please see my entry on this topic at WebMD
I recently met a patient who asked me to be his oncologist, requesting a change from his present oncologist. I knew that his oncologist was a skilled and kind physician so I wondered why.
"Why would you like me to be your doctor now?" I asked.
"Because Dr. X wanted to give me that drug Avastin! The FDA has just taken away approval for that drug. He wants to give me a useless therapy, so I have no faith in him," he replied.
"But you have colon cancer and Avastin is approved for that use and can improve the effectiveness of chemotherapy. Its rejection by the FDA was only in breast cancer."
"Still, I don't want it. I read the New York Times articles on it and it doesn't work," he said.
We chatted for awhile longer and I tried to get him to understand that one drug can have different effects on different cancers, work for some, fail for others. I convinced him to go back to his regular oncologist, who had recommended an appropriate treatment for him.
Avastin works by diminishing the blood flow to a cancerous tumor and often helps chemotherapy to work. So is Avastin a useful drug against cancer? There are different ways of looking at this question. At the level of drug approval, Avastin is FDA approved to treat a variety of cancers including metastatic colorectal, lung, and kidney cancer as well as glioblastoma (a brain tumor). It gained this approval in the first two because it improved overall suvival of patients when added to chemotherapy (the benefit was 4-5 months for colorectal and 2 months for lung). In the case of glioblastoma, the FDA approved it based on small trials showing a benefit in a cancer that desperately needs new treatments (the gold standard randomized, phase III trial was not required). The drug was approved for use in metastatic breast cancer when one trial did show an overall survival benefit but this approval was overturned when additional clinical trials failed to demonstrate a similar benefit; also the drug has toxicities so if there is not a real benefit, then the risks outweight the gains and it is best not used.
The drug is not FDA approved for ovarian cancer although it is commonly used now to treat this cancer. In other cancers, such as metastatic pancreatic and prostate, the trials with Avastin failed to show a meaningful benefit, so the drug is not used in these diseases. Basically, at this point, Avastin has been tested against every common cancer; it is helpful in some and not helpful in others.
As a single agent to treat cancer, Avastin is just not very potent. From both the published literature and my personal experience in treating a variety of cancer patients (and talking with colleagues who treat the cancers that I do not), I will state that overall, Avastin cannot actually shrink or control colon, lung or breast cancer without the addition of chemotherapy. It can however control/stabilize or even shrink, for a period of time, glioblastomas and ovarian cancers that have been previously treated. I have actually been quite impressed with the ability of single agent Avastin to shrink and control for six months or more, advanced, heavily pre-treated ovarian cancer.
All of the above aside, Avastin may still benefit some individuals with breast cancer. The big problem is we cannot predict who they are. Many patients petitioned the FDA to retain access to Avastin because they believe the drug is benefiting them; I have no doubt that this is true (it would be optimal if the FDA could find a way to allow such patients to continue the drug that is clearly benefiting them). But the FDA has made a decision that not enough patients benefit or we cannot determine ahead of time who they are, so Avastin cannot be recommended across the board for all patients with advanced breast cancer, especially in light of the possible severe side effects with the drug and its exorbitant cost.
The cost of cancer medicines is breaking the banks of Medicare and patients (private insurers continually raise their rates to cover costs) as well as forcing the closing of many oncology practices across the country. Access to basic cancer care and medicines is being jeopardized because of the exorbitant costs of the new biologic medicines. Unless these medicines can show at least a meager, repeatable improvement in survival for patients battling cancer, then they should not be approved and patients should not be given them in false hope.
There is good news on the prostate cancer front. Whereas men first diagnosed focus on whether or not to treat the disease and if so, whether to use surgery or radiation, many will also have to receive treatment when the PSA rises or the disease turns metastatic years down the road. This is where the new progress has been.
Within only the past year, the FDA has approved a new cancer vaccine (Provenge), a new chemotherapy drug (Jevtana) and a new hormone therapy (Zytiga) to treat the advanced stages of prostate cancer, which typically involves metastases to the bones and abdominal lymph nodes. Previously, oncologists prescribed chemotherapy when hormone therapies stopped working. Now, they can prescribe Provenge if the cancer is not causing pain and hope to stave off the initiation of chemotherapy for some time. Once chemotherapy is needed, the main drugs previously available were docetaxel (Taxotere) and mitoxantrone (Novantrone). Now, most oncologists will use Zytiga and then Jevtana after Taxotere stops being effective. These new advances will undoubtedly lead to prolonged survivals for many men battling stage IV prostate cancer.
