Cancer: The new normal? | Siddhartha Mukherjee
As our population ages, the question is not if wewill encounter this illness in our lives, but when. Is it time we stopped fighting and learned to live with it?
On the morning of 19 May 2004, Carla Reed, a30-year-old nursery teacher and mother of three young children, woke up in bed with a headache. "Not just any headache," she says, "but the kind of numbness that instantly tells you that something is terribly wrong."
Late in April, Carla had discovered a few bruiseson her back. They had suddenly appearedone morning, like strange stigmata, then grown and vanished over the next month, leaving large, map-shaped marks on her back. Almost indiscernibly, her gums had begun to turn white. By early May, Carla, a vivacious, energetic woman, could barely walk up a flight of stairs. Some mornings, exhausted and unable to stand up, she crawled down the hallways of her house on all fours to get from one room to another. She slept fitfully for 12 or 14 hours a day, then woke up feeling so overwhelmingly tired that she needed to haul herself back to the couch again to sleep.
Carla and her husband saw a general physician and a nurse twice during those four weeks, but she returned each time with no tests and withouta diagnosis. Ghostly pains appeared and disappeared in her bones. The doctor fumbled about for some explanation. Perhaps it was amigraine, she suggested, and asked Carla to trysome aspirin. The aspirin simply worsened the bleeding in Carla's white gums.
On the afternoon of 19 May, Carla dropped her three children with a neighbour and drove back tothe clinic, demanding to have some blood tests. Her doctor ordered a routine test to check her blood counts. As the technician drew a tube of blood from her vein, he looked closely at the blood's colour, obviously intrigued. Watery and pale, the liquid that welled out of Carla's veins hardly resembled blood. She waited the rest of the day without any news. At a market the next morning, she received! a call.
"We need to draw some blood again," the nurse from the clinic said.
"When should I come?" Carla asked. She remembers looking up atthe clock on the wall. Inthe end, commonplace particulars make up hermemories of illness: the clock, the children, atube of pale blood, the tightening tone of a voice on the phone. "Come now," she thinks the nurse said. "Come now."
I heard about Carla's case at 7am on 21 May. Thesentence that flickered on my beeper had thestaccato and deadpan force of a true medical emergency: "Carla Reed/New patient with leukaemia/14th floor/Please see as soon as youarrive."
Leukaemia is cancer of the white blood cells cancer in one of its most explosive, violent incarnations. Its pace, its acuity, its breathtaking, inexorable arc of growth forces rapid, often drastic decisions; it is terrifying to experience, terrifying to observe and terrifying to treat. Thebody invaded by leukaemia is pushed to itsbrittle physiological limit every system, heart, lung, blood, working at the knife-edge of its performance. Blood tests performed by Carla's doctor had revealed that her red cell count was critically low, less than a third of normal. Instead of normal white cells, her blood was packed with millions of large, malignant white cells blasts, inthe vocabulary of cancer.
When I arrived, Carla was sitting with peculiar calm on her bed, a schoolteacher jotting notes. ("But what notes?" she would later recall. "Ijustwrote and rewrote the same thoughts.") Her mother, red-eyed and tearful, sat silently inachair bythe window, rocking forcefully. The din of activity around Carla hadbecome almost ablur: nurses shuttling fluids in and out, interns donning masks and gowns, antibiotics being hung on IV poles to be dripped into her veins.
I explained the situation as best Icould. Her day ahead would be full of tests, a hurtle from one lab to another. I would draw a bone marrow sample. More tests would be run ! by patho logists. But the preliminary tests suggested that Carla had acute lymphoblastic leukaemia (ALL) one ofthe most common forms of cancer in children, but rare in adults.
I laid out the odds. Once the diagnosis had been confirmed, chemotherapy would begin immediately and last more than a year. Carla's chances of being cured wereabout 30%.
"Thirty per cent I would repeat that number tomyself at night," she says. "Not even a third. Ifsomeone gave me 30% odds in a game, would Itake the odds?"
The morning after Carla arrived at the hospital, I took her consent forms for chemotherapy that would allow us instantly to start pumping poisons into her body to kill cancer cells. Chemotherapy would come in three phases. The first would last about a month. The drugs given inrapid-fire succession would hopefully send the leukaemia into asustained remission. They would certainly kill her normal white blood cells as well. Her white cell count would drop in freefall, all the way to zero. For a few critical days, she would inhabit one of the most vulnerable states modern medicine can produce: a body with no immune system, defenceless against the environment around it.
