Staging depends to a large extent upon radiology, and this is the most commonly used tool to evaluate the response of cancers to therapies. Anatomical imaging by plain films, computed tomography (CT), ultrasound and magnetic resonance imaging (MRI) are the standard methods. Using the correct terms impresses other clinicians and may make a trip to the radiology department less daunting for junior doctors requesting an investigation. X-rays measure radiodensity (radiolucency and radio-opacity) and ultrasound measures echogenicity and echoreflectivity, whilst CT scans report attenuation values measured in Hounsfield units and MRI reports signal intensity.

CT scanning is the production of three-dimensional images using X-rays that have been directed through tissues and the images produced depend on the density of the tissues. CT was developed in the 1970s by Sir Godfrey Hounsfield and Allan McLeod Cormack who shared the Nobel Prize in 1979. The first CT scanner built at EMI Central Research Laboratories is said to have been funded by the success of the Beatles who were signed to the EMI label. CT measures the attenuation of different tissues to ionizing radiation and calculates a mean value for a volume of tissue known as a voxel. This is displayed on a two-dimensional image as a single pixel. The attenuation is calculated relative to water, which has a Hounsfield unit (HU) value of 0, so high attenuation tissues have a positive HU value (e.g. bone +400 HU) and low attenuation tissues a negative HU value (e.g. fat −120 HU). Different window settings are used to look at different ranges of the Hounsfield greyscale. For example, in the bone windows setting, the lungs will look uniformly black, whilst in the lung windows, the bones look uniformly white. Intravenous iodinated contrast agents improve the sensitivity and specificity of CT but are contraindicated in patients with asthma, allergies to contrast or poor renal function.

The prevention of cancer by surgery has expanded greatly in recent years with the identification of individuals at high risk of developing malignancies because they have inherited germline genetic mutations associated with cancer predisposition. However, perhaps the most widespread example of surgical cancer prevention is the role of orchiopexy in the management of undescended testes. Undescended testes are the most common birth defect of the male genitalia, affecting up to 3% of live births. Although in many cases the testes will descend to the scrotum during the first year of life, undescended testes are associated with a 4–40-fold increased risk of malignancy, especially testicular seminoma. Orchiopexy, surgery to move the undescended testis into the scrotum, has been shown to reduce infertility, although it remains controversial whether it also reduces the risk of malignancy. Nevertheless, it certainly makes the detection of testicular tumours easier to recognize and diagnose at an earlier stage.

Oncological diagnosis hinges on histopathology and surgeons play a major role along with interventional radiologists in obtaining tissue specimens. Whilst aspiration cytology and fine-needle biopsies can be undertaken radiologically or endoscopically, more extensive incision or excision biopsies require surgical involvement. Careful specimen orientation and inking prior to histological sectioning may be required to assess the status of tumour margins. The optimal surgical approach and biopsy technique for tumour sampling must take into account concerns about contaminating new tissue planes with cancer cells that could jeopardize subsequent therapy. For example, thoracoscopic pleural biopsy of mesothelioma may result in needle-track metastases along the path of surgical instrumentation. The risk of this surgical spread of the cancer is reduced in mesothelioma by postoperative radiotherapy to the biopsy track. Surgery had a major role in the staging of tumours prior to the development of improved radiological techniques and a staging laparotomy was routine care in the management of Hodgkin’s disease until the late 1980s. Surgical staging retains a role in the management of ovarian epithelial cancer and the surgical placement of radio-opaque titanium clips (that are non-ferrous and thus safe in the MRI scanner) may guide postoperative radiotherapy in some tumours.

The surgical treatment of cancer includes definitive curative surgery (with or without adjuvant treatments), debulking operations, metastasectomy and endocrine ablation surgery for advanced diseases, although the latter is largely historical as pharmacological hormone manipulations have taken over most of this role. It is really important to avoid unnecessary surgery in patients with extensive unresectable cancer whilst ensuring that patients with potentially curative tumours are not denied surgery. The treatment of cancer by multidisciplinary teams including radiologists, pathologists, physicians and surgeons is designed to ensure the right patients have the right operations at the right time. For example, this approach aims to guarantee that patients who are candidates for neoadjuvant down-staging therapy prior to surgery are not wheeled straight into the operating theatre.

