen (PSA) and/or abnormal findings on digital rectal examination (DRE), such as a nodular or irregular prostate. The role of PSA in screening is controversial as it is non-specific to malignancy (may be elevated secondary to DRE, ejaculation, or benign pathology such as prostatitis).

A minority of patients present with symptoms and/or complications of metastatic disease, e.g. bone pain, fragility fractures, obstructive renal failure and rectal bleeding. Metastatic spinal cord compression may be the first presentation of metastatic prostate cancer and is an oncological emergency. Back pain which is new, progressive and/or severe is usually the primary feature and any additional neurological deficit is usually a late sign. Any clinical suspicion warrants urgent investigation with an MRI whole spine.

Diagnosis of prostate cancer

If prostate cancer is clinically suspected on the basis of history and clinical examination, NICE recommends multi-parametric MRI prostate as the first-line investigation. This is to help identify whether biopsy is necessary and, if so, identify potential targets for biopsy. In patients who are too frail or multimorbid for radical prostate cancer treatment (i.e. surgery or radiotherapy) then MRI is not indicated.

Biopsy enables Gleason histological grading and is done under ultrasound guidance either via the rectum (transrectal ultrasound, TRUS) or perineum. The majority of patients experience haematuria and blood in their semen. Less common but more serious complications include sepsis, clot retention, rectal bleeding and severe haematuria.

Further staging with isotope bone scans is not performed routinely but is required for those with high-grade tumours, tumours that have spread outside of the prostate capsule and/or with clinical or biochemical evidence of bone metastases.

Management of prostate cancer

Management of localised prostate cancer

Patients should undergo risk stratification taking into consideration their Gleason grade, PSA, TNM staging and life expectancy (determined by age and comorbidities).

There are two main radical (potentially curative) options which should be considered in patients with localised prostate cancer, particularly in those with greater life expectancy. All radical options carry a risk of loss of sexual function.

  • Radical prostatectomy ± pelvic lymph node dissection
  • Radical radiotherapy, either external beam or brachytherapy

Additional treatments include:

  • Androgen deprivation therapy may also be offered to patients depending on risk stratification
  • Docetaxel may be used in high risk cases, in conjunction with androgen deprivation. The most important side effect to be aware of is neutropenic sepsis

Those with low risk disease, or with a preference to postpone treatment, may be offered active surveillance during which they are monitored for signs of progression and radical treatment is initiated only once such signs arise:

  • PSA every 3-4 months for the first year
  • Digital rectal examination at 1 year
  • Multi-parametric MRI at 12-18 months
  • After the first year, PSA 6 monthly and rectal examination yearly

Contrast this to watchful waiting, which describes cases where a patient does not ever plan to go on to have curative treatment, either out of preference or due to poor performance status and therefore ineligibility. Usually an annual PSA is performed.

In both active surveillance and watchful waiting a rise in PSA or other abnormality triggers further investigation and/or MDT discussion.

Active surveillance Watchful waiting
Strategy aimed at cure – patients with localised prostate cancer, usually very low-risk disease, opt for close monitoring and proceed to curative treatment only if and when their tumour shows signs of progressing Strategy aimed at control but not cure – patients with localised prostate cancer who do not wish to ever have curative treatment opt for androgen-deprivation therapy to be deferred

Management of locally advanced prostate cancer

Patients with tumour fixation to or invasion of adjacent organs are considered curable but are at very high risk of recurrence and/or progression. If fit, they should be offered either:

  • Radical prostatectomy with extended pelvic lymph node dissection; those with positive lymph nodes should be offered adjuvant radiotherapy or androgen-deprivation therapy;
  • OR radical radiotherapy with long-term androgen-deprivation therapy.

Management of metastatic prostate cancer

Prostate cancer with distant metastases is not considered curable and treatment is aimed at controlling disease and maintaining quality of life. Both specialist urological services and palliative care should be involved from the outset to help with symptom control and holistic needs of the patient.

