Cancer Radiation

>> okay. we're going to get started. and today dr. nichols couldn't come and lecture on radiation oncology so i'll give the second lecture on small cell lung cancer. the first speaker is ravi madan talking about prostate cancer,

m.d. from the new jersey medical school, residency subsequently in internal medicine, joined the nci medical oncology branch in 2005, and holds a joint appointment in the medical oncology branch and laboratory of tumor immunology and biology. he's a staff clinician in

genitourinary malignancy branch. ravi? >> i want to apologize for being late. i was in clinic. i got nervous that the radiation guy wasn't going to be here. i know nothing about that, i have three or four slides on it

but you'll be able to tell how little i know from that part of the equation. so we're talking about prostate cancer, which doesn't immediately come across as perhaps most interesting disease to some of you, it's not always thought of as perhaps one of the

more innovative fields, but what you'll see is there's been a lot of innovation and a lot has been achieved in a short period of time. now we have to figure out what to do with all that data. what i'll try to go over today really is how we manage these

patients, the first half of the talk talks about the disease, and curative therapies, the second half tries to talk about metastatic treatment to try to delay progression and palliation. so i work here so i have no disclosures.

, you know, i think i went over educational objectives, the out line is as i've alluded to so we'll go from there. also, if there are any questions feel free to interrupt me, make sure i'm not misleading the crew, and i'll try remember to repeat them because i think they

are being webcast or recorded or something. so this is perhaps one of the more important slides i'll show, it highlights the kind of treatment landscape for prostate cancer as it changes. the way the graph works is you start off with newly diagnosed

disease, local therapies are potentially curative. as the disease recurs, castration or lowering of testosterone is the primary way to control this disease once it's no longer curative, that's because testosterone or androgen bind to androgen receptor,

fueling it, that's the make focus. death occurs the this point here. you see below classification of symptoms. it often takes a long time in the disease course to develop symptoms and they gradually

escalate. obviously it also takes a long time for the disease to become metastatic. the term castration sensitive and castration resistant i'll introduce them now. castration sensitive means if you lower the hormone, lower the

testosterone, you control the disease. if the tumor marker goes down, the disease can stay contained. when the disease grows, despite castration levels of testosterone that's considered castration resistant. it makes sense after you've

heard it. you see as of 2005 this is kind of where we were. docatelo was approved in 2004. until then we had hormonal manipulation. there was a decade where everybody combined their favorite drug with docataxel, in

2010 therapeutic cancer screen came along, radium 223, a pharmaceutical agent, you see the time frame where these treatments can be implemented. a second line chemotherapy also a taxane showed improvement survival in 2010. two hormonal therapies were

approved in 2011 and 2012 for patients who already had chemotherapy and later studies proved it was beneficial for patients who had not received chemotherapy with metastatic some are duplicated but all improve survival in metastatic

resistant. the most remarkable fact is they are essentially from -- i'm sorry, 16 therapies, but from might have modalities, a vaccine, a chemotherapy, hormonal therapies, and radiopharmaceutical. let's get to the basics and then

talk about the therapies at the end. prostate cancer affects a lot of people, 220,000 men diagnosed each ear. unfortunately 27,000 will die in 2015 from prostate cancer. lifetime risk of having the disease is 1 in 6, 1 in 8

depending on the survey. greatest in incidence, second most lethal can area. risk factors are not immediately clear. there are some indirect evidence that maybe racially african-americans have more lethal disease than caucasians,

and asians actually have less lethal disease when it comes to prostate cancer. highlighted by some of this. there's not clear genetic predisposition. there's so many men afflicted it's difficult. there's data that environmental

impact is possible, maybe that's why you see differences between caucasian and african-americans and asians. obesity is implicated in many cancers, prostate cancer is one of them. what about preventing prostate cancer?

this seems like always a big deal. studies were done to see if we could prevent prostate cancer. i think as you go through your courses it's good to hear a cautionary tale. who drugs 5alpha reductase inhibitors block it in men

treated with these therapies. two same class medications from two separate trials, there was some suggestion that these preventive measures increase the grading of the disease, and i'll come back to grading in a second. but that was -- that could be

explained away but the fundamental issue here is that these treatments came with side effects. there were some side effects of altering the testosterone in men and largely patients would go on it but wouldn't stay on it for a long period of time.

we always talk about preventing cancer but when it comes to treatment that prevents cancer you have to be realistic in terms of side effect you think your patients are going to be willing to take on. in tamoxifen in breast cancer not commonly used but effective.

there's interest in vitamins and minerals, the select trial looked at vitamin e and selenium. and unfortunately despite data about free radicals et cetera, that was no protective benefit, but it was a large effort that was done in it.

mixed signals really with prevention. i mention grading. this is under the microscope. and how we try to describe it, understand how aggressive the disease can be or will become, so basically a score is given to the tumor when we look at it

under the microscope from 1 to 5. 1 is almost never reported. 5 is extremely disorganized, basically a scale of anarchy or poorly differentiated cells with higher numbers. so when you see a prostate cancer, it usually is followed

by what's called a gleason score, there's always two of them. one is the one that's in the most dominant part of the pathological field, the other is in the secondary or second most predominant. the scale goes up to 5, so that

means they have gleason 4 plus 4, something to understand. intermediate risk is anything that's gleason 6 or less. gleason 7 is -- i'm sorry, gleason 6 or less is low risk. gleason 7 is intermediate risk. gleason 8, 9 or 10 are high risk.

that comes into play a little bit when we decide how to treat these diseases. staging, another obligatory, it's easier if you stage to 1, 2, 3, and 4. stage 1 is one lobe, 2 is two lobes, means it's broken out of one of the two lobes, and stage