Another recently announced advance affects even more men, the 30% of men treated for local prostate cancer who will subsequently experience a rise in the PSA years before the development of metastatic disease. Traditionally, urologists have administered testosterone blocking medicines such as Lupron, which can lower the PSA for years. Unfortunately, the big side effect of these medicines is impotence; other side effects include hot flashes, bone thinning, loss of muscle mass, loss of body hair, increased risk of heart disease and gynecomastia (growth of breast tissue in men). A recent study showed that when the PSA rises after initial therapy and androgen blockade is used, these injections can be given intermittently rather than continuously without interruption. This means that testosterone can rise at times, allow potency and improved quality of life, but not affect overall survival. Intermittent hormone ablation therapy will greatly improve the quality of life of men with prostate cancer.
The bone marrow biopsy is a mysterious and often feared procedure. This should not be the case. In reality, it is a very safe and important test that is usually associated with only minor pain and discomfort. The procedure is performed by a blood specialist (hematologist), usually to evaluate an abnormality of the blood counts: if the red blood cells, white blood cells or platelets are too high or too low or when a blood cancer is suspected (the three main types are leukemia, lymphoma and multiple myeloma). To learn about blood counts and blood cancers, please consult my book.
There are two parts to the procedure, the aspiration and the biopsy. The most important part, however, is the preparation. [Caution: stay off other internet websites that scare the dickens out of people about this procedure!] The patient is made to expose the hip areas (lower pants and underwear to just above the knees) and to either lie on their side or flat on their stomach. The doc then sterilizes the skin over the area of the bone called the iliac crest (top of the ilium or hip bone); this will feel wet. Then he/she will inject a little lidocaine under the skin, which smarts (like getting that first novacaine injection by the dentist). Then a longer needle is passed under the skin to the outer surface of the iliac crest and this area is generously injected with lidocaine; this usually does not hurt and the patients feels only numbness wthen the doc probes with a sharp needle. Once this important preparation is done, the rest should go easily for the patient and the hematologist.
Next, the aspiration is performed. The doc will insert a special aspiration needle into the bone, just under the surface, to penetrate the squishy innter marrow. He/she will then suck out a few cc's of liquid marrow into a syringe; this will feel weird and sometimes can be painful for a few seconds. Once the liquid marrow is obtained, the aspiration needles is withdrawn. The liquid is divided into three portions: 1) Spread on a slide to analyze the individual marrow cells; 2) Sent for genetic/DNA analysis; and 3) Sent for flow cytometry. Please consult Fighting Cancer with Knowledge and Hope to learn more about these tests.
Finally, a longer needle which has an inner trochar surrounded by an outer hollow shell is inserted into the bone. The doc will first penetrate the outer bone and remove the inner trochar. He/she will then twist and turn the hollow "coring" needle and apply gentle pressure to go in about 2-3 centimeters. The biopsy specimen is inside this needle and once the pushing stops, the doc will grip the specimen by the flip of a switch on the needle (or other method depending on the kit) and remove the entire apparatus. The patient experiences a strange sensation during this portion of the procedure; sometimes there is a moment of sharp pain but often there is not. Once the doc is done, the assistant will clean and dress the hole (smaller than a pencil eraser) and the patient is usually asked to rest for a few minutes to allow the stress of the procedure to pass.
That's all there is to it! Though not pleasant, the bone marrow biopsy is safe, important and usually performed in 15 minutes (allow an hour for preparation before and rest afterwards).
I know what you are thinking. "There is an error in the title of this blog post! Chemotherapy destroys the immune system! How could it boost the immune system? What is this guy thinking?" Well, let's take a look at things from another angle.
As an oncologist for nearly twenty years, I have cared for a great many patients with cancer. I have always been amazed at how certain individuals diagnosed with an incurable cancer live years beyond their expected prognoses whereas others succumb much sooner. Researchers have been unable to explain why this is so but for cancers such as pancreatic cancer, no clearly identifiable factor of either the cancer or the patient can predict who will do well with treatment and who will derive little benefit. One important area of cancer control that is difficult to measure is a patient's immune response to their cancer. Could it be that differences in the immune systems amongst individuals determines survival or that cancer treatments such as chemotherapy can actually boost the immune system in certain situations? I went searching the medical literature for some answers.
