This is dr kevin ryanmd mba facp and hematologist oncologist here, medical oncologist professor and retired colonel and cancer survivor and this is when tumor is the rumor and cancer is the answer. Modeled after my non profit book of the same name available on the web site of the same name you can find it on the web site and a lot more, interviews, films excerpts on the site and it is also available on amazon in all formats it is also on my blog off the web site say name and on www.w4cs and in a few days iheart radio
Think of this show as a mixture of nova and the wonderful world of disney- what is chemo and how does it work
For this show the word “chemotherapy” when used without any modifying terms, will refer to drugs used to fight malignant cells. Typically, these drugs are given in some kind of standardized regimen, either alone or in some well thought out rationally designed and previously tested and developed manner to fight cancer. We are not talking about immunotherapy and targeted molecular therapy although you can make an argument for the former being included
Sadly and fascinatingly, the field owes a lot to the observed effects and later understood chemistry of what lethal mustard gas was doing to humans in ww i. Without too profound a modification, so called nitrogen mustard became one of the first successful agents against human malignancy. Then the fda and national institutes of health and national cancer institute for all intents rose to master the how of safe and expedient new drug development and testing .
The noticing of the mustard gases’ affect on the bone marrow in patients with cancers of cells of part of the immune system, known as lymphomas, led in december 1942 to several patients with advanced lymphomas getting the compound by vein with massive improvement that was dramatic but short lived. After the war records were declassified, the race to exploit what these drugs were doing and use of them against cancer was underway. Soon, mustine, the first chemotherapy drug, was developed. Since then, many other drugs were used in combination and remissions with cures of some lymphomas, one in particularly known as hodgkin’s disease or hodgkin’s lymphoma were being tentatively reported. After that, drug development has exploded into a multibillion-dollar industry, although the principles and limitations and rules of new chemotherapy development discovered by the early researchers still apply.
Cancer cells not only tend to divide and have children or daughter cells more often than their normal counterparts, they keep doing it, your liver does not keep growing, it knows when it has reached just right “liverness” and if the injury is not too bad it will regenerate right back, after some types of injuries, to just right “liverness”- no more no less. Not so with malignancy.
Chemotherapy can try to take advantage of that growth trait of cancer cells but this means one may see affects on other rapidly dividing cells such as bone marrow, digestive track, and hair follicles. Obviously, and particularly in the case of the bone marrow, decrease in normal marrow contents can occur known as “myelosupression”, this can be dangerous and require careful monitoring and support. This is when and if red cell counts fall with serious anemia, platelets fall increasing the risk of bleeding and certain types of white blood cells fall dramatically increasing the risk of infection.
Notionally, the overarching purpose of cancer chemotherapy may in some cases be expressed as palliative, which means there is no hope of cure. In such cases, the treatment is intended to alleviate symptoms and perhaps prolong life and do so in a manner the patient agrees was worth the effort as it is often not free from toxicities that must be weighed against benefit.
Then there is therapy clearly planned as a regimen intended for cure. This is an all out attack against all the cancer cells with or without surgery or radiation or other therapies as part of the plan. Thus, the oncologist will tend to give doses known to have the power to kill cancer cells and support the patient through the dangers and toxicities possibly requiring hospitalizations or transfusions or other support, as the goal of cure is possible. Dosing at full dose and on time is a consistent theme.
Then there is the use of chemotherapy before a primary modality of therapy, which might be radiation or surgery, to reduce the burden of cancer cells and eradicate non-local metastasis or sites of spread as well as make surgery more feasible with a better result. This is called neoadjuvant chemotherapy and it may have cure as intent.