4 means metastatic, localized stage stage 1 and 2, locally advanced stage 3 and advanced stage 4. i mentioned great therapies, how do we decide -- cancer sounds like it should be treated but the time line of the disease as you'll see in later slides

allows for more discussion about whether patients need to be treated. also these are often older men. we're not practicing ageism or saying that old people don't deserve therapy. but if you're 78 years old, and you're diagnosed with low grade

prostate cancer, and you have heart disease, diabetes and history of a stroke, you may not live long enough from your other what we call competing morbidities to die from your so the reality is if you have a patient who is maybe 75 years old, and has all these other

morbidities, maybe you shouldn't even be checking psa anymore or looking for the cancer if they have other things. by the same token, if you have an 85-year-old who is healthy as can be, and is diagnosed with intermediate, you might want to cure that patient because he

might have another decade to live. it's kind of a give and take and there's no hard and fast rules but a general outline. to define a couple terms that get thrown around in prostate cancer, watchful waiting and active surveillance, if you're

not doing therapy. watchful waiting, they both sound like the same thing. one sounds more politically correct. watch for waiting says, like i said, a patient who you don't think you need to treat, you're not going to check psa or

monitor for the disease. if they develop symptoms you'll take care of it. active surveillance is different, however, this is, okay, they are kind of -- i may or may not treat this patient but i'll follow their psa, if there's big changes in the

disease burden, maybe i'm more inclined to treat them, just to define terms that get used in prostate cancer a lot. active surveillance hints at intent to treat at some point. okay. you're either going to love this slide or hate this slide.

i think it's helpful in defining what i was talking about earlier. from older data, but it still applies except you almost never see anyone diagnosed with gleason 5 or less prostate it's showing broken by year, 50-59, 70-7 with intervening

boxes, gleason 6, 7, so low risk, intermediate risk, and high risk. and then it shows death from disease within 20 years, okay? what you see in the dark gray color is people dying of their light gray is dying of everything else.

so this goes again to what i said. if you have a patient who is in their 70s, with, you know, other comorbidities, they are more likely to die from other things in the light gray than dark gray. maybe you don't need to treat

them and give them side effects of therapy with surgery or radiation an attempt to cure them if they are more than likely to die from somebody else. the flip slide, you have a very aggressive disease in a young patient, you see their mortality

risk from prostate cancer is extremely high. this illustrates what i've outlined, you take into a lot of account where they are in this gleason score, how aggressive the underlying disease is and how healthy the patient is in terms of competing comorbidity.

i'm going to show you data basically that gives proof for what you probably already would believe if i didn't show you data. not surprisingly, if you do surgery on patients, you have a high risk of curing them, if you do nothing and improve survival

is what we're trying to say surgery is one of the interventions. with prostate cancer, this study was done a long time ago showing surgery did improve survival compared to watchful waiting. radiation therapy is a another curative treatment, again i

mentioned earlier, i'm not a radiation oncologist but you can basically shoot different electrons and protons and photons at the tumor in a targeted manner with the goal of destroying cancer cells, damaging dna, et cetera, and curing patients of these

prostate cancer, so for a subset of patients, radiation is a curative therapy. when it's localized. so surgery and radiation are only effective at curing the disease really when it's contained in the prostate, radiation may be effective if

there's a couple lymph nodes around the prostate that can be radiated. brachytherapy is another form of radiation, men prefer it from a time standpoint. the standard radiation therapy occurs on daily doses every six weeks.

brachytherapy you go to the doctor once, they implant radioactive seeds in the prostate, and then it slowly emits radiation over a periodof again a curative measure but generally only beneficial to patients with one type of prostate cancer, low risk.

aggressive cancer is generally not been shown to be that responsive to this therapy. also if you have a large prostate, so prostate size varies and there's different ways it can be measured but patients who have a very large prostate, brachytherapy doesn't

deliver radiation appropriately, and therefore unfortunately the therapy is not a good option. so aggressive disease and large prostate, brachytherapy is not an option but you'll see men like this, it's a treatment with potential cure. what are some complications from

radiation? you can get colitis or irritation of the bowel, leading to diarrhea or inflammation of the radiation. erectile dysfunction with both. and risk of secondary malignancy even 15 to 20 years later, maybe bladder cancer 15 or 20 years

after radiation for curative prostate therapy. i think i took my slide out for surgery complication. sorry. when you're looking at surgery and radiation trying to compare what a patient should do, generally surgery has more

incontinence, radiation has more urinary retention, think of it that way. there have been no studies that definitively show which are better. mainly because men are not willing to be randomized to surgery or radiation.

generally they come in with a fixed opinion of whether they want surgery or don't so trials largely have been unsuccessful because we can't accrue to those studies. i mentioned earlier there is rationale to deprive the testosterone or androgen to the

tumor, with either pharmacologic therapy or removal of the testicles, that can improve survival, and in some patients not healthy enough for surgery may not be candidates for surgery, primary androgen deprivation surgery is one possibility of delaying onset of

metastatic disease and symptoms, but not a curative therapy. even though the cancer needs androgen to survive, depriving of it androgen is not a way to cure it of the disease. i'm going to go over this quickly because i think that it's not as valuable in the

context of this course, but what about combining some of these things? there is data that shows surgery combined with hormones, with radiation, and radiation combined with hormones increased cure rates over surgery alone in these two cases, radiation alone

in this case, but it's in a subset of patients so you know this has been looked at. in breast cancer they give neoadjuvant therapy to shrink the tumor. in prostate cancer that's not shown to be an effective technique.