In hormone-naive patients, the first line is androgen-deprivation (hormone) therapy, also described as medical castration. This aims to reduce testosterone levels, helping to shrink the tumour and/or prevent further growth.
Gonadotropin-releasing hormone (GnRH) agonists such as goserelin and leuprorelin provide negative feedback to the hypothalamic-pituitary axis to suppress testosterone levels. Side effects include fatigue, loss of libido, erectile dysfunction, hot flushes, emotional lability and depression. On initiation there is a testosterone surge, which can cause a tumour flare, manifesting clinically as an exacerbation of bone pain and renal failure, and may prove life threatening. Therefore androgen-deprivation therapy should be preceded by initiation of an anti-androgen such as bicalutamide, which produces androgen receptor blockade.

GnRH antagonists are an alternative to GnRH agonists. The only one available in the UK is degarelix. This does not cause tumour flare, so anti-androgen therapy is not required. It is indicated when patients have spinal metastasis.

Bilateral orchiectomy is a surgical option for androgen deprivation therapy that may be considered.

Androgen-deprivation therapy is more effective when taken in combination with other systemic therapies, usually either abiraterone (inhibits adrenal production of testosterone, must be taken in combination with prednisolone) or docetaxel chemotherapy.

This may be followed by several lines of alternative systemic therapies in patients whose disease progresses despite effective castration, described as castration- or hormone-resistant prostate cancer. The details of this are beyond the scope of this chapter. Of note, however, are specific options for patients with bony metastases in hormone-resistant prostate cancer:

  • Palliative radiotherapy, simple analgesia and IV bisphosphonates can help with bone pain. Bisphosphonates can also be used to treat hypercalcaemia of malignancy.
  • Denosumab can be used to prevent skeletal-related events, including pathological fractures and metastatic cord compression.

Management of the side effects of prostate cancer treatments

Radiation enteropathy

Radiation to the pelvis, for example when radiating prostate cancer, can damage nearby structures including the bowel or rectum. It is a common phenomenon: of patients who receive abdominal or pelvic radiotherapy, 60-80% will experience bowel toxicity.

In patients with suspected radiation-induced enteropathy, flexible sigmoidoscopy is the first-line investigation to rule out bowel cancer and inflammatory bowel disease, but also analyse the extent of radiation-induced enteropathy if it is ultimately diagnosed.

If symptoms are experienced in the first 3 months following radiating it is considered acute radiation enteropathy. Acute radiation enteropathy symptoms include diarrhoea, abdominal pain, nausea and vomiting. If loperamide does not work, octreotide can be considered.

Beyond the first 3 months, it is considered delayed. Delayed radiation enteropathy symptoms include dysfunctional absorption of nutrients or abnormal peristalsis. The treatment approach is more complex than for acute symptoms, and must be tailored specifically to the individual. It is a chronic and progressive disorder requiring a multidisciplinary team approach.

Both types of radiation enteropathy have high morbidity, affecting quality of life for cancer patients.

Rectal radiation injury (radiation proctopathy) is common when treating prostate cancer. First-line treatment is sucralfate enemas, which can cause dramatic improvement in symptoms. If radiation proctopathy is hemorrhagic, endoscopic intervention may be required to stop the bleeding.

Radiation-induced cystitis

Radiation to the prostate can cause bladder wall inflammation and scarring, which can be short term or chronic, and can result in cystitis. Conservative management includes good oral intake of water. If symptoms persist despite this, specialised options include intravesical injection of medications such as sodium hyaluronate (brand names Cystistat or iAluRil), or hyperbaric oxygen therapy. Rarely, the bladder may need to be surgically removed to help with symptoms.

Androgen-deprivation therapy side effects

There can unfortunately be many side effects to androgen-deprivation therapy. Some examples with their management are:

  • Hot flushes: medroxyprogesterone is first line.
  • Gynaecomastia: in those starting long-term (planned for at least 6 months) of bicalutamide, prophylactic radiotherapy to the breast buds is first line, and should be offered within the first month of treatment. Second line is tamoxifen.
  • Osteoporosis: is also an issue with long-term deprivation therapy as it can result in fragility fractures. A risk assessment for the individual patient should be calculated e.g. FRAX score. Bisphosphonates are first line or denosumab is second line in patients identified as having osteoporosis and on androgen deprivation treatment.

