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VERY GOOD NEWS

Cancer Statistics Report: Deaths Down 20% in 2 Decades - The American Cancer Society has announced its estimates of new cancer cases and deaths expected in the US this year. Read some of the most widely quoted cancer statistics in the world.

A New Era of Hope

Cancer was recognized thousands of years ago, but only recently have we felt comfortable mentioning “the C word” and discussing this disease openly. The pink ribbon and the yellow LIVESTRONG wristband are symbols recognized the world over and represent our collective hope for the conquest of cancer. We are more comfortable talking about cancer because of the many improvements in treatment that have come about in the past forty years. Almost everybody knows somebody who is a survivor. Advances are announced frequently in the news. Surgery is becoming less invasive, radiation therapy more pinpointed and intense.

Understanding the Chemotherapy Process

THE MODERN ERA OF CHEMOTHERAPY

Talking about chemotherapy is like talking about the weather: on any given day, in any part of the world, there can be perfect calm or there may be a blizzard. When discussing the side effects of chemotherapy, just as when discussing the weather, it is important to avoid generalizations and not lump all chemotherapy together. The specific drugs, doses, and schedules in which chemotherapy is given as well as the patient’s constitution determine how well it is tolerated. Whereas some chemotherapy regimens are very hard on the body, others are compatible with normal routines. Before receiving chemotherapy, patients are usually given fact sheets describing the possible (likely and less likely) side effects of each medicine as well as the opportunity to meet with an oncology nurse to talk about what to expect.

Fears about chemotherapy drugs can cause great anxiety among those about to undergo treatment. A great deal of misinformation exists about their side effects. Some of this is a holdover from days long gone when cancer patients receiving chemotherapy frequently experienced nausea and vomiting as well as a greatly diminished ability to prevent certain infections. We are now in the modern era of chemotherapy, in which many of the most severe side effects have been greatly improved by a host of medications.

My intent is not to minimize the serious side effects that chemotherapy can sometimes cause and about which there is ample information. My goal is to clarify the misconceptions about chemotherapy that I frequently hear from new patients in my oncology practice.

MYTHS AND FACTS ABOUT CHEMOTHERAPY

Myth: Chemotherapy always causes nausea and vomiting.

Fact: If you are about to receive chemotherapy, visit the infusion suite where your treatment will be administered. Look around. You will see other patients receiving intravenous medications. Some will be reading, others listening to music or having a conversation. You will even see many of them eating. But you will probably not see anyone vomiting. When a cancer patient sits down to receive chemotherapy, the first medications the oncology nurse will hang on the IV pole are not the cancer-fighting drugs but rather premedication’s or “premeds.” Premeds include antinausea and other medications that reduce the risk of side effects. Advances in new medicines that prevent nausea and vomiting have dramatically improved the tolerability of chemotherapy. As a result, the chemotherapy session is often anticlimactic, even uneventful. Once at home, nausea may or may not occur. It might begin the night of treatment or the next day. If nausea does occur, then antinausea medications should be taken as directed by your oncology doctor or nurse.

Before you begin chemotherapy, make sure your doctor gives you a prescription for one (or more) of these medicines in case you need them; better to have them on hand and unused than having to call for them at 3:00 am. If they are not sufficient, call your doctor’s office at any time of the day or night and speak to the oncologist on call for help.

The chances that nausea and vomiting will occur depend on the type of chemotherapy drugs administered and on the individual; every person will react differently. Your oncology team will tell you whether the drugs you will receive are associated with a low, intermediate, or high risk of nausea. Medications and other techniques to prevent the symptoms (such as sea bands, eating ginger, and smelling lemons) will be recommended accordingly. If after the first chemotherapy session you experience excessive nausea and/or vomiting, a change in antinausea medication will be prescribed to improve the situation for the next treatment.

Overall, most patients experience only mild nausea after chemotherapy. For some, nausea may last for one or a few days and then disappear. Others find that they always have a low level of nausea while undergoing therapy that does not prevent them from eating; still others come to expect “one good puke” the morning after that rights their systems. Whichever pattern you may experience, the management of this miserable side effect is infinitely better than it was a decade ago.

