Electromagnetic radiation

X-rays and gamma-rays (γ-rays) are part of the electromagnetic spectrum; the former are produced artificially and the latter from naturally occurring or artificially produced radioisotopes. Megavoltage X-rays for therapeutic purposes are produced by a linear accelerator (Figure 36.1) by accelerating electrons to high kinetic energies on to a target composed of tungsten or gold. Kinetic energy given up by the electrons is converted to high-energy X-rays. γ-rays are emitted as byproducts of radioactive isotopes (e.g. iridium-192) undergoing decay to reach a stable nuclide.

Figure 36.1 A linear accelerator and radiotherapy treatment room. The linear accelerator can rotate 360° around the treatment couch, which is also able to rotate about its axis, allowing the patient to be treated using beams from multiple directions. The patient is monitored during treatment using cameras, and communication is possible using a microphone.

X-rays and γ-rays are characterized by very short wavelengths and high frequencies, and consist of packets of energies (photons) capable of tissue ionization. Higher energy photons have greater tissue penetration. Photon energies in the range of 6–15 million electron volts (megavolts, MV) are typically used for pelvic irradiation, although higher energies may be required for obese patients to achieve adequate dose to the centre of the pelvis. Use of photon energies less than 4 MV can result in greater dose variation within the patient.

Particulate radiation

This consists of atomic subparticles: electrons (negatively charged), protons (positively charged), neutrons (no charge) and negative π-mesons. Only electrons are commonly used in clinical practice. High-energy electrons are produced in a linear accelerator from which the target has been removed. Electrons react more rapidly with tissue compared with photons, and have a depth–dose profile which follows a plateau for a distance depending on the electron energy, followed by a rapid dose fall-off. Electrons are useful for the treatment of superficial tumours, allowing sparing of deeper structures which reduces treatment-related morbidity.

Proton beam radiotherapy has generated increasing interest in recent years. The dose distribution of a monoenergetic proton beam increases slowly with depth but reaches a sharp maximum near the end of the particle’s range (Bragg peak) with subsequent rapid dose fall-off. This has the attraction of precisely confining the high-dose region to the deep-seated tumour volume whilst minimizing the dose to the surrounding normal tissues. The availability of proton beam therapy remains restricted by the limited number of cyclotron machines available globally for the production of protons.

Concomitant chemoradiation

Cisplatin-based chemoradiation became the standard of care in cervical cancer following an alert issued by the National Cancer Institute in 1999. The benefit of chemoradiation in cervical cancer over radiotherapy alone has been confirmed by recent meta-analyses. Concomitant chemotherapy may have an additive or synergistic effect when combined with radiotherapy. Perceived benefits include increased tumour sensitization to radiotherapy and eradication of systemic micrometastatic disease.

Radiotherapy fractionation

Conventional practice involves once-daily treatment giving five fractions per week using 1.8–2 Gy/fraction. Modified dose-fractionation schedules have been investigated in an attempt to improve cure rates. Hyperfractionated radiotherapy is the delivery of two or more fractions per day using smaller doses per fraction to deliver a higher total dose over the same time period compared with standard fractionated radiotherapy. An interfraction gap of a minimum of 6 h is recommended for recovery of normal cells. Advantages of this approach include delivery of a higher total dose to improve tumour eradication whilst allowing sufficient time for normal tissue repair between fractions. Accelerated radiotherapy refers to the delivery of radiotherapy over a significantly shorter period of time by delivering six or more fractions per week, with an interfraction gap of a minimum of 6 h. The total dose and dose per fraction remain the same as for standard treatment. Delivering radiotherapy over a shorter period of time reduces the negative effects of accelerated repopulation seen in some cancers. Hypofractionated radiotherapy delivers radiation treatment over a shorter period of time by using fraction sizes larger than 2 Gy/fraction. However, such an approach increases the risk of late normal tissue toxicity, as normal tissues are more sensitive to larger doses per fraction compared with tumour cells. In order to reduce this risk, the total dose of radiotherapy is reduced to deliver the same biologically effective dose. Hypofractionated radiotherapy is commonly used in palliative radiotherapy to minimize patient inconvenience and to optimize resource utilization.