References

Lung cancer

Ava Zamani and Christie Mellor

Epidemiology of lung cancer

Lung cancer is the third most common cancer in the UK. Risk factors are a mixture of non-modifiable – primarily age – and modifiable – primarily smoking (active and passive), exposure to occupational chemicals (asbestos, more rarely radon gas), and exposure to ionising radiation. A majority of cases are linked to smoking and considered largely preventable.

Pathology of lung cancer

Lung cancer has been classically divided into small cell and non-small cell types. Small cell lung cancers (SCLC) account for approximately 20% of all cases, whilst the majority are non-small cell lung cancers (NSCLC). ‘NSCLC’ is a blanket term comprising a variety of histological types including adenocarcinoma (approximately 40% of cases), squamous cell carcinoma (SCC, approximately 30%), large cell carcinoma, and other rarer histological types.

Adenocarcinoma of the lung is the most common histological type both overall and in non-smokers. Adenocarcinomas usually arise in the lung periphery. By comparison, SCCs typically arise centrally and cavitation may be another distinguishing feature. SCLCs are aggressive tumours arising from neuroendocrine cells, typically of the larger airways. SCLCs tend to carry a worse prognosis and a majority of patients already have distal metastases at the time of diagnosis (de novo metastatic disease).

Common sites of lung cancer metastasis include the adrenal glands, bone, brain, liver and other parts of the lung.

Presentation of lung cancer

Symptoms include cough, haemoptysis, dyspnoea, recurrent chest infection, chest pain, hoarse voice, and symptoms of metastatic disease. Presentation may be delayed, in part as symptoms may be dismissed as side effects or benign complications of smoking.

Two-week-wait referral criteria are outlined in the table below.

Refer if any of: Offer urgent chest X-ray if:
  • Signs suggestive of lung cancer on chest X-ray
  • Aged 40 and over with unexplained haemoptysis
 Aged 40 and over with any one of

  • Persistent/recurrent chest infection
  • Finger clubbing
  • Supraclavicular/cervical lymphadenopathy
  • Thrombocytosis

Aged 40 and over with any two* of

  • Cough
  • Fatigue
  • Shortness of breath
  • Chest pain
  • Weight loss
  • Appetite loss

*or if they have any one with a smoking history

The various classical and/or emergency presentations of lung cancer depend on histological type, site within the lung, and disease stage at presentation:

  • SCC classically causes hypercalcaemia secondary to parathyroid hormone-related protein (PTHrP) release. Hypercalcemia has a range of clinical manifestations (e.g. constipation, confusion, thirst, depression, renal stones). The typical ECG finding is a shortened QTc (corrected QT interval).
  • Both adenocarcinoma and SCC are classically associated with hypertrophic pulmonary osteoarthropathy (HPOA), which manifests as digital clubbing and painful inflammation of the interphalangeal, metacarpophalangeal and metatarsophalangeal joints.
  • SCLC may feature ectopic secretion of antidiuretic hormone (ADH) or adrenocorticotropic hormone (ACTH), giving rise to an SIADH (syndrome of inappropriate antidiuretic hormone secretion) or Cushing’s syndrome, respectively. Cushing’s syndrome can be differentiated from other causes of raised cortisol with several investigations. ACTH is raised, and cortisol levels remain high (i.e. are not suppressed) with both the low- and high-dose dexamethasone tests.
  • SCLC may be associated with paraneoplastic Lambert Eaton myasthenic syndrome (LEMS), a progressive disease of the neuromuscular junction. It results in muscle weakness that improves with exercise (with proximal lower limb muscles affected first), cranial nerve palsies, autonomic dysfunction (e.g. constipation and dry mouth) and areflexia.  In 60% of patients, there is underlying SCLC, so screening for this is essential. Other less common underlying malignancies include NSCLC, lymphoproliferative disease and prostate cancer.
  • Pancoast tumours (of the lung apex) may present with upper limb pain and weakness resulting from invasion of the brachial plexus and with an ipsilateral Horner’s syndrome resulting from compression of the thoracic sympathetic chain.
  • Emergency presentations of lung cancer include superior vena cava obstruction (SVCO), of which lung cancer is the commonest cause, and metastatic spinal cord compression, which, if suspected, requires MRI of the whole spine to be performed.
Adenocarcinoma Squamous cell carcinoma Small cell lung cancer
– Typically peripheral

