Royal North Shore Hospital
St Leonards, NSW
It is almost 30 years since US President Nixon declared “War on Cancer”. Cynics would say it was a ploy to distract attention from the Vietnam War, then grinding to a close. A National Cancer Act led to the identification of funding for Comprehensive Cancer Centres, and a massive increase in resources for basic cell biology research with the hope of uncovering the magic bullet that would be “a” cure for cancer that wouldn’t cause collateral damage for normal cells. Until recently, the billions were pouring into the black-hole and there was little change in the types of therapy the average cancer patient received, although outcomes improved inch by inch with better application of conventional therapy in a multidisciplinary setting.
For the past five years however there has been a new sense of excitement at international research meetings, followed by ripples in the clinical world, and the first agents based on our new understandings of molecular pathways controlling cancer formation have at last emerged into the clinic. Understanding the genes controlling cellular growth, which are overactive in cancer cells, has allowed development of targeted molecules to interrupt these pathways. Some agents target cell surface receptors (Trastuzumab, Cetuximab), others the signalling pathways connecting receptor to nucleus (Imatinib, Iressa), and others nuclear structures directly (Oxaliplatin). In order to improve the therapeutic index, drugs which are preferentially activated by enzymes within malignant cells deliver a high dose to cancer cells and spare normal tissues (Capecitabine). Agents which target the normal cells that are recruited into assisting in metastasis formation (bisphosphonates) aim to render the environment hostile to cancer cell growth. Each of these agents is described in more detail in the articles in this series, and all are based on fundamental insights into cancer cell biology that have emerged within the past 30 years. Each targets better the malignant cell, and has fewer side effects than conventional chemotherapy. Antiangiogenic agents are also promising, but as yet have not entered clinical practice and are not reviewed here.
Yet it turns out that curing cancer does not require a single bullet – more a steady stream of machine-gun fire. Each of these agents is given continuously – this has become possible as their toxicity is more manageable. We anticipate that they will work even better when combined with one another, or with conventional chemotherapy and radiotherapy. Perhaps we will be maintaining control or remission, rather than “curing”? Cancer treatment may become like treatment of blood pressure or diabetes or asthma – rarely are these cured, and combination oral therapy is the norm. Nixon presumably did not envisage we would be “sleeping with the enemy”.
What is clear is that these agents challenge our paradigms – oral administration allows patients coveted freedoms, yet the potential for toxicity requires that supervision be maintained, perhaps in different ways. Prospective pharmacoeconomic evaluation will be critical as overall costs of these agents are high – they are harder to produce and have been tooled up out of expensive basic research, the markets are small for individual agents, chronic use and combinations will add to the overall outlay. For these reasons the developmental emphasis should shift to the incorporation of these agents into definitive treatment and adjuvant treatment strategies. Meanwhile improved survival and quality of life for patients with advanced cancer will be the immediate outcome of their availability in Australia, assuming we can find a mechanism to pay for the peace.