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Understanding and Prevent Cancer

5.1 An Unlimited Capacity for Growth

The growth of cancer is very much on the minds of all those affected by this disease: patients, physicians, and researchers.

When a cancer patient wonders how long it has been from the time his or her cancer first started to when it was diagnosed, he or she is asking about the growth rate of the cancer. Another way to phrase this question is: “How fast is the cancer growing?”

When a patient asks if the cancer is in “remission,” he or she is really asking if the cancer has stopped growing and, more to the point, started to shrink. On the other hand, if the patient is told that the cancer has “relapsed,” then it means the cancer is growing again.

The Meaning of Remission

There are two main types of remission:

Partial or complete. In a partial remission, the cancer shrinks in size by at least 30 percent; in a complete remission, the cancer becomes undetectable. In the past, cancer doctors and researchers believed that only treatments that achieved remission could benefit patients.

However, some newer cancer treatments, called targeted therapies, not only improve quality of life but prolong life merely by “freezing” or stabilizing the growth of cancer (without necessarily shrinking tumors); this has led to a new mindset about the goals of therapy. Especially for cancers that are not considered curable, prolonged stabilization of the cancer can be as worthy a goal as obtaining remission.

Oncologists (physicians with advanced training and certification in the medical care of people with cancer) have the same concerns as patients, but with a focus on how the health of their patients is or will be affected by cancer growth. For each patient, oncologists weigh several factors to assess and anticipate the growth potential of a cancer.

These include:

(1) Examining the pathology report, which can indicate the aggressiveness of the cancer and its potential to return after treatment;

(2) Determining how rapidly any symptoms caused by the disease have developed; and

(3) Assessing the extent of the cancer as determined by imaging tests (CT scans, MRIs, bone scans, and PET scans) and blood tests.

Some types of cancer generate a protein, called a “tumor marker,” that is released into the bloodstream and can be measured through a simple blood test. Although very elevated tumor marker levels often indicate an aggressive cancer, these tests are conducted primarily to track the progress of treatment (as a cancer is successfully treated, its tumor marker will fall).

The main tumor markers are:

Major cancer tumor markers (blood tests)

Tumor marker - Cancer

AFP, HCG - testicular, liver (AFP only)

CEA - colorectal

CA 15-3, CA 27-29 - breast

CA 19-9 - pancreatic, biliary tract

CA-125 - ovarian

PSA - prostate

M-protein; free light chains multiple - myeloma

LDH - lymphoma

Beta-2 - microglobulin myeloma, lymphoma

Oncologists process all this information to determine if a cancer is fast or slow growing and if it has a high or low potential to spread to other organs. Oncologists must see the full cancer landscape for each patient, that which the affected person could not possibly see.

Following these assessments, the oncologist makes recommendations as to whether treatment should be started urgently (the same day) or in the near term (in a few days or weeks), or whether treatment can be deferred based on the future behavior of the cancer (that is, no treatment is necessary at present). For example, a person who experiences sudden back pain and is found to have a rapidly growing tumor that is pressing on the spinal cord requires urgent treatment to alleviate pain and prevent paralysis.

In contrast, a seventy-five-year-old man with a slow-growing prostate cancer that is not causing any symptoms may never need the cancer treated. All of these clinical lines of thought revolve around the growth properties of the cancer in question. For each patient, the growth assessment of the cancer is best understood through discussions with the oncologist.

Cancer researchers are also focused on growth as they work to discover new and better ways of treating cancer.

Scientists study the molecules inside cancer cells that stimulate them to multiply and grow. By understanding how these important molecules work, researchers can develop drugs that will block them from functioning. The hope is that interfering with these critical targets will cause the cancer cells to die.

These growth targets and the drugs designed to block them are discussed later.

We’ve established that growth is central to thinking about cancer. But what does it mean for cancer to grow, and to grow in an unlimited way? What actually is growing?

The answer is the number of cancer cells. All cancers start with one cell, and that cell multiplies to form the tumors that are ultimately detected. One cell becomes two cells. These two cells then duplicate themselves to become four cells, which multiply to eight cells, and so on, until there is an entire population of cells.

It is generally thought that one billion cancer cells need to have formed before a cancer can be detected. This is the number of cells present in a one-centimeter tumor (nearly a third of an inch).

