Cancer is as old as mankind – older even, since dinosaurs endured it. Where there is life there is the chance that the machinery running the cells will go wrong, leading to uncontrolled growths which the ancients recognised and named.
Greek physician Hippocrates compared the finger-like projections from a tumour to a crab – an odd image, since few tumours actually resemble crabs, but it stuck. The Roman physician Celsus, active in the first century BC, coined the word cancer from the Latin word for crab.
Early treatments for cancer were either fanciful or too awful to contemplate. Apothecaries stocked up on boar’s tooth, fox lungs, tincture of lead, ground white coral and other equally unlikely remedies, while barber-surgeons occasionally undertook mastectomies without anaesthetic in insanitary conditions.
In the 18th century, the Scot John Hunter, one of the founders of modern surgery, declared that if a tumour had not invaded nearby tissue and was moveable, “there is no impropriety in removing it”.
The discovery of general anaesthesia in the middle of the 19th century set off a golden age of surgical innovation. The American surgeon William Halsted pioneered radical cancer operations, attempting to outpace tumour growth by more and more extreme removal of tissue, in the belief – only partly true – that recurrence meant that some of the tumour had been left behind. He proved that surgeons could remove cancers, but whether patients were thereby cured was less clear. Some were, most were not.
The fashion for radical surgery left many patients disfigured, but it also left a legacy. One of Halsted’s students at Johns Hopkins Hospital in Baltimore, Hugh Young, was directed by him to focus on urological cancers. Young protested he knew nothing of urological surgery. “I know you don’t know anything, but we believe you can learn,” replied Halsted haughtily before stalking off. Young learnt well, developing radical prostatectomy, the removal of the prostate gland which cured many men with prostate cancer and continues to do so more than a century later.
Radiation kills healthy cells as well as cancer cells, but cancer cells are easier to kill because they are dividing faster
Surgery remains a mainstay of the treatment of solid cancers, but until it was joined by drugs and radiation – the modern troika that propels cancer care – its impact was limited. Radiation came first, pioneered in 1896 by a medical student, Emil Grubbe, barely a year after Wilhelm Röntgen discovered X-rays. Grubbe and his successors found that X-rays and other forms of radiation could indeed kill tumours. They did not fully understand why, but we now know that the treatment worked by breaking the DNA that is found in every cell and controls the process of cell division. Radiation kills healthy cells as well as cancer cells, but cancer cells are easier to kill because they are dividing faster.
Not for the first or last time, hubris crept in. Siddbartha Mukherjee, a cancer doctor and author of The Emperor of All Maladies, a prize-winning history of cancer, quotes a Chicago physician as saying of radiation therapy in the early-1900s: “I believe this treatment is an absolute cure for all forms of cancer. I do not know what its limitations are.”
Not so fast. Radiation could not deal with tumours that had spread, and it caused collateral damage, in many cases provoking fresh cancers. Grubbe himself died riddled with cancers caused by his experiments, but he must have been a tough character, since he survived to the age of 85. As Mukherjee writes: “Radiation was a powerful invisible knife – but still a knife. And a knife, no matter how deft and penetrating, could only reach so far in the battle against cancer.”
Anti-cancer drugs made their entrance in the 1940s. In a grim paradox, the first was nitrogen mustard, a poison gas used to slaughter soldiers in the trenches of the First World War. Soldiers who survived exposure to it suffered the destruction of their lymphocytes – white blood cells – and needed regular blood transfusions. This selective action against a particular type of cell suggested that nitrogen mustard might be used to treat lymphoma, a tumour of the lymph system. It worked and nitrogen mustard, rechristened mustine, became the first licensed chemotherapy agent.
Other drugs appeared in rapid succession, some triggered by biological insight, others by pure guesswork. One of the most striking of the former was aminopterin. Sidney Farber at Boston Children’s Hospital, aware of work by British haematologist Lucy Wills, who had shown that some forms of anaemia could be cured by Marmite, a condiment rich in folic acid, decided to treat his childhood leukaemia patients with folic acid. Not only did it not work, it made things worse, hastening the children’s deaths.
Undaunted, he decided to try antifolates, drugs that block rather than encourage the growth of white blood cells. To his delight aminopterin, a drug synthesised by chemists at Lederle Laboratories, caused near-miraculous remissions of leukaemia in some patients. Alas, the disease soon returned. But Farber’s brave trial, ridiculed by colleagues, was the first step in treating childhood leukaemia, whose ultimate success remains perhaps the greatest triumph ever achieved by chemotherapy.