Dose prescription

A radiotherapy prescription specifies the total dose to be given, the total number of fractions to be used, the dose per fraction, and the overall treatment duration. The total dose required to eradicate a tumour is dependent on the tumour volume to be treated. Whereas a dose of 50 Gy in 25 fractions treating five times per week over 5 weeks is sufficient to eradicate microscopic disease in 90% of cases, doses above 66 Gy using 2 Gy/fraction over 6.5 weeks are required to eradicate macroscopic disease. Where delivery of radical radiotherapy with curative intent is not possible because of tumour-related (e.g. tumour volume, metastatic disease) or patient-related (e.g. poor performance status) factors, palliative radiotherapy may be considered to alleviate distressing symptoms. Doses typically used include 8 Gy in a single fraction, 20 Gy in five fractions over 1 week or 30 Gy in 10 fractions over 2 weeks.

Radiotherapy planning

The aim of radiotherapy planning is to deliver a homogenous dose to the primary tumour and potential areas of micrometastatic disease whilst minimizing the dose to the organs at risk. Accurate tumour localization is central to radiotherapy planning, and it is important to have the following information to hand: findings of clinical examination including examination under anaesthesia, operation notes and intraoperative findings, histopathology report and the results of any radiological investigations including computed tomography (CT), magnetic resonance imaging (MRI) and ¹⁸FDG-positron emission tomography (PET) scans.

Simulator-based radiotherapy planning has been superseded by CT-based planning which allows more accurate visualization of the tumour and organs at risk. Where appropriate, coregistration of MRI and CT images provides greater certainty and clarification of anatomy. Coregistration of functional imaging scans (e.g. PET scan) with planning CT scans may provide yet more sophisticated radiotherapy planning. The simulator — a diagnostic X-ray machine connected to a television screen which emulates a treatment machine — continues to have a useful role for palliative radiotherapy planning. It is also useful in the minority of cases where CT scanning is not possible due to patient obesity or other patient-related factors.

Planning procedure

A vaginal examination is performed prior to the CT scan to determine the extent of vaginal involvement and the most inferior aspect of the tumour. The patient is scanned in the supine position unless a belly board is used to displace the small bowel anteriorly to minimize small bowel irradiation, in which case she is placed in the prone position. A vaginal probe can aid in defining the extent of vaginal involvement, although this is not universally utilized. Rectal contrast may be used to delineate the rectum and sigmoid. Intravenous contrast may be administered to enhance identification of blood vessels which are anatomical landmarks for the regional lymph nodes. A CT scan is performed using 2.5–5-mm slices from the third lumbar vertebra to 5 cm below the ischial tuberosities. The superior border is extended to include the lower thoracic vertebrae if para-aortic lymph node irradiation is required. The patient is asked to have a comfortably full bladder to reduce the volume of small bowel within the pelvis. Following acquisition of CT images, permanent tattoos are marked on the patient’s skin as reference points for aligning her in the correct position for each fraction of treatment.

Conformal radiotherapy

The CT scan images are subsequently transferred to a computer terminal (Figure 36.2) with software allowing delineation of target volumes and organs at risk according to recommendations from the International Commission on Radiation Units and Measurements. The gross tumour volume includes the palpable and/or radiologically visible tumour; it is absent if it has been surgically resected. The clinical target volume (CTV) involves the gross tumour volume and potential areas of microscopic disease (e.g. pelvic lymph nodes and parametria in cervical cancer). The CTV is grown by a margin to allow for internal organ motion and geometric uncertainties in treatment delivery; this is called the ‘planning target volume’ (PTV). The organs at risk for pelvic radiation include the rectum, bladder, small bowel and both hip joints. The kidneys and spinal cord are the dose-limiting organs at risk when radiating the para-aortic lymph nodes. The clinician specifies the dose fractionation to be used in the radiation treatment of the patient.

Figure 36.2 The planning computer showing a treatment plan and dose–volume histogram.