Myth: Chemotherapy wreaks havoc on the immune system.

Fact: This fear relates to the fact that some (but not all) chemotherapy drugs can lower the white blood cell (WBC) count and, consequently, the body’s ability to fight certain infections. The specific kind of WBC that protects against bacterial infections is called a neutrophil; a low neutrophil count is called neutropenia. A normal neutrophil count is above 1,800 in Caucasians and 1,400 in African Americans. The risk of infection rises substantially when the neutrophil count is less than 1,000 and especially under 500. Infection is often heralded by a fever called neutropenic fever. This can be life threatening when not addressed in a timely manner.

If you are receiving chemotherapy and you experience a fever (100.4 degrees or above), contact your oncologist right away, even if it is the middle of the night. Do not take fever-reducing medicines on your own and try to sleep it off. Owing to major advancements in science, medications now exist to bolster a person’s WBC and neutrophils; they have dramatically reduced the risk of severe infections experienced by cancer patients. They include: filgrastim (Neupogen), sargramostatin (Leukine), and pegfilgrastim (Neulasta, a longer-acting Neupogen), which are administered as subcutaneous injections. These “drugs” are actually natural chemicals made by our bodies to stimulate bone marrow function.

Surprisingly, most of the infections that affect the neutropenic cancer patient come from the body; the E. coli and other bacteria that normally reside in the intestinal tract are a major source. Other sources of infection may be rotten teeth, breaks in the skin, or catheters placed for the purpose of receiving chemotherapy.

Oncologists may prescribe a WBC growth factor in two ways:

(1) To treat neutropenia (and especially neutropenic fever) when it occurs after cancer treatments; or

(2) To prevent neutropenia through administration of the medication on the day or days following chemotherapy.

Only some patients undergoing chemotherapy will require the use ofa WBC growth factor. Their need depends on the intensity of the cancer treatment as well as on aspects of their condition and history. Patients who have had chemotherapy or radiation therapy in the past, those with low blood counts before starting chemotherapy (for reasons their doctor should investigate), and the elderly are more prone to develop neutropenia from chemotherapy.

It is important to realize that WBC growth factors do not eliminate neutropenia and the risk of infection; despite their use, strong chemotherapy will still cause neutropenia. Rather, by minimizing the duration or number of days of neutropenia, WBC growth factors limit the time during which a patient is most susceptible to infection.

Although there will always be a risk of infection with chemotherapy, the proper use of WBC growth factors and antibiotics, along with the oncology team’s close attention to the patient’s condition, has made “a wreck of the immune system” a thing of the past.

Myth: Chemotherapy always causes baldness.

Fact: Some but not all chemotherapy drugs cause significant hair loss. Science has not found a way to prevent this side effect. The hair will grow back, usually beginning about four to six weeks after the completion of therapy. In some cases, hair may regrow while a patient is receiving the chemotherapy that made it fall out in the first place (this does not mean that the chemotherapy is no longer working). The first growth is like peach fuzz; eventually resulting in a wavy, soft new head of hair (sorry, but gray hair will not come back as dark hair). In contrast, some chemotherapy drugs may only cause hair thinning, and others will have little effect on hair growth. Many patients find it best to prepare for possible or expected hair loss by visiting a wigmaker before their hair falls out and by cutting their hair short once chemotherapy has started; they should carry a prescription for a “cranial prosthesis” so that the cost is covered by insurance. Any cancer center is clearly full of individuals (patients and staff) who are familiar with this process and able to provide excellent advice.

Myth: Chemotherapy causes weakness and an inability to carry out normal activities.

Fact: If you are experiencing symptoms from cancer, then effective chemotherapy will make you feel better, not worse. Only when the cancer is treated can the body heal.

