Introduction

Systemic therapies form the basis for medical oncology and a significant amount of clinical oncology in the UK. The description is broad and can be thought to include any treatment which is given to a patient which will be absorbed systemically and could potentially affect the whole body. Traditionally this would be thought to be chemotherapy but the definition also includes hormonal treatments, chemical adjuncts, immunotherapy, biological agents and systemic radiotherapy treatments. Each will be discussed and examples given with reference to the appropriate chapters for more detail.

This chapter gives an overview of the practical aspects of various systemic therapies (Box 4.1). A detailed pharmacological discussion is beyond the scope of this book but further reading is suggested for those interested.

Aim of systemic treatment

Before recommending or prescribing a systemic treatment the aim of the treatment has to be understood (Box 4.2). This, in addition to a knowledge of the specific disease and treatments that are effective for that tumour, will dictate the type of treatment offered and its likely intensity (Box 4.3). Treatment intensity should be greatest in those conditions where the intention is cure, and there is some evidence in certain tumours (e.g. bone tumours) that increased toxicity during chemotherapy is related to improved survival. When the treatment is not curative significant toxicity is unacceptable.

In acute leukaemias the curative chemotherapy is given in various phases (Box 4.4).

Chemotherapy

Chemotherapy involves the treatment with cytotoxic chemicals to kill cancer cells. Its benefit depends upon the high proliferation rate of cancer cells compared with the non cancer cells in the body. The discovery of nitrogen mustard and its effects on proliferating cells was discovered in both World Wars, but only put into practice to treat leukaemias and lymphomas in the 1940s (Figure 4.1). Later that decade aminopterin was shown to induce remissions in leukaemia, although the majority of patients relapsed and died. In the following 10 years different classes of chemotherapeutic agents were discovered. Most of these were directed against DNA synthesis or cell division. In the 1970s cytotoxic agents were seen to impact significantly on the cure of specific cancers such as testicular cancer and leukaemia (Box 4.5). This improvement in survival was due not only to the development of new drugs but also to the understanding of how to combine them.

Figure 4.1 Milestones in the development of systemic therapy for cancer.

Classes of chemotherapy drugs

Chemotherapy agents are divided into different categories according to their mechanism of action. The rationale behind chemotherapy is to inhibit or kill rapidly dividing cancer cells. This may be due to the drug acting at a particular point in the cell cycle (cell cycle-specific) or is independent of the cell cycle (cell cycle-non specific) (Figure 4.2). Boxes 4.6 and 4.7 give examples of different classes of drugs in each of these categories with some specific examples.

Figure 4.2 Cell cycle showing phases of cell replication and division. Cancer cells progress rapidly through this but may be inhibited at various points.

Box 4.6
Cell cycle specific chemotherapy drugs

Antimetabolites	S phase	e.g. methotraxate, capecitabine
Vinca alkaloids	M phase	e.g. vincristine, vinorelbine
Taxanes	M phase	e.g. paclitaxel, docetaxel
Epipodophyllotoxins	G2, S, premitotic, topo II	e.g. etoposide
Camptothecans	S phase, topo I	e.g. irinotecan, topotecan

Box 4.7
Cell cycle non-specific chemotherapy drugs

Antitumour antibiotics	e.g. doxorubicin, mitomycin-C
Alkylating agents	e.g. ifosfamide, chlorambucil
Nitrosoureas	e.g. lomustine, carmustine

How does chemotherapy work?

Tumour cells are detectable by conventional means at 10⁹ cells (equivalent to 1 g tumour or 1 cm tumour) and continue to grow without treatment. Patients usually die if they remain untreated or after unsuccessful treatment when the tumour load reaches 10¹² cells. When a chemotherapy regime is given to a sensitive tumour it causes cell death in a proportion of the cancer cells (log kill). In a chemo-sensitive tumour, each course of chemotherapy (see Box 4.9) results in a proportional cell kill and with a few courses of chemotherapy, tumour may not be detectable by conventional means (called complete response to treatment). At this point there is a possibility of <10⁹ cells remaining and stopping treatment at this point may lead to an early progression/relapse of disease. Hence patients with chemo-sensitive tumours receive additional courses of chemotherapy to bring down the number of tumour cells to an absolute minimum. However this does not necessarily result in complete removal of tumour cells at the end of chemotherapy and it is believed that the normal body immunosurveillance will help to achieve a cure in some instances. In some patients, cancer can grow back at any point of time (relapse) during the conventionally undetectable phase (see Box 4.8). In some other patients, the tumours do not respond to chemotherapy (resistance to treatment) which requires change of treatment (Figure 4.3).