The ability to detect cancer when far fewer cells are present is a high priority of cancer research. While the growth of cancer cells is certainly a bad thing, the growth of healthy cells is of course, necessary for our bodies to function properly.

The difference between normal cell growth and cancer cell grow this that normal growth is always precisely timed and controlled. For example, when a human fetus is developing, cell growth is explosive because one fertilized egg must give rise to the trillions of cells that ultimately compose a body. Yet the process of making the heart, brain, or any other organ is tightly regulated: cells stop growing once the correct organ pattern is laid down. In fact, when an organ reaches maturity, most of its cells lose the capacity to multiply.

This is why our heart cannot replace damaged cardiac muscle after a heart attack and why our bodies cannot heal a spinal cord injury by making new nerve tissue.

Mature adult organs have a limited capacity to regenerate, with the exception of the liver, the inner lining of the intestines, and the bone marrow.

Fetal tissue, on the other hand, has the full capacity to form new cells, which is why fetal stem cells (the cells with the greatest regenerative capacity) are being studied as a way to help victims of numerous illnesses and injuries, such as Parkinson’s disease and spinal cord damage.

The hope is that if fetal stem cells are implanted in an environment of nerves, for example, they will sprout new nerve cells to replace the damaged ones.

The major exception to the rule that adult cells do not multiply freely is cancer.

Cancer cells derive from the cells of our fully formed organs, but they have found a way, through genetic mutation, to bypass the natural brakes on cell growth. By sustaining alterations to DNA elements that control growth, cancer cells acquire a limitless ability to multiply. In addition, they become impervious to the checks and balances that our bodies have developed to restrain rebellious cells.

Fortunately, other factors limit the size of any tumor (cancers do not just grow and grow). Yet because of this powerful growth engine, cancer must be fought with strong treatments, such as chemotherapy and radiation that attempt to stop this growth in its tracks.

The differences in growth between normal cells and cancer cells can be exploited by chemotherapy and radiation, which preferentially attack the actively dividing cancer cells.

Can we determine the exact growth rate of a cancerous tumor? No.

At this time, there is no precise way for doctors to assess the growth rate of a particular cancer. The technology has not yet been developed. Moreover, such a measure would be a complicated affair, because cancers change their growth patterns as they increase in size (the rate of growth slows as they get bigger) and as they are exposed to treatments (which attempt to slow the rate of growth considerably). But if such a test were available, it would undoubtedly show that no two cancers grow at exactly the same rate.

Across the vast spectrum of cancer and its many different types is an even greater range of growth rates.

Some cancers grow fast, and some grow slowly. This rate relates mainly to the specific constellation of molecules that define each cancer (no two cancers are exactly alike). For most tumors, changes in size are a balance between factors that promote growth and others that limit growth, such as the available supply of blood and nutrients. In fact, some cancers grow so slowly that they remain the same size from month to month or even from year to year.

Although cancer is commonly thought of as a disease caused by cells “growing out of control” or “running amok,” this simple conception of cancer is inaccurate. I have been caring for B. seventy-five-year-old man who recently received his first treatments for a non-Hodgkin’s lymphoma (a cancer of an immune cell called a lymphocyte) that was diagnosed when he was fifty years old. Throughout much of the intervening twenty-five years, B. experienced what we call “stable disease.” He carried on with his life with his cancer untreated. Periodic CT scans showed that the tumors were either the same size or only slightly larger from one year to the next.

Stable disease is when a person and his or her cancer live in peaceful coexistence - a period when the cancer is not growing much and the body’s natural defenses can keep it in check. It also implies that the cancer is not causing the patient any symptoms, so he or she is not ill. In the past year, however, Don’s lymphoma grew more rapidly, a situation termed “progressive disease,” which necessitated his treatment. Yet despite the diagnosis of cancer many years ago, Don has lived a full and active life before, during, and after its treatment.

The message of B. story is that many cancers do not grow like wildfire. For sure, some do develop rapidly, such as the blood cell cancers acute leukemia and high-grade lymphoma and aggressive forms of the more common organ-derived cancers. But for others, the dominant problem with cancer cells is not that they are growing out of control and forming large tumors but that they just won’t die once they are formed.