For any cancer patient, however, chemotherapy may certainly contribute to weakness. The longer treatments go on, the more likely it is that fatigue will be a part of a patient’s life. But this fatigue is usually not debilitating. Most patients undergoing chemotherapy will be able to function in their lives with some modifications. Parents may need help at home; workers may need to cut back their hours or take time off to complete treatment; travel is often minimized. The types of treatments and the patient’s physical condition and age are again critical determinants of the severity of fatigue.

Anemia, or a low red blood count, is one reason for weakness. Some cancers suppress bone marrow activity, which can lead to anemia before chemotherapy starts. Blood levels of folic acid, vitamin B12, and iron should also be checked; the oncologist may need to consider unrelated bone marrow disorders if severe anemia is present and unexplained.

When chemotherapy causes anemia, it is not immediate but rather emerges after two or three cycles of treatment. Chemotherapy may lower red blood production just as it does white blood cell production. In such cases, injections of red blood cell (RBC) growth factors, called erythropoietin (Procrit) or darbopoietin (Aranesp), are administered. Erythropoietin is the hormone that our kidneys normally make to stimulate the bone marrow to generate red blood; all patients receiving dialysis for kidney failure receive these medications.

Other factors that may contribute to weakness include insufficient rest, inadequate nutrition, depression, anxiety, stress, and psychological distress caused by what cancer is doing to the patient’s life. I encourage every cancer patient to discuss these issues with his or her oncologist and to seek help in addressing them with professionals such as clinical social workers and psychiatrists. There is no value in suffering through cancer and its treatments; the short-term use of medications or psychological counseling can do a world of good.

Myth: Chemotherapy destroys good cells along with the bad.

Fact: Each chemotherapy drug has a number of well-established side effects that oncologists discuss with their patients before treatment.

Most centers provide patients with chemotherapy fact cards or sheets that describe common and less common side effects caused by the drugs to be used. Similar to common medications filled by prescription, the lists of possible side effects from a chemotherapy drug are long (and often frightening). And like any other medication, only a fraction of the listed side effects will occur; the intensity of each side effect will also vary from person to person.

Just as only certain chemotherapy drugs cause significant nausea, hair loss, or fatigue, some drugs are associated with the potential to cause damage to the heart, lungs, kidneys, reproductive organs, or other organs. This damage, or decline in function, may be temporary or long lasting. It may be mild (not noticed by the patient) or “clinically significant,” which means that the problem is affecting the patient’s ability to function normally. In order to monitor “the rest of the body” and not just the cancer, vital organ function is tested at regular intervals during cancer treatment and for many years after treatment has finished.

It should be noted that if a patient has some impairment of vital organ function before beginning treatment (such as kidney insufficiency or congestive heart failure), then some chemotherapy drugs will be administered in reduced doses and others will be avoided.

Even for those chemotherapy drugs associated with damage to a particular organ, the damage is usually avoided if precautions are taken. For example, when the drug cisplatin (Platinol) was introduced in the 1960s, its anticancer activity was remarkable, but it also caused kidney failure in the first studies and was nearly abandoned. Fortunately, it was shown that if extra fluids were given intravenously along with the drug, kidney failure could be averted. Cisplatin went on to cure testicular cancer and is used safely today in a variety of cancers. Patients receiving cisplatin today are told to drink fluids liberally before and for twenty-four hours after administration.

As part of the education process before chemotherapy, cancer patients will be informed of any possible organ damage from the drugs they will receive and any precautions that may be taken to minimize these risks. Some side effects are hard to prevent, such as the sensation of tingling and/or numbness in the tips of the fingers and toes, called peripheral neuropathy. Culprit drugs include bortezomib (Velcade), cisplatin (Platinol), docetaxel (Taxotere), oxaliplatin (Eloxatin), paclitaxel (Taxol), vinblastine (Velban), and vincristine (Oncovin). Although the symptoms of peripheral neuropathy diminish over time, they may persist, even faintly, for months or years after treatment. Because of this, patients are monitored closely for early symptoms so that the treatment regimen can be altered (if possible) to prevent severe neuropathy. Oncologists may also prescribe medications to alleviate the symptoms, such as amitriptyline (Elavil), nortriptyline (Pamelor), gabapentin (Neurontin), pregabalin (Lyrica), and duloxitene (Cymbalta). The usefulness of supplemental vitamins E, B6, and B12 is under study. Caution: alcoholic drinks may worsen peripheral neuropathy.