Following the process described above, a radiotherapy treatment plan is produced by medical physicists using complex computer algorithms which simulate the effects of a radiation beam passing through the designated area and the radiation dose deposited at any one site. Three or more beams are typically required to produce a homogenous dose for the radiation of pelvic cancers; the use of two beams increases the volume of bowel receiving radiotherapy and risk of radiation enteropathy. However, the use of two opposing anterior–posterior beams is necessary for irradiation of carcinoma of the vulva due to irradiation of inguinal lymph nodes. Modern linear accelerators contain computer-driven multi-leaf collimators which shape the radiation beams to improve conformity to the PTV and to shield the organs at risk. These have replaced the lead blocks previously manually placed in the beam to provide shielding of the organs at risk, thus speeding up the treatment process and reducing the heavy manual work required of therapy radiographers.

The final radiotherapy plan comprises the following information: the number of beams used to optimize conformity to the PTV, beam energies, beam direction, use of wedge angles and multi-leaf collimators to improve PTV conformity, and the dose distribution and percentage dose received by the PTV. A dose–volume histogram is provided to determine the dose being received by the PTV and organs at risk. The final plan is checked and approved by the clinician prior to implementation of the radiotherapy plan (Figure 36.3). Verification checks are performed to validate the treatment plan and to detect for any unforeseen errors prior to starting radiation treatment. A standard dose prescription for carcinoma of the cervix is 45–50 Gy in 25–28 fractions using 1.8 Gy/fraction over 5–5.5 weeks.

Figure 36.3 A computed tomography (CT) slice from a four-field conformal radiotherapy plan to treat a patient with carcinoma of the cervix. The green area represents the clinical target volume (CTV) consisting of the primary tumour plus a margin for microscopic disease and the pelvic nodes. The organs at risk are also drawn on the CT slice: rectum (blue), urinary bladder (purple) and femoral heads (yellow).

Image courtesy of Professor Peter Hoskin, Mount Vernon Hospital, Northwood.

The patient is treated in a specially designed room to prevent radiation of personnel outside the room. The patient is positioned on the treatment couch with reference to the tattoo marks (Figure 36.4). Computerized transfer of planning data from the planning computer to the linear accelerator minimizes the risk of human error in transferring data. The radiographers control the linear accelerator from outside the room using a console which is used to start and stop the radiation beam, and to set the duration of treatment and the dose to be delivered. The patient is monitored using cameras in the treatment room, and communication with the patient is possible via a microphone. These safety features are designed to optimize radiation treatment and are subject to frequent quality assurance checks.

Figure 36.4 Patient lying on the couch of a linear accelerator.

Virtual simulation

The planning CT scan images can be reconstructed using computer software to provide a digitally reconstructed radiograph (DRR). Bony landmarks are used for radiotherapy planning with the clinician using the computer software to place the radiation beams on to the DRR. This is akin to conventional radiotherapy. The advantages of virtually simulated radiotherapy planning include: the clinician is able to visualize the pelvic soft tissues by using the CT scan images, thus ensuring the tumour is encompassed within the radiation field; radiotherapy planning is less time-consuming compared with conformal radiotherapy; the clinician can apply multi-leaf collimators at the time of planning to optimize shielding of the organs at risk; and a dose distribution can be provided by the medical physicists to ensure that the PTV is receiving the prescribed dose. The disadvantages of virtually simulated radiotherapy planning are that it is not suitable for producing complex radiotherapy plans, and a dose–volume histogram cannot be provided to determine the dose being received by the organs at risk. Virtually simulated radiotherapy (Figure 36.5) is frequently utilized for pelvic radiotherapy for the reasons outlined above.

Figure 36.5 Anterior (A) and right lateral (B) views of a virtually simulated radiotherapy plan for carcinoma of the cervix. The superior border has been extended superiorly to include the common iliac lymph nodes. The red (A) and green (B) delineated areas denote the planning target volume; the white rectangles represent the multi-leaf collimators used to shield organs at risk which do not need to be irradiated.

Images courtesy of Professor Peter Hoskin, Mount Vernon Hospital, Northwood.