Box 4.9
Cycles of chemotherapy

What is a cycle?

A cycle is a complete treatment from the first day of one cycle to the first day of the second cycle. For many regimens this means a 3 or 4 week period of time (depending on the dose determining toxicity and its recovery period). Over that time drugs may all be given on day 1 only or can be given at several time points in those few weeks.

How many cycles of chemotherapy?

For curative treatment, further cycles of chemotherapy are needed after a conventional clinical response, to tackle the clinically undetectable tumour burden (Figure 4.3). Hence the amount of chemotherapy may vary from a few cycles to months to years depending on the specific cancer (e.g. acute lymphatic leukaemia needs more than a year of chemotherapy, whereas in choriocarcinoma two more courses of chemotherapy is given after a complete tumour marker response).

For many adjuvant treatments, traditionally 6 cycles of chemotherapy are given. (e.g. breast cancer usually 6–8 courses of chemotherapy depending on the regime).

In palliative treatments it is important to assess response (usually after 2–3 courses of chemotherapy) before continuing with treatment but if responding patients may continue for up to 6 (to 8) cycles depending on toxicity and the drugs involved.

The concept of a cycle does not fit with certain therapies such as hormonal treatments or with tyrosine kinase inhibitors as these drugs are continued for a finite number of years or until progression.

Box 4.8
Why not give treatment more often to prevent tumour regrowth?

Unfortunately giving treatment at an increased frequency (or intensity) also increases the toxicity of the treatment. Although some regimens have been able to achieve increased dose frequency with additional drugs to support the patient (e.g. use of granulocyte-colony stimulating factor [G-CSF] to avoid life-threatening neutropenic sepsis).

Figure 4.4 shows response of the bone marrow to chemotherapy after chemotherapy given on day 1. Neutrophils fall to their minimum between days 10 and 14 in a standard 21-day cycle. If G-CSF is given the neutrophils may not drop to such a low number.

Figure 4.4 Neutrophil response during a cycle of chemotherapy.

Figure 4.3 Cancer growth and response to treatment.

Rationale for combining chemotherapy agents

In clinical practice cancer cells tend to develop resistance to a single drug by further gene mutations, or development of cellular pumps which reduce the dose of drug received by the tumour cells. Consequently the tumour will have a period of sensitivity followed by a rebound tumour regrowth. This may be partly due to the fact that not all tumour cells are passing through the same point of the cell cycle at the same time. Combining drugs allows the oncologist to direct agents with different activities or against different parts of the cell cycle simultaneously. The idea is that this increases cell kill at the time of each treatment but also reduces the development of drug resistance.

Planning a combination chemotherapy regimen requires some knowledge of the mechanisms of action of the individual drugs, their dosing for particular cancers and their toxicities (see Box 4.10).

Box 4.10
How do you decide which drugs to combine for a given cancer?

• Activity and scheduling: Each drug must have shown activity for that type of cancer when given as a single agent and be given in a similar scheduling and dosing (synergistic activity).

• Mechanism of action: Ideally the drugs should have different, complementary mechanisms of action (a measure to prevent resistance).

• Toxicities: The toxicities of the drugs should also be different to minimize overall toxicity.

e.g. Combination of gemcitabine and carboplatin in lung cancer:

Activities and scheduling

• Carboplatin and gemticabine – each has a single agent response of ≤20% in lung cancer and is given 3-weekly.

Mechanism of action (Figure 4.5)

• Carboplatin (cell cycle non-specific) act by forming DNA adducts which prevents DNA synthesis

• Gemcitabine (cell cycle specific) – pyramidine antimetabolite

Toxicity

• Carboplatin: dose limiting toxicity is thrombocypenia

• Gemcitabine: dose limiting toxicity is neutropenia

Combination of carboplatin and gemcitabine results in 30–50% response rate and the dose limiting toxicity is thrombocytopenia.