If the leukaemia did go into remission, then we would "consolidate" and intensify that remission over several months. That would mean more chemotherapy, but at lower doses, given over longer intervals. She would be able to leave the hospital and return home, coming back every week for more chemotherapy. Consolidation and intensification would last for eight additional weeks, perhaps longer.
The worst part I kept for last. ALL hasan ugly propensity for hiding in the brain. The intravenous chemotherapy that we would give Carla, nomatter how potent, simply couldn't break into the cisterns and ventricles that bathed her brain. The blood-brain barrier essentially made the brain into a "! ;sanctua ry" for the leukaemia cells. To send drugs directly into that sanctuary, the medicines would need to be injected directly intoCarla's spinal fluid, through a series of spinal taps. Whole-brain radiation treatment highly penetrant x-rays dosed directly through her skull would also be used against leukaemia growth inher brain. And there would be even more chemotherapy to follow, spanning two years, to"maintain" the remission, if we achieved it.
Cancer is not one disease but many diseases more than 100 different types and subtypes, anillness so impossibly multifarious that it defies the very limits of classification. And yet Carla's leukaemia cancer of white blood cells shares adeep biological commonality with breast, stomach or lung cancer. In all cases, the fundamental aberration is the same: cancer originates in a cell that cannot stop dividing. That this seemingly simple mechanism cell growth without barriers can lie at the heart of this multifaceted disease is a testament to the unfathomable power of cell growth. Cell division allows us as organisms to grow, to adapt, to recover, to repair to live. And, distorted and unleashed, it allows cancer cells to grow, to flourish, to adapt, to recover and torepair: to liveat the cost of our living. Cancer cells grow faster, adapt better. They are more perfect versions of ourselves.
How did Carla's body create such a cell? What, more generally speaking, causes any normal cell to lose control and begin to grow uncontrollably? Until the mid-1970s, very little was known about this process. Researchers knew that exposure to certain chemicals (such as benzene or cigarette smoke) could increase the chances of developing cancer. Inthe 1770s, an English surgeon, Percivall Pott, had noted that adolescent chimney sweeps chronically exposed to chimney sootcould develop cancers of the scrotum, where minuscule particles of tar and soot were often trapped. These ag! ents wer e called "carcinogens", but therewas little knowledge about how such agentsmight work or how they might elicit uncontrolled growth.
Many scientists, on the other hand, argued thatcancer was caused by viruses particularly retroviruses. Retroviruses are unique in the sense that the genes of these viruses can physically attach themselves to the DNA of the cell. Genes control the growth of cells. And so cancer, it was thought, was unleashed when a retrovirus gene attached itself to the cell's DNA, thereby delivering a genetic signal to alter cellular growth.
In the winter of 1976, a lanky, self-possessed scientist named Harold Varmus, along with JMichael Bishop, a virologist originally from Pennsylvania, both working in SanFrancisco, proposed a startling theory of cancer's genesis that reconciled the virus and chemical theories. Varmus and Bishop discovered that the genes that unleash cancer are typically already present in every normal cell. Retroviruses cause cancer, Varmus and Bishop found, by forcing a growth-inducing gene into the DNA of a cell. Chemical carcinogens, on the other hand, activate or inactivate genes bymutating DNA, and thus distort growth-controlling genes. Thus lung cancer occurs when a chemical in cigarette smokemutates a gene that controls the growth ofa lung cell, thereby eliciting uncontrolled growth. But, notably, lung cancer can also occurin a man or woman who has never smoked: a lung cell, reproducing itself, might make arandom error in copying its genes, thus generating the same mutant gene that eventuallyunleashes uncontrolled growth.
Most normal cells, even rapidly growing normal cells, will proliferate over several generations and then exhaust their capacity to keep dividing. What allows a cancer cell to keep dividing endlessly, without exh! austion or depletion?