Conventional radiotherapy

Conventional external beam radiotherapy uses bony landmarks to define the target volume for pelvic radiotherapy. A simulator film is obtained after the patient is aligned on the simulator couch using orthogonal lasers. Cross wires mounted in the light beam from the simulator define the size of the area to be treated, and anterior–posterior and lateral pelvic X-rays are obtained as permanent records. The clinician is able to identify areas where shielding can be applied to reduce dose to the organs at risk (Figure 36.6). As diagnostic X-rays have poor soft tissue resolution, the clinician must rely on information gathered from clinical examination and radiological investigations to determine the target volume. Studies have reported underdosing of the regional lymph nodes in up to 40% of patients using conventional radiotherapy. However, conventional radiotherapy planning still has a role in centres where access to CT planning software is restricted due to resource implications, in patients unable to fit into a CT scan machine due to gross obesity, and in palliative radiotherapy.

Figure 36.6 Anteroposterior (A) and lateral (B) X-rays of the pelvis showing the superior, inferior and lateral margins. The triangular areas are protected from the beam. The patient has had a lymphangiogram.

Intensity-modulated radiotherapy

Intensity-modulated radiotherapy (IMRT) is generally regarded as a significant advancement in the development of conformal radiotherapy. A major advantage of IMRT is the ability to generate PTVs which conform to targets which are concave in the plane of the incident beams, which is not possible with standard conformal radiation. This is achieved by using numerous non-coplanar beams of varying intensity to improve conformity to treatment targets whilst further reducing the dose to selected organs at risk. However, IMRT results in a larger volume of normal tissue receiving low doses of radiation; one of the concerns of IMRT is that, over a period of time, this may result in a higher incidence of secondary malignancies and other unwanted late toxicities.

IMRT may be inverse- or forward-planned. In inverse-planned IMRT, the clinician specifies the dose constraints within the patient and an inverse-planning algorithm computes the beam modulations required to produce the specified dose distribution. A number of planning cycles may be required to produce an ‘optimized’ dose distribution. Forward-planned IMRT utilizes a limited number of non-coplanar beams of different weighting to deliver a more conformal plan. An additional advantage of IMRT is that it is possible to allocate different dose targets within a single treatment volume by a process called ‘simultaneous integrated boost IMRT’.

A number of studies investigating the role of IMRT in cervical and endometrial cancer have been published in the literature. The majority are single-centre retrospective analyses involving fewer than 100 patients.

Whilst the use of IMRT may be promising, there are insufficient long-term data regarding its efficacy and safety in the treatment of gynaecological malignancies. Concerns have been raised regarding the use of IMRT because of the poor visualization of the cervix on CT scans. The use of MRI/CT fusion is currently being explored. IMRT should be regarded as an experimental treatment in gynaecological cancers, and its use should be confined to clinical trials until there are convincing data for its role in these cancers.

Radionuclides used in gynaecological malignancies

Radium-226 was the first radionuclide used in gynaecological brachytherapy. It has a half-life of 1620 years and decays by alpha emission to its gaseous daughter product, radon-222. There were several disadvantages associated with the use of radium-226, including emission of high-energy photons which required thick shielding and storage of the daughter nuclides for prolonged time periods. Radium-226 has been replaced with more convenient radionuclides such as caesium-137, cobalt-60 and iridium-192. Other artificially produced radionuclides are likely to become available for brachytherapy use in the future.

Dose rates in brachytherapy

Moderate-dose-rate (MDR) and high-dose-rate (HDR) brachytherapy are commonly used in gynaecological malignancies. Whilst there is no universally accepted definition of dose rate, it is generally accepted that MDR uses dose rates of 1–12 Gy/h whereas HDR refers to dose rates greater than 12 Gy/h. Sufficient data are available to suggest that both are equally effective in achieving tumour control when used in the treatment of gynaecological malignancies. MDR brachytherapy is typically delivered over a period of 12–14 h, and thus requires inpatient treatment in an appropriately designed room. The patient is required to remain flat and immobile during this period to prevent displacement of the applicators. MDR brachytherapy has the radiobiological attraction of allowing treatment to be completed in a short period of time, thus reducing the negative effects of tumour repair and repopulation. Advantages of HDR brachytherapy include shorter treatment times, allowing outpatient-based treatment and the reduced risk of applicator displacement during treatment. However, HDR brachytherapy requires fractionation of treatment to reduce the risk of late tissue toxicity, with three to six fractions being delivered on a weekly basis. This leads to prolongation of the overall treatment time, associated with a theoretical disadvantage of allowing tumour repair and repopulation between treatment fractions. Pulsed-dose-rate (PDR) brachytherapy utilizes HDR treatment to simulate LDR brachytherapy to minimize the radiobiological disadvantages of prolonging overall treatment time. In PDR brachytherapy, pulses of HDR treatment are repeated at short intervals to simulate LDR brachytherapy.