Figure 4.5 Rationale for the combination of gemcitabine and carboplatin.

Actions of specific drug classes (Figure 4.6)

Cell cycle phase specific drugs act on cells within a particular phase of the cell cycle.

Figure 4.6 Sites of action of various chemotherapeutic agents.

Antimetabolites

These drugs are developed to mimic naturally produced metabolites, purines, pyrimidines or folates essential to the synthesis of nucleic acids and DNA (S phase) preventing the correct incorporation of purines or pyrimidines in the DNA structure. They therefore prevent DNA replication and lead to cell death. They are most effective against tumours with a high growth fraction and similarly have predominant toxicities on normal tissues with high cell turn over (e.g. mucosal epithelium and gastrointestinal tract). Examples are methotrexate, cytosine arabinoside, capecitabine, gemcitabine and 5-fluorouracil (5-FU).

Vinca alkaloids and taxanes

Either derived from plant alkaloids or synthetic derivatives of them, they interfere with mitotic spindle assembly in M phase causing metaphase arrest. Vinca alkaloids are extracts of the periwinkle plant. They bind to microtubular proteins which are essential to the formation of the mitotic spindle of dividing cells. Taxanes cause mitotic arrest by forming abnormal spindle fibres. One of the common toxicities of these agents is peripheral neutropathy. Examples are vincristine and paclitaxel.

Epipodophyllotoxins

A plant derived compound (from the mandrake plant) which acts at several parts of the cell cycle. They prevent entry into G1/2 and the S phase but also have activity on topoisomerase II. Topoisomerases are the enzymes responsible for maintaining the topology of DNA. Common toxicity is myelosuppression. An example is etoposide (VP-16).

Camptothecans

This group inhibit topoisomerase I, a nuclear enzyme responsible for maintaining nuclear structure, which interferes with both transcription and replication of DNA by preventing DNA supercoiling. They act in S phase. Their name is derived from the tree Camptotheca acuminata. Examples are irinotecan and topotecan.

Cell cycle phase non-specific drugs act at any point in the cell cycle.

Antitumour antibiotics

This group of drugs interfere with DNA-directed RNA synthesis by intercalating between the base pairs of DNA and generating toxic oxygen-free radicals, causing single or double stranded breaks. Most of these drugs are isolated from a number of Streptomyces bacteria. Common toxicities include mucositis and myelosuppression. Examples are epirubicin and bleomycin.

Alkylating agents

These bind to DNA adding alkyl groups to the cancer cells which results in cross-linking and strand breakage of the DNA with destruction of the DNA template. Destruction of the DNA template stops replication and leads to cell lysis. Examples are chlorambucil and platinums such as cisplatin and carboplatin.

Nitrosoureas

Nitrosoureas are lipid soluble alkylating agents which also destroy DNA preventing any further DNA synthesis. Due to their lipid solubility they can cross the blood–brain barrier into the CNS (see Box 4.11) and are used in several CNS protocols. Examples are lomustine and carmustine.

Box 4.11
Sanctuary sites

Systemic treatments by definition are thought to act at all areas of the body via the bloodstream. However there are areas which have been referred to as sanctuary sites as traditionally chemotherapy is not thought to access them via the bloodstream. These are the central nervous system and the testes. The central nervous system is separated by tight junctions from the cerebral vasculature such that most drugs do not cross the blood–brain barrier. For this reason disease in this area often has to be treated directly by the intrathecal route or using radiotherapy. Some fat soluble drugs e.g. nitrosoureas are thought to be able to cross this barrier. It is also possible that in advanced disease where the vasculature is abnormal and friable that many drugs will be able to enter the brain even if not lipid soluble.

The testes are also a sanctuary site such that testicular biopsies may be performed to assess involvement in acute leukaemia and in testicular tumours, the cancerous testicle needs to be removed even after intensive chemotherapy.

Delivery of chemotherapy

Consent

Prior to the prescribing and administration of chemotherapy, a definite histological diagnosis (exceptions include germ cell tumours and choriocarcinoma where elevated tumour markers in the appropriate clinical setting is sufficient) and informed consent is necessary. Informed consent is obtained after detailed discussion of benefits and side effects of the treatment (Box 4.12).

