The Cancer Chronicles Page 12
Everything doesn’t fit into a neat picture. Cancer rates might appear higher in one country than another because of the availability of screening tests. Cancer in urban areas is more likely to be noticed than cancer in the countryside. Beyond the statistical uncertainties, a mix of ingredients—diet, genetics, and cultural practices—can cause surprising variations. The prevalence of mouth cancer in India may come from the chewing of betel nuts and, of all things, reverse smoking—with the lit end of the cigarette inside the mouth. Drinking scalding hot maté may explain the high rates of esophageal cancer in some South American countries. Japan, an affluent society, still leads the world in the rate of stomach cancer. The reason is often laid to diet—a cultural preference for salty fish. Breast cancer in Japan is low for such a developed nation but it is rapidly catching up.
One day, trying to absorb all of this, I holed up in my office and began unpacking the most recent SEER statistics. Concentrating on overall cancer rates can smear over some interesting details, and I wondered what might be lurking underneath. The prime mover in driving down the numbers has been a decline or leveling off in what are by far the most common cancers—cancer of the prostate in men, cancer of the breast in women, and lung and colorectal cancer in both women and men. At the same time, the cancers that appear to be rising—melanoma, for example, and cancer of the pancreas, liver, kidney, and thyroid—are among the rarest. The annual incidence of pancreatic cancer is 12.1 cases per 100,000, compared with 62.6 cases for lung and bronchial. Year by year the figures fluctuate ever so slightly. With numbers so low, it can be difficult to tell if the increases are real or illusory—artifacts created by better reporting and early detection.
That is one of the gnawing difficulties of epidemiology. The scarcer the cancer the more subject the numbers are to random fluctuations, the statistical equivalent of noise. Childhood cancers are among the very rarest, ranging in incidence from 0.6 cases per 100,000 for Hodgkin’s lymphoma to 3.2 for brain and nervous system cancer and 5.0 for leukemia. Death rates from these malignancies have fallen to about half of what they were just a few decades ago—one of medicine’s great triumphs. But trends in incidence—how many children get cancer in the first place—are almost impossible to decipher. While there is slight evidence of an overall increase, it’s very hard to tell. A rise from 11.5 total cases per 100,000 in 1975 to 15.5 in 2009 looks scary. But for the years in between the numbers jump all over the place. The rate was nearly the same, 15.2, back in 1991. The following year it was down to 13.4 and eleven years later, in 2003, it was 13.0. The year after that it was 15.0, then 16.4, then 14.2. What will it be next? You might as well flip a coin.
Every cancer tells a different story. For many years lung cancer declined among men because of the delayed effects of giving up cigarettes. Women started smoking later in the century and so their rates continued to climb. Only recently have they taken a downward turn. A spike in breast cancer in the last quarter of the twentieth century—including the tiny, slow-growing in situ tumors that some doctors don’t think should be classified as cancer—may be explained both by better diagnosis and earlier menarche. The recent improvement in the numbers may be partly because of a drop in the use of hormone replacement therapy during menopause. Rising rates of melanoma, which began long before the discovery of the ozone hole, is often attributed to the popularity of sunbathing, tanning salons, and skimpier clothing that protects less flesh from ultraviolet rays. Another reason may be international travel. People from northern climes with lighter skin are now more likely to spend time in sunnier places. What may appear to be a climb in childhood malignancies, the National Cancer Institute suggests, is probably because of better imaging technologies and the reclassification of some benign tumors as malignant. Childhood obesity may conceivably be involved.
You can parse the numbers as finely as you like. Digging into the voluminous SEER figures, one can break out individual cancers by sex, age, race, and geographical locale. Choose a combination of demographics, and different cancers zigzag up and down. Cancer occurs more often in black men than in white men—but less often in black women than in white women. Crack the numbers open further and prostate, lung, colorectal, liver, pancreatic, and cervical cancer are all higher in black Americans, while their rates are lower for skin and uterine cancer and for malignant brain tumors. Darker skin pigments offer protection from sunlight. But the other discrepancies are harder to untangle. Many minorities might be expected to suffer from poorer nutrition, higher rates of smoking and alcoholism, and lower quality medical care—and to live in more polluted areas and work at riskier jobs. But Hispanics, American Indians, Alaska Natives, and Pacific Islanders get significantly less cancer than blacks or whites. There are so many variables involved.
Burrow deeper and more incongruities arise. For all races the incidence of brain cancer ranges in recent years from 4.23 cases per 100,000 in Hawaii to 7.54 in Iowa. That might raise suspicions of an agricultural influence. I wondered what was happening next door to Iowa in Kansas and Nebraska, but these states don’t participate in SEER. For liver cancer Hawaii tops out at 10.68, with Utah at the bottom with 3.94. Is that because of teetotaling Mormons or a difference in the prevalence of hepatitis virus? Hours later, wading out of the numerical morass, I despaired of ever making sense of it all. How much easier cancer would be if it were obviously driven by chemical contaminants. Instead there is a muddle of many little influences. High among them is entropy—the natural tendency of the world toward disorder. Of the multiple mutations it takes to start a cancer there is no way to know which was caused by what. Or, in the case of spontaneous mutations—copying errors—if there was a cause at all.
I imagined an army of clones, genetically identical, going through life under the same conditions in the same geographic locales. They would eat the same foods, engage in the same behaviors, and some would die of cancer by the time they were fifty or sixty while others would succumb decades later to something else. As Doll and Peto put it, “Nature and nurture affect the probability that each individual will develop cancer.” But it is luck that determines which of us really do.
Chapter 8
“Adriamycin and Posole for Christmas Eve”
Among the chemicals on the National Toxicology Program’s list of carcinogens is a simple-looking molecule called cisplatin. It is formed when a platinum atom bonds with two chlorine atoms and two ammonia groups. First synthesized in 1844 by an Italian chemist who was experimenting with platinum salts, cisplatin received little attention for more than a century. Then in the early 1960s it was found to have powerful biological effects.
Like so many scientific discoveries this one was serendipitous—a foray into one hypothesis veering unexpectedly in another direction, answering questions no one had known to ask. In his laboratory at Michigan State University, Barnett Rosenberg was exploring how cells behaved in the presence of electricity. He had been struck by how much the stringy, stretched-out shape of a cell undergoing mitosis resembled the field lines that appear when a magnet is held beneath a sheet of paper sprinkled with iron filings. The means by which a cell divides were poorly understood, and he wondered whether some electromagnetic effect might be involved.
Reducing the problem to simpler terms, he placed two metal electrodes in a dish of single-celled organisms, Escherichia coli, and applied an electrical current. Before long the bacteria stopped dividing. Each one, however, continued to elongate, producing new protoplasm that extended spaghetti-like until the cell was some three hundred times longer than it was wide. He turned off the current and the cells began dividing normally again. It was like having his finger on a mitotic on-off switch.
Decades later he still remembered the moment: “God, you don’t often find things like that,” he said. He immediately began thinking about cancer. “If we could control the growth of a cell with an electric field, we could control some cells with a frequency of one sort, other cells with a frequency of another, and then we could attack a tumor
by choosing a unique frequency and affecting only the tumor cells and not normal cells.” But then came a bigger surprise. It wasn’t electricity that was interfering with mitosis. The electrodes that had been used in his experiment were made of platinum, an element he had chosen specifically because it was chemically inert. But through the process of electrolysis some platinum ions were getting into the solution where they combined with other atoms to form cisplatin.
Rosenberg went on to test the molecule’s effects on metazoans, creatures like us that consist of many cells. Just a pinch of pure cisplatin was enough to kill a mouse. But in very dilute doses it would cause sarcoma tumors to shrink. Cisplatin also had the power to arrest other cancers, and over the years scientists discovered how that works. Before a cell can reproduce, the double helix must relax its windings so that the molecular information can be copied and passed on to the next generation. Cisplatin caused bridges to form between the two helical strands. This chemical straitjacket blocks mitosis and sends the cell into turmoil. It tries to recover by dispatching DNA-repairing enzymes. When that fails, apoptosis is initiated and the cell destroys itself. Cisplatin can affect any cell in the body, but since cancer cells divide at a faster rate they bear the brunt of the attack. Once the cancer is destroyed, the rest of the body stumbles, as best it can, back to health.
After clinical trials in the 1970s to determine how much cisplatin you could give people without killing them, it was approved by the Food and Drug Administration. It became known as the penicillin of cancer. Because of its effect on other rapidly dividing cells—hair follicles and cells in the gastrointestinal lining and bone marrow—there were sickening side effects. Patients would suffer a bone chilling nausea and their hair would fall out. Kidney and nerve damage might occur, and since cisplatin monkeyed with a cell’s DNA it raised the risk of causing a secondary cancer alongside the one the oncologists had been enlisted to treat. The trade-off was usually worth it. For testicular cancer the cure rate approached 100 percent. Other tumors were less responsive, but the chemical, often combined with radiotherapy, could slow cancers of other organs and extend lives. Sometimes it could save them.
Cisplatin, we learned in the days after Nancy’s surgery, was one of the agents that would be used in an attempt to kill any remaining metastases that might be hiding inside her, capable of smoldering for many years. She would also get doxorubicin, which like cisplatin operates by interfering with the replication of DNA. Doxorubicin has its own curious tale. The ruby in its name comes from its origin as a red pigment produced by a strain of bacteria. The microbes were discovered inhabiting soil in Italy, and the drug is also called Adriamycin, after the Adriatic Sea. A pretty name, but it too is on the official list of suspected carcinogens. In addition to its nauseating side effects it can push down your white blood cell count, increasing vulnerability to infections. Worst of all it can damage the heart, with reports that the risk increases when Adriamycin is combined with paclitaxel, another mitosis inhibitor that Nancy would be getting. None of this is worse than being dead. Paclitaxel (or Taxol) was originally isolated from the bark of the Pacific yew tree, Taxus brevifolia. This discovery was not serendipitous but the outcome of a government program to systematically screen thousands of plants to find substances that were cytotoxic but tolerable—even if just barely—to the human body. That is the brutal nature of chemotherapy. The first chemo agents were derived from mustard gas, whose antimitotic effects were discovered in victims of chemical warfare. Mustargen, which is used against Hodgkin’s lymphoma and other cancers, is also called nitrogen mustard and is covered under the 1993 Chemical Weapons Convention.
Every tumor is unique, an ecosystem of competing cells that are constantly evolving, adapting to new threats. Striking a cancer with a combination of different drugs increases the odds of killing it. Nancy’s three-pronged onslaught would be especially fierce. The source of her metastasis was initially believed to be endometrioid adenocarcinoma, the most common uterine cancer and one with a pretty good survival rate. But when the postsurgical report came back from the pathology lab, the story became more complicated. Of all the lymph nodes that had been removed only two appeared to be cancerous, and the adenocarcinoma that had been found in her endometrium was judged to be low grade, meaning that the cells had not undergone very many mutations and remained well differentiated. For the most part they still resembled endometrial cells. Invasion into the uterine lining was superficial. None of that made sense. How would so weak-willed a cancer have metastasized so quickly?
The answer seemed to lie in a polyp, a centimeter in size, that had also been excised from the endometrial tissue and biopsied. These cells were much less differentiated and resembled what pathologists call a papillary serous tumor, a type often found in ovarian cancer and one of the most pernicious kinds. But neither the surgeon nor the pathologist saw signs of cancer in the ovaries, which had been removed during the hysterectomy. What had marched with such determination down the round ligament and into the inguinal area was apparently a very rare cancer called uterine papillary serous carcinoma. What little has been published about it can hardly be more discouraging: “UPSC has a propensity for early intra-abdominal and lymphatic spread even at presentation,” one oncologist has written. “Unlike the histologically indistinguishable serous ovarian carcinomas, UPSC is a chemoresistant disease from its onset.…The survival rate is dismal, even when UPSC is only a minor component … and widespread metastasis and death may occur even in those cases in which the tumor is confined to the endometrium or to an endometrial polyp.” This new diagnosis, “mixed adenocarcinoma with areas of papillary type intermediate grade,” was not clear-cut. The cells in the nodule lacked one of the familiar characteristics—small protuberances or nipples that the pathologist called papillary fronds. But every cancer is different, and UPSC was the pigeonhole with the closest fit.
Looking back years later at the medical records, I see that there were hints of UPSC, or something like it, almost from the start—a sentence in the very first pathology report noting that the cells examined just after the lump appeared had a “micro papillary architecture.” If the doctors had suspected from that observation that UPSC was a possibility, they didn’t tell us. It was strange that this was the malignancy growing inside her. UPSC is typically a cancer of older, thinner women striking long after menopause and is especially common among African Americans. It is not believed to be tied to increased estrogen exposure and the matter of not bearing children. “There are no risk factors,” as two authors bluntly put it. According to one article, as few as 5 to 10 percent of women with stage 4 UPSC—what Nancy had—were alive after five years.
After we read the prognosis, I found an essay, “The Median Isn’t the Message,” which Stephen Jay Gould, the evolutionary biologist, had written after he was diagnosed at age forty with mesothelioma. This rare cancer, associated with exposure to asbestos, usually affects the tissue surrounding the lungs. Gould’s was in his peritoneum, the lining of the abdominal cavity. Once he had recovered from surgery and was beginning chemo, he began researching like mad, quickly discovering that the cancer was considered incurable and that the median mortality after diagnosis was eight months. On its face that would suggest that he would probably die within a year. But Gould began unpacking the statistics. The median, as he explained in his essay, is very different from the mean, or average. It is the halfway point between a range of numbers. If you have a group of seven people and are told that the median height is five foot eight then you know that three of the people are shorter and three are taller. What that doesn’t tell you are the extremes. The range of heights might be typical, clustering around the median. But you could also have some abnormally short people all under five feet high, or human beanpoles, or any mix of these and still come out with a median of five foot eight, as long as that was the height of the middle person in the group.
With age of survival, Gould assured himself, there was more likely to be an excess of giants than midget
s. The lowest number you could possibly have is zero—the patient is diagnosed at death—but the highest number was essentially open-ended. Plotted on a graph with eight months as the midpoint, the distribution would be asymmetrical: squeezed on the left side between zero and eight but stretched out to the right, including survival times of twelve months, twenty-four months, or many more. As he read about the cancer, Gould found that there were indeed people who had survived for several years. He assured himself that he had every reason to believe he was in that long, right-skewing tail. He was young, otherwise healthy, and as a Harvard professor had access to the best medical care, including a new experimental treatment. “All evolutionary biologists know that variation itself is nature’s only irreducible essence,” he wrote. “Variation is the hard reality, not a set of imperfect measures for a central tendency. Means and medians are the abstractions.” Gould ended up way out on the tip of the tail. He lived for almost twenty more years, dying in 2002, a year before Nancy’s diagnosis, of a metastatic lung cancer that his doctors said was unrelated. Nancy was not an abstraction. She was young, healthy, her doctors appeared to be among the best. We hung on to that notion as she began her chemotherapy.