An emerging, although highly controversial, answer to this question is that cancer's immortality, too, is borrowed from normal physiology. The human embryo and many of our adult organs possess a tiny population of stem cells that are capable of immortal regeneration. Stem cells are the body's reservoir of renewal. The entirety ofhuman blood, for instance, can arise from asingle, highly potent blood-forming stem cell (called a haematopoietic stem cell), which typically lives buried inside the bone marrow. Under normal conditions, only a fraction of these blood-forming stem cells are active; the rest are deeply quiescent asleep. But if blood is suddenly depleted, by injury or chemotherapy, say, then the stem cells awaken and begin to divide with awe-inspiring fecundity, generating cells that generate thousands upon thousands of blood cells. In weeks, a single haematopoietic stem cell can replenish the entire human organism with new blood - and then, through yet unknown mechanisms, lull itself back to sleep.
Something akin to this process, a few researchers believe, is constantly occurring in cancer or at least in leukaemia. In the mid-1990s, John Dick, aCanadian biologist working in Toronto, postulated that a small population of cells in human leukaemias also possess this infinite self-renewing behaviour. These "cancer stem cells" act as the persistent reservoir of cancer generating and regenerating cancer infinitely. When chemotherapy kills the bulk of cancer cells, a small remnant population of these stem cells, thought to be intrinsically more resistant to death, regenerate and renew the cancer, thus precipitating the common relapses of cancer after chemotherapy. Indeed, cancer stem cells have acquired the behaviour of normal stem cells by activating the same genes and pathways that make normal stem cells i! mmortal except, unlike normal stem cells, they cannot be lulled back into physiological sleep. Cancer, then, is quite literally trying to emulate a regenerating organ or perhaps, more disturbingly, the regenerating organism. Its quest for immortality mirrors our own.
In July 2009, exactly five years after I had looked down the microscope into Carla's bone marrow and confirmed her first remission, I went to visit her. Just before I left the hospital, I glanced quickly at the first note I had written on her admission in 2004. As I had written that note, Irecalled with embarrassment, I had guessed thatCarla would not survive even the induction phase of chemotherapy.
But she had made it; a charring, private war had just ended. In acute leukaemia, the passage of five years without a relapse is nearly synonymous with a cure. I handed her the flowers I had brought and she stood looking at them speechlessly, almost numb to the sheer scale of her victory.
I asked Carla how she thought she had survived. Howhad she managed, through the long days of that dismal summer, to drive to thehospital, wait in for hours as her blood tests were run, and then, told that her blood counts were too low for her tobe given chemotherapy safely, turn back and return the next day for the same pattern to be repeated?
"There was no choice," she said, motioning tothe room where her children were playing. "Myfriends often asked whether I felt as if my lifewas somehow made abnormal by my disease. I would tell them the same thing: for someone who is sick, this is their new normal."
Taken to its logical extreme, the cancer cell's capacity consistently to imitate, corrupt and pervert normal physiology raises the ominous question of what "normality" is. Ifthe genes that unleash many forms of cancer are already present in every cell, then these cancers canno longer be imagined as "exogenous" or "unnatural" phenomena. Cancer is inherently stitched into our genetic ! being. Q uite possibly, as it has been for Carla, cancer is our "new normal". The question then will not be if we will encounter this immortal illness in our lives, but when.
It is important not to be too glib about this idea. Certain cancers arecaused largely by preventable exposures to carcinogens or viruses. Lung cancer is directly linked to smoking. Liver cancer has been long associated with inflammation and repair in liver cells caused by hepatitis B and C virus. Cervical cancer is often caused by asexually transmitted papilloma virus. These cancers do not arise accidentally or "naturally", but are caused by particular behaviours or exposures that can be modified and changed.
But for many other cancers many types of breast or prostate cancer, for example there is no identifiable or modifiable risk aside from age itself. These cancers seem to arise not because we have exposed ourselves to a known chemical or behaviour, but because our genes themselves are vulnerable. Our cells divide as we age, and there are errors in copying genes from one division to the next. As mutant genes encrust upon mutant genes in our bodies, our cells are inevitably tugged towards uncontrollable growth cancer.
Indeed, in the developed world where many other diseases have been eliminated, and thus men and women are living longer and longer therise of cancer incidence has paralleled the risein life expectancy. In the US, for instance, lifeexpectancy grew over the last century, from the late-40s in 1900 to the mid-70s in 2000. Cancer incidence grew in parallel as well: in 2010, one intwo men and one in three women will bediagnosed with cancer in America. If half of allmen and one-third of all women face this disease during their lives, then in what sense is aperson who develops cancer "abnormal"? Mightthe growing spectre ofcancer force us to rethink the metaphors and images that surround this illness?