Box 4.12
What do your patients want to know about their systemic treatment?

• The intended benefits (improvement in survival or symptoms)

• Names of the drugs

• Major and frequent side effects

• What to do and who to call with problems and when

• How the drugs will be given (oral, IV bolus, IV infusion)

• How long it will take to give the drugs

• How often will they have treatment and for how many cycles

• When they need to come back to hospital for treatment and for an appointment

Prescribing chemotherapy

Prescribing and reviewing chemotherapy charts is an important role of an oncologist. Many hospitals now have charts which have preprinted chemotherapeutic and supportive drugs on the charts (Figure 4.7) which require only a dose calculation, patient details and test results to be added. Others have electronic systems with that information included. Some of these charts are very simple with all supportive drugs included. In some hospitals however the entire chart has to be written by hand and safety checks are especially important in that case. Before the chart is written, given that chemotherapy is toxic, a number of calculations and checks have to be made. These are summarized in Box 4.13.

Figure 4.7 A sample chemotherapy prescription chart.

Box 4.13
Pre-prescribing chemotherapy checks

• Is the allergy box filled in and does it contain anything which causes concern for the chemotherapy or supportive drugs?

• Is this the correct chart for that treatment?

• Is the performance status appropriate for the type and intent of treatment?

• Are the height and weight accurate and up to date?

• Is the body surface area correct? (Have your own calculator or check on a computer).

• Has the baseline imaging been performed and the mid treatment imaging booked to allow assessment of response?

• Has a GFR been performed (for drugs such as carboplatin, ifosfamide)?

• Has a MUGA been performed (for anthracyclines and herceptin)? Does the next MUGA need to be booked?

• Has the patient previously received a similar drug which limits the dose and (e.g. anthracyclines) has the cumulative dose been recorded?

• Are the appropriate blood results available and are they in the correct range for the drugs being given? Has there been a significant deterioration in a blood result which could be attributable to one of the chemotherapy drugs?

• Does the dose need modifying on the next cycle due to toxicity? (you may only know this after reviewing the patient).

• Does the patient have significant co-morbidities which due to the toxicities of the chemotherapy may require dose reduction?

Chemotherapy is generally calculated based on the surface area of an individual. This is an historic phenomenon based on the extrapolation of doses administered to animals (given as dose per surface area) in preclinical models. However the initial human surface area calculations were based on hemi-body moulds created from wrapping brown paper around a small number of cadavers some of whom were children. In addition many other drugs are given to adults in a flat (or standard) dosing such as paracetamol. Some studies suggest that giving everyone the dose calculated for the average surface area of 1.7 m² was as effective as calculating the specific dose for an individual, but for most drugs the use of surface area calculations continue.

Some drugs are not metabolized in the same way. Carboplatin is the classical example of this type of drug. During the original phase I studies the dose limiting toxicity of carboplatin was thrombocytopenia. However, unlike other drugs, there appeared to be no relationship between the dose administered according to mg/m² and the degree of thrombocytopenia. It was known that carboplatin is excreted almost entirely by the kidney and Calvert and colleagues then realized that the drug’s toxicity was related to the glomerular filtration rate (GFR). This gave rise to the Calvert formula which is used to prescribe carboplatin (Box 4.14). It requires knowledge of the GFR, ideally calculated by nuclear medicine scan.

Box 4.14
Prescribing carboplatin: AUC and the Calvert formula

The required dose is calculated by the following formula:

where AUC is the area under the curve. It refers to increasing dosages which have an increasing effect until the effect plateaus and any increase in dose results only in increased toxicity. In general AUC values are in the range 5–7 in adults but up to 9 in children.

Some recent drugs, especially the small molecules such as the tyrosine kinase inhibitor, imatinib, are given as a standard dose which is the same for all patients. For imatinib the standard dose is 400 mg per day.