if patients have surgery, and then they have a lymph node that's positive, if you give those patients hormone therapy immediately, they live longer than if you don't give them hormone therapy until they have metastatic disease. data needs to be taken with a

grain of salt because it doesn't allow for you to start treatment if they are node positive at surgery like before they get metastatic disease, so in an extreme setting hormone situation is beneficial in the adjuvant situation, certainly for oncologists it's a good

board question they ask a lot. it's one of the indications of adjuvant therapy in prostate this kind of makes sense, this study showed improvement in overall survival and metastasis-free survival if you have t3 disease. in cancer has broken out of the

prostate when you do surgery or have a positive margin, there's something left behind to radiate so those patients do better. this makes intuitive sense. this doesn't always happen in oncology where the study that you do that makes sense actually plays out like you think it

should but in this case it does. it makes sense if you have local disease left after surgery that radiation could be curative. hormone therapy when combined with radiation can delay recurrence of delays and improve survival. there's different timeframes,

intermediated risk is six months. high risk patients again, gleason 7, 8, 9, psa greater than 20 and other characteristics, they give hormone therapy for two to three years. so global big picture overview

of kind of curative -- attempts to cure the disease in prostate cancer, unfortunately not everybody is that possible, and about 20 to 40% of patients who have curative surgery radiation will ultimately develop recurrent disease. i'll stop there.

are there any questions? it can get confusing with all this data about curative attempts at prostate cancer, but any questions about surgery or if you have questions about how we choose or how patients choose, that's a good question because there's not a real --

you sit down with a patient and say, these are your options, these are your side effects. what are you most comfortable with? obviously it's easy if patients have heart disease and they are not a candidate for surgery, but that's kind of a big elephant

gunshot of curative therapy. so any questions about that yes? >> (inaudible). >> are things changing? the answer is yes. i'll tell you how we diagnose we take a guy with a high psa, this is a year ago, two years

ago, things are changing, high psa, and get them to the operating room and the urologist, not me but a urologist basically sticks needles anywhere in the prostate, 12 random spots, and hopes you hit the tumor. just think about that with colon

or breast cancer. you think a patient has cancer, let's stick a needle randomly in that organ and hope we get a diagnose. that's changed now. in technology that was largely developed here by pete choyke and the molecular imaging and

peter pinto in urology, they developed the ability now for the first time to actually see the tumors within the prostate, so now we can say your psa is high, let's get an mri, there's the tumor, let's stick a needle in that, changing things radically.

now a patient that had gleason 7 disease, biopsy the tumor which we can now discretely see within the mri, images of the prostate, and then basically say, all right, your tumor is pretty small, discrete, we can follow it. it's a 7 but not the dominant

one so maybe you're a candidate for surveillance. we need to investigate can we surveil these people annually with mris instead of annual biopsy which has been the standard. things are changing dramatically, a very perceptive

question. 60 to 80% of patients who are diagnosed with localized disease can be cured. so for patients who have recurrent surgery -- recurrent psa after surgery radiation, often they present to the doctor with a rising psa with criteria

for recurrent disease. for patients with surgery it's possible to have salvage radiation that may be curative but it's variable how effective therapies can be. our approach can primarily to deprive the tumor of testosterone, and that's again

done with orchieectomy or shots. a study looked at continuous deprivation versus intermittent, versus just testosterone suppressed for rest of your life and after a decade the survival was roughly equivalent. side effects include sexual dysfunction, fatigue, weight

gain, hot flashes, with intermittent they don't have to continue experience the side this slide also hints at the time line of the disease. remember that 10 years i mentioned earlier? unfortunately other people will be giving you talks during this

lecture series about other cancers. you're doing small cell next? so those time lines are much, much different. that also factors in when we choose our therapies in prostate cancer, oftentimes we're talking about a decade of life after

diagnosis which unfortunately is not a luxury most patients have with cancer. and this study highlights -- it's older data. don't worry about the bullets but they saw on average patients with surgery are biochemical recurrence disease, rising psa

was detected two years later. it's about five to eight years before on average they develop metastatic disease, and then could be three to five years until patients passed away from cancer, very long time lines, and opportunities for us to intervene at different points to

try to make these time lines even longer. metastatic prostate cancer again in terms of newly diagnosed 4 to 10% show up with metastatic cancer largely because of screening in this cancer, certain recommendations, screening is a separate issue

but i'm happy to answer questions if there's time at the end, but as screening goes down you expect this number to go up. in europe and other countries where screening is not done, you see much greater presentation of patients with metastatic when patients do get metastatic

disease and prostate cancer 90% patients have metastatic disease to the bone, that's just for reasons we don't fully understand. it could be a soil type thing where that's just a nurturing microenvironment, things people are investigating.

10% of patients will have soft tissue disease alone, but that does not mean if you only have soft tissue disease you're going to do worse. this is retrospective data, from a chemotherapy trial that led to approval of docataxel. patients with bone disease about

the same whether they had bone disease alone ore bone disease with other sites. lymph node only disease did really well. for a while here, this still happens, doctors in the community will see a patient who only has lymph node disease with

metastatic prostate cancer and think that's unusual, i don't see this, it must be worse, i'm sending this patient to the nci. reality these patients do quite well. it's a little lesson, unusual doesn't always mean worse. now, liver, not surprising with

this data, patients who have liver disease do worse in metastatic prostate cancer, and this isn't that uncommon amongst other cancer types of a well. i mentioned adt, there's different ways to implement it. i won't go into different treatments but you can remove

the testicle, they are your primary source of androgen production in your body. you could have production from the adrenal glands, we'll get into that later with one of these therapies. there's ways to manipulate the endocrine system with lhrl

agonists or antagonists, tricking the body through direct antagonism or feedback inhibition, you remember from your endocrine days, into not sending a signal to the testicles to produce more testosterone. so i don't think that -- i'll