Let's use the example of pancreatic cancer. The most commonly utilized chemotherapy drug to treat pancreatic cancer is called gemcitabine (Gemzar is the trade name). Most of my long term pancreatic cancer survivors have been on gemzar for years. So, I wondered if this chemotherapy or any chemotherapy drug can actually boost a patient's immune system to help fight their cancer. In fact, there are scientific reports of gemcitabine stimulating the production of immune cells called dendritic cells in the patients given the chemotherapy. Dendritic cells provide the bridge of recognition between the target of the immune system (such as cancer cells) and the T-cells that attack the target. Also, research testing novel ways of harnessing the immune system to recognize cancer have found that chemotherapy actually helps in this immune recognition.
All of this may seem out of left field because we are bombarded by the slogan, "chemo destroys the immune system." As I explain in my book, certain chemotherapy drugs can reduce the numbers of infection fighting cells called neutrophils, leading to fever and infection. Fortunately, growth factors such as neupogen can speed the recovery of neutrophils after strong chemotherapy. But for other types of chemotherapies that are not so strong, such as gemcitabine, perhaps in some situations, in some patients, the chemotherapy is doing way more good than anyone suspects (except for a few researchers from Japan). Perhaps chemotherapy is killing cancer cells and boosting the immune system to fight the cancer all at the same time. Now that is food for thought and worthy of further study!
Recently in my practice I met an 80 year old woman with lung cancer. Her story began only a year earlier, when she underwent surgery at another hospital to remove a stage 1B non-small cell lung cancer. This is an early stage of lung cancer (out of 4 stages) with a 65-70% cure rate. But something went wrong only one year after surgery. She became suddenly short of breath and developed fluid around the lung that had been operated on. The radiologist and surgeon thought it was "post-operative" changes and monitored her. Her symptoms worsened, however, and the fluid in the lung was sampled and found to contain cancer. A PET scan showed that the cancer had metastasized to other regions of her body. So, at 80 years of age, with a rapidly growing, metastatic lung cancer causing her to be short of breath, have severe chest pain and lose weight and functional capacity, was there any real hope for her survival? Thanks to the modern era of lung cancer treatment, the answer is yes.
The patient was a non-smoker. Approximately 10% of lung cancers occur in non-smokers. In this population, the cancer is fueled by specific genetic changes, rather than the multitude of changes wrought by the carcinogens in tobacco. Two of these changes have been identified:
1) EGFR 2) ALK.
Today, if a non-smoking or remote smoker (last cigarette over 25 years earlier) develops the adenocarcinoma type of lung cancer, then the tumor should be tested for "mutations" in EGFR and ALK. For unknown reasons, EGFR mutations occur more commonly in women, whereas ALK mutations occur more commonly in young men.
If a patient's tumor has a mutation in EGFR, then the pill erlotinib (Tarceva) should be prescribed rather than chemotherapy as the inital treatment. If an ALK mutation is found, then referral to a clinical trial for an ALK inhibitor should be sought. The drug Crizotinib is the lead compound in this area. The great benefit of these targeted pill therapies is that they can result in excellent cancer responses, sometimes for years, and have greater convenience and fewer side effects than chemotherapy (although they do have side effects). Ultimately, most patients will still require chemotherapy as the beneficial effects of the targeted therapies do wear off. This is due to resistance of the cancer to these treatments; clinical trials of new drugs to overcome this resistance are also underway.
As for my 80 year old patient, her lung cancer had a mutation in EGFR, so I prescribed erlotinib. Three months later, she has a facial rash (like acne, that is treatable) but her chest pain is gone, shortness of breath improved and life as she knew it seems to be returning.
Clearly, the targeted therapy of lung cancer is the silver lining in a disease previously associated with only dark clouds.
This has been a tough week for breast cancer survivors. On the medical front, the benefits of taking extra vitamin D has come under question and the ability of the bone-strengthening drug Zometa to prevent a cancer recurrence may not be as great as we thought. On the personal front, the death of Elizabeth Edwards was a true, heartfelt blow to all cancer survivors and most people. Still, there are messages of hope in all of these events.
Vitamin D is an essential vitamin for strong bones. Adequate levels in the body are needed to prevent thin bones and osteoporosis. It is unique among vitamins in that the human body can make it upon exposure of the skin to sunlight. Beyond these established facts, however, lies a large body of suggestive medical studies that link the vitamin to the prevention of cancer and health of the immune system. In the past few years, a medical bandwagon has arisen that doctors and patients have jumped onto. Many patients have vitamin D levels checked by their doctors and many are told they are deficient. Many more individuals who are not deficient believe that extra vitamin D can improve their health, even prevent cancer, and take thousands of units of extra vitamin D daily.