This leads us to the second essential property of cancer.

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5.2 An Inability to Die

 

It is written in Ecclesiastes, “To every thing there is a season . . . A time to be born, and a time to die.”

So it is with the cells of our body; so it is not for cancer cells.

Each cell is born with a finite, predetermined life span.

Some cells are meant to live for just a few hours, others (such as our brain cells) to survive all our lives.

In addition, as cells undergo subtle changes as part of the normal aging process and experience the wear and tear of life in the body, some accumulate sufficient damage that requires their removal and replacement.

In order to maintain just the right balance of cells at all times, our bodies have developed an elaborate biological system.

This system clears out defective cells, eliminates diseased ones, and removes older ones to make room for new ones.

The system actually operates inside each cell that is to be eliminated. When a cell’s “time is up,” a large network of molecules within the cell, which had been maintained in an inactive, or “locked-down” state, is liberated.

This set in motion a cascade of chemical reactions that cause the cell’s various internal parts to dissolve, leading to cell suicide; the cell breaks into smaller units that are carted off by scavenger immune cells.

To ensure that the process of cell suicide never fails, Mother Nature has programmed it into our genes - that is, the DNA of nearly every living cell has within it the potential to take a dagger to the heart of that very cell.

The process is called “programmed cell death,” or apoptosis. In Greek, apoptosis means “falling off” or “dropping off,” as in leaves from a tree or petals from a flower.

Apoptosis is rarely mentioned in mainstream media reports on science and medicine.

This is unfortunate, because apoptosis plays a pivotal role during the development of animals and in their health and disease. For example, when a tadpole metamorphoses into a frog, its tail disappears because the tail cells undergo apoptosis.

To sculpt the fingers and toes of the developing human fetus out of an amorphous mound of tissue, the cells between the individual digits undergo apoptosis and fade away.

When a virus infects us, it survives in our bodies by living inside certain cells; to rid the body of the virus, our immune system forces the infected cells to undergo apoptosis, taking the virus down with them. Slowly debilitating diseases of the nervous system, such as Parkinson’s disease and Alzheimer’s disease, are characterized by the progressive loss of nerve cells in the brain, which undergo premature apoptosis.

Why is apoptosis so important to cancer?

The answer is that cancer cells have a diminished ability to undergo apoptosis. That is, they resist the signals that tell a normal cell to die. They ignore their programmed life span and fail to commit suicide when they are old; they live on in the face of injury after wear and tear; they resist the immune system’s attempt to delete them.

Cancer cells can do all these things because they have an altered genetic program of apoptosis wrought by changes (mutations) in their DNA.

The result is that, inside a cancer cell, the programmed cell death apparatus is in perpetual lockdown. If left to their own devices, most cancer cells in any tumor would fail to die and the tumor mass would keep growing.

Fortunately, cancer cells’ resistance to apoptosis is relative; many cancers will undergo apoptosis when targeted by anticancer treatments.

As we know, some cancers are more successfully treated than others.

Curable cancers (for example, testicular cancer and Hodgkin lymphoma) rapidly undergo apoptosis upon treatment; whereas those that are difficult to cure fail to undergo total apoptosis in response to treatment (treatment resistance is explained in later).

Causing the death of cancers through apoptosis is a major goal of cancer therapies and of course the main desire of cancer patients.

In sum, the capacity to die exists within all cells.

In nature, life and death are equally important and must be in balance.

Normal cells obey the internal commands of their predetermined life span or the external cues of the body and commit suicide when so directed.

Cancer cells disregard these signals and resist apoptosis.

They have acquired an inability to die; the goal of cancer treatments is to overcome this barrier to their destruction.

 

 

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5.3 An Ability to Spread (From the site of Origin)

“Was the cancer caught in time?” This is one of the first and most important questions patients ask when they are diagnosed with cancer. With this question, they are asking if their cancer was detected before it had a chance to spread to other parts of the body (a process called “metastasis”).

It is commonly thought that if a cancer has not metastasized, then it is curable, but if it has metastasized, then it is not curable. For many cancers, this is true, but there are many exceptions, so it is important to avoid generalizations. For example, if lung cancer has spread to the liver or brain, then it is rarely curable (note that I did not say “never curable” because there are people who have beaten advanced lung cancer).