skip to an important slide. this is very relevant especially for men on hormone therapy. there's a lot of therapies in part of what we have to do as clinicians is figure out from the side effect standpoint which are best for the patient so you have to know the side effects a

little bit. i don't expect you to memorize this but get a feel for what the side effects are. i mentioned this already. sexual issues, physical changes including weight gain, i didn't mention this. there's increased risk of

diabetes and heart attacks. it's not dramatic but sufficient for you to be aware of as a clinician and there can be emotional and cognitive issues as well. just something we have to talk with our patients about. again, i mentioned concept of

castration resistant disease or met statics castration resistant disease, patients diagnosed, not cured, disease spread to the bones, lymph nodes or both and despite suppression it continues to grow as measured by psa or radiographic images so that's what we call metastatic

castration resistant prostate cancer or met statics crpc, a field where all the therapies are approved because if you're a pharma company you can't wait 15 years to get your drug approved because you miss your patent so you want to get a time line where the time lines are three

or four years, all the things i'm going to talk about now were approved in metastatic disease. azole is anti-fungal, these were used in the '80s. really before 2010 beyond docatatxel, these was our arms. someone made a billion dollars making an updated version of

ketokonazeol, these are the first generation, more historical footnote. this is what we have as we move forward. these are the therapies that i showed earlier on the slide which were all aimproved, docataxel in 2004, the rest

since 2010. now the studies in a led to their fda approval so you can have a sense of how the studies were done and what the drugs are. docetaxell, it's a taxane, discovered from trees initially in the pacific northwest, the

pacific yew tree. this also highlights the fact that in my world we think we know how the therapies we're using actually work and we maybe don't really know as much as we thought. docetaxel is a taxane, as you remember from biology classes

microtubules are required for treating the spindle in mitosis. that's probably not the reason. it comes down to the angio receptor. newer data suggests the way this drug works in prostate cancer, it prevents the andro receptor from once once activated in the

membrane to be pulled down into the nucleus with microtubule, in that sense inhibition has its greatest effect. in that context, maybe it's less surprising, the only two chemotherapies that are have shown clear benefit and prostate cancer for survival are taxanes

because they both inhibit microtubules, targeting androgen receptor translocation, highlights the androgen receptor is important. but this wasn't known in 2004 when this data was finalized, published in the new england journal.

the three-arm study, interesting not a placebo, it alleviated symptoms, and they looked at two dosing schedules. why was prednisone included? this is just to give you a highlight of how clinical trials are done. i'd like to give you scientific

explanation but they said let's compare this to prednisone, anti-inflammatory, so in order to do a balanced study they said you can't just give mitoxontrone, let's give with docetaxel, peeking behind the curtain not everything is clear rational and scientific as you

may think. results show docetaxel at least statistically had an improvement in survival in patients with metastatic castration resistant prostate cancer and this led to fda approval. i've talked at patient groups all over the place, and i can't

tell you how many men when i put up this slide say that's why i'm never getting chemotherapy, i'm not going to get chemotherapy to improve my life by 1 1/2 months, okay? here is the tricky part about why you have to know studies and how they were done.

i didn't mention this on the last slide about this study had a crossover. that means if you got mitoxontron with progression you were allowed docetaxel. previously patients lived ten months so what you're seeing is what you see with any study with

a crossover, that is you're underestimating the overall survival benefit. so usually when i explain that most people kind of come around and think that, okay, maybe chemotherapy is okay. if they don't usually their wife will yell at them and they

understand better. but it is an important thing again, the general concept as you move forward looking at different trials of things. always understand nuance like crossover which can influence the data. but nonetheless this was

sufficient for fda approval, and it improved not just survival but there was quality of life benefits, improvement in pain, and i already went over the clinical significance of the 2 1/2 months. here is a side effect, there are a lot with chemotherapy.

big things are neuropathy that can happen, some degree of fatigue, diarrhea and constipation, any chemotherapies that suppression of neutrophils or neutripenia, you need to give growth factor support to these patients or if you want to lower the dose, most side effects are

manageable but we have patients getting docetaxel for 3, 4, 5 years intermittently, so you can get through the side effects but it's good to understand you can't deny there are toxicities. what happened for the next six years?

nothing. all the trials were negative. a therapeutic vaccine came around and we had our next therapy that improved survival with metastatic disease, so this is amino therapy, before the checkpoint inhibitors, stimulating the immune system to

fight through leukapheresis, immune cells are exposed to cytokine, in this case on the surface of cancer cells, infused in the patient, each infusion is done every two weeks for a month, so three infusions, this was the this was the end result of the

study, these patients probably had earlier disease but therapies might have been better too. they might have gotten chemotherapy on the back end. this data to this day is very controversial. i won't go into this in detail

unless there's time or questions at the end but there's an overlap, there was no short-term progression, people thought the data was fraudulent, how can you live longer? amino therapy works better than standard cyto toxics. we're seeing this with

checkpoint inhibitors. another phase 3 study showed the same thing but people are unshakable they don't believe the therapy works, what happens when you're a first in class agent and everyone is used to using chemotherapy or something. still there's controversy.

i think this works but my opinion is biased, but the data is the data. two phase 3 studies say it's positive. checkpoint inhibitors now show the same thing, often no short-term changes but the long term survival.

very well tolerated. there was fever, chill, a hint of stroke that stand out in post marketing, very well tolerated, probably best in patients with indolent disease. this is as second generation of the anti-fungal ketokonazole thought to have perhaps impact

on sip 17. this is how your body goes from cholesterol to androgens, but if you block that, you can block secondary production of testosterone and other androgens in a patient that's already castrate from decreased testiccal production.

