Cancer Organizations

>>> good afternoon, a nice beautiful day, nice fall afternoon. farah zia got her degree at george washington university, subsequently was a clinical fellow here at nci, and she's now a medical officer in the division of cancer treatment and

diagnosis. her title, overview of breast cancer. farah? >> terry, thank you. looks like the mic is working. you can hear me. thank you for coming today. the topic today is breast

it's kind of a broad topic, so i'm going to try to touch on the different areas that you might be interested in. so i think that people often forget the strides we're making in cancer research. unfortunately there are so many cancer deaths that we still see.

so i thought i would start by looking at how breast cancer was yesterday, and then talk about what it is today. so in 1975, the incidence rate for female breast cancer in the united states was 105 new cases diagnosed for every 100,000 women in the population.

the mortality rate was 31 deaths for every 100,000 women, from 1975-1977, 75% survived five years. among white females, the relative survival rate was 76%, among african-americans it was 62%. in 1975 mastectomy was the only

accepted surgical option for the treatment of breast cancer. only one randomised trial of mammography for breast cancer screening had been completed. several other trials were just beginning. clinical investigation of combination chemotherapy using

multiple drugs with different mechanismings of action and of hormonal therapy at post surgical or adjuvant treatment was in its earliest stages. listen to this, you can imagine the strides we've made. in the mid-1970s, clinical evaluation of the drug tamoxifen

as a hormonal treatment of breast cancer was just in the 1970s, no gene associated with increased breast cancer had been identified as of yet. how about breast cancer today? for the years 2007-2011, the incidence rate for female breast

cancer was 125 new cases women. the mortality rate -- so i want to point out that the incidence rate actually has gone upn but i would say that's due more to early detection, the use of mammography. and 12.3% of women will be

diagnosed, using data from 201920 twin. 2009 to 2011. among white women the five-year relative survival rate was 91%, among african-american women it was 78%.

the increase in breast cancer survival seen since the mid-1970s has been attributed to both screening and improved treatment. this graph is showing incidence and mortality by race, looking at the years 1975-2010. and for african-american

females, we can see that the incidence rose sharply from 1975 to 1990. then it reached a plateau, and rose between 1980 to 1985, more recently the incidence has declined and reached a plateau. mortality has been slowly declining for both

african-american females and white females, but there remains a disparity in african-american females that do have a higher mortality. this graph is showing u.s. mortality rates for cancer of the breast and the lung and bronchus.

from 1975 to 1990, the mortality for lung cancer steadily increased and reached a plateau for white females and african-american females. the mortality rates for breast cancer have declined since 1990, so again you are seeing a clear disparity exists between white

females and african-american females. for both white females and african-american females, lung cancer though still is a higher mortality rate. what is breast cancer? cancer that forms in the tissue of the breast and usually the

ducts, the tubes that carry milk to the nipples, and lobules as well, occurs in men and women but rare in men. this slide is showing you the structure of the breast. the breast is composed mainly of fatty tissue. so fatty tissue, which contains

a network of lobes. these are the lobes, within the lobes are the lobules. there's tiny ducts that conduct the glands, globules and lobes. age is a risk factor. also if you have had a prior breast cancer that puts you at risk of having a second breast

also if you have a high risk pre-malignant lesion like lobular carcinoma or hyper hyper plagia that will put at risk, or early menarche, have you have not have children that puts you at risk or had your first child at the age of greater than 35,

you are again exposing your body to more estrogen, thought of as a risk. women who have a history of breast biopsies, for example it could be for fibro cystic diseases puts them at higher risk of having breast cancer. patients who have radiation

exposure before the age of 40, for example patients who had hodgkins lymphoma and they have been treated with radiation to the media stinum and in some cases developed breast cancer. ma'am graphic density, dense breasts is a risk factor. also lifestyle factors, alcohol,

lack of exercise, obesity and you know obesity, you produce more estrogen in the body. family history is an important risk factor, if your mother, sister or daughter developed breast cancer before menopause you are three times more likely to develop a disease.

if two or more close relatives have developed breast cancer, you are also at increased risk. we know genetics plays a big role. breast cancers have been linked to mutations. brca1 is related to familial breast and ovarian cancer, brca2

is linked to familial breast p53 and rb-1, her-2/neu also linked to breast cancer. women with mutations in p53 and brca1 have a lifetime risk of 85%. i'm going to talk about early detection. i want to point out october is

breast cancer awareness month so you might want to share some of this information with a family member, your mother, sister, an aunt. the american cancer society guidelines, annual mammograms at age 40, continuing as long as a woman is in good health,

clinical breast exams every three years for women in their 20s and 30s, annually after the age of 40. breast self exam is an option for women starting in their 20s and i'll talk about that in a minute. the breast self exam, that's an

opportunity for a woman to become familiar with her own body, so if there is a change it can be detected quickly. if