Delivery systems in gynaecological brachytherapy

The manual insertion of radioactive sources into tumours has almost become obsolete and has been superseded by afterloading systems. Afterloading involves the initial placement of non-radioactive applicators within the patient with subsequent insertion of the radioactive material. This has the advantage of significantly reducing the risk of exposing personnel to the radioactive sources. The use of machine (remote) afterloading techniques virtually eliminates the risk of radiation exposure for all personnel, and has become the standard of care in gynaecological brachytherapy.

Intracavitary brachytherapy

This technique is routinely used for the radical treatment of cervical cancer where hysterectomy has not been performed, and occasionally in patients with inoperable endometrial cancer. The procedure is carried out under general anaesthesia unless contraindicated, in which case spinal anaesthesia provides a suitable alternative. The patient is examined to assess tumour size and parametrial involvement, and a urinary catheter is inserted. Following cervical dilatation, a sound is used to assess the uterine length. The width of the vaginal vault is estimated to guide the applicator sizes required. The intrauterine tube is inserted first, followed by the vaginal applicators. A rectal retractor may also be inserted to push the anterior rectal wall further away from the applicators; alternatively, a gauze pack may be used to achieve this purpose and also to secure the applicators in place. A simulator film is taken with the applicators in place once the patient is awake, which is then transferred on to a planning computer to allow dosimetry calculations to be performed. The patient is treated in an appropriately shielded room using a remote afterloading system (Figure 36.7). The patient is monitored via a camera inside the treatment room, and a microphone can be used to communicate with the patient. Once treatment is completed, the applicator and gauze packing are removed and the patient is discharged home.

Figure 36.7 A remote afterloading high-dose brachytherapy machine. Once the applicators are inserted and a radiotherapy plan is produced, the applicators are attached to the machine using cathethers. The patient is treated in the room in isolation to allow protection of staff from the ionizing radiation.

A number of applicator systems are available for intracavitary brachytherapy, all of which are based around the principle of delivering a high radiation dose to the cervix, parametrium and upper vagina. Two main types of applicator are available (Figure 36.8a,b,c).

Figure 36.8 Different types of applicators available for intracavitary brachytherapy. (A) Intrauterine tube and two ovoids, which is used as the standard applicator system for delivering intrauterine brachytherapy, although some centres use the intrauterine tube and ring applicator shown in (B). Other brachytherapists advocate the use of a single line source as shown in (c). An example of a vaginal cylinder applicator used for vaginal vault brachytherapy is also shown (D).

Image B–D courtesy of Nucletron.

The Manchester system was developed to calculate and describe the dose distribution for intracavitary brachytherapy. The system specified activity loadings for the intrauterine tube and each ovoid to give a dose defined to a defined reference point, called ‘Point A’. This is defined as being 2 cm lateral to the centre of the uterine canal and 2 cm superior to the mucous membrane of the lateral fornix along the line of the uterine canal. An additional point (Point B) placed 3 cm lateral to Point A is used to calculate the dose received by the pelvic side wall.

Conventionally, a total dose of 75–85 Gy is delivered to Point A. Following external beam radiotherapy with a dose of 45–50 Gy in 25–28 fractions, a dose of 25–27 Gy is delivered to Point A using MDR brachytherapy. A number of recommendations exist for the total dose and number of fractions used for HDR brachytherapy. The most commonly used dose fractionation is 21 Gy in three fractions using 7 Gy per fraction.

