History
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 recognized and named.
Greek physician Hippocrates compared the finger-like projections from a tumor to a crab – an odd image, since few tumors 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 anesthetic in insanitary conditions.
In the 18th century, the Scot John Hunter, one of the founders of modern surgery, declared that if a tumor had not invaded nearby tissue and was moveable, “there is no impropriety in removing it”.
The discovery of general anesthesia 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 tumor growth by more and more extreme removal of tissue, in the belief – only partly true – that recurrence meant that some of the tumor 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 discovery of general anesthesia 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 tumor growth by more and more extreme removal of tissue, in the belief – only partly true – that recurrence meant that some of the tumor 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.
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 tumors. 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 tumors 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 tumor 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 hematologist Lucy Wills, who had shown that some forms of anemia could be cured by Marmite, a condiment rich in folic acid, decided to treat his childhood leukemia 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 leukemia in some patients. Alas, the disease soon returned. But Farber’s brave trial, ridiculed by colleagues, was the first step in treating childhood leukemia, 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.
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 leukemia, 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 tumors. 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 tumors 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.
Ref: Medical Daily