But how much proof is there that extra vitamin D can prevent cancer? What levels in the blood define vitamin deficiency? Can a person take too much vitamin D and do themselves harm? These questions were the topic of an important new report from the Institute of Medicine, entitled "Dietary Reference Intakes for Calcium and Vitamin D." The researchers who wrote this report reviewed all of the available evidence about calcium and vitamin D and answered the questions posed above. I obtained a copy of this report and reviewed its 300+ pages. It should give us all pause. Essentially, the committee concluded:
I recommend that everyone check out the weblink above and read more about the recommended intake of calcium and vitamin D. Future studies may be able prove a stronger link between supplemental vitamin D and the prevention of cancer; in the mean time, don't overdo it.
Zoledronic Acid to Prevent a Cancer Recurrence
In 2009, a study of 1803 premenopausal women with early stage breast cancer who were treated with endocrine therapy (such as Tamoxifen) after surgery were randomized to receive (or not receive) infusions of the bone-strengthening drug zoledronic acid (Zometa). Zometa is commonly used to treat patients whose cancer has already spread to the bones. The aim of the study was to determine if the drug could prevent a cancer relapse if used early in the course of the disease. Indeed, Zometa did show a statistically significant (3.2% absolue, 36% relative) reduction in the cancer relapse rate. But this was just one study. Still, there was great enthusiasm for it and many oncologists awaited confirmatory studies. Unfortunately, a study just presented and reported on in The New York Times did not support the above study. At this time, the role of zoledronic acid in the prevention of breast cancer remains unproven; most oncologists will likely reserve its use for postmenopausal women. Further studies underway will clarify the best way to use Zometa and a newer bone-strengthening drug called denosumab.
Regarding Elizabeth Edwards, I can only extend my sincere condolences to her family and many friends. She was an extraordinary, highly gifted woman who faced incredible challenges in her life with which we can all empathize. As the son of a single mother who raised three children on her own, I am sensitive to the struggles of such women. I listened to the audio version of her book Resilience, in which her poignant, searching voice brought the listener just a little closer to the tragic events in her life, such as the loss of her son and private/public betrayal by her husband. Cancer, in comparison, seemed to be something she was just going to deal with. She did so with incredible dignity and resilience. Cancer survivors can honor her memory by trying to do the same, as hard as that may be at times. Appreciate each day of life, it is the greatest gift.
I am grateful to Kathy LaTour and CURE Magazine for the review of my book just posted on the CURE website. Please check it out!
The most precious things in life are life itself, good health and the happiness and well-being of our loved ones. When a person is diagnosed with cancer, these important things become jeopardized. Life itself may be shortened by the cancer or at least have the potential to be. A person facing an incurable cancer must balance the reality of the diagnosis (the "expected" outcome) with the hope and real possibility of a long survival; many understandably even hope for a cure against the odds. This balance is best achieved with the guidance of a supportive physician who understands the range of a poor prognosis (for example, some may live the expected six months with advanced stage pancreatic cancer whereas others may live many years) and never takes hope away. But this skilled clinicial will also be frank with their patients about when treatments will no longer likely work and when it is best to focus on pure comfort and freedom from symptoms and chemotherapy until the end of one's life. These are hard discussions to have and take skill wrought through experience and true concern for one's fellow human beings; some call it compassion.
Yet, many in our country do not have such discussions with their physicians. Either the physician does not discuss prognosis enough or a patient is not ready or willing to discuss the reality that they have been affected by a disease that will likely take their life. In the case of incurable cancers that have been treated with all known effective therapies, some physicians continue to discuss another type of chemotherapy at a time when the discussion should be about no more chemotherapy. Some patients embark on inconvenient journeys to big cancer centers in the hopes of finding cures that don't exist. Some travel and put themselves through needless stress for the same treatments that can be delivered close to their homes, by highly experienced oncologists who choose to practice in the community rather than in a big hospital.
These issues are eloquently discussed by Dr. Atul Gawande in a recent article in the New Yorker called, Letting Go. I highly recommend that every cancer patient and physician read this article. Discuss it with your oncologists. It will help you strike a balance betwen treatment and no treatment and help guide the important discussions about life and death that cancer patients must have with their oncologists. Rather than increase stress and anxiety, discussing these issues lessens anxiety by deepening the bond between patient and physician and allowing the patient and their loved ones to be clear about what is best when time is short.