One way we imagine cancer, at least, is changing.In the past, cancer was typi! cally im agined as an acute disease, treated with surgery, radiation and chemotherapy. And the trifecta of assaults led to only two possible outcomes. Either cancer was eradicated from thebody in other words "cured" or it remainedrecalcitrant to treatment, and was "incurable". The metaphors attached to cancer followed this binary outcome. Patients fought a"battle" with cancer. If cancer was defeated, then patients "won" the war. If patients lost the battle, the cancer was victorious. There was no intermediate outcome no truce.
But for many forms of cancer, this binary description no longer captures the truth. Take, for instance, a young woman with breast cancer. She may initially have surgery to remove the primary tumour from herbreast. But we now know that surgical removal of the tumour may not cure such a patient outright. Microscopic deposits of cancer cells may be left behind aftersurgery that can be eradicated only withchemotherapy and radiation, typically administered over several months. And more drugs and treatments might follow. If her canceris of a particular subtype, she may receiveanti-oestrogen therapy for several years. During this time, and for decades after, she maybe tested with mammography to detect earlybreast cancer in her other breast. Her daughters may be tested for carrying genes thatpredispose tobreast cancer. Indeed, her course of therapy might stretch into five oreven 10 years, perhaps even to the next generation. Suspended in limbo, she will be neither cured, nor deemed incurable neither cancer-free norcancer-afflicted. Rather, cancer will become achronic condition for her; she will live in its immediate shadow for decades, never quite certain about her outcome. The combination ofsurgery, chemo and radiation will likely extendher survival but, having entered the world of cancer, her life will be permanently altered. As it did for Carla, for her, cancer will become the new "normal".
Such cases are not rare in cancer. A di! sease ca lled chronic myelogenous leukaemia (CML) once carried dismal survival figures: most patients died within three to five years. But anewdrug called Glivec has transformed thisformof cancer. CML patients who respond toGlivec appear to live nearly as long as patientswithout any form of cancer; their life expectancy is virtually identical to age-matched men and women. And yet, notably, Glivec doesnot cure CML; it converts this leukaemia into a chronic disease. The leukaemia cells remainabated as long as treatment continues. Ifthe drug is stopped, even for a few weeks, theleukaemia cells return in the bone marrow and blood. For CML patients on Glivec, then, leukaemia defines their normal state of living. They live, age, bear children, work, travel andcelebrate holidays in the shadow ofCML, andin the company of an orange pill that keepsthem alive.
Perhaps cancer defines the inherent outer limitof our survival. As our cells divide and ourbodies age, and as mutations accumulate inexorably upon mutations, cancer might well bethe final terminus in our development as organisms. Cancer is stitched into our genome, itis a flaw in our growth, but this flaw is ultimately deeply entrenched in ourselves. Wecan rid ourselves ofcancer, then, only as much as wecan rid ourselves of the processes inour physiology thatdepend on growth ageing, regeneration, healing, reproduction.
Is the end of cancer conceivable in the future? Is it possible to eradicate this disease from our bodies and our societies for ever? Or should our goals be more modest?
The English epidemiologist Richard Doll likedtosay that "death in old age is inevitable, but death before old age is not". Perhaps Doll'sfavourite aphorism represents a more reasonable proximal goal to define success inthewar on cancer. It is possible that we are fatally conjoined to this illness, forced ! to playi tscat-and-mouse game for the foreseeable future ofour species. But if cancer deaths can beprevented before oldage, if the terrifying game of treatment, resistance, recurrence andmore treatment can bestretched out longerand longer, then it will transform the waywe imagine this ancient illness. Given whatwe knowabout cancer, eventhis would represent a technological victory unlike any otherin our history. Itwould be avictory overourown inevitability a victory overourgenomes.
This is an edited extract from The Emperor Of All Maladies: A Biography Of Cancer, by Siddhartha Mukherjee, published by Fourth Estate at 25. To order a copy for 20 (including UK mainland p&p), call 0330 333 6846, or go to guardian.co.uk/bookshop.
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