– Clubbing 2° to HPOA

 – Typically central

– Hypercalcemia 2° to PTHrP

– Clubbing 2° to HPOA

 – Typically central

– Hyponatraemia 2° to SIADH

– Less typically, Cushing’s syndrome

– LEMS

Diagnosis of lung cancer

CXR is often the first-line investigation, but CT chest, abdomen and pelvis is the investigation of choice in all patients with suspected lung cancer. PET scan may also be done. Tissue to confirm the diagnosis may be obtained with endobronchial ultrasound (EBUS) or, if not accessible by EBUS, on CT-guided percutaneous biopsy or video-assisted thoracoscopic surgery (VATS).  Pleural fluid may additionally be aspirated and sent for cytology. Pleural tap results suggestive of malignancy are an exudate (protein >30 g/L) with high LDH, low pleural pH (<7.3) and low glucose (<3.4 mmol/l), and with lymphocytosis or blood in the sample.

Management of lung cancer

All patients with lung cancer should be counselled regarding smoking cessation and supported with the prescription of nicotine replacement therapy and referral to community cessation services.

Management of NSCLC

Early NSCLC: Radical lobectomy with lymph node sampling should be considered for all patients with early NSCLC. Lobectomy carries fewer short-term complications and better preserves lung function than a pneumonectomy.

If ineligible for surgery, radical radiotherapy may be considered. This includes stereotactic ablative radiotherapy (SABR), a particularly precise type of radiotherapy appropriate for smaller tumours, which restricts damage to nearby structures.

Eligibility for surgery should be determined through assessment of operative risk. The following factors should be taken into consideration:

  • Performance status
  • Presence of comorbidities
  • Global risk score to estimate risk of operative mortality
  • Cardiac investigations – ECG and echocardiography are usually required; exercise stress testing for reversible myocardial ischaemia may be required depending on the presence of cardiac symptoms and risk factors
  • Lung function tests – FEV1 and TLCO (transfer factor of the lung for carbon monoxide) should be measured in all patients, and postoperative dyspnoea should be predicted

Following surgery, adjuvant chemotherapy (a cisplatin-based combination regimen) is offered to those with adequate performance status, depending on staging. Neoadjuvant chemotherapy is only available as part of a clinical trial.

Locally advanced NSCLC: Locally advanced disease involving mediastinal lymph nodes is also potentially curable, and surgery with chemoradiotherapy should be considered. If this is not an option, radical radiotherapy is an alternative.

If operable, lobectomy with lymph node dissection should be offered if technically feasible and if the patient is suitably fit (see above for eligibility criteria). Patients may be offered either neoadjuvant or adjuvant chemotherapy.

Patients whose tumours are inoperable should receive concurrent platinum-based chemotherapy and radiotherapy (radical chemoradiotherapy) as a non-surgical treatment pathway, and this may be followed by durvalumab (an anti-PD-L1 [programmed death-ligand 1] immune checkpoint inhibitor) in PD-L1-positive patients. Pneumonitis secondary to radiotherapy ± durvalumab is the main adverse event.