Some chemotherapy drugs as well as radiation therapy may contribute to (or directly cause) the development of new cancers many years after treatment. Treatment-related cancers are called secondary cancers. This is not a common occurrence, although its frequency is not known with certainty because of the difficulty in distinguishing secondary cancers from new cancers that were destined to arise anyway. As more people are cured of cancer, the true incidence of treatment-related cancers will become clearer. Cancer survivors are routinely monitored for secondary cancers by their health care team.

If a particular treatment is linked to subsequent cancers, then researchers have tried to find equally effective alternatives. An example would be the change from a chemotherapy regimen called MOPP to another one named ABVD for the treatment of Hodgkin lymphoma; ABVD offers a lower risk of leukemia and even better outcomes. Also, lower doses of radiation are now being used to treat Hodgkin lymphoma in order to minimize the risks of future breast and lung cancers. Visit www.cancer.net to learn more about the short-term and possible long-term effects of chemotherapy.

Myth: Once chemotherapy is started, it cannot be stopped until the recommended treatment course has been completed

Fact: As a patient, the decisions to initiate and terminate medical treatments are your own. Chemotherapy may be stopped after the first cycle, the first injection, the first pill. If you are a patient and you feel strongly about terminating treatments prematurely, then it is extremely important that you discuss your reasons for doing so with your oncologist.

It may be possible to rectify unpleasant reactions to treatment or change the therapy to a more acceptable alternative. If in the end, you wish no further treatment, the oncologist should honor and respect your wishes. Yet the end of cancer treatment does not mean the end of patient care; ongoing physical symptoms and emotional distress caused by cancer will still need to be addressed. Good communication is the key to a rewarding and strong patient-physician relationship.

In conclusion, chemotherapy saves lives. It can cure some cancers and extend survival in many others. But the drugs can be unpleasant and cause unwanted side effects, even though the “chemotherapy experience” has dramatically improved in recent years. And it has been known for decades that chemotherapy alone cannot eradicate the advanced stages of the most common cancers. For this reason, researchers have been dissecting the molecular details of cancer cells in the hopes of uncovering targets for more selective and, it is hoped, more effective drugs. The targeted therapies that have resulted have already begun to revolutionize the management of cancer.

Understanding Targeted Therapies for Cancer

Targeted Therapies

A seventy-five-year-old woman with non-Hodgkin’s lymphoma was experiencing weakness and discomfort from enlarged lymph nodes in her neck. She had numerous other medical problems, and her health was too poor for chemotherapy. She received a targeted therapy called Rituxan for one month. She experienced only mild fatigue from the medicine. Her lymphoma responded completely, and she remains without evidence of the disease six years later.

A sixty-five-year-old man developed a recurrence of kidney cancer twenty years after it was removed. The cancer was extensive in his liver and pancreas, and he was extremely weak; it did not respond to interferon, and chemotherapy was felt to be useless. He was treated with a targeted pill called sunitinib (Sutent). Almost overnight he felt better, and after two months his cancer had shrunk dramatically in size. The cancer was controlled in this way for two years, with minimal side effects from treatment.

A fifty-year-old woman was admitted to our hospital with fever, abdominal pain, and jaundice. Her health had been declining for several months; now she could barely walk and couldn’t eat. She was found to have colon cancer that had formed extensive metastases throughout the liver. We initiated treatment with three chemotherapy drugs (known as FOLFOX) plus a targeted therapy called bevacizumab (Avastin). After a week she could leave the hospital. After two months of regular treatments, she was pain-free, gaining needed weight, and back to full activity levels. CT scans showed that the liver tumors had shrunk by more than 50 percent. After six months of treatment the liver tumors were barely detectable.