That came from a combination of drugs administered together, which is now typical of the chemotherapeutic regimens for most cancers. The treatments were tough, the doubters many. “It took plain old courage to be a chemotherapist in the 1960s and certainly the courage of the conviction that cancer would eventually succumb to drugs,” says Vincent DeVita, who was instrumental in developing a combination of drugs that raised the survival rate for Hodgkin’s disease from zero to over 70 per cent. It took huge resilience from the patients, too.
Targeted therapies substitute subtle intervention for brute force, aiming to disable or block processes that enable cancer cells to grow, divide and spread
The virtue of chemotherapy is that it can, in principle, seek out cancer cells wherever in the body they are, even if they have spread. The first cancer to be cured was choriocarcinoma, a rare cancer of the placenta, using methotrexate which is still a useful drug 60 years later.
But the biggest improvements in outcomes came from combining surgery with drugs – adjuvant therapy. Radiation may also be used in a triple-pronged attack designed to wrestle the cancer into submission. The gains are usually incremental rather than spectacular, but they add up.
Modern chemotherapy no longer relies exclusively on drugs that are in essence poisons. Targeted therapies have been developed that substitute subtle intervention for brute force, aiming to disable or block processes that enable cancer cells to grow, divide and spread. These include trastuzumab (Herceptin) for breast cancer, imatinib (Glivec) for chronic myeloid leukaemia, and certuximab (Erbitux) for colorectal, lung, and head and neck cancers.
Better targeting was made possible by a discovery at Cambridge in 1975, when César Milstein and Georges Köhler found how to make antibodies, in pure lines and in any amounts. Antibodies form a key part of the immune system, homing in on specific targets in the body (usually germs), so these man-made antibodies could be used as satnavs homing in on tumours. They can work in various ways, by blocking growth signals, carrying radioactive particles or chemotherapy drugs to the target, or by blocking the growth of blood vessels that tumours need to survive.
While new therapies are welcome, no single treatment is ever going to “cure” cancer. Progress is stepwise, sometimes appearing frustratingly slow – but progress it is.
COUNTDOWN OF CANCER PIONEERS
3000 BC The earliest known description of cancer is in an ancient Egyptian textbook on trauma. Known as the Edwin Smith Papyrus, it describes eight cases of tumours or ulcers of the breast that were removed by cauterisation with a tool called the fire drill. The document says of the disease: “There is no treatment”
460-370 BC The origin of the word cancer is credited to the Greek physician Hippocrates, who is considered to be the Father of Medicine. Hippocrates used the terms carcinos (Greek for crab) and carcinoma to describe non-ulcer forming and ulcer-forming tumours
28-50 BC Roman physician Celsus translates the Greek term into cancer, the Latin word for crab
130-200 AD Greek physician Galen uses the word oncos (swelling) to describe tumours. Although the crab analogy of Hippocrates and Celsus is still used to describe malignant tumours, Galen’s term is now used as a part of the name for cancer specialists – oncologists
1628 Post-mortem examinations by English physician William Harvey lead to an understanding of the circulation of blood through the heart and body that had until then been a mystery
1665 Robert Hooke publishes Micrographia, which presents several accounts of observations through the use of the microscope
1676 Anton van Leeuwenhoek, a Dutch trader, scientist and pioneer of microscopy, observes water and was surprised to see tiny organisms – the first bacteria observed by man
1713 Italian doctor Bernardino Ramazzini reports the virtual absence of cervical cancer and relatively high incidence of breast cancer in nuns, and wondered if this was in some way related to their celibate lifestyle. This was an important step towards understanding the role played by hormones, such as hormonal changes in pregnancy, and sexually transmitted infections and cancer risk
1760s John Hunter operates on patients in London with early-stage tumours
1761 John Hill, a London physician, records an early observation linking tobacco, specifically snuff, and cancer in his analysis Cautions Against the Immoderate Use of Snuff
1775 Percival Pott of Saint Bartholomew’s Hospital in London describes an occupational cancer in chimney sweeps, cancer of the scrotum, caused by soot collecting in the skin folds. Many more studies subsequently identify a number of occupational carcinogenic exposures and lead to public health measures to reduce cancer risk at work
1779 The first cancer hospital in France is forced to move from the city of Reims because people feared the disease would spread throughout the city