Metastatic NSCLC: This is incurable, and any treatment has palliative intent. Three modalities of treatment exist:

  1. Targeted therapy, chosen based on the presence of specific mutations. Examples include:
    • Tyrosine kinase inhibitors (TKI) – may be offered first line in inoperable locally advanced or metastatic NSCLC with proven mutations. Examples include erlotinib, gefitinib and afatinib, all for tumours with epidermal growth factor (EGFR) mutations. An EGFR-TKI can be used alongside chemotherapy if the patient is fit enough to tolerate it.
    • Crizotinib – with a mutation of the anaplastic lymphoma kinase (ALK) gene. This is a second-line option for patients who have had platinum-based chemotherapy.
  2. Immune checkpoint inhibitors (immunotherapy) – for those with no targetable mutation, but with proven PD-L1 expression, e.g. pembrolizumab.
  3. Chemotherapy – histology-specific chemotherapy, usually including a platinum-based drug, may be given to those fit for treatment who have no targetable mutation and with a contraindication to immunotherapy.

Management of SCLC

Very early SCLC: SCLC is usually advanced at presentation and only a minority of patients with very early disease qualify for surgical resection aimed at cure. As in NSCLC, extensive work-up is required to ensure fitness for surgery (see above for eligibility criteria). In the minority of patients with SCLC who do proceed to surgical resection, nodal dissection should be performed and adjuvant chemotherapy offered.

Locally advanced SCLC: Nodal disease may be treated curatively with radical chemoradiotherapy.

Metastatic SCLC: Chemotherapy is the mainstay. A platinum-based drug (carboplatin/cisplatin) and etoposide are usually first line. Patients may be eligible for combination with immunotherapy. Atezolizumab is a type of immunotherapy (PDL-1 inhibitor) licensed for extensive small cell lung cancer.

References

Colorectal cancer

Ngozi Ekpemandu

Overview of colorectal cancer

This is the third most common cancer and second most common cause of cancer death in the UK. It is usually adenocarcinoma.

Approximately 25% of the population are at increased risk, including those with:

  • Two or more first-degree relatives with colorectal cancer, or one if the disease was diagnosed under 55 years
  • Extensive, long-standing inflammatory bowel disease
  • Family history of familial adenomatous polyposis (FAP) or hereditary non-polyposis colon cancer (HNPCC), in which the inherited risk for developing colorectal cancer is autosomal dominant

Screening for colorectal cancer

In England, people aged 60-74 (50-74 in Scotland) years are invited to participate in the bowel cancer screening programme. Those aged over 74 may request screening. Eligible patients are sent a faecal immunochemical test (FIT) through the post and those with abnormal results are offered a colonoscopy. At colonoscopy, approximately:

  • 5 out of 10 patients will have a normal exam
  • 4 out of 10 patients will be found to have polyps
  • 1 out of 10 patients will be found to have cancer

As most cancers develop from adenomatous polyps, those at increased risk of developing colorectal cancer are offered surveillance colonoscopies ranging from once a year to every five years with the aim of excising polyps if and when they are considered to have malignant potential.

Diagnosis of colorectal cancer

Colonoscopy is the first-line investigation. Double-contrast barium enema and CT colonoscopy are alternative investigations for if a patient is not fit for colonoscopy.

Once a diagnosis of colorectal cancer is made, a CT chest, abdomen and pelvis is required for staging.

CEA is a tumour marker associated with colorectal cancer. However not all tumours secrete this, and it is not specific (may be raised in conditions such as IBD). It is mainly used for disease monitoring, as levels correlate with disease burden.

Sporadic colorectal cancer

Sporadic (95%) cases of colorectal cancer develop in those with no family history as a result of a sequence of genetic mutations or deletions. It is a relatively common cancer in those over 60 years of age, with the majority of cases arising from adenomas which transform into cancer over 1-2 decades.

Resection of the primary cancer and/or limited metastasis is usually done with curative intent. Chemoradiation in addition to surgery can improve outcome in some patients

Hereditary non-polyposis colorectal carcinoma

Hereditary non-polyposis colorectal carcinoma (HNPCC, 5%), also called Lynch syndrome, is an autosomal dominant condition due to mutation in mismatch repair genes – MSH2 in 60% of cases and MLH1 in 30%. The lifetime risk of colorectal cancer is around 80%. There is also increased risk of other ‘Lynch cancers’: endometrial, ovarian, urinary tract, stomach, small bowel and hepatobiliary.