In contrast, testicular cancer that has spread to the same locations is potentially curable, as evidenced by the superhuman cyclist Lance Armstrong, who overcame testicular cancer that spread to his brain.

Another common reason to ask if the cancer was caught early enough is that many people have fears about chemotherapy and hope that if their cancer is contained, then locally directed therapies, such as surgery or radiation, will be all that is required for them to beat their cancer.

This fear is understandable because chemotherapy drugs are strong medicines that can cause serious side effects. But extreme aversions to chemotherapy need to be dispelled because these medicines save lives.

And chemotherapy administration today causes far fewer side effects than in the past. Many cancer patients today can live reasonably normal lives, even work and enjoy leisure activities, while undergoing chemotherapy treatments. I am always amazed at how many patients in our outpatient infusion room are eating away while chemotherapy drips into their arm through an intravenous line. Many have a bagel in one hand, an IV pole in the other, and are scooting around talking to others to pass the time. This could not have happened twenty years ago, when nausea and vomiting wracked patients and kept them in their hospital beds.

To describe how cancer spreads, I need to introduce some medical terms. The organ where a cancer originates is called the “primary” site. The breast is the primary site in breast cancer, the prostate the primary site for prostate tumors, and so on. For example, a breast cancer begins in a breast cell that becomes transformed into a cancer cell and multiplies into a tumor that becomes detectable. This same process is repeated during the birth of every cancer. The main primary sites of origin for cancers affecting men and women we speak later.

The locations in the body where a cancer spreads are called “metastatic” or secondary sites. Metastatic sites develop when individual cancer cells leave the primary tumor mass and travel to another location in the body, where they grow into tumors. Although a cancer can spread to virtually any part of the body, each type is associated with certain “preferred” distant sites. Knowledge of these sites guides the initial assessment of the extent of disease (called the “staging workup”). For example, a patient with newly diagnosed lung cancer will undergo: a CT scan of the chest to search for spread of the disease to other parts of the lungs as well as lymph nodes in the chest; a CT scan of the abdomen to search for metastases in the liver and adrenal glands; an MRI of the brain to search for cancer there; and either a bone scan or a PET scan to detect any bony metastases (a PET scan is also useful for detecting cancer in other parts of the body, but not the brain). It is important to understand that wherever metastases are found, they are still composed of the same cancer cells as those found in the primary cancer. An analogy used by one of my colleagues is that an Italian who moves from Italy to the United States is still an Italian! 

Another example would be that of the patient with ovarian cancer I described earlier. Although cancerous growths were found in her lungs, A. did not have lung cancer. Instead, she had ovarian cancer that had metastasized to the lungs. The same ovarian cancer cells that were detected when her ovarian tumor was biopsied would be found in her lung tumors if they had been biopsied. For any cancer, this principle is true.

Prostate cancer that has spread to the bones is not “bone cancer” but still prostate cancer, now also growing in the bones; pancreatic cancer that has spread to the liver is not “liver cancer” but the same pancreatic cancer cells that have now traveled to the liver.

One colleague mine recently cared for a thirty-five-year-old man who came to our hospital emergency room complaining of severe back pain. M. put off coming to the hospital because he was frightened that he would be told he had cancer, and so he delayed seeing a doctor. He worked in construction and kept blaming his symptoms on his work. By the time M. came to the hospital, he had been suffering for months, was in excruciating pain, and was having great difficulty moving his arms, which had become numb.

On physical examination, M. was found to have a large mass replacing his testicle. CT scans of his spine showed a tumor pressing on his spinal cord, which explained the pain, arm weakness, and numbness he was experiencing. CT scans of the rest of his body showed widespread tumors throughout his lungs and in the lymph nodes of his abdomen and pelvis. The testicular mass was removed in surgery and revealed testicular cancer. M. asked him if he needed a biopsy of the other tumors,  and he told him he did not. From knowing that testicular cancer spreads by way of lymph nodes in the abdomen to the lungs and other organs, he concluded that the presentation, or entire picture, of his condition was compatible with all the masses being derived from the original cancer in his testicle. The same cells would be found in the other tumors. No further biopsies were needed. M. received four months of strong chemotherapy treatments, and his cancer went into remission. Additional surgery was eventually needed, but the cancer is, we hope, cured.