Most early curative surgery aimed to remove tumours en bloc, that is, with the draining lymph nodes. In recent times, surgeons have developed the use of more conservative function-preserving operations. Examples of the latter include wide local excision rather than mastectomy and partial nephron-sparing nephrectomy rather than radical nephrectomy for small renal tumours. A further development in surgery for skin tumours was introduced by Dr Frederic Mohs in the 1930s when he was still a medical student at the University of Wisconsin-Madison. Mohs’ surgery for skin tumours involves sectioning the tumour and mapping its surgical margins during the operation to ensure completeness of tumour resection. Instead of using a breadknife and the pathologist looking at each slice, the Mohs’ technique is more like a vegetable peeler with the pathologist examining each peeling for residual cancer involvement during the surgery. Whilst this is a more laborious technique, it is especially valuable for tumours at specific anatomical sites such as the eyelids and in recurrent disease (see Fig. 32.6, p. 262).

Debulking operations that do not result in complete surgical removal of the tumour are not always futile. They can provide important clinical benefits in selected tumour types, including ovarian cancer and primary brain tumours, and are usually followed by either chemotherapy or radiotherapy. Debulking surgery forms part of the treatment algorithm in several uncommon tumours such as thymomas and pseudomyxoma peritonei. Mucin secretion into the abdominal cavity by mucinous adenocarcinomas most commonly arising in the appendix is the usual cause of pseudomyxoma peritonei. The term “myxoma” is derived from the Greek for mucin, but the etymology of the medical terms myxoma and pseudomyxoma seem to have got mixed up. Myxomas are benign pedunculated connective tissue tumours usually arising in the atria of the heart and are not mucinous, whilst pseudomyxoma peritonei fills the abdominal cavity with true jelly-like mucin.

The surgical resection of secondary deposits may seem perverse since the presence of metastases implies systemic dissemination of the cancer. Nevertheless, surgical oncologists have embraced this approach enthusiastically, mainly on the basis of relatively weak evidence from uncontrolled retrospective series that have been interpreted as demonstrating a survival benefit. The resection of lung, liver and brain metastases has become a part of the routine treatment strategy for a number of types of cancer. The most common indication for surgical metastasectomy is for hepatic secondaries from colorectal cancer. The rationale for this approach is based upon reported 5-year survivals of around 30% in patients undergoing surgery compared to around 10% in those who received chemotherapy. However, there are no randomized controlled studies that support hepatic metastasectomy and the case series are inevitably confounded by selection and reporting bias. Similarly, pulmonary metastasectomy has been widely adopted for osteogenic sarcomas, soft tissue sarcomas, renal cell tumours and melanomas, and cerebral metastasectomy has also been advocated in a similar spectrum of malignancies. In contrast to metastasectomy, the surgical resection of residual masses following the completion of chemotherapy forms part of the multidisciplinary treatment of advanced non-seminomatous germ cell tumours to remove residual differentiated teratoma that could relapse at a later date. Finally, surgical endocrine ablation is nowadays rarely indicated for metastatic cancer although surgical castration is occasionally performed for advanced prostate cancer.

Surgery has an important role in the optimal management of oncological emergencies, in particular, metastatic spinal cord compression where rapid surgical decompression reduces neurological disability (see Cord compression in Chapter 46). Surgical decompression and spinal column stabilization should be offered to patients with a good prognosis and needs to be undertaken as swiftly as possible, preferably before patients lose the ability to walk. The optimal neurosurgical approach will depend upon the anatomical site of compression and the stability of the spine. If spinal metastases involve the vertebral body or threaten spinal stability, posterior decompression should always be accompanied by internal fixation with or without bone grafting.