Routes of chemotherapy administration

Systemic treatments can be given by a number of routes. Chemotherapy is usually given intravenously (IV) but some drugs can be given orally and some as both IV and orally. For some intravenous drugs there are several ways to administer it. For example, 5-fluorouracil (5-FU) can be given as a daily bolus for 5 days every 3 weeks (Mayo regimen) or as a 48 hour continuous infusion every 2 weeks (modified de Gramont) (p. 165). This drug needs prolonged or repeated exposure as it acts in S phase but these two methods produce different toxicity profiles with the Mayo regimen producing more significant stomatitis and myelosuppression whereas modified de Gramont produces significant palmo-planter erythema. Although many clinicians believe the two methods to be equally effective, randomized trials have not been performed for all cancer types so that some oncologists will only prescribe the method used in the original trials.

Some drugs can also given either intrathecally (Box 4.15 and Figure 4.8) or via the intraperitoneal route (Box 4.16 and Figure 4.9).

Box 4.15
Intrathecal (IT) chemotherapy. WARNING – this route can be hazardous!

Drugs delivered directly into the CSF via the intrathecal route can be used to prevent or treat meningeal disease. Prophylactic treatment is given commonly in ALL and in high grade lymphomas likely to involve CNS.

It can be given via lumbar puncture or a central reservoir (Ommaya reservoir) placed by a neurosurgeon in the ventricles.

Extreme care must be taken to prevent administration of a drug not licensed for intrathecal administration as this can be, and has been, fatal. Strict policies should therefore be adhered to and IT chemotherapy should not be given on the same day as intravenous chemotherapy.

Drugs safe to give intrathecally:

• Methotrexate

• Cytosine arabinoside

• Thiotepa

Figure 4.8 Ommaya reservoir.

Box 4.16
Intraperitoneal chemotherapy

Surgical placement of a catheter directly into the peritoneum to administer chemotherapy via the peritoneal fluid has been used in several malignancies, notably ovarian cancer and mesothelioma. It allows for large concentrations of drugs to be placed in close contact with peritoneal metastases. Much lower concentrations will also enter the bloodstream. It has shown to be effective in ovarian cancer but is associated with increased toxicity (both systemic and local) and abdominal pain.

Figure 4.9 Diagram to show intraperitoneal port and catheter.

More recent drugs again have a range of administration routes from intravenous, e.g. monoclonal antibodies, to subcutaneous, e.g. vaccines, to oral, e.g. tyrosine kinase inhibitors. Patients often prefer an oral route of administration or a short intravenous infusion to minimize their time in the hospital but they need to understand that toxicities from oral drugs (e.g. capecitabine) can be as great as those from intravenous drugs and that oral chemotherapy is not a ‘gentle option’.

Toxicity recording

In order to minimize side effects and to evaluate how changes in treatment have affected these side effects or the patient’s symptoms due to the cancer, accurate recordings of drug toxicity (Box 4.17) must be made. Ideally this should be recorded on a flow chart so that progress can be monitored. It also allows the clinician to record dates of future scans which can be reviewed prior to further treatment. Toxicity should be scored according to an internationally accepted system such as the National Cancer Institute Common Toxicity Criteria and Adverse Events version 3 (NCI CTCAE v3) which can be found at: http://www.fda.gov/cder/cancer/toxicityframe.htm.

Box 4.17
Chemotherapy toxicities

Acute toxicities are those which occur within a treatment cycle in contrast to late effects which can occur many years later and are covered in (p. 58). Each drug will have its own specific acute toxicities but the following are common to many classes of drugs:

• Nausea and vomiting: tend to occur within hours or days of the chemotherapy but should be controlled with appropriate anti-emetics.

• Diarrhoea and constipation: can occur due to chemotherapy, e.g. diarrhoea after ifosfamide or due to anti-emetics, e.g. constipation with 5HT3 antagonists such as ondansetron.

• Mucositis: inflammation of the gastrointestinal tract is common with some antimetabolites and anthracyclines. It tends to peak the week after day 1 of treatment.

• Myelosuppression causing anaemia or neutropaenia is common to many classes of chemotherapy. It usually occurs 7–10 days after treatment but in some drugs such as nitrosoureas it occurs later (3–4 weeks) which accounts for the longer treatment cycle.

