CANCER

What is cancer?

Cancer is a disorder in which there is unregulated multiplication of cells in the body. The resulting cell mass, called a tumour, may eventually develop its own blood system (Figure 1) and begin to invade neighbouring organs. Some cancers, known as 'malignant', shed cells into the blood or lymph and these cells become trapped in small blood vessels in organs such as the liver, lung or brain, where they form secondary tumours called metastases. Metastatic disease cannot be cured. In late disease, tumours release substances that depress appetite and cause weight loss and often lead to death from overwhelming infection, such as pneumonia. This section considers research on medical treatments for solid tumours (see Leukaemia for research on blood cancers).

Tumours can develop in any organ. Depending on where they arise, they pose very different medical and management problems. Some can be treated medically, but many are hard to cure except through surgical or radiological treatment. However, advances in medical research have made many more treatable, and today many of those who have cancer live longer than previously, and with a better quality of life.

Who does cancer affect and what does it cost?

Cancer can affect anyone, and there can be few families that do not have a relative or friend who has some form of cancer. It affects one in three people at some time in their lives, though some tumours are much less common than others. In the UK, the commonest form in women is breast cancer, followed by colorectal (bowel), lung, ovarian and uterine cancer. In men, prostate cancer is the most common, followed by lung, colorectal and bladder cancer.

The NHS is estimated to have spent £3.4 billion treating cancer in 2003-04. To this figure must be added the costs for community health services, non-professional (family) carers and lost productivity.

Present treatments and shortcomings

It is not possible to detail here all the available treatments for cancer and their side effects, many of which are well known. Radiotherapy, surgery and chemotherapy are all used for treatment, depending on the tumour type. There are several classes of chemotherapy agents and it is common for cancer specialists to use combinations of several medicines, to maximise their effectiveness. Some can make the recipient feel very unwell, causing nausea and loss of hair, and depress the immune system, leaving the patient vulnerable to infection. Other side-effects include loss of fertility, as well as liver or cardiac damage. Supportive medications, such as anti-emetics, may be given to minimise adverse effects. Medicines used for hormone-dependent tumours (e.g. breast and prostate cancer) are generally better tolerated than the older alkylating agents.

Radiotherapy may be helpful in reducing the size of a tumour before surgical removal or to eliminate any cells remaining after surgery. Chemotherapy used for this purpose is known as adjuvant therapy. The disadvantages of radiotherapy mainly arise from the unavoidable irradiation of surrounding healthy tissue or organs - the intestines and kidneys are particularly sensitive. The shortcomings of chemotherapeutics, apart from their toxicity, relate mainly to lack of efficacy. Many tumours are initially very responsive to chemotherapy, but the impact on survival still remains small in many cases and complete cures are difficult to achieve. Hence there is a great need for more effective and less toxic forms of medication for most solid tumours.

What's in the development pipeline?

The development of new anti-cancer medications is made especially difficult by the fact that cancerous cells differ very little from the non-cancerous cells from which they arise. Designing medicines that act selectively on tumour cells and not, or as little as possible, on healthy cells depends on developing a deep knowledge of the causes of malignant transformation, and of the biological changes that distinguish a cancerous cell from a normal one. Knowledge of the molecular, genetic and biological characteristics of tumour cells has improved greatly in recent decades and newer anti-cancer medicines are generally much more specific in the way they work than older cytotoxic (cell-killing) medicines.

Many clinical development projects are underway to develop new treatments for cancers, and it is not possible to do more than summarise a few of the new projects that concern the major types of cancers. Table 2 gives an overview of where companies have investigations in progress.

BREAST CANCER is often treatable with surgery, followed by radiotherapy or chemotherapy. For the majority whose breast tumours are dependent on steroids for growth, steroid receptor blockers such as tamoxifen can prevent recurrence and the development of metastases. Other compounds of this type include toremifene (Fareston, Orion) and, for advanced breast cancer, fulvestrant (Faslodex, AstraZeneca) and the aromatase inhibitors anastrozole (Arimidex, AstraZeneca), exemestane (Aromasin, Pfizer) and letrozole (Femara, Novartis). In advanced metastatic breast cancer where cytotoxic therapy has failed, the microtubule inhibitors paclitaxel (Taxol, BMS), docetaxel (Taxotere, sanofi-aventis) or vinorelbine (Navelbine, Pierre Fabre) may be considered. The monoclonal antibody trastuzumab (Herceptin, Roche) has also been shown to improve survival in advanced breast cancer where the tumour is herceptin receptor (HER2)-positive.

New compounds which work in a wide range of ways are in clinical development. Three new microtubule-disrupting agents are in Phase 3 trial: Eisai's E-7389, sanofi-aventis's XRP 9881 (larotaxel), and Bristol-Myers Squibb's ixabepilone, an agent of a new type that binds to microtubules in a different way from taxanes. Schering also has a compound of this type (ZK-EPO) in Phase 2 trial, Bristol-Myers Squibb also has a new taxane (BMS- 184476) at Phase 2, and sanofi-aventis's new taxoid (XRP 6258) has reached this stage as well.