Vaginal vault brachytherapy

Following hysterectomy, women with cervical or endometrial cancer with pathological features suggestive of a high risk of relapse are often recommended to have adjuvant radiotherapy, including vaginal vault brachytherapy where appropriate. Vaginal vault brachytherapy is increasingly being used as the sole adjuvant treatment for endometrial cancer in women with intermediate–high risk of pelvic relapse. A number of vaginal applicators are available for use, including vaginal cylinders (Figure 36.8D) of varying sizes, vaginal ovoids or individualized vaginal moulds. Applicator insertion may be carried out on the ward or in the brachytherapy suite, although some brachytherapists prefer the procedure to be carried out in theatre under general anaesthesia.

Following insertion of the applicators, patients undergo the same planning process as for intracavitary brachytherapy. Following external beam radiotherapy (45 Gy in 25 fractions), a dose of 15 Gy is prescribed to 5 mm if using MDR brachytherapy. If using HDR brachytherapy, 12 Gy in two or three fractions may be prescribed.

Interstitial brachytherapy

Interstitial brachytherapy is used for the treatment of tumours of the vagina and vulva, either as primary treatment for small tumours or to boost the primary tumour following external beam radiotherapy. It can also be used for palliating symptoms for locally recurrent or metastatic cancers of the vagina and vulva. Either LDR iridium wire interstitial implants or HDR afterloading implant techniques can be used for perineal implants using some form of perineal template (Figure 36.9). Perineal implants are performed under general or spinal anaesthesia. Computer-based planning allows for more accurate visualization of the tumour in relation to the implant (Figure 36.10).

Figure 36.9 A Martinez universal perineal interstitial template for interstitial treatment of carcinoma of the vagina.

Image courtesy of Nucletron.

Figure 36.10 Computed tomography slice showing perineal brachytherapy to treat carcinoma of the right vaginal wall. Packing is applied within the vagina to keep the left vaginal wall away from the radioactive sources, thus minimizing radiation toxicity.

Image courtesy of Professor Peter Hoskin, Mount Vernon Hospital, Northwood.

Image-guided adaptive brachytherapy

Simulator-based dosimetry for intracavitary brachytherapy relies on doses to points (e.g. Point A) rather than to volumes. For advanced cervical tumours, prescribing to Point A may lead to tumour underdosage as a proportion of the tumour may lie outside the high-dose envelope. Image-guided adaptive brachytherapy uses CT and/or MRI imaging to allow visualization of the tumour in relation to the applicator and the organs at risk at the time of brachytherapy to enable dose adaptation to the target whilst improving the sparing of normal tissues (Figure 36.11). The possibility of fusing FDG-PET images with planning CT software provides another potential avenue for the use of adaptive brachytherapy to improve tumour control.

Figure 36.11 (A, B) Image-guided brachytherapy showing the treatment of a patient with cervical carcinoma with right parametrial involvement using interstitial brachytherapy. Treatment is performed using standard intracavitary treatment and interstitial brachytherapy to boost the right parametrium, thus allowing greater conformity of treatment using image-guided brachytherapy.

Images courtesy of Professor Peter Hoskin, Mount Vernon Hospital., Northwood.

Image-guided adaptive brachytherapy is a relatively new concept for the treatment of cervical cancer, and is only available in a few centres. Some of the challenges to the widespread adaptation of this technique include: the availability of CT- and MRI-compatible applicators, the availability of software to define applicator geometry for CT and MRI, coregistration of pelvic CT and MRI images, and a limited number of published clinical results. Image-based adaptive brachytherapy continues to generate significant interest, with the potential of improving tumour control and significantly reducing treatment-related morbidity.

Routes of administration

Alkylating agents

These drugs cross-link DNA strands and intracellular proteins by forming covalent bonds between highly reactive alkylating groups and nitrogen groups on the DNA helix. This either prevents division of the helix at mitosis or transcription of RNA, and results in imperfect division and cell death.

The most frequently used alkylating agents in gynaecological cancers are carboplatin and cisplatin. Previously used agents include cyclophosphamide, ifosfamide, chlorambucil, melphalan and treosulfan. Some alkylating agents may be taken orally.