TARGETING THE CANCER GENERATOR

The best way to cure a medical disorder is to understand its causes and then block or reverse them. For example, coronary artery disease can be caused by too much cholesterol (along with other risk factors); one way to lower cholesterol levels is with “statin” drugs, which block an enzyme critical for its synthesis in the liver. Ulcers are caused, in part, by excess stomach acid; drugs that block the molecules responsible for acid production, such as omeprazole (Prilosec), help heal ulcers. The targeted therapy of many human ailments has proven to be effective and safe. A similar approach to the treatment of cancer has been the light at the end of the tunnel of cancer researchers for the past fifty years.

Some genes are overactive, leading to excessive cell growth, whereas others are underactive, allowing this growth to be unrestrained. Thus most targeted cancer therapies aim to shut down the function of an overactive gene or replace an underactive one (this is much more difficult). Many of the overactive genes are part of the communications network I described above; they give rise to receptors and signaling molecules that are always turned on. Like an electrical circuit that cannot be shut off, overactive receptors and signaling molecules repetitively fire, creating supercharged cancer cells that have their own internal generators.

The drugs described below aim to stop these misfiring: the result may be the restoration of calm and the slowing of growth or, better yet, the death of cancer cells. There are thousands of potential targets in cancer cells; advances in chemistry and computing are greatly accelerating the discovery of drugs that can bind too many of them. This class of drugs will likely represent the great bulk of new cancer therapies in coming years.

TARGETING RECEPTORS

Drugs like cetuximab (Erbitux) for colorectal and head and neck cancers, rituximab (Rituxan) for lymphoma, and trastuzumab (Herceptin) for breast cancer are administered intravenously. Once in the bloodstream, they act like heat-seeking missiles, locating cancer cells wherever they lurk and gripping onto them via one specific receptor target (among thousands of receptors) that projects from the outer surface of the cells. The result is that the receptors stop transmitting growth signals inside cancer cells.

Many drugs in this class are modifications of large molecules called antibodies, which our bodies normally generate against infectious agents such as bacteria. Cancer-fighting antibodies are also called monoclonal antibodies. Because of their structural similarity to infection-fighting molecules, cancer-fighting antibodies are also believed to stimulate the immune system to attack cancer cells once they attach to them. Monoclonal antibodies coat the surface of cancer cells, shut down receptor activity, and (hopefully) lead to cancer cell death. A second way to target cancer receptors is with drugs that pass inside the cell and bind to the parts of receptors in direct communication with the inner world of cells. Although the receptor can still receive signals from the outside, it cannot transmit these signals internally if it is bound by these drugs. The drugs in this class are commonly called small molecule inhibitors because they can pass freely into cells (their small size also allows them to be given as pills). Examples include erlotinib (Tarceva), approved for lung and pancreatic cancer; sunitinib (Sutent), approved for kidney cancer and GIST tumors; and lapatinib (Tykerb), approved to treat breast cancer.

TARGETING SIGNALING MOLECULES

The communications pathway from surface receptors to DNA involves hundreds of different molecules. Silencing a critical signaling molecule in this network can disrupt the growth and survival signals on which cancer cells rely. Without these signals, cancer cells can die. By analogy, suppose a courier has to deliver a package on the other side of a river and has to cross a bridge. But when he arrives at the bridge, he finds that it has collapsed; the package will not reach its destination. By shutting down important targets that a growth signal must use to travel inside a cell, drugs called signal transduction inhibitors effectively “collapse bridges” throughout cancer cells. Examples of signal transduction inhibitors include imatinib (Gleevec) for CML and GIST tumors and sorafenib (Nexavar) for kidney and liver cancer. Many new drugs in this class of cancer fighters will become available in the future.

TARGETING BLOOD VESSEL GROWTH: ANGIOGENESIS INHIBITORS

For a cancer to survive, it needs oxygen and nutrients delivered by an adequate blood supply. A growing cancer stimulates certain cells in nearby blood vessels to make new blood vessels for itself. These are called endothelial cells; the process of making new blood vessels is called angiogenesis.