Diagnosis is suspected if there are 3 or more affected relatives (one of whom must be 1st degree) from 2 successive generations, of whom one was affected when under 50 years old. Asymptomatic relatives of patients with Lynch syndrome may be offered genetic testing.

Colonic surveillance at least every other year is advised from age 25 to 75, with the aim being early detection of Lynch syndrome-associated cancers and surgery where necessary.

Familial adenomatous polyposis

Familial adenomatous polyposis (FAP, <1%) is an autosomal dominant condition due to mutations in the APC tumour suppressor gene located on chromosome 5. It is associated with multiple colorectal adenomas, which are initially benign but likely to undergo malignant transformation. Those with FAP are also at an increased risk of developing duodenal tumours.

Diagnosis is through genetic testing of suspected individuals. Surveillance sigmoidoscopy is advised from 12 years, with prophylactic surgery usually undertaken before the age of 25 depending on the number and size of polyps and degree of dysplasia.

Gardner’s syndrome is a variant of FAP characterised by retinal pigmentation, osteomas of the skull and mandible, thyroid carcinoma, and epidermoid cysts on the skin.

Peutz-Jeghers syndrome

This is an autosomal dominant condition characterised by numerous hamartomatous polyps in the gastrointestinal tract. Malignant transformation of the polyps is rare, however around half of patients with this condition will have other gastrointestinal tract cancers (including colorectal). Peutz-Jeghers syndrome is associated with mutations in the LKB1 or STK11 genes.

Clinical features include pigmented lesions on lips, oral mucosa, face, palms and soles. Small bowel obstruction, often due to intussusception, is a common finding. Intestinal polyps can present with vomiting and abdominal pain. Symptoms of ileus, gastrointestinal bleeding, and secondary anaemia may occur as complications from the polyps.

Management is usually conservative, addressing any complications that arise.

References

  • Ian B. Wilkinson et al. Oxford Handbook of Clinical Medicine. 10th ed., Oxford University Press, 2017, P. 521-527
  • Lance P. Recent developments in colorectal cancer. J R Coll Physicians Lond. 1997 Sep-Oct;31(5):483-7. PMID: 9429181; PMCID: PMC5420963
  • National Cancer Intelligence Network. Colorectal Cancer Survival by Stage – NCIN Data Briefing. London [Internet]: NCIN; 2009. [cited 2023 March 30]. Available from: https://www.ncin.org.uk/publications/data_briefings/colorectal_cancer_survival_by_stage.aspx
  • T. Philip Chung, James W. Fleshman, The Genetics of Sporadic Colon Cancer, Seminars in Colon and Rectal Surgery [Internet], Volume 15, Issue 3,2004,Pages 128-135,ISSN 1043-1489. [cited 2023 March 30]. Available from https://doi.org/10.1053/j.scrs.2005.02.001
  • DermIS Dermatology Information System, Peutz-Jeghers syndrome [Internet].  [cited 2023 March 29]. Available from https://www.dermis.net/dermisroot/en/42633/diagnose.htm
  • McGarrity TJ, Amos CI, Baker MJ. Peutz-Jeghers Syndrome. 2001 Feb 23 [Updated 2021 Sep 2]. In: Adam MP, Mirzaa GM, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2023. [cited 2023 March 29]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1266/
  • Carethers JM, Jung BH. Genetics and Genetic Biomarkers in Sporadic Colorectal Cancer. [Internet]. Gastroenterology. 2015 Oct;149(5):1177-1190.e3. doi: 10.1053/j.gastro.2015.06.047. Epub 2015 Jul 26. PMID: 26216840; PMCID: PMC4589489. [cited 2023 May 22]. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4589489
  • National Institute for Health and Care Excellence (NICE). Testing strategies for Lynch syndrome in people with endometrial cancer. 2020 [cited 2023 Aug 04]. Available from https://www.nice.org.uk/guidance/dg42/chapter/1-Recommendations

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