Radiation is like rain:

• The amount of rain falling is the activity (measured in Becquerel – Beq)
  
• The amount of rain hitting you is absorbed dose (measured in Gray – Gy)
  
• How wet you get is dose equivalent (measured in Sievert – Sv)

The dose of radiotherapy is defined as the amount of energy deposited in tissues and is measured in Grays (Gy) after Hal Gray, a British pioneer of radiation biology and physics who also established the Gray Laboratories at Mount Vernon Hospital. One Gray is the dose absorbed when 1 J (joule) is deposited in 1 kg of tissue. Each Gray per cell causes approximately 10,000 damaged DNA bases, 1000 damaged deoxyribose sugars, 1000 single strand breaks, 40 double strand breaks, 150 DNA–protein cross-links and 30 DNA–DNA cross-links. Radiation can have an effect at any point in the cell cycle, although it is only at the time of mitosis that cell death occurs. Therefore, there can be a time lag of days, weeks or even months between the radiotherapy and the full effects of the treatment becoming manifest. Typical radiotherapy doses for solid epithelial tumours are 60–80 Gy. This is delivered as multiple fractions over time for several reasons. Dose fractionation allows normal cells to recover from sub-lethal damage between fractions, whilst tumour cells are less efficient at repairing damage. Dose fractionation also ensures that tumour cells in different phases of the cell cycle are exposed to radiation since it causes greatest damage in the G2 and M phases. The exact scheduling and fractionation of radiotherapy varies but in general doses of around 2 Gy are delivered on a daily basis 5 days a week. In some circumstances, more frequent dosing has been shown to be more efficacious but is of course more demanding on resources. For example, continuous hyperfractionated accelerated radiotherapy (CHART) involves radiotherapy delivered three times a day, every day of the week, usually for a fortnight.

Radiotherapy utilizes X-rays, electron beams and β- or γ-radiation produced by radioactive isotopes. X-rays are produced when a high-energy electron beam that is produced by heating an electrode in a vacuum, strikes matter. The energy of X-rays can be changed by altering the voltage input to the cathode of the X-ray tube that accelerates the electrons.

Superficial voltage machines operate at 50–150 kV, and their energy does not penetrate more than 1 cm below the surface of the skin. They are used chiefly to treat superficial skin cancers. Orthovoltage machines that yield X-rays of 200–300 kV of energy penetrate to a depth of 3 cm. Metastases in bones close to the skin surface (ribs, sacrum) are frequently treated on these machines. Megavoltage radiotherapy machines usually use a cobalt-60 source that produces X-rays of 1.25 MeV on decaying to nickel-60. The cobalt-60 sources are contained within a protective lead shield and an adjustable window in this shield allows regulation of the γ-ray beam. However, there is considerable scatter of the beam, limiting the focus and the relatively short half-life of the cobalt source means that it needs to be replaced every 3–4 years and that treatment times may become prolonged as the cobalt nears the replacement date. It is speculated that cobalt-60 sources could be used by terrorists to produce a “dirty” bomb, a conventional explosive device to which radioactive material has been added.

Tumour resistance to radiotherapy appears to be an intrinsic property of that cancer, rather than an acquired attribute selected for by treatment, as in the case of chemotherapy. Indeed, the radiation sensitivities of many types of tumours are relatively predictable. The response of tissues both malignant and normal to fractionated radiation depends upon the “5 Rs”:

• Repair
  
• Reassortment
  
• Repopulation
  
• Reoxygenation
  
• Radiosensitivity

In this context, repair is recovery from sub-lethal damage and is dependent on DNA repair mechanisms. Reassortment refers to the cell cycle phase of the tumour cells. Cells in G2 and M phases are most susceptible to radiotherapy, so after a first dose, cells in G1 and S will make up a greater proportion of the live tumour cells. Depending on the timing of the subsequent fraction of radiotherapy, these cells may have progressed or “reassorted” to G2 and M phases with increased sensitivity. Repopulation is the ability of tumour cells to grow and divide between doses of radiotherapy; this is a particular problem with prolonged fractionation and delayed fractions. Hypoxic cells are relatively radioresistant, and after the first fractions of radiotherapy, the death of sensitive cells reduces the competition for oxygen in the tumour, and cells that were hypoxic previously become reoxygenated and hence more susceptible to radiation. Different cell lineages are more or less radiosensitive, and these differences are in part intrinsic and independent of environmental factors. Amongst the factors that influence the radiosensitivity of tumours are the DNA repair genes, the production of free radical scavenging molecules (e.g. glutathione-S-transferases, superoxide dismutases, glutathione peroxidase), genes controlling apoptosis and cell cycle regulatory genes.