Angiogenesis inhibitors are drugs that stop endothelial cells from forming new blood vessels. They do this by jamming their communications networks. Just as in cancer cells, endothelial cell growth signals are transmitted through receptors and signaling molecules. Drugs such as bevacizumab (Avastin), sunitinib (Sutent), and sorafenib (Nexavar) affect the function of these molecules, causing blood vessels that feed a cancer to wither and die. Angiogenesis inhibitors may also have a direct effect against cancer cells because some of their targets are also present on cancer cells themselves, not just on their surrounding blood supply; they may thus have a dual cancer-fighting effect.

TARGETED THERAPIES

Are targeted therapies “magic bullets”?

Although targeted therapies were developed with the hope that they would be magic bullets that would neatly eradicate cancer through the selective targeting of one critical molecule, in general they have fallen short of this lofty goal. No cancer is considered curable by treatment through a targeted therapy alone, except perhaps for some cases of CML treated with Gleevec. This does not mean that targeted therapies have not helped many cancer patients, because they have. It probably means that the bar was set too high and that researchers expected targeted therapies to be “home runs” instead of the singles and doubles they have turned out to be.

The reason for the muted success of targeted therapies is that most cancers are caused not by one genetic derangement but by several; no one target functions as an Achilles heel. The next generation of targeted therapies is being designed to block several communication molecules from functioning. In this way the “magic bullet” concept will likely give way to the “magic shotgun.”

Can targeted therapies be used instead of chemotherapy?

Targeted therapies have not eliminated the need for chemotherapy. The three patient vignettes presented at the beginning of this section illustrate the three uses of targeted therapies: (1) as an alternative to chemotherapy when both have activity against a cancer (such as in low-grade lymphomas, when Rituximab alone may be an effective therapy); (2) where chemotherapy has a limited role (such as in kidney cancer and GIST tumors); and (3) to complement chemotherapy (such as in breast, lung, and colorectal cancers). The combination of the most effective chemotherapy drug(s) plus a targeted therapy is becoming a prevalent way to treat cancer.

For example, because all cancers need a blood supply to grow, angiogenesis inhibitors are being successfully combined with chemotherapy to treat a broad array of cancers. Because not all targeted therapies work well with all types of chemotherapies, clinical trials are necessary to establish which combinations work best.

If angiogenesis inhibitor drugs decrease blood flow to a tumor, how can they improve the effectiveness of chemotherapy?

For any cancer-fighting drug to work, it must have access to the cancer through the bloodstream. It is therefore counterintuitive that angiogenesis inhibitors, which diminish tumor blood flow, should improve the effectiveness of chemotherapy. Here is one possible explanation why it works: Consider a new ball of string, neatly wound around and around into an organized pattern. Next, imagine giving that ball of string to a playful cat and returning an hour later. You would find a disorganized heap of string, with the strands nicked and torn in many places. Now imagine that the string represents blood vessels: the new ball represents the pattern of blood flow in a normal organ, whereas the string damaged by the cat represents the course of blood vessels in a tumor.

Angiogenesis inhibitors actually help reorganize the frantic pattern of tumor blood vessels by repairing the nicks that make them leaky and diverting blood from the most injured ones. As a result, tumor blood vessels become “normalized,” and blood distribution actually improves, though it is diminished overall. The result is that chemotherapy has improved access to cancers when given with angiogenesis inhibitors.

Do targeted therapies cause side effects?

Like any drug taken for any purpose, unintended effects may occur with these medications. Generally speaking, targeted therapies are easier to tolerate-less hair loss, smaller declines in blood counts, and less nausea. For example, Rituxan is much gentler than chemotherapy for lymphoma, and Gleevec causes far fewer side effects than interferon or a stem-cell transplant for CML.