There is alot of talk in the world of cancer today about "personalized cancer medicine" (PCM). PCM means that a cancer patient's treatment is specifically tailored to that individual's cancer based on the results of sophisticated genetic analyses, such as determining the complete DNA sequence (called the genome) of the cancer. PCM aims to deliver what oncologists and patients want and need: the right treatment for the right patient. This of course is the ideal. Some cancer organizations have declared that we are now 'in the era of personalized cancer medicine.' And start-up biotech companies are offering (for a price not covered by insurance) to perform a "genomic analysis" of an individual's cancerous tumor. So, it is timely and important to ask, Are we there yet? Are we at the point of being able to treat each patient uniquely based on the complete DNA structure of their cancer? The answer is actually no, we are not there yet. Still, mainy things can be learned about the cancer treatment of today and tomorrow by discussing PCM.
The Origins of Cancer and The Need for PCM
At its most basic level, cancer represents the conversion of a previously healthy, well-behaved cell in the body into a cell that can grow, spread and survive better than all the other cells. This transformation can only come about when the DNA of the cell becomes irreversibly altered. Not just a little altered but VERY altered. Recent analyses of the complete DNA sequences from a patient with leukemia and another with lung cancer disclosed tens of thousands of differences in the cancer DNA compared to the patients' normal cell DNA. The investigators whittled down these many differences to the dozen or so key genetic changes that drive the cancers and which could be targeted by drugs. But when they tested other patients with the same type of cancer (such as acute myeloid leukemia or AML), they discovered that although some changes are shared, many others are unique to each individual case. Truly personalized cancer medicine then would involve determining the DNA changes in each person's cancer and having at our disposal the medicines capable of blocking the key bad genes that are overactive and restoring the good ones that have been lost (these medicines are yet to be discovered, the main reason why we are not ready for PCM). Many good minds believe that being able to achieve this level of specificity in cancer treatment will lead to cures and billions of research dollars are being invested in this approach. No doubt, PCM will revolutionize cancer treatment. But if we are not at they point of PCM, where are we in the treatment of cancer?
The Modern Era of Cancer Treatment: Targeted Therapies
Today's cancer treatments do tailor therapies to patients to some extent. A traditional example would be the use of hormone therapies such as tamoxifen or letrozole to treat breat cancer that is estrogen receptor positive. A more up to date example would be to test a lung cancer for a mutation in a gene called EGFR and if a mutation is present, treat the patient with erlotinib (Tarceva) rather than chemotherapy; erlotinib specifically blocks the activity of EGFR. These treatments and many others are called "targeted therapies" because they target one or a few specific molecules in the cancer cell. Many cancers today are treated with targeted therapies, often in conjunction with chemotherapy. Additional examples include the use of Herceptin plus chemotherapy to treat breast cancer that is "Her2 positive;" the use of Rituxan to treat B-cell non-Hodgkin's lymphoma; and Imatinib (Gleevec), nilotinib or dasatinib to treat chronic myelogenous leukemia. The newest advances include PARP Inhibitors to treat breast and ovarian cancers and RAF Inhibitors to treat melanoma.
In fact, nealy all of today's advances in cancer treatment are based on the development of targeted therapies. Yet, although targeted therapies represent major advances in how cancer is treated, their main deficiency is that they are not leading to cures. Better outcomes, longer lives, better quality of life for sure, but not the eradication of cancer (so far). The reason is that each drug only targets a few of the genes that drive a cancer. And there are dozens that must be targeted. But it is not so easy as just combining two, three or four targeted therapies; there are often more toxicities with this approach and less success than anticipated.
The Way Forward
We are presently in the era of targeted therapies and this approach will continue for many years. Many new types of targeted therapies will be approved to treat cancer in the years to come. Clinical trials are widely available that are testing these new medicines and I encourage all cancer patients to inquire as to their availability. At the same time, researchers are making strides in reducing the cost and improving the speed of determining all of the DNA changes in an individual cancer. But this analysis will only be useful if we can act on the results: if the medicines are available that block the bad genes and restore the good genes that have been lost and if we know how to combine all these medicines in people without doing more harm than good. This will take many years to work out in clinical trials. For now, pay attention to advances in cancer, participate in clinical trials and don't pay for sophisticated, costly tests that your oncologist does not recommend.
I realize these issues are complicated. I am happy to answer your question, please email me!