who is the other testosterone coming from? it's thought the adrenal glands can supply secondary, and maybe suppression from the testicles is not perfect but what's popped up in recent years is resistance mechanism that's especially sinister in you try to an throw

pro morphias even a little bit. they can create their own fuel source and basically that is an escape mechanism how you get growth. study was done in chemotherapy patients who already received chemotherapy, randomized

patients with placebo or abiraterone, with this that lived for 15 months, based on data in 2011 it was a breakthrough and fda approved. for 20 years, i didn't go back to historical stuff but in 1944 huggins was a nobel prize winning researcher who said

androgens are important in prostate cancer, it fuels we developed therapies in the '80s and in the '90s and 2000s we did combination chemotherapy studies, forgot androgen receptor was so important but this study came back and said our older drugs

weren't that effective, even in castration resistant disease you can get survival benefits. so now we've reopened the door, and this drug was approved. there was a study in chemo naive patients that was done, you see there was a large survival advantage in most patients as

well, so now abirateron is approved for all patients with you get cortisol elevation when you suppress this aspect of the steroid production. that leads to edema, hypertension, and some fatigue. you can get liver abnormalities,

generally well tolerated medication. this treatment is administered with prednisone to minimize some cortisol surplus side effects, unlike docetexal there's a stronger rationale to use it. enzalutamide blocks the androgen receptor, this prevents them

from getting to the androgen receptor, compared to an older version of this drug bicalulatamide. it's better at getting to the nucleus, interacting with dna, it's always very much better than our older version and not surprisingly it's more effective

at extending life as was demonstrated in this study, again in patients who already had chemotherapy first. you see there was an extensive improvement in survival from 18 months to 14 months, or 13 1/2 and this was approved by the fda in 2012.

this is highlighting a little bit of a problem that i think we're going to start seeing more of. enzalutamide is effective, no one doubts that. this trial was done really after these were approved, in pre-chemotherapy patients

there's a statistically significant difference in survival between these two lines but you can see it's only about two months. this is a problem in breast cancer which is now we've been using in all these other studies survival as an end point to

demonstrate your drug works, your new drug. it might be something that given all the therapies that are available survival signal will get lost if you treat the patients accordingly. in breast cancer they have been working on this for two decades.

and we've been working on this for two or three years. we have to figure out if there are better ways to evaluate the efficacy of these drugs besides survival, and there have been some thoughts since that looked like they may work but then they didn't and that's part of the

controversy. so it's good to have new therapies, it just makes us think more and that's probably not a bad thing. enzalutamide is well tolerated, you can move it up to patients who don't have metastatic disease, a decade to live,

highlighting how well tolerated it is. fatigue is real in some patients. even patients, one guy in his 40s with metastatic disease, he's almost to the point of refusing the drug because he can't stay awake on the drug.

we've tried to come down on the dose. very well tolerated but variability in side effects. this is a second line taxane, approved in prostate cancer, these circle hydroxy groups are what differentiate from docetaxel.

this wasn't on anyone's radar screen, but was done in patients who progressed on docetaxel, progression was three months on everything. patients who got chemotherapy lived three months longer than patients who didn't. this led to fda approval as

this was actually preceded, abiraterone in approval, before all these drugs were available, so there was enthusiasm. it's just another cautionary tale, when this data was presented, with the toxicity, there was about five or six per cent of patients that had

neutripenic that led to death, the vast majority is accrued the united states, we have greater access to growth factor support and things like that. so i don't think this drug has ever recovered from the fact they reported 6% -- 5 or 6% incidence of neutropenic death.

other people start off with reduced dose and the drug doesn't work. it highlights the fact sometimes if you have a drug and it's effective, if you do the study the wrong way it might never get used the way you intended. just a global lesson there.

my last therapy that's recently approved in prostate cancer is radium 223, a bone-targeted radiopharmaceutical that shoots off alpha particles. i've told you i'm not a radiation oncologist, that highlights the fact i know very little about physics.

alpha particles are very heavy from what i'm told, when they get shot off this radioactive particle they don't go far, when it binds to an area in the bone with pros indicate cancer you don't are electrons or protons shooting off which kill platelets.

alpha particles are a shorter destruction radius, more likely to impact tumor, less likely to impact blood cells, better tolerated version of radiopharmaceutical compared to older ones, this was a study done, you see a trend here, radium versus placebo, there was

a survival advantage, this was a very heterogeneous population but still a clear-cut survival advantage. interestingly, other radiopharmaceuticals which had leader lied lighter particles demonstrated palliative benefit

but not survival seen in this study. people like me, oncologists, aren't sure where to put this. they wait for patients to have symptomatic disease and then treat it like we use the old drug, symptomatic relief, we try to maybe do some studies to

highlight how this drug could be used better but i think that for a lot of patients though it is well toll tolerated. it's remarkable when you see in a short period of time, five years, you've got two hormone therapies, a chemotherapy, immune therapy, the first modern

immune therapy i would say, and then radiopharmaceutical, five therapies, approved. six total in a very short period of time, the culmination of a lot of research in the years before that. what we still don't know and need to investigate, the

sequence that's combination. we have to do the studies to do that. here the side effects with radium, it's well tolerated. what about the group of patients that walk into their doctor's office, have a normal testosterone and have metastatic

disease? castration sensitive prostate they took -- they asked in 2007 what if we added chemotherapy for six cycles of chemotherapy, in these newly diagnosed met statics patients who haven't received real therapy? they saw one of the biggest

readouts we've ever seen. a 13 1/2 month improvement in survival, because you're starting earlier, where if you add chemotherapy to the initiation of hormone therapy, you got the profound benefit. this doesn't apply to every patient, this is a game changer,

we're looking at ways to improve. i won't go into a lot of details on that. it's very well tolerated. one thing that i highlighted in my talk but couldn't get into, we don't know the best way to sequence therapies.