In contrast to neoadjuvant therapy, adjuvant chemotherapy is a post-primary treatment modality or given after primary treatment, typically radiation or surgery, to mop up supposed remaining local, as well as distant cancer cells. This therapy is done based on the understanding for a particular cancer that both local or especially distant development of cancer is at risk to occur post original therapy but may not ever or rather take a long symptom free time to do so with the adjuvant therapy being given after local therapy. It is done also because it is known to decrease the risk of relapse especially when one looks at the original stage remember these are all individual decisions
| There are about 500 drugs approved and mainly used for the treatment of or directly in principal support of the treatment of human cancer. Broadly, chemotherapy is the treatment of cancer with drugs that can destroy cancer cells by impeding their growth, reproduction and spread. Thus we can broadly classify drugs by names that are meaningless to many but will ring bells with anyone one who has taken a few chemistry courses.
Amazingly, many of these come from stumbled upon observations in the plant and animal kingdom. Others are products of so-called rational drug design. The national cancer institute (nci) and other nations institutes has played an active role in the development of drugs for cancer treatment with over half of those drugs currently used coming from the us national cancer institute (nci) drug development program. Consider this; over 400,000 compounds have gone through nci screening and are in its drug repository of which 80,000 have been screened since 1990. Drugs can enter any level of this program depending on how much is already known regarding them. Thus, it is a system designed to not waste time. The nci supports the majority of clinical trials in the world with over 1500 ongoing at one time which have some major nci connection. Then there are some private foundation funded trials and university trials and other nations bringing the total to over 2000 ongoing per year in the u.s., representing well over 70% of all trials worldwide.
The sales of cancer drugs will grow at nearly double the rate of the global pharmaceutical market and may pass $150 billion by 2018, according to ims health, the leading provider of information services for the healthcare industry who covers markets in 100+ countries around the world. Expensive new treatments, an increasing number of patients on chemotherapy in major markets and evidence that more people in emerging markets are gaining access to modern targeted therapies will contribute to sales of cancer drugs growing at a compound rate of 12 to 15 percent, ims said.
In 2008, u.s. Sales of oncology products exceeded $50 billion. This comprises nearly 17 percent of all of worldwide pharmaceutical sales growth for that year. As techniques to diagnose disease earlier as well as detect spread or metastatic disease earlier develop and the understanding on a genetic and immunologic basis of each patient’s cancer cells abound, much more elegant and specific therapies will rapidly shuttle their way through the fda’s drug approval pipeline. This will not slow down.
In 2007, titus plattel, ims vice president for oncology showed laser accurate vision when correctly predicting that, “double-digit sales growth in oncology drugs (would be) fueled by increased use of targeted therapeutic agents introduced over the past 10 years… (in addition to ) first-time innovations coming to the market and longer treatment periods for growing numbers of patients,” indeed, since 2007 over 60 new and important chemical entities were released as safe and effective either alone or in combination with other drugs or types of therapies contributing to the exploding cost of treatment.
The more we learn of the why of the development of malignant cells that escape or overcome immunologic surveillance and destruction and the how of their potential and timing for spread on a basic science , genetic and immunological and clinical level, the more that knowledge will be exploited. The distance from laboratory bench to patient’s bedside will continue to shrink as not only new drug classes with mechanisms of action helpful to many sufficiently similar patients will be proven safe and effective but the more so-called tailor made therapies for your specific cancer could become a reality.
“ten years ago it was all about chemo,” said dr. Kim lyerly, director of the duke university comprehensive cancer center at the 2007 american society of clinical oncology annual meeting (largest cancer care meeting in the world). “this time you walk down the convention center and it’s all about new targets. And we can get more mileage out of these drugs if we can predict who will respond.”
Here is a brief explanation of the how of present anti cancer chemotherapy therapy.
Chemotherapy is the use of powerful medicines to kill cancer cells. However, not all chemotherapy agents act the same way. Some of the newer therapy is aimed at specific targets within cells and not principally at highly dividing ( multiplying) cells. Nonetheless, the idea is either to try to exploit some level of an achilles heel present in the malignant cell that is either absent or not as crucial for cell survival in healthy cells. This can be done directly or by means of a cascade of events.
