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

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