1838 German pathologist Johannes Müller demonstrates that cancer is made up of cells and not lymph, but he believes cancer cells did not come from normal cells. Müller proposes that cancer cells developed from budding elements or blastema between normal tissues
1846 General anaesthesia is demonstrated by William Morton in Boston, Massachusetts
1855 Rudolph Virchow, a student of Johannes Müller, coins his now famous aphorism omnis cellula e cellula (every cell stems from another cell). With this approach, Virchow launches the field of cellular pathology
1860 German surgeon Karl Thiersch shows that cancers metastasise through the spread of malignant cells and not through some unidentified fluid
1880s William Halsted develops radical mastectomy for breast cancer in New York
1896 Emil Grubbe uses X-rays to treat breast cancer in Chicago
1900 Thor Stenbeck, a Swedish physicist, cures a skin cancer patient with small daily doses of radiation
1902 The Imperial Cancer Research Fund (ICRF) is formed in the UK, driven by doctors and surgeons concerned about the suffering and loss of life from cancer. Their work focuses on studying cancer in the laboratory to find new approaches for treatment
1910 Peyton Rous at the Rockefeller Institute in New York shows that a transferrable agent, later shown to be a virus, can transmit cancer in hens
1911 ICRF discovers that some cases of breast cancer in mice run in families, suggesting there might be a hereditary component to the disease. However, the first inherited breast cancer gene, BRCA1, isn’t found until 1994
1913 The American Cancer Society is founded by 15 physicians and businessmen in New York as the American Society for the Control of Cancer; the current name was adopted in 1945
1915 Abbie Lathrop, a mouse fancier and breeder, and Leo Loeb, a pathologist, working at Lathrop’s mouse farm in Grancy, Massachusetts, show that some cancers are driven by hormones
1920s The British Empire Cancer Campaign is set up, focusing on testing new treatments in patients
1926 Janet Lane-Claypon publishes a groundbreaking comparative study of 500 breast cancer cases and 500 control patients of the same background and lifestyle for the British Ministry of Health
1939 Gordon Ide at Rochester University, New York, suggests tumours might generate a substance that encouraged the growth of blood vessels to sustain them
1947 Sidney Farber in the Children’s Hospital in Boston puts leukaemia into brief remission with a drug, aminopterin
1949 The US Food and Drug Administration approves the first chemotherapy drug, based on a poison gas from the First World War
1956 Metastatic cancer is cured for the first time when methotrexate is used to treat a rare tumour called choriocarcinoma
1958 Combination therapy, using several drugs at once, is shown to cure leukaemia by James Holland, Emil Freireich and Emil Frei in a trial in three American hospitals
1965 Vincent DeVita and colleagues at the US National Cancer Institute in Washington show combination therapy can cure advanced Hodgkin’s lymphoma
1971 Godfrey Hounsfield, working for EMI at Hayes, Middlesex, invents the CT scanner which improves imaging for both surgery and radiation treatment
1975 César Milstein and Georges Köhler at Cambridge invent monoclonal antibodies
1975 Larry Einhorn of Indiana University shows combination therapy can cure 70 per cent of advanced testicular cancer cases
1981 Trials organised by Bernard Fisher, a Pennsylvania surgeon, show that removing just the tumour and not the whole breast works equally well for early breast cancer
1984 Harald zur Hausen discovered first HPV16 and then HPV18 responsible for approximately 70 per cent of cervical cancers. He won a 2008 Nobel Prize for the discovery that human papillomaviruses cause cancer
1994 The first inherited breast cancer gene, BRCA1, is found
1997 Rituximab, the first drug based on a monoclonal antibody, is licensed
1998 Herceptin, a monoclonal antibody drug aimed at hormone-sensitive breast cancer, is licensed
2001 Imatinib (Glivec) a drug that interrupts tumour signalling pathways is licensed for chronic myeloid leukaemia and also found to be effective against gastrointestinal stromal tumours
2002 The Cancer Research Campaign merges with the Imperial Cancer Research Fund to become Cancer Research UK
2004 Avastin, the first drug to inhibit blood vessel formation by tumours, is licensed
2006 Vaccine against human papilloma virus, the cause of ovarian cancer, is licensed
2010 A new bowel cancer screening technique, known as a bowel scope, which could save thousands of lives is rolled out
2011 Scientists make progress in deciphering the molecular signature of prostate cancer and find a new accelerator gene that drives the growth of breast cancer
2012 Cancer Research UK scientists discover that breast cancer is in fact ten separate diseases
2013 Research reveals 80 new genetic variations that increase the risk of breast, ovarian and prostate cancers
2014 UK death rates for breast, bowel, lung and prostate cancer combined are down by almost a third in 20 years. And the World Health Organization’s International Agency for Research on Cancer has now identified more than 100 chemical, physical and biological carcinogens