Still, substantial side effects may occur with some targeted therapies, and they tend to increase the toxicities of chemotherapy when used in combination. For example, drugs that block a molecule called the epidermal growth factor receptor (EGFR) on the surface of cancer cells, such as Erbitux, Vectibix, and Tarceva (called “EGFR inhibitors”), often cause an acne like rash on the face and upper body that may be severe; helpful medicines include topical hydrocortisone cream 1 percent or 2.5percent, clindamycin 1 percent gel, pimecrolimus cream (Elidel), and oral doxycycline or minocycline twice daily. In the case of severe skin reactions, the targeted medicines may need to be stopped temporarily or their dosages reduced to allow the skin to recover. Interestingly, some rash is a good thing: patients who develop any rash with EGFR inhibitors usually experience better control of their cancer than those who do not. It is important to inform your oncologist when a faint rash begins and not wait until it has become very bothersome and prominent; early intervention is the best way to prevent severe skin reactions.

Another type of skin reaction to cancer-fighting medications, called “hand-foot syndrome,” may occur with the targeted therapies Sutent and Nexavar as well as with some chemotherapy drugs, such as Xeloda, Doxil, and 5-FU. In hand-foot syndrome, the hands and feet become dry, reddened, painful, and swollen; there may also be skin breakdown and blisters on the palms and soles. Moisturizers and emollient preparations such as Bag Balm and Udder Cream are often helpful, and your oncology team may recommend other measures. Again, early intervention is the key to preventing severe hand-foot syndrome. Finally, angiogenesis inhibitors constrict blood vessels not only inside tumors but also in other parts of the body. As a result, they often cause some degree of high blood pressure (which may require antihypertensive medication) and are associated with an increased risk for kidney damage, bleeding, stroke, and coronary artery blockage. Patients with a history of these or other medical conditions may not be suitable candidates for these drugs.

Your oncologist will discuss the possible benefits and risks of taking any targeted therapy with you. As always, the choice of cancer therapy depends on the optimal treatment for the disease, your health, and your preferences.

Visit www.cancer.net  and learn more about managing the side effects of targeted therapies.

Will targeted therapies be tailored to each patient in the future?

Patients want to take drugs that will work for them, and doctors only want to prescribe such drugs. The advent of targeted therapies offered the promise of matching the choice of cancer-fighting drug to measurable characteristics of a patient’s cancer. For example, if drug A targets molecule Z on cancer cells, then those cancers with the most Z should respond the best to drug A. But in what has been the source of great frustration to patients, physicians, and researchers, this simple relationship has not held up for many targeted therapies.

For example, Erbitux binds specifically to EGFR. Yet the amount of EGFR on a person’s cancer cells does not predict how well the cancer will respond to Erbitux. Similarly, Tarceva and Iressa are small molecule inhibitors of EGFR that are used to treat lung cancer; the likelihood of a cancer responding to these drugs is only weakly related to the levels of EGFR present on the cancer cells.

So what does determine the response to a targeted therapy if not the presence of the target? It turns out that for several targets, its structure or shape rather than its absolute amount best determines how a cancer will respond to a targeted therapy. For example, if a lung cancer contains an abnormal (mutant) form of EGFR, then there is a much greater chance that Tarceva or Iressa will shrink the cancer; such mutations are found in only 10 percent of all non-small cell lung cancers, often in those who either never smoked or stopped smoking more than twenty-five years before their diagnosis.

New techniques are emerging that will make it easier to detect overactive communications pathways or mutations in specific molecules in the tumor specimen of each patient. In the future, cancer therapies will increasingly tailor the medicines chosen to the specific molecular alterations contained in any given cancer rather than relying only on the type of cancer a person has.

Are there other kinds of targeted therapies besides those discussed?

You’ve heard the saying, “Build it and they will come.” Well, if a target exists in cancer cells, then scientists will try to target it. Hundreds of targeted therapies are currently being tested. Many will targetcancer cells directly, and others will target the immune system, tumor blood vessels, or the normal organs in which metastatic cancers grow (such as the bone and liver). Some will be specific to one cancer type, others broadly active against a large number of different cancers. Access to some of these new treatments can be found at www.clinicaltrials.gov.

Whenever possible, support cancer research to help bring new therapies to the clinic.