there are studies going on now. it's a tricky thing. what's become clear in the last two years or so is that the androgen receptor, it's key, there are clones that can develop over time have every part of the androgen receptor except the receptor.

it doesn't have an extracellular ligand binding domain for the testosterone. what that means is all your therapies that lower testosterone, all your therapies that block testosterone don't work in those clones. that's what's being seen now is

a lot of different -- what we call of these andro receptor variants, activated despite eradication of testosterone from the tumor microenvironment, now we have to figure out ways to interfere with that. it's barrier methods or testosterone suppression and

those clones won't work. also speaks to the heterogeneity of the disease. i'm going to stop there with five minutes for questions or a break before your next lecture. i thank you for your kind attention. everybody stayed awake.

i'm super impressed. thank you for your time and attention. >> (inaudible). >> great question slower pace of disease, not like showing up in your office with like cancer in three places and a month later ten places.

slower pace and smaller volume. i think that's globally true for multiple cancer. >> now we're going to talk about small cell lung cancer, the neuroendocrine tumor. prostate cancer like most

cancers are epithelial cancers, this is the neuroendocrine it kills about 25,000 patients in the u.s. annually, it's responsive to chemo and radiation therapy. but rapidly occurs, median survival time is less than one year.

for the small cell lung cancer, cells are small, there's big nuclei, scant cytoplasm. what are the symptoms of small cell lung cancer? traditionally people have coughs. shortness of breath, trouble going upstairs, she was very

surprised then when she went to see the physician and they diagnosed lung cancer. so as the lung cancer progresses, there can be pneumonia, bronchitis, and the worst sign if you have bloody sputum, that means you have a lot of cancer.

it's diagnosed with chest x-ray, but you can also put a tube down your throat, bronchoscopy, if you find a lesion, you can do a needle aspirate, and ascertain the presence of tumor, fluid between the lungs and the chest wall is thorocentesis, and spiral ct, this is sensitive but

the problem then is there's false positives that result, with spiral ct the hope is you can diagnosed lung cancer earlier when it's in a more minimal stage to surgical resection, if you could identify the cancer in stage 1, then you can do the resection.

so this is the chest x-ray, and you see a mass of tumor here in the lungs, this is the ct scan, and you see here a tumor that developed with time, and this is the broncoscopey, on the left you see something budding from the thorax. and you would then do a section

of this, and ascertain if this were a tumor or not. so in terms of staging of the lung cancer, well, it's often diagnosed in stage 4, where metastasis has occurred, but you can identify it early, then it's more amenable to treatment. and so the tumors, they could be

detected when they are a few centimeters in size, and then when they are greater than 7 centimeters oftentimes they can undergo metastasis at that point. so we mentioned about the ct scan, you can also use mri, with pet scanning oftentimes what

you do, glucose, radionucleide scanning, looking for hot spots, metastasis to the bone and you can look in the chest cavity between the lungs for tumors. so if you undergo surgery, the median survival time is 6.5 months, if you undergo

radiotherapy the median survival time is 10 months. in all cases, the patients usually live less than a year. so in terms of chemotherapy, many drugs have been used. there's carboplatin, agents that affect tubulins, there are

inhibitors such as vp-16, a wide variety of drugs that can be used and frequently what's done is combination chemotherapy, so in this case cyclophosphamide, vp-16 is an inhibitor and they abbreviate. this can be combined can

chemotherapy, you can increase the five-year survival from 6% to 30%. the problem is small cell lung cancer often undergoes relapse. we mentioned cancer is a moving target. when you have lung cancer it results because you're smoking

cigarettes, so this takes 20 to 30 years to develop, you get a first clone of cells, this may be sensitive to chemotherapy, but a second clone may grow out and this is resistant to the chemotherapy and this is what will kill you. often times after relapse

chemotherapy is uneffective. i had one cell that got it to the brain and died within two the brain has many growth factors that facilitates the growth of the tumor. epithelial cancers they have a feel for how the cancer

progresses but there's no such knowledge known about small cell lung cancer. it's probably initiated by tobacco smoke carcinogens, but what cells become the small cell no one knows, it's an area that's a great mystery.

cigarette smoke has nicotine in these are g protein coupled receptors, ultimately leading to akt phosphorylation and increased survival. nnk, one of the unique things it's metabolized would a unique metabolite that can be measured

in the urine of patients presence indicates exposure to cigarette smoke, it can increase in smokers and nonsmokers who breathe in secondhand. within of the unique things nci did in the '80s was cell lines. i collaborated with the group up

here, they would get bone marrow aspirates from patients and then the tumors were mechanically disassociated and cell suspensions obtained, the cells were cultured in a serum free medium containing selenium, igf-1 and transferrin, in 1 out of 6 patients they were able to

get a cell line. this illustrates small cell lung cancer transferrin provides iron to the cells and many dna igf 1 binds to tyrosine kinase receptors. we mentioned before the small

cell lung cancer has granules, they undergo exocytosis, they come back and bind to cell surface receptors stimulating proliferation further. in many cancers you don't have a lot of cell lines to work with. but over a period of 20 years nci developed hundreds, small

cell lung cancers, characterized by high levels of grp, neural enzymes, and high levels of enzymes such as dopa decarbolyxase. strangely, this small cell lung cancers grew as floating aggregates, they didn't adhere

to the dish, non-small cell lung cancer cells were all epithelial and they were all adherent. so the neuroendocrine small cell lung cancer cells are different. one of the animal models is the a/j mouse which gets adenomas on the lung. and the phospholipids in the

cancer cells can be metabolized to arachidonic acid. so in colon cancer it was found that non-steroidal anti-inflammatory drugs which inhibit prostaglandin synthesis decrease proliferation and are chemo preventive, and in lung cancer, the aspirin also worked

inhibiting the growth and if you added increasing amounts of prostaglandin e-2 the growth returned to normal, so it is a growth factor. another thing that inhibitedthe enzyme is endomethicine, reducing formation of tumors in the lung of the mice.