• Infection: is a common source of morbidity for chemotherapy patients but the risks should be minimized by avoiding treating with neutrophil counts which are too low. Dental assessment should also be made before treatment to reduce the risk of oral sepsis and invasive dental procedures should be avoided during chemotherapy. Infection risk is greatest 7–15 days after treatment but can occur at any time which is why fever in a patient on chemotherapy should always be taken seriously.

• Fatigue: a common side effect of many treatments which tends to become more significant over the course of a treatment. It can occur at any time in the cycle but tends to be worse within the first few days of treatment. Patients given steroids as part of their antiemetics can experience increased fatigue the day after the steroids stop.

• Hair loss: is common with many (but not all) drugs. It starts within two weeks of the first treatment so wig referrals should be made before treatment to best match hair colour and style. Alternative is use of scalp cooling which only works for selected chemotherapy regimes.

• Taste change: is very common and can add to problems with appetite.

When consenting patients, do not forget the late effects (p. 58) as these can be significant. Figure 4.10 gives an example of a toxicity chart.

Figure 4.10 Example of a toxicity chart.

Dose adjustment

Although supportive drugs to minimize side effects are usually given prophylactically significant toxicity can occur. Initially the aim would be to change or add to the supportive drugs to reduce toxicity, e.g. different or additional anti-emetics for nausea control, or use of G-CSF to prevent neutropenic sepsis. If the toxicity has been significant, such that it has not resolved with adjustment of supportive drugs, a dose reduction should be made. For example recurrent neutropaenic sepsis which occurs even after prophylactic G-CSF requires dose reduction. For clinical trials there will also be specific instances when this should occur and the protocol must be followed in this case. In general, a reduction of 20–25% is made but this depends on the drugs being given, whether all or only one of them is likely to be the cause. It also depends on the intended outcome of the treatment and the likely effect that dose reduction will have on the outcome. For example it is known that the survival benefit from adjuvant chemotherapy can be reduced by a reduction in dose intensity. However if the patient has suffered a life-threatening infection associated with the treatment, the risk of death as a complication of continuing the same dose of treatment may be greater than that of recurrence of the cancer.

Complementary therapy interactions

Many patients, especially with advanced cancer, take additional treatments or complementary therapies. Each hospital has a different policy about whether patients are allowed to take complementary medicines alongside their chemotherapy. However it is important to take a full history of these and ensure that certain complementary treatments which can interact with chemotherapy or other drugs. A specific example is St John’s wort which many patients take for mild depression. It is metabolized by the cytochrome p450 isoenzymes, especially CYP 3A4 and can significantly interfere with the doses of several systemic treatments including etoposide and the tyrosine kinase inhibitor, imatinib.

Other classes of systemic therapy

Although chemotherapy has been the mainstay of systemic therapy, the development of alternative methods of treatment has occurred in the last 20 years, many of which have made significant improvements in survival. Some of these have been developed against a particular target specific to the cancer, whereas others have broader actions.

Bisphosphonates

Bisphosphonates represent a good example of an adjunct in the treatment of cancer. These agents were originally developed to treat osteoporosis but have been shown to be active in stabilizing bony metastases in a number of malignancies and have also been shown to reduce visceral metastases in breast cancer. The exact mechanism for this latter activity is unknown. They can be given intravenously or orally. Examples include pamidronate and zoledronic acid.

Antibodies

Antibodies are immunoglobulins produced by plasma B cells in response to antigens. Several tumour cells express specific antigens which are not produced by normal cells and these have been the target for the development of monoclonal antibodies to these specific antigens. To date the most successful drugs in this class are rituximab and transtuzumab. Rituximab is directed against CD20 found on B cells and the addition of rituximab to standard chemotherapy for B cell lymphomas has significantly improved survival. Transtuzumab has been developed to target the HER-2 receptor which is found in 25% of breast cancers. Initially used in metastatic disease but then in the adjuvant setting for women with HER-2 receptor positive breast cancer, this has also seen a significant improvement in survival. Other antibodies have been developed with a wider range of action such as bevacizumab which targets the vascular endothelial growth factor receptor. This has shown some improvement in survival in several cancers, which are covered in appropriate chapters. The toxicities of these drugs are different to cytotoxics with allergic reaction being one of the most significant.