New monoclonal antibodies are also in development for treating breast cancer:

• Bevacizumab (Avastin, Roche), which binds to vascular endothelial growth factor (VEGF) and prevents it from stimulating the growth of new blood vessels into tumours, is authorised for use in colorectal cancer and is now in Phase 3 trial in metastatic breast cancer
• Cetuximab (Erbitux, Merck Pharmaceuticals), also available for use in colorectal cancer, is now in Phase 2 trial for breast cancer treatment. It binds to epidermal growth factor (EGF) receptors on tumour cells, inhibiting cell growth and repair, and is given together with chemotherapy
• Adecatumumab (MT201), which binds to a tumour cell surface protein known as epithelial cell adhesion molecule (Ep-CAM), enabling antibodies and the complement system in blood to kill the tumour cells selectively, is being developed in Phase 2 studies by Serono
• Antisoma's AS1402, which binds to the MUC-1 cell membrane protein of tumours of epithelial cell origin, helping the body to kill them selectively, has progressed to Phase 2 trial in metastatic breast cancer
• Amgen's denosumab, which binds to a key protein (RANK ligand) of bone cells, has been shown in Phase 2 trials to suppress the bone turnover (leading to pain and fractures) associated with metastases in patients with advanced breast cancer and is now in Phase 3 trial
• Imclone Systems has IMC-18F1, binding to the type 1 receptor for VEGF, in Phase 1 trial.

Tyrosine kinase inhibitors make up another class of new medicines for treating breast cancer. Lapatinib (Tykerb, GlaxoSmithKline) inhibits the tyrosine kinase associated with cell proliferation, tissue invasion and metastasis in various cancers. In a Phase 3 trial in advanced or metastatic breast cancer, lapatinib, given together with capecitabine, significantly increased the time to tumour progression. Lapatinib is being studied further for its potential in treating metastases that have spread to the brain.

Other late-stage projects involve new oral therapies or developments of agents already authorised for use in other cancers. In Phase 3 trial are the aromatase inhibitor exemestane (Aromasin, Pfizer) for prevention rather than treatment, capecitabine (Xeloda, Roche) for use in combination with other agents, and the compound temsirolimus (Wyeth), which arrests cell growth and is in development for advanced breast cancer. Pfizer has sunitinib malate, which inhibits the growth of a new blood supply into tumours, in Phase 3 study and a similar compound (SU-14813) at Phase 2. Other compounds at Phase 2 include ispinesib (Cytokinetics) that stops cells proliferating and lonafarnib (Sarasar, Schering-Plough), another cell growth inhibitor.

COLORECTAL CANCER (CRC) is a major cancer type in which chemotherapy may have only moderate success, partly because the disease is often not detected until an advanced stage. Chemotherapy is often used after surgery (adjuvant chemotherapy) or to shrink the tumour in advanced disease. The medicines most often used for this purpose are 5-fluorouracil (5-FU), which is often given together with folinic acid (Isovorin, Wyeth), irinotecan (Campto, Pfizer), and oxaliplatin (Eloxatin, sanofi-aventis). The combination of 5-FU, folinic acid and oxaliplatin is often known as the FOLFOX regimen. Capecitabine (Xeloda, Roche) and tegafur-uracil (Uftoral, Merck Pharmaceuticals) are compounds that are broken down to 5-FU at the tumour site and are taken orally, whereas 5-FU itself is given by injection. More recently, two monoclonal antibodies have been made available for use in metastatic colorectal cancer (CRC). These are bevacizumab (Avastin, Roche) and cetuximab (Erbitux, Merck Pharmaceuticals).

As in breast cancer, new monoclonal antibodies are among the agents being developed as new therapies for colorectal cancer. Panitumumab (Amgen) has been shown to reduce the rate of tumour progression in people with metastatic CRC who had failed to respond to chemotherapy. (Panitumumab is also in clinical trials against lung and head and neck cancer.) Matuzumab (Merck Pharmaceuticals) is a monoclonal antibody against Epidermal Growth Factor Receptor (EGFR - a receptor on cells that responds to a factor that promotes the growth and division of cells) that is currently in Phase 2 trial in CRC. Mapatuzumab (Human Genome Sciences) is a monoclonal antibody that acts by making tumour cells self-destruct through a natural process known as programmed cell death (called apoptosis). This antibody is also in Phase 2 trials. In addition, Roche is conducting a Phase 3 study of bevacizumab (Avastin) to see whether, in combination with the FOLFOX regimen, or in combination with oxaliplatin + capecitabine, it can reduce the risk of the cancer recurring in people with no evidence of disease after curative surgery for CRC. Merck Pharmaceuticals is also continuing to explore cetuximab (Erbitux) combinations with irinotecan and oxaliplatin in additional Phase 3 trials at earlier stages of CRC.

Several small molecule compounds have reached Phase 2 testing, including pemetrexed from Eli Lilly, Cytokinetics’ ispinesib, and sunitinib malate (Sutent, Pfizer).

Oxford Biomedica has reported promising Phase 2 results in trials in metastatic CRC with a therapeutic vaccine (TroVax) that introduces a gene into tumour cells to stimulate an immune response. Survival results were sufficiently encouraging for this vaccine to be taken into Phase 3 study in early stage CRC.

Survival rates in CRC have been improving steadily over the last 30 years and the average 5-year survival rate now exceeds 50 per cent. Many factors have contributed to this, but it is encouraging to see that chemotherapy results have also improved over this period. With the planned introduction of a national screening programme for CRC, and the identification of new tests for detecting the disease, more cases may be detected in the early stages of disease, where the outcome of treatment is better. If this can be achieved, then the prospect is for continuing improvement in coming years.