You should spend about 20 minutes on Questions 1–13, which are based on Reading Passage 1 below.
A Chemical Against Leukaemia: Sidney Farber and the Birth of Chemotherapy
In the first half of the twentieth century, a diagnosis of leukaemia in a child was almost always fatal. The disease caused the bone marrow to produce vast numbers of abnormal white cells that crowded out normal blood cells. Children became anaemic, suffered infections and bled easily. Doctors could offer little more than blood transfusions and comfort, and most young patients died within months. The idea that a chemical might attack cancer cells was regarded with deep suspicion; surgery and radiation were the only accepted treatments, and both were of limited use against a cancer that had already spread through the bloodstream.
The term 'chemotherapy' was not new. It had been coined by the German physician Paul Ehrlich in the early twentieth century to describe the use of chemicals to kill disease-causing organisms without harming the patient. Ehrlich's own success, an arsenic compound called Salvarsan used against syphilis, had shown that a synthetic chemical could be a selective weapon. But cancer was different: cancer cells are the body's own cells, altered by mutations, so finding a chemical that would kill them while sparing normal tissue seemed almost impossible. Most researchers concentrated on radiation and surgery.
Sidney Farber was born in Buffalo, New York, in 1903, the son of Jewish immigrants. He graduated from Harvard Medical School in 1927 and trained in pathology, the study of disease through the examination of tissues. By the 1940s he was pathologist-in-chief at Children's Hospital Boston, where he performed autopsies on children who had died of leukaemia. The experience convinced him that the disease had to be attacked with drugs, not merely with the scalpel or the X-ray machine.
Farber's opportunity came from an unexpected direction. Researchers had discovered that folic acid, a vitamin essential for cell division, could cure one kind of anaemia. When it was given to children with leukaemia, however, their disease appeared to accelerate, which suggested that the abnormal cells depended on the vitamin. Farber reasoned that a drug that blocked folic acid might slow the proliferation of leukaemic cells, even if it harmed normal tissues too. He obtained a compound called aminopterin, an antifolate synthesised by chemists at Lederle Laboratories, and began to test it on children whose disease had not responded to other treatments.
The first results, reported in the New England Journal of Medicine in 1948, astonished the medical world. Farber treated sixteen children with acute lymphoblastic leukaemia. Ten of them entered a temporary remission: their bone marrow cleared of leukaemic cells, their blood counts improved, and they returned home for weeks or months. The drug, however, was far from safe. It caused severe toxicity, including mouth ulcers, hair loss, and damage to the liver and kidneys. The remissions were temporary, and the disease returned in every child. Yet the trial had proved something no one had shown before: a chemical could kill cancer cells in the human body and restore a child to health, if only for a short time.
The results were greeted with scepticism by many physicians. Some argued that the remissions were merely temporary and that the drug was too dangerous to use widely. Others doubted that a single chemical could ever cure a disease as complex as cancer. Farber, however, was convinced that the principle was sound. If one drug could produce a remission, combinations might produce longer ones. He began to advocate the systematic testing of chemicals against cancer, a proposal that laid the foundation for modern chemotherapy.
Farber understood that the work required more than laboratory space. In 1947 he founded the Children's Cancer Research Foundation, a small laboratory and clinic in Boston. The following year, the foundation teamed up with the Boston Braves baseball team to create the Jimmy Fund, a charity that raised money from the public. The fund became one of the most successful medical charities in the United States. It allowed Farber to expand his research and to provide 'total care' for children with cancer, treating not only the disease but also the emotional and social needs of the patient and family.
In the 1950s, Farber became a national figure in cancer policy. He argued that the federal government should invest heavily in research, and he helped to establish the Cancer Chemotherapy National Service Centre in 1955, a programme to screen thousands of chemicals for anticancer activity. He also promoted combination chemotherapy, in which several drugs are given together to reduce the chance that cancer cells will become resistant. This approach would later transform the treatment of childhood leukaemia.
Farber died in 1973, two years after President Nixon signed the National Cancer Act, which greatly increased federal funding for cancer research. He had lived long enough to see chemotherapy become an accepted part of cancer treatment, though not long enough to see the cures that he had hoped for. The foundation he created continues today as the Dana-Farber Cancer Institute. Acute lymphoblastic leukaemia in children now has a high cure rate, thanks to the combination therapies that Farber's work made possible.