Immune therapy

In addition to antibodies, which may be considered an immune treatment, there are also a group of drugs which act by modifying the immune response of the host (patient) in general, rather than targeting a specific molecule or receptor. Examples in this group include interferons and interleukins. High dose interferon has been used in melanoma (p. 235) and interleukin-2 has some efficacy in renal cell carcinoma (p. 176). Interferon and interleukin both produce systemic side effects of an immune response which resemble a viral infection, e.g. fever, fatigue, myalgia and headache.

Small molecules

Small molecules are drugs developed with a specific target, usually to a cellular pathway or molecule within that pathway. Examples include tyrosine kinase inhibitors (TKIs) and mTOR inhibitors. TKIs can be specific to a particular tyrosine kinase, e.g. imatinib, or may have activity across a number of kinases, e.g. sunitinib. Figure 4.11 shows an example of a tyrosine kinase signalling pathway using c-KIT. Once the receptor is bound it sets off a cascade leading to further cell proliferation. Some of the cascade steps are common to pathways involved in many cancers such that effective inhibitors to one protein could be useful drugs in a range of cancers.

Figure 4.11 Simplified diagram to show signalling pathway of the tyrosine kinase c-KIT and the cascade that follows once the receptor is bound. Targets are being developed to several proteins along this pathway including raf, MEK, P13K and AKT.

Systemic radiotherapy

In general radiotherapy is directed against a specific site in the body. Generally a radioisotope scan is done to assess the uptake by the specific tumour prior to giving definitive radioablative dose (for example, see p. 282). Doses can be repeated several times but there is a risk of late myelodysplastic syndromes.

Assessment of response to treatment

Systemic treatments are often given to treat metastatic disease or neoadjuvantly prior to surgery. In these cases an assessment needs to be made to ensure that the treatment is effective (Figure 4.12) so that an alternative treatment may be considered and to avoid inappropriate toxicity. Most often this assessment is made radiologically (e.g. by CT or MRI) by Response Evaluation Criteria in Solid Tumours (RECIST) criteria (Boxes 4.18 and 4.19, Table 4.2). An understanding of these terms is necessary in the management of all cancers, even if alternative means of assessment may also be used (e.g. see section on gastrointestinal stromal tumours, p. 261). However for some tumours or in the adjuvant setting RECIST terms may not adequately describe response. In adjuvant treatment where the aim is to cure, the overall survival and sometimes the progression free survival are the key indicators of success. For clinical trials this may take many years to assess so sometimes other indicators are used. These include pathological response for tumours such as bone tumours or breast cancer in whom the patients have been given neoadjuvant treatment. The degree of cell necrosis or pathological response reflects prognosis in these groups. For gastrointestinal stromal tumours which have been treated with a targeted treatment, imatinib, the response assessed by RECIST criteria may not reflect the true response. For these tumours, and other sarcomas there may not be an obvious reduction in the size of the tumour, and yet the patient feels better. Radiologically this is usually accompanied by a change in the density of the tumour becoming more cystic and less dense. For gastrointestinal stromal tumours new criteria (Choi criteria) have been applied to these tumours to take these changes into account (p. 263).

Figure 4.12 CT scan showing a large recurrent uterine sarcoma prior to chemotherapy (A) and after 6 cycles of treatment demonstrating a complete response (B). The patient went on to have radical radiotherapy and remains free of disease 6 years later.

Table 4.2 RECIST response criteria

In addition, particularly in the context of clinical trials the term Clinical Benefit is used. This takes into account not only the obvious CR and PR RECIST responses but also those tumours which may be stable by RECIST, but treatment has also been associated with an improvement in symptoms. For palliative treatments this is clearly important.

The future of systemic treatments (Box 4.20)

This chapter has highlighted the growth and growing diversity of systemic treatments for cancer from early fortuitous discoveries of chemotherapeutic agents to the idea of targeted treatments. The future of systemic therapies lies in the development of more specific and less toxic drugs, and the methods to best assess them. It also remains to be discovered how is the best way to combine drugs, e.g. cytotoxic with a small molecule or a number of targeted small molecules without chemotherapy. This, along with the changing arena of clinical trials, represents one of the great challenges for the future oncologist.