The origins of chemotherapy for cancer lie in the use of biological warfare during the First World War, most hauntingly described in Wilfred Owen’s poem “Dulce et decorum est”. Following the extensive use of chlorine gas in trench warfare, the German Army first released mustard gas at Ypres on the night of 12–13 July 1917. Mustard gas had been synthesized in 1854 by Victor Meyer and was noted to be a vesicant in 1887. As a weapon of mass destruction, mustard gas, or Yperite as it was then known, had the advantages over chlorine of requiring smaller doses, being almost odourless and remaining active in the soil for weeks. The British gas casualties from 1914–1918 reveal the greater fatalities with mustard gas. Mustard gas exposure causes a severe blistering rash and conjunctivitis followed by myelosuppression after around 4 days. During the Second World War, the only use of mustard gas resulted in an own goal when the Luftwaffe sunk the USS John Harvey off Bari harbour in southern Italy in 1943. The ship was carrying 2000 M47A1 bombs containing a total of 100 tonnes of mustard gas, and the American sailors who survived developed conjunctivitis and skin blistering followed by a steep fall in their white cell counts, as documented by the naval surgeon Colonel Stewart Alexander. Meanwhile at Yale University, Alfred Gilman and Louis Goodman were using the closely related nitrogen mustard (mechlorethamine) initially in murine lymphoma models. In 1944, the first patient with lymphosarcoma (high-grade non-Hodgkin’s lymphoma) was treated, and although Mr J. D., a 48-year-old silversmith, achieved a temporary remission of his tumour, he later died of bone marrow failure.

The subsequent development of chemotherapy following this fortuitous finding as a by-product of biological warfare, owes much to luck and trial and error rather than design. One serendipitous discovery was made by Barnett Rosenberg, a physicist at Michigan State University in 1965. He studied the effects of electric currents on Escherichia coli by using platinum electrodes in a water bath and found that they stopped dividing but not growing, leading to bacteria up to 300 times longer than normal. This was found to be due to cisplatin, a product from the platinum electrodes, which was interfering with DNA replication. By the end of the 1960s, a number of cytotoxic drugs from natural sources had been identified. In 1971, President Nixon, losing the war in Vietnam, declared war on cancer, signing the Cancer Act and establishing a drug discovery programme at the National Cancer Institute (NCI). This project trawled though thousands of natural chemicals in search of potential cytotoxic agents. It was not until the 1990s that rational drug design targeting known tumour-related features emerged. Examples of this include trastuzumab, a monoclonal antibody raised against erbB2/neu/Her-2 in breast cancer and imatinib, which inhibits the adenosine triphosphate (ATP) binding site of brc-abl fusion protein kinase in chronic myeloid leukaemia. In 2013, over 125,000 cancer patients in England were treated with systemic anticancer therapy receiving over 538,000 cycles of treatment.

The main actions of chemotherapy are focused on killing rapidly dividing cancer cells and hence many of their toxicities arise because of the effects on normal cells with high rates of turnover. Indeed, the side effects of chemotherapy may be divided into the predictable toxicities that are common, often dose related and usually related to the mechanism of action of the drug. In contrast, idiosyncratic side effects are usually rarer, unrelated to dose or mechanism of action but tend to be drug specific. The predictable effects of chemotherapy on fast dividing normal cells (bone marrow, gastrointestinal tract epithelium, hair follicles, spermatogonia) will be a consequence of inhibition of cell division and are especially found with cell cycle phase-specific cytotoxics. In contrast, the side effects on slow-growing cell types will occur most frequently with drugs that are not cell cycle specific, such as the alkylating agents that introduce DNA mutations into these cells, resulting in secondary leukaemias and other tumours.

The side effects of chemotherapy may be divided into three time groups: (1) immediate effects that occur within hours, (2) delayed effects that occur within days, weeks or months but are generally manifested whilst the full course of chemotherapy treatment is ongoing and (3) late effects that occur months, years or decades after the chemotherapy has ceased. The top five side effects ranked by patients according to severity are nausea, fatigue, hair loss, concern about the effects on friends and family and finally vomiting. The immediate toxicities include nausea and vomiting, anaphylaxis, extravasation and tumour lysis. The delayed side effects are the most abundant and include alopecia, myelosuppression, stomatitis and the majority of the unpredictable toxicities. The late effects of chemotherapy include infertility and secondary malignancies.

The main predictable delayed side effects of chemotherapy are alopecia, bone marrow suppres- sion and gastrointestinal mucositis.