His legacy, however, is not without complications. Chemotherapy remains toxic, and many cancers still resist it. The remissions that Farber first observed were short-lived, and the drugs he pioneered were crude by modern standards. Yet the principle he established — that cancer can be treated with chemicals — remains the foundation of cancer medicine.
You should spend about 20 minutes on Questions 14–26, which are based on Reading Passage 2 below.
How Cancer Grows and Spreads
Cancer is not a single disease but a collection of disorders that share a common feature: cells divide when they should not. In a healthy body, cell division is tightly controlled by signals that tell a cell when to grow, when to rest and when to die. Cancer begins when mutations in a cell's DNA disrupt these controls. A single mutation is usually not enough; most cancers require a series of genetic changes accumulated over years. As the abnormal cells multiply, they form a mass called a tumour. If the tumour remains confined to its original site, it is described as benign; if it invades nearby tissue, it is malignant.
Two broad categories of gene are central to cancer. Oncogenes are mutated versions of normal genes that promote cell growth; a change that makes them permanently active can drive relentless division. Tumour suppressor genes normally act as brakes, repairing damaged DNA or triggering cell death if repair fails. When both copies of a tumour suppressor gene are inactivated, the brake is lost. The best-known example is TP53, often called the guardian of the genome, which is mutated in a large proportion of human cancers. Inherited mutations in genes such as BRCA1 and BRCA2 raise the risk of breast and ovarian cancer, but most cancer-causing mutations are acquired during a person's lifetime rather than inherited.
Cancer cells also ignore the signals that normally stop division when tissue is damaged or crowded. Normal cells respond to contact with neighbours by ceasing to divide, a phenomenon called contact inhibition. Cancer cells lose this response and continue to multiply, piling up into a disorganised mass. They may also produce their own growth factors, creating a feedback loop that sustains their proliferation. Many modern targeted drugs work by blocking the specific signalling proteins that drive this loop, although resistance often develops as new mutations appear. The pathways involved are often shared by normal cells, which is why these drugs can have serious side effects.
A tumour cannot grow beyond a few millimetres without a blood supply, because it needs oxygen and nutrients and must remove waste. Cancer cells therefore secrete substances that stimulate the formation of new blood vessels, a process called angiogenesis. The best-known of these substances is vascular endothelial growth factor, or VEGF. Normal angiogenesis is essential in wound healing and in the female reproductive cycle; in cancer, the process is hijacked and remains permanently switched on. Drugs that block VEGF or its receptors can slow tumour growth by cutting off the blood supply, but they are not curative on their own and can cause side effects such as high blood pressure.
To spread, cancer cells must first break away from the original tumour. They often undergo a change known as the epithelial-mesenchymal transition, which makes them more mobile and allows them to penetrate the basement membrane that separates the tissue from the surrounding stroma. The basement membrane is a thin layer of proteins that normally holds cells in place; its breakdown is a critical step in invasion. Once inside blood or lymph vessels, the cells become circulating tumour cells. Most die quickly, battered by the immune system and the physical stresses of the bloodstream. A tiny fraction survives, becomes trapped in narrow capillaries, and squeezes through the vessel wall into a new organ. This process is called metastasis, and it is responsible for the majority of cancer deaths.
Even after a cancer cell has reached a new organ, it may not grow immediately. The 'seed and soil' hypothesis, proposed in the late nineteenth century by the English surgeon Stephen Paget, suggests that a tumour cell (the seed) can only colonise tissue (the soil) that provides a suitable environment. Some cells remain dormant for years, kept in check by the immune system or by the absence of growth signals. Later, if conditions change, they may begin to divide and form a secondary tumour. This dormancy helps to explain why cancer can recur many years after apparently successful treatment.
The immune system can recognise and destroy many abnormal cells, but cancer cells evolve ways to evade it. They may reduce the expression of proteins that mark them as dangerous, or secrete substances that suppress immune cells in their vicinity. Some tumours exploit checkpoint proteins, which normally prevent the immune response from becoming excessive, by switching them on to switch off attacking T cells. Drugs called checkpoint inhibitors block these proteins and have produced remarkable, though sometimes temporary, responses in cancers such as melanoma and lung cancer. They do not work for every patient, and they can cause the immune system to attack healthy tissues.