so in the lung then there's three major types of cells, the alveoli, you see scattered immunoreactivity here, this is a key enzyme that gets turned on by growth factors in the cancer cells. in the bronchus, in the muscle lay, there's lots of cox2 amino

activity, and in the bronchial scattered amino reactivity, brown in color. so it showed intense staining in all three lung compartments, as well as the adenoma, the tumor. and here there's two types. here we're adding increased

amounts of egf and the 2 mrna is going up. so the 2 then gets turned on by growth factors, releasing lots of prostaglandin e-2 that can lead to growth stimulation. we mentioned before that the egf receptor is a big player in lung cancer, especially when it's

mutated. and we found if we added an antagonist of the prostaglandin e 2 receptor then the stimulation of the egf receptor was (indiscernible) and downstream we found it would phosphorylate erk and enter the nucleus and cause growth factor

production. so the prostaglandin e 2 then is derived from the acid and its production is especially increased, in the cancer cell. and then when the nucleus was stimulated various growth factors get produced, an angiogenic factor, and this

can be blocked using h-89 which inhibits activity. the prostaglandin e 2 when it binds to the receptor can increase the cyclic a and leads to phosphorylation of creb. prostaglandin e 2 it gets increased in the cancer cells and it binds to this receptor,

the ep2 receptor. the ep2 receptor can activate other factors in the cancer cell to produce egf alpha. what we see here is basically a cycle that happens a lot in the lung cancer cells, one of these cycles goes to the egf receptor, when that gets turned on cox2

gets turned on, and then this leads to increased expression of various growth factors. what's unique is you have a g protein coupled receptor, ten turning on each f receptor, a strong kinase receptor that can create havoc. , ,

a n d lead to a deadly situation, so the cox inhibitors they are very intriguing but the thing you have to watch out for is they can cause stomach ulcers. and so subsequently they

developed selective cox2 inhibitors, it has minimal side effects, and so they are doing clinical trials now using celecoxib and lung cancer patients to see if this can be an effective therapy. we'll look at some of these similarities of the small cell

lung cancer and we'll be focusing on the rb retinoblastoma gene, retinoblastoma gene is a tumor suppressor, as is p53, and fhit, and bcl gets overexpressed, this is bad because bcl-2 increases survival of the cancer

for p53 it immediate (inaudible) when rb gets mutated, or there's other factors that occur leading to it's inactivation then the cells can't rest, cancer cells try to grow as rapidly as possible. so in tissue culture,

essentially these cells double every day. and the fhit gene is the triad, and it was very interesting because it's located in chromosome 3p, chromosome 3p is one of the chromosomes that gets deleted early in the carcinogenic process for small

cell lung cancer, and so they thought additionally that fhit might be the tumor suppressor gene that's very important on chromosome b 3, so this is still an area that they are investigating. and finally, we get to bcl-2, which is overexpressed, and

bcl-2 suppresses apoptosis, and inhibits responses to chemotherapy and radiation therapy. so they are currently investigating ways to minimize the effects of bcl-2. if the small cell lung cancer, there's a lot of genetic

abnormalities, and you see we have allelic loss in many chrome soaps, especially 3p and 17p where the p53 gene is. and we'll be going through microsatellite instability, myc overexpression, c-kit overcompression and bombesin/gastrin releasing

peptide. there's deletions in 5q, 13q, and 17p. so in lung cancer, another thing they see is there's many macro satellite alterations, such as two to five base pairs get repeated, dozens of times. and as a result then there's

laddering that results from mutations in dna mismatch repair enzymes and microsatellite instability may be useful for early diagnosis of lung cancer, using sputum, bronchiole washings or blood. so myc is a nuclear oncogene that's associated with growth

and myc heterodimerizes with max, and facilitating cell-cycle progression. and lkb, it's a tumor suppressor. it's an enzyme that's activated in half the small cell lung cancer patient causing phosphorylation of ampk,

resulting in tumor growth suppression. so the igf 1 is an important tyrosine kinase receptor, so the igf 1 binds to the tyrosine kinase and this one's rather unusual because it's got two alpha subunits and two beta subunits, the alpha subunits

bind to the igf 1, and the beta subunits have these tyrosine kinase activities. and so here is a western blot where we're seeing binding to the alpha subunit, and we actually used a monoclonal antibody against the igf 1 receptor to inhibit growth.

so here you see using this monoclonal antibody in nude mice, tumor growth is dramatically slow in the presence of the antibody. so igf 1 enhances the survival of small cell lung cancer cells, in ticket goes to the kinase and akt gets phosphorylated,

resulting in increased cancer cell survival. and another entity that comes in, here we see the tyrosine kinase receptor for amino dimer, then causing the phosphorylation of the kinase, activating it, leading to phosphorylation of akt, phosphorylated akt

ultimately causes increased expression of bcl-2 which will increase cancer cell survival. another factor in the small cell lung cancer is the scf, and this ligand then binds to the c-kit receptor which is also a tyrosine kinase receptor. so the c-kit receptor binds the

scf and then we get increased tyrosine kinase activity, akt. and finally what i found is early in the 1980s, we found that the small cell lung cancer cell lines at eye level especially the grp, and so

initial studies utilized monoclonal antibody, against the growth factor, and we see the nude mice, they had large tumors, but if they were treated with this antibody, the tumors were very small in size. and this is actually then developed in patients, but only

one patient out of 13 responded. subsequently we moved on to other things and here you see a typical structure of a g protein coupled receptor, it crosses membrane seven times, an intracellular c terminal, the third intracellular loop stimulates production of second

messengers. the grp receptor surprisingly is on the x chromosome. and as a result then the females are going to have more of the grp receptor than are the males. and currently studies are investigating, females are more susceptible to lung cancer

because of the localization of this g protein coupled receptor and here we're looking at cells as they respond when you add the bombasine or grp, we loaded up cells with dye and we see within a few seconds after addition of the growth factor, the cells start to turn yellow in color.