Both cisplatin and carboplatin contain platinum. They act in a similar way to alkylating agents, forming DNA adducts. Both are given intravenously but, because of its potential nephrotoxicity and associated hypomagnesaemia and hypokalaemia, cisplatin requires a forced diuresis and electrolyte replacement. It is also associated with severe nausea and vomiting which require potent antiemetic therapy. Peripheral neuropathy and ototoxicity are recognized side-effects which can be disabling and are usually dose related. Cisplatin has little myelotoxicity except for anaemia.

Carboplatin is less frequently associated with nephrotoxicity or neurotoxicity, and is also less emetogenic. It may be given as a short outpatient infusion. The most common side-effect of carboplatin is bone marrow suppression, with thrombocytopenia being a particular problem, especially in the context of impaired renal function. There is increasing recognition that platinum-associated hypersensitivity reactions are seen when carboplatin is used in the second-line setting. Data suggest that more than 10% of patients treated with carboplatin will experience this reaction, which can vary from a mild rash to hypotensive shock. A variety of desensitization schedules have been devised; however, patients can be challenged with cisplatin if it is felt to be too dangerous to continue with carboplatin.

Ifosfamide is an alkylating agent which is activated by hepatic microsomal enzymes. Bone marrow suppression is the dose-limiting toxicity and it also causes marked alopecia. It is excreted in the urine in the form of active metabolites, which can cause severe chemical cystitis when given in high doses unless mesna (sodium 2-mercaptoethanesulphonate) is administered at the same time to protect the bladder mucosa. In addition, ifosfamide may cause a fatal encephalopathy and must only be given after reference to a treatment nomogram.

Antimetabolites

These compounds closely resemble metabolites essential for the synthesis of nucleic acids and proteins. They are incorporated into natural metabolic pathways and enzyme systems, and disrupt the cellular mechanism. Each antimetabolite acts at different sites in the pathway of nucleic acid synthesis. These drugs include 5-fluorouracil (5-FU), methotrexate, capecitabine and gemcitabine.

Vinca alkaloids

Vinka alkaloids act during the metaphase of mitosis, probably through toxicity to the microtubules of the mitotic spindle. Peripheral and autonomic neuropathy are particular problems with vinca alkaloids, particularly vincristine. In addition, they are very irritant and are best injected into a fast-flowing drip. Vincristine is one of the very few chemotherapeutic drugs that is not myelotoxic.

Topoisomerase inhibitors

There are two different types of topoisomerase inhibitors. Both interfere with the transformation of DNA which is required for mitosis. Topoisomerase-1 inhibitors include topotecan and irinotecan, and topoisomerase-2 inhibitors include the epipodophyllotoxins (e.g. etoposide) and the anthracyclines [e.g. doxorubicin (including liposomal doxorubicin) and epirubicin].

Bleomycin

Bleomycin is another antitumour antibiotic which causes DNA strand breakage, thus interfering with DNA replication. It is not myelotoxic; however, the most important side-effect is pulmonary fibrosis, which is dose related and not often seen at a cumulative dose below 300 mg/m².

Taxanes

The taxanes include paclitaxel (Taxol) and docetaxel. They work by promoting microtubule assembly and stabilizing tubulin polymers, which results in the formation of non-functional microtubules, thus inhibiting mitosis. Taxol is active in ovarian and breast cancers as well as in many other tumours. Hypersensitivity reactions are less commonly experienced with a premedication cocktail of antihistamines, H₂ antagonists and steroids. The vast majority of patients develop total alopecia. Other side-effects include nausea, vomiting, peripheral neuropathy and myalgia. It is now usually given as a 3-h infusion in a non-PVC system by the manufacturers. When combined with a platinum agent, Taxol should be administered first to reduce toxicity and increase synergism. The reverse is the case for combination with doxorubicin.

Docetaxel has a slightly different side-effect profile compared with Taxol, with a reduced incidence and severity of peripheral neuropathy but a higher incidence of bone marrow suppression.