Tumours are not uniform collections of identical cells. As they grow, different cells acquire different mutations, creating a diverse population. This heterogeneity is one reason why cancers become resistant to treatment: a drug may kill most cells, but a few with a particular mutation survive and multiply. Cancer stem cells, a subpopulation with the ability to self-renew and generate new tumour cells, may also contribute to resistance and relapse. Researchers are exploring combination therapies, liquid biopsies that detect tumour DNA in the blood, and treatments that target the tumour's surroundings as well as the cancer cells themselves.
You should spend about 20 minutes on Questions 27–40, which are based on Reading Passage 3 below.
The Price of a Few Extra Months
Should health systems pay for cancer drugs that extend life only briefly?
In many countries, the arrival of a new cancer drug is reported as a breakthrough, even when the evidence shows that it extends life by only a few weeks. The price of such drugs can be tens of thousands of pounds or dollars per patient per year. Health budgets are finite, and every pound spent on one treatment is a pound not spent on another. This creates an uncomfortable question for publicly funded health systems: should they pay for a drug that offers a small chance of a short extension of life, or should they spend the same money on treatments that benefit more people? The question is not abstract. It is faced by committees in Britain, Australia, Canada and many other countries, and it is one of the most emotionally charged issues in medicine.
The most powerful argument for paying is compassion. For a patient with advanced cancer, a few extra months may be precious: time to see a grandchild born, to settle affairs, to live without the fear of imminent death. Clinical trials measure survival in months, but patients and families measure it in experiences. This impulse is sometimes called the rule of rescue: the strong urge to save an identifiable life, whatever the cost. Patients with rare cancers make a related argument. Because their diseases are uncommon, trials are small and the evidence is uncertain, but they should not be abandoned simply because their numbers are few. Pharmaceutical companies add a third argument: high prices fund research and development, and without the prospect of reward, new drugs would not be developed at all.
The central economic objection is opportunity cost. A health system that pays £100,000 for a drug that adds three months of life may have to deny other treatments that offer much greater benefit for the same money. In England, the National Institute for Health and Care Excellence (NICE) decides whether drugs should be available on the National Health Service. It uses quality-adjusted life-years, or QALYs, to compare treatments. A QALY combines length of life with quality of life; a year in perfect health is worth one QALY, while a year with severe disability may be worth less than one. NICE has generally been willing to approve treatments costing up to around £20,000 to £30,000 per QALY, though it has some flexibility for end-of-life care. If a drug costs far more, NICE may reject it, and patients may then campaign for access.
Critics argue that QALY calculations undervalue treatments for people near the end of life. A few months may be worth more to a dying patient than a year of moderate improvement to someone else. NICE's end-of-life criteria allow it to accept higher costs for drugs that extend life by at least three months in patients with less than two years to live. But this raises questions: why should a month of life be worth more to a cancer patient than to a patient with heart failure? Some also argue that QALYs discriminate against disabled people, because a disability reduces quality-of-life scores. Others reply that without some measure of cost-effectiveness, the system would be unsustainable, and that ignoring cost is itself a form of discrimination against patients whose treatments are denied.
Health systems have tried several practical approaches. Price negotiation is one: in Australia, the Pharmaceutical Benefits Advisory Committee negotiates prices with manufacturers before a drug is subsidised. In England, the Cancer Drugs Fund was created in 2011 to give patients access to drugs that NICE had not approved, and it was later reformed to collect data while drugs are used. Risk-sharing agreements require manufacturers to refund the cost if a drug does not work as expected. Managed access allows patients to receive a treatment while more evidence is gathered. Value-based pricing ties the price of a drug to the benefit it delivers. Transparency is also essential: clinical trial results should be published, because hidden data make it impossible to judge value.
In my view, health systems must be prepared to say no. A system that pays any price for any drug, however small the benefit, is not compassionate; it is unjust, because it takes resources from other patients. But the decision must be made transparently, with patients involved, and with a clear explanation of what is being given up. The answer is not to abandon cost-effectiveness but to refine it: to give more weight to treatments for rare cancers and for patients near the end of life, while insisting on fair prices. A few extra months can be precious, but they are not the only thing that matters. A health system must also protect the many patients whose lives can be saved or improved by treatments that are less newsworthy but more effective.
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