and the response is rapid and within a few minutes the cells, cellular calcium returns to normal levels. so we can then use the cellular calcium as an indication of expression to the growth factor, and then antagonists were developed for the receptor that

lock the calcium response. antagonists are small alkaloids, small molecules. and they inhibit the growth of the lung cancer cells, and here we see that the peptide we mentioned before, they can cause transactivation of the egf receptor resulting in

phosphorylation, and the antagonist blocks the tyrosine phosphorylation of the egf similarly they increase the phosphorylation of erk, which then goes into the nucleus and causes growth factor expression and the antagonist blocks that so these antagonists then

inhibit growth, but what's very interesting is we mentioned before that gefitinib treats patient with egf receptor mutation, and this cell line had a wild type receptor but we found that the antagonist potentiated the effects, so the potency was increased about

ten-fold. we're currently in the process of doing studies to see if this occurs pre-clinically in mice as so the signal transduction mechanisms then are fairly complex, because we have the g protein coupled receptors, it elevates calcium, but then it

causes activation of other proteins, such as protein kinase c, sark, ultimately leading to receptor and when that gets phosphorylated, erk can be phosphorylated altering gross factor expression, leading to phosphorylation of akt and increased cellular survival.

so these growth factors then don't work independently, they work together to stimulate cancer cellular proliferation. in summary then for the small cell lung cancer it's a neuroendocrine tumor that initially responds to chemotherapy, but subsequently

relapse occurs in the patient. and multiple clinical trials are in progress to try to improve the treatment of small cell lung cancer but we've still got a long ways to go. so we want to close by talking about smoking. and most lung cancer occurs in

people who smoke cigarettes, and so the reason lung cancer has leveled off in terms of the number of deaths now is because in this country we have lots of anti-smoking measures going on. the most effective thing they found initially was just raising the tax on cigarettes, make the

cigarettes so expensive that people can't afford to buy as many of them. and so this is proven especially effective with teenagers. but if you do smoke, now we've developed a whole series of drugs as well that you can use to try to decrease your

dependency on the cigarettes. we have nicotine replacement therapy, which includes gum, nicorette, or a patch, nicoderm or a nasal spray, nicotrol. here you're basically trying to inject nicotine into the patient, short term, so that they don't have to smoke.

the second approach is using pills, people who stop smoking often get very depressed, so this drug bupropion or you may see a commercials for chantix, and this reduces the smoking urge and withdrawal symptoms. but the best way to give up smoking is just to go cold

turkey and you can get assistance from health care professionals or use various medications, those people who try to stop smoking they are not successful the first time. and they have to try again and again, so early failure is a normal part of trying to stop

smoking. and also smoking cigarettes of course leads to nicotine addiction, and we mentioned that going cold turkey after a gradual reduction of the number of cigarettes you smoke each day is ultimately the most successful way.

when you stop smoking within 20 minutes your blood pressure and heart rate decrease, within 12 hours carbon monoxide levels return to normal, within two days your sense of smell and taste return, within nine months there's a decrease in cough and shortness of breath, and within

ten years the risk of stroke is normal and risk of dying from lung cancer is reduced significantly. so as you all know in a government there's no smoking allowed on the nih campus. and there's lots of health benefits from stopping smoking.

so in this country we have 45 million smokers but now we have 45 million ex-smokers as and their risk of dying from lung cancer slowly decreases but elsewhere in the world smoking is on the increase such as china, and so we know in about 20 years in china they are going

to have a big increase in the amount of lung cancer patients and so we have various programs interact with other countries where the smoking rate is going up. and here is some references. and that's about it. any questions?

(inaudible) >> well, ten years ago none of these pills and nicotine delivery systems were present. and as a result, the number of smokers was very, very high. and now you see because of all these sophisticated methods now, the number of ex-smokers is very

high in this country. and the number of new smokers is gradually gone down, but especially in men the number of deaths from lung cancer has gone down dramatically but unfortunately then the women started smoking and now they have sort of leveled off, so the

number for a while on tv you would see these commercials about the new women and they would be smoking cigarettes, and now we don't allow any smoking commercials on tv anymore. >> well, see, there's a problem with the nicotine replacement therapy because nicotine itself

sort of increases your risk for lung cancer, because the nicotine binds to the one receptor that's on the cells, so when you're using the nicotine delivery systems you only use them for a short time, a month or two at most. because if you were to use them

all the time, that would increase your risk of lung cancer. so all of these drugs, it's nice that they help people stop smoking but then you don't want people getting addicted to the drug. because they have nicotine.

>> yeah. the question is about the vaporizers to deliver the nicotine, and personally i don't think that's a very good idea. you know, then you're sort of breathing it in and it's getting deep into your lungs, whereas if you're ingesting it, you're not

going to get as much in the lungs. it's going to go into the stomach and be metabolized elsewhere. so i think the vaporizers may be more effective at delivering the nicotine but that's not necessarily a good idea.

that will do it till next week. we'll have class on monday and radiation oncology lecture then.