Bone marrow suppression

This is a side-effect of almost all of the chemotherapy agents because of their action on bone marrow stem cells, the exceptions being vincristine and bleomycin. The blood count must be checked regularly and before each course of treatment. Neutropenia can result in infections not only from infective organisms such as Staphylococcus aureus, but also from opportunistic organisms which normally cause no problems in healthy individuals. Fungal infections also occur. Infections need to be treated aggressively as they can be life-threatening. Granulocyte colony-stimulating factors increase the tolerance of bone marrow to chemotherapy, reducing the incidence of secondary infections. Thrombocytopenia and anaemia may also occur and may need correction.

Alimentary tract toxicity

Nausea and vomiting are common side-effects of chemotherapy but can be well controlled with the armamentarium of antiemetics currently available to oncologists. Mucositis can result in patient discomfort, but is usually manageable with appropriate advice and appropriate treatment. Diarrhoea is a commonly encountered side-effect of 5-FU and its prodrug capecitabine, but it is usually self-limiting and can be easily managed with loperamide or codeine phosphate. Patients with DPD deficiency can develop fulminant diarrhoea due to 5-FU-induced colitis.

Alopecia

Alopecia is a common problem encountered with some agents but is seldom permanent.

Reproductive system

Chemotherapy may cause permanent infertility, but many young women successfully treated for germ cell tumours have had normal pregnancies. Cytotoxic drugs during pregnancy, particularly in the first trimester, can result in spontaneous abortion or congenital abnormalities. Young women undergoing treatment for gynaecological cancers are often rendered postmenopausal and may require hormone replacement therapy to reduce the long-term effects of early menopause. Other associated effects, such as loss of libido and vaginal dryness, can have a significant impact on the patient’s quality of life.

Heart

Doxorubicin can cause cardiomyopathy which can result in heart failure. The risk is dose related. If the total dose is kept below 450 mg/m² and it is not used in patients with impaired cardiac function, cardiotoxicity is rarely seen.

Lungs

Bleomycin can cause pulmonary fibrosis and severe respiratory distress. Therefore, chest X-rays and respiratory function tests are essential before treatment. Anaesthesia after bleomycin also carries an increased risk, and anaesthetists need to be aware that the drug has been given in the past.

Kidneys

Nephrotoxicity is a serious complication of cisplatin and resulted in fatalities until forced diuresis was found to reduce renal damage. The toxicity is dose related. To avoid serious renal damage, serum creatinine should be measured before every course. If it increases by more than 25% over the pretreatment value, a creatinine or ethylenediaminetetra-acetic acid clearance should be performed. If the clearance is less than 50 ml/min, the dose should be reduced by 50%. If the clearance is less than 40 ml/min, cisplatin should be discontinued.

Carboplatin has largely replaced cisplatin in the treatment of ovarian cancer as it is less nephrotoxic.

Nervous system

Cisplatin causes a dose-dependent peripheral neuropathy and high-tone deafness. The taxanes, paclitaxel in particular, are associated with peripheral neuropathy which can lead to loss of sensation and muscle weakness. Autonomic neuropathy is also a recognized side-effect of the taxanes. Vincristine can also result in peripheral and autonomic neuropathy. Treatment with ifosfamide can result in encephalopathy, especially in patients with a low serum albumin concentration.

Skin toxicity

Extravasation of some intravenously administered chemotherapeutic agents (e.g. vincristine and doxorubicin) can give rise to phlebitis or thrombosis which can be avoided by giving bolus injections into a free-running infusion. If such drugs leak out into the subcutaneous tissues, they can result in marked morbidity, including large painful ulcers and loss of function. 5-FU, capecitabine and liposomal doxorubicin are associated with PPE, which is usually self-limiting and resolves on cessation of treatment. The taxanes are associated with nail toxicity manifesting as hyperpigmentation, cracking and loss of nails.

Allergic reactions

This can be encountered with any chemotherapeutic agent, usually in the context of rechallenging patients with the same agent, but is also infrequently seen with the first cycle of treatment. Reactions can vary from mild symptoms to anaphylactic reactions requiring inpatient treatment including cardiopulmonary resuscitation.