Cancer in Older Adults

Hormone Therapies

Breast and prostate cancers are unique among cancers in that they depend for their survival on the body’s hormones. The discovery that manipulating the endocrine system could affect the growth of cancer was made in 1896, when a Scottish surgeon named Sir George Beatson reported that several women with advanced breast cancer experienced dramatic shrinkage of their tumors after he removed their ovaries. By performing this surgery, Beatson had removed the major source of the hormone estrogen from the women’s bodies. Although estrogen had not yet been discovered, he knew that the ovaries could powerfully influence breast activity after observing that farmers removed the ovaries of cows after they gave birth, causing them to produce milk indefinitely. Fifty years later, other pioneering surgeons found that castration induced remissions of advanced prostate cancer; in these cases, production of the hormone testosterone was drastically reduced.

Researchers continue to focus on ways of manipulating the endocrine system in order to treat or prevent breast and prostate cancers. Surgery to remove the ovaries or testes remains an important weapon. In addition, an expanding array of drugs has become available. Some provide an alternative way of lowering estrogen or testosterone levels, whereas others prevent the hormones from acting once they reach a cancer.

THE BASIS OF HORMONE THERAPY

All hormone treatments ultimately work by blocking the signals generated inside cancer cells by estrogen or testosterone. Like a plant deprived of sunlight and water, hormone-dependent cancers cannot survive without their hormones. Therefore, the therapies that are commonly called “hormone treatments” are actually antihormone treatments.

How does estrogen initiate each menstrual cycle? How does testosterone induce facial hair? Why do these hormones stimulate breast and prostate cancers to grow? Whichever hormone function we consider, they all boil down to the actions of two pairs of molecules: estrogen plus the estrogen receptor (ER) on the female side and testosterone plus the androgen receptor (AR) on the male side. The ER and AR are collectively called hormone receptors.

The attachment of a hormone to its receptor inside a cell is like a baseball landing in a mitt.

In contrast to the growth receptors described before, hormone receptors exist inside cells, not on their surfaces. Once a hormone enters a cell and finds its receptor, the two go together to attach to DNA. This attachment turns on the DNA and results in the activation of a multitude of genes, accounting for the cell’s response to that hormone. For example, breast cells respond to rising levels of estrogen during puberty by maturing; breast cancers that contain the ER (75 percent of them) respond to estrogen by proliferating. Regardless of the type of cell affected, all of these hormonal changes are caused by estrogen binding to the ER. There are two main approaches to stopping the hormonal stimulation of cancer. The first is to reduce the levels of estrogen or testosterone by halting its production. In breast cancer, leuprolide (Lupron), goserelin (Zoladex), and similar medicines prevent the ovaries from making estrogen by blocking cues from the brain that regulate the ovaries. Anastrazole (Arimidex), exemestane (Aromasin), letrozole (Femara), and otheraromatase inhibitors prevent fat and other body tissues from making estrogen. In prostate cancer, Lupron and similar medicines prevent the testicles from manufacturing testosterone by blocking cues from the brain that tell them to do so. Ketoconazole prevents the adrenal glands from making testosterone.

The second approach is to prevent the hormone from attaching to its receptor. The following drugs bind to hormone receptors, blocking estrogen and testosterone from binding to them; as a result, these hormones cannot influence cell behavior. In breast cancer, tamoxifen (Nolvadex) binds to the estrogen receptor and blocks estrogen from binding to it. Fulvestrant (Faslodex) binds to the estrogen receptor and causes the cell to destroy the receptor so that estrogen has no target. In prostate cancer, flutamide (Eulexin), bicalutamide (Casodex), and nilutamide (Nilandron), called antiandrogens, attach to the androgen receptor and prevent testosterone from binding to it. The use of Lupron (or similar drugs) plus an antiandrogen is called “complete androgen blockade”: Lupron dramatically lowers (but not to zero) the amount of testosterone in the bloodstream, and the antiandrogen prevents any remaining testosterone from binding to its receptor. Without the hormonal signals that sustain them, breast and prostate cancer cells wither and die.