Some chemotherapy drugs affect the behavior of cancer cells without directly attacking them and some directly attack the dna of the cells, preventing them from multiplying or by triggering their ultimate demise. Others do not act directly; they target the molecular abnormality in certain types of cancer. Depending on their biochemical mode of action, chemotherapy drugs (also called an antineoplastic or cytotoxic drug that means toxic to cells or cell killing) are grouped into different therapeutic classes i will mention you may find it useful to have a deeper understanding of just what drugs are being used and why. Feel free to talk with your treating physician regarding these drugs and their combinations. This may also be of great help when looking on the web for new clinical trials and treatments with different combinations than what you have seen. It will also help you understand the differing spectrum of toxicities that may occur with these drugs. By no means is this a chemistry course but it is a window of clever attacks by anticancer drugs
Alkylating agents (also called dna damaging agents): alkylating agents form chemical bonds with the dna of cells of all kinds but more so with those that are more actively dividing (more target available). The drugs incorrectly link rungs on the ladder like structure that dna can be envisioned as; a ladder of two legs of what are called nucleotides that match up only one complementary or matching like a puzzle base pair at their ladder rungs. The pair called a always matches up with t and g always matches with c at the rung area. Then the whole ladder is twisted and folded. The explicit pattern of those “rung-connected pairs” with nonsense spaces and other fillers and such is your dna. That code, when read through unzipping and sending a messenger of the unsoiled code to protein factories of the cell are instructions for proteins of all the functions of your body. If the code is wrong or unreadable all manner of havoc can break loose in this intricate system. Alkylating agents can stop tumor growth and set the stage for tumor cell death directly or in time by creating cross links of chemical bonds in the ladder of the two complementary strands that should not be there. So linked, cells cannot go through the normal cycle of cell division, repair, and production of daughter cells as they are unable to reproduce their dna, an essential step to cell division . Alkylating agents include several drugs, the most common are: cisplatin, carboplatin (paraplatin), ifosfamide, chlorambucil, busulfan, and thiotepa.
Anti-metabolites: these anticancer agents work by inhibiting the synthesis of nucleic acids (dna, rna), which are essential in cell division and the making of daughter cells. So, while not making wrong chemical bonds as the drugs above, the outcome is very similar. Normal cells which divide rapidly will be adversely affected. The benefit comes from the fact that unless and until cancer cells show resistance specifically (unusually) or generally to these drugs, they are often initially more sensitive to the effects of these drugs than normal cells during the necessary processes of cell multiplication. In nature, cancer cells divide more frequently than normal cells; and therefore any halt in cell division affects cancer cells more than healthy cells.
The antimetabolites are among the oldest chemical agents used in chemotherapy and are broadly divided into three groups depending on their therapeutic action.
Antitumor antibiotics: antitumor antibiotics are a class of chemotherapy drugs used to treat many malignancies such as acute myeloid leukemia, breast cancer, and non-small cell lung cancer. These drugs act by preventing cell division in both cancerous cells and healthy cells that multiply rapidly so the therapeutic index or margin of safety between where they seriously impair normal cells versus irreversibly damage cancer cells is very narrow. The most common antitumor antibiotics include :
Hormones: some cancers- especially breast and prostate are either hormone-dependent or hormone sensitive cancers this can be both a positive or negative effect and drugs are used to exploit this. Hormone therapy can be used to block hormonal stimulation by acting at various aspects of their metabolism, thus stopping or slowing tumor growth. For example, some drugs manipulate circulating testosterones affect on prostate cancer; other drugs interfere with hormone responsive breast cancer cells ability to reproduce and thrive in a progesterone or estrogen rich environment. Some drugs work at local cancer cell receptors and some work distantly in aspects of the endocrine system to include the brain in areas such as the pituitary gland and elsewhere. It is really rather marvelous the ways that these cells mimic and try to exploit the norm as well as the ways science has uncovered this and exploited them doing so.