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6. Understanding How Cancer Spreads

The ability of a cancer cell to spread - to break away from the original tumor and grow in another location in the body - is a defining trait of cancer. In normal tissues, the cells are tightly bound and have snug “stitching” between them, like the patchwork pieces of a quilt. Benign growths, such as moles or warts on our skin, are also made up of cells that are tightly bound and cannot travel or invade the healthy tissue underneath them. For this reason, benign tumors are cured once they are removed.

Inside a cancerous growth, however, are cells that have found a way to separate from their neighbors, to loosen and dissolve the stitching that binds them. The freed cells can then be swept away by the flow of blood in a nearby blood vessel to other locations in the body. The ability of cancer to form new blood vessels is called “angiogenesis”; this property is essential for a cancer to grow beyond a very small size and to have a chance at gaining access to the circulation. Cancer cells also travel through another network of vessels, called lymphatic vessels. These channels drain our organs of excess fluid and debris and also serve as a highway on which immune cells travel throughout the body. Once cancer cells enter the bloodstream or lymphatic channels, few of them actually form metastases (fewer than 0.1 percent of circulating cancer cells). Some are killed in the circulation, whereas others die after a period of attachment to a distant organ. Even those that do establish a home in a new location may never develop into harmful tumors. Some will enter a period of prolonged dormancy, whereas others will multiply and die at equal rates, yielding a lack of net growth. These varied fates of disseminated cancer cells help explain how some metastases can manifest themselves ten or more years after the original cancer was treated: for unknown reasons, the dormant or nonproductive cancer cells suddenly acquire the ability to duplicate themselves successfully without limit.

If metastasizing cancer cells can be thought of as the “seed,” then the new environments in which they are trying to grow (most often the liver, lungs, bones, and brain) can be thought of as the “soil.” The “seed versus soil” hypothesis of cancer growth was first introduced more than a hundred years ago. For the past century of cancer research, the focus has been on understanding how the seed grows, ignoring the contribution of the soil, but this is changing. We now know that the organs to which cancer cells spread must provide growth-promoting chemicals as well as a blood supply if the cells are to grow there; similarly, plants grow better in fertile rather than barren soil. Provocative new research suggests that one person’s soil may be different from another’s. In other words, one person’s liver may be more hospitable to cancer metastases than another person’s liver. The factors that determine these differences await further discovery. The final and most straightforward way that cancer spreads is by direct invasion of nearby tissues. A growing tumor can expand beyond the site of origin and take root in nearby structures. For example, a bladder cancer can break down the bladder wall and invade the nearby rectum; a large thyroid cancer can extend out of the thyroid and into the muscles of the neck; a lung cancer can invade an overlying rib and cause severe pain.

In these situations, the cancer is said to be “locally advanced,” in contrast to metastatic cancer, which is defined by distant spread in the body. The distinct ways in which locally advanced and metastatic cancers are treated we speak later. There are some common misconceptions about how cancer spreads. Some people avoid undergoing operations to remove cancerous tumors because of a mistaken belief that the disease is spread through the air during surgery. And I have heard patients wonder if cutting into a tumor as part of a biopsy before its removal, or even in the more definitive surgery, can spread cancer in the body. With regard to the first belief, cancer cells cannot become airborne, nor can they survive in the air even if they were to become airborne. Certainly, if this were the case, coughing or the sharing of body fluids could spread cancer.

Infections can be spread in these ways, but cancer cannot. With regard to the second concern, isolated reports of cancers tracking along biopsy routes have been reported, but this is not believed to be a significant way cancer is spread. In sum, a cancer diagnosis represents the point of discovery of a process that began with the conversion of a healthy, controllable cell into one that can grow (multiply), spread, and survive without regulation. These properties constitute the foundation of cancer. They are central to understanding the diagnosis, behavior, and treatment of any cancer.

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7. Diagnosis, Staging, Curability

 Real story

 I first met J. when he walked into my office with his children for a consultation. He was in his sixties, of average build, with a gentle face, curly gray-black hair, and the appearance of someone whose work was physical. He wore jeans and a T-shirt with a pack of cigarettes rolled up in one side. His hands were rough, his talk straight. I would later come to know him as a happy, garrulous, backslapping man, a man’s man who would do anything for his friends and family. In time, he would come to treat me as a son and endlessly philosophize about life, women, and what counted, hoping something would sink in that might do me good; sometimes I even managed to get a word in edgewise about his health.

On that day, however, J. was a crushed man, for he had recently been diagnosed with advanced cancer and told that it was “terminal.” Two weeks before we met, he had gone to the emergency room complaining of sudden, severe abdominal pain. A CT scan revealed multiple tumors in his abdomen and liver. Soon after, he underwent a liver biopsy, and it showed “poorly differentiated carcinoma.” He met with an oncologist who told him he had, not liver cancer, but a type of cancer called “unknown primary.” This diagnosis means that a cancer starts in an organ (such as the breast, pancreas, lung, or prostate) and spreads to other regions in the body but the original cancer can no longer be found. J. was told that he had a very aggressive form of it and that his life span would be measured in months, even with treatment. To make matters worse, J. felt that the doctor was matter-of-fact and offered him no hope, something he could not accept.

With his head hung down and eyes glazed red with emotion, J. gave me a soft-handed shake as he sat down. He shook his head to clear away the heavy webs of grief and spoke in a steady voice. “Doc, I’ve come to you because I know about you. I heard you came from that big cancer center in … I know what I have is not good, but I’ve come to you for hope. I need someone to help me fight this battle, even if I lose the war.” His devastated children nodded and touched him as if to transfer some of their strength.

It is moments like these that make me feel as though my head is in a vice. I so want to make things better. I want to be a magician, defy the reality of a bad diagnosis, and pull the proverbial rabbit from a hat. But I know the difference between wiggle room and a fait accompli. In this case, although I thought the other doctor would be correct in the end, I saw one little stone left unturned. “I spoke to the pathologist who read your biopsy. I asked him to perform additional testing on the sample, which can sometimes indicate the exact organ of origin. But he is unable do so because the sample is too small. Your first biopsy was taken under CT scan guidance. Though it may not change anything, I want you to undergo surgery so we can have a larger chunk of tumor for analysis.”

I felt that if I could not help him to live for much longer, I could at least give this man what he needed right then, a true sense of hope. He needed to leave my office believing that I believed there was hope for his survival and that I would fight for it. “Doc, I know you’re not a miracle worker, but I feel you’ll fight for me. I’ll do whatever you say if you think it can possibly help.”

The operating surgeon removed the needed piece of cancer but could do little more than that because of the large masses of tumors that filled J. abdomen and liver. Yet the surgery was worth it. The new pathology report changed the diagnosis. J. did not have a carcinoma; instead, he had a rare type of sarcoma (a tumor derived from the supportive, connective tissues of the body) called GIST.

When J. returned to my office with his wife, S., it was clear that his condition was deteriorating fast. His eyes had a sunken look, he was visibly in pain, and his belly was swollen. “J., you have a rare type of cancer called GIST, which stands for  gastrointestinalstromal tumor,” I said. “Our current methods of treating cancer with chemotherapy and radiation are useless against this cancer. But I have made some calls and found out that an important clinical trial is studying a drug called STI-571 to treat GIST. The drug is working wonders in patients with leukemia and appears very promising against GIST. I have spoken with the people in charge of the study. They’re expecting you.”

I walked them to the door and gave S. two prescriptions. On one I wrote “Oxycontin,” for pain. On the other I wrote “STI-571,” with the contact phone number. “Don’t leave the city without it,” I whispered in her ear. S. bear-hugged me and looked me right in the eyes, speaking volumes without words; she turned away and they were gone.

One month later, J. strutted into my office, and I laid eyes on a new man. “Hey, Doc, how are you? I’m great, no pain, eating again, hasn’t felt better in months!” He had an impish grin and twinkling blue eyes and gripped me in a strong handshake.

J. was in the original group of patients who received STI-571 (later named imatinib/Gleevec) in a clinical trial that demonstrated its remarkable activity against GIST. He went on to live another two and a half very enjoyable years and touched the lives of many others.

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