Monoclonal antibodies: these were a giant breakthough at the lab bench of the late eighties and are now expolding in medicine such as rheumatoid arthritis and psoriasis and more than just cancer all of us are equipped with an amazingly intricate immune surveillance system that has a liquid ( antibodies and cytokines and inter leukins and interferon and more) , and a cellular system somewhat analogous to a complete army of intelligence cells, short lived marines, cannibalizing cells and a metaphor that really does go on and on. The immune system is wonderfully connected and communicates rapidly with all of its aspects. We fight bacteria, cancers, viruses, anything we sense as foreign, such as organ transplants and of course tumors. The noble prize in 1975 went to scientists who discovered we can engineer antibodies highly specific for just one foreign entity one single tiny foreign enitity as long as it can be recognized and seen as foreign. One can then imagine how the race was on to make these antibodies against cancers and perhaps even attach payloads of radiation or biologic toxins and chemotherapy as well as to try to deliver cancer cell specific therapy .think of somewhat like a silver bullet in some cases, the antibody alone does the trick. The whole point is specificity leaving healthy tissues and cells alone while trying to target something very unique about the cancer cells thus addressing the achilles heel notion that was raised earlier. This is now a multibillion-dollar industry and growing rapidly.
Of course, never underestimate the workarounds cancer cells already have or develop and they are many and can develop very quickly but overall, the direction of research and therapy with monoclonal antibodies is positive with this notional type of approach. A common bottom line of therapy is the antibody singles out the cancer cell and deprives them of something essential, blocks some important pathway or delivers a payload of something toxic. In many cases, it triggers the cancer cells to commit suicide by many different mecanisms. In the beginning, these antibodies used mouse cells to make the antibodies and humans reacted with anti-mouse human antibodies. I was on the first team to publish the building of techniques to humanize these antibodies. In so doing we “ saw”, by tacking radioactive light to the antibody, breast cancer metastasis in a patient which other scans could not see.i was on active duty then or otherwise i would be a very rich man today oh well was not meant to be and it was exciting to be first in short order, a billion dollar industry was thriving principally involving non hodgkin’s lymphomas and soon other cancers on a large scale. Among drugs classed as monoclonal antibodies include:
· Herceptin, used in the treatment of breast cancer.
· Rituximab, used to treat lymphoma and other similar malignancies.
· And many more.
Podophyllotxin – podophyllotxin is a plant-derived (american and endangered himalayan mayapple) compound from which we get two drugs. These make cells get hung up and unable to proceed to multiply just before the life cycle phase called g one. This is the starting of doubling up their dna prior to dividing . It also blocks cells caught past g1 trying to actually make the double dna ( to give half to each daughter cell). We see what these drugs, etoposide and teniposide do but we still cannot clearly state exactly how. The mechanism of its action is not yet fully known. Owing to the rarity of their plant of origin scientists are trying to find the genes for the dna codes (just like forensic scientists do in crime solving) to be able in time make the chemicals in the lab by teaching certain cells to be factories for the chemical and they are suceeding.
Nanoparticles – now this sounds like science fiction picture this. These particles fall in the size between atoms and small molecules and can be designed to be identical to each other. They are finding increasing use in biomedicine. For example, some of our drugs are very insoluble using conventional techniques. By getting the essential active agents into the size of nanoparticles it allows a highly concentrated delivery of drugs. Here is one example of getting clever and combining breakthroughs nanoparticles made of magnetic material can be used to concentrate agents at tumor sites in the body that have been first identified with monoclonal antibodies with a few atoms of iron attached. You now have tumor sitting vulnerable to agents affiliated with external magnetic fields. This is a novel way to localize at the near atomic level a highly toxic therapy that might well leave other wise non engaged ( magnetically speaking ) tissues alone. Think of as a laser site whose focus is as tight as a few molecules on target.
Electro chemotherapy: this is the idea of somehow giving a physical chemistry or immunologic or biochemical fingerprint to that which you want to singularly find and eliminate. Imagine injecting a chemotherapeutic drug that is then followed by application of high voltage electric pulses locally to the tumor that opens and facilitates the passage of some drugs that normally cannot get transported across the cancer cell wall defenses to it interior. Early work with the antitumor antibiotic bleomycin and the alkylating agent cisplatin is showing some benefit in combination for treatment of skin cancers or those just under the skin no matter what the original tumor type may be. Using this as a cue, endoscospists (clinicians using flexible fibreoptics scopes to look into tubular structures, such as the gi track) are combining these lessons to catch tumors at extremely early phases avoiding more invasive surgery later. The idea is to minimize impact on normal surrounding functioning cells, specifically target, and then eliminate the tumor cells because of either identifying them easily or using techniques to which they are uniquely vulnerable. This should result in an increased tumor kill and/or reduced toxicity.
Specially targeted delivery vehicles may be shown to have a differentially higher affinity for tumor cells by interacting with tumor-specific or tumor-associated antigens. In addition to their targeting component, they also carry a payload – whether this is a traditional chemotherapeutic agent, or a radioisotope or an immune stimulating factor. These vehicles will vary in stability, selectivity and targeting motif but they all have the same aim of increasing the maximum effective dose that can be delivered to the tumor cells.
The hope and some cases reality is that reduced systemic toxicity means that they can also be used in sicker patients, and that they can carry new chemotherapeutic agents that would have been far too toxic to deliver via traditional systemic approaches. Think of the drone technology we now have in warfare that is designed for the drone to single out a vehicle with a specific license plate or some other highly specific trait with laser accuracy and spares all non intended targets while delivering a payload.
More non dna or antigen targeted therapies
Some cancers, one in particular known as chronic myelogenous leukemia, has a well defined defect known as the philadelphia chromosome wherein in the malignant cells and all its children one portion of genes or dna material have a highly specific deletion and movement to other section of dna strands making a chromosome known as the philadelphia chromosome ( named after the city it was discovered in …by a woman). This leads to the bone marrow cells getting a message to code for a category of gene family known as a type of tyrosine kinase which leads to out of control, and overtime bone marrow activity. The disease was only curable by bone marrow transplant with highly matched donors and recipient. The death rate from therapy was high with more likely death rates if you wait too long to try the risky transplant. In time, rational drug design and targeted drug therapy led to an almost non-toxic pill that blocks the aberrant type of tyrosine kinase the aberrant mimicking malignant kinase the philadelphia chromasome in the cancer cells gave the instructions to make that is seen in the disease. Now most patients have high quality remissions if not cures.- from a highly non toxic pill with response rates of over 90% that are probably cures instead of waiting with the chroninc disease to convert to acute leukemia and then a transplant being the only hope and a very very high mortality rate
Other targeted therapies : in one form of acute leukemia a class of drugs known as the retinoids yes like the aniti acne family of drugs were discovered to force the arrested maturity of one type of adult leukemia into maturation and eventual control. These retinoids drugs are being looked at in multiple malignancies : bexarotene, isotretinoin, tretinoin and atra. In addition we now see exciting work with:
Vaccines : the well known example is to prevent a large proportion of cervical cancers. And now hpv vaccination works
Also vaccine work is early but encourqaging with a modifiend virus vaccine in the most lethal from of brain cancer
In sum, the more we understand that which confers malignant behavior to malignant cells as well as all the special tricks and traits malignant cells use, the more we single out those seeming advantages as targets for design of increasingly specific therapy with decreasing toxicity. The same holds true for finding the vulnerabilities some of these cancers have separately or in excess to their normal counterparts.
Thus, we see how the word chemotherapy is not only complex and colorful but not at all necessarily a bad thing. Furthermore, the search for new and more specific agents from the plant and animal kingdom for rational drug design and tailored therapy have brought us over 500 approved effective compounds. More on the types of therapy and beauty of the rationally designed clinical trials comes later.
So what is the scope of lay knowledge of malignancy
Numerous studies have assessed in not only western nations but worldwide the extent of knowledge and understanding of cancer by the nonprofessional. It matters little if one is asking about the diagnosis, biological behaviors, types, effects, and benefits of therapies, causes or odds of response and long term effects; the fund of knowledge by the layman is abysmally low. Hearing this hopefully you see that all manner of research has and is going on and is very clever and building on itself this underscores the argument supporting the need for books such as mine abd this radio show as well as reminds us of the enormous power anxiety has in this disease due to lack of knowledge. The gap of fact versus fiction existing in the non-professional population is a mish mashed jumble with lack of clarity and discernment on all fronts. It is driven by fear …of the unknown.
| People in rich and poor nations alike have faulty understandings of the causes of cancer and need further education as to how to fend off the disease. Studies have shown that in all parts of the world there is a greater tendency to believe that factors out of our individual control as opposed to lifestyle choices are the main cause. The sentiment that we are tossed to the winds of fate or bad luck from genes is largely present and of course, wrong. After simply aging how we have lived is a major factor
A 2007 report, based on a survey sponsored by the international union against cancer (uicc) of nearly 30,000 people in 29 countries was released at the start of a four-day world cancer congress in geneva. In high-income countries like australia, britain, canada, greece, spain and the united states, as well as low-income nations the survey found refusal to recognize that alcohol consumption increases the cancer risk ran at 30-50 percent of the population. Of course, cancer risk rises as alcohol consumption rises.
There was overall denial that obesity is a cancer risk factor and a greater belief that fruits and vegetables consumption increasing in the standard western diet will have a more powerful impact that moderation of alcohol and cessation of smoking. This is of course, wrong.
Strikingly, there was an unfounded perception that stress posed an ominous proven danger as regards developing cancer similar to the common understanding of the credible data regarding stress as a contributing factor to heart disease.this too is wrong just like living near high voltage power lines or using cell phones. There is a lot of crap out there
Air pollution was also incorrectly held as a major remember we said major cause of cancer. “in general, people in all countries are more ready to accept that things outside of their control might cause cancer, like air pollution, than things that are within their own control, such as being overweight which is a well-established cancer risk factor,” declared the uicc.
| The survey showed that in low and middle-income countries, people were more pessimistic about the chances of treatment curing cancer.
In the poorest countries 48 percent felt not much could be done once the disease had taken hold. In middle-income countries, 39 percent had the same view, but in the richest countries, pessimists totaled only 17 percent. The problem with the fatalistic view, said the uicc, was that it could deter people not only from seeking treatment but also from participating in cancer screening programs that can save many lives.
This is only a snapshot of studies that echo the same point. The fund of knowledge what we think we know by non professionals and accuracy of that knowledge regarding causes, methods of diagnosis, treatment modalities and odds of response, morbidity of treatments and frankly most of the relevant aspects of human malignancy are archaic and a poor reflection of reality meaning of the truth why; because it is the very nature of a beast with so many frightening faces.
Cancer is a disease not always externally seen that can affect anyone in any organ, spread at will causing all manners of havoc and whose therapies, without guidance and correct counseling are held by many to be worse than the disease. It is a disease that can cause inexplicable wasting and distant effects from only local tumors and alter quality of life in dizzying arrays. This is why the profound anxiety. Imagine a process wherein a few cells somehow imitate their benign counterpart organ on a genetic level. Then add in their selective growth advantage ; not stopping, not staying put and then tricking and fooling the defenses of the body, escaping detection and eradication and using the body’s own building blocks to spread. Then they require typically difficult intense therapies to eradicate which may not be sufficiently cancer specific to spare normal functions and tissues so that not only the disease causes all manner of impairment of health quality issues and risks, but so may the therapy. Imagine the problems that arise when the scope of accurate, sufficiently detailed knowledge of the enemy is sparse and largely incorrect. Thus again, the need for this show and my book.
Any more questions?????
This has ben dr kevin ryanmd mba facp and hematologist oncologist here, medical oncologist professor and retired colonel and cancer survivor and this has been when tumor is the rumor and cancer is the answer. Modeled after my non profit book of the same name available on the web site of the same name you can find it on the web site and a lot more, interviews, films excerpts on the site and it is also available on amazon in all formats i am signing off radio www.w4cs.com the cancer support radio program remind you the program is archived here and the iheart radio as well as the www.w4cs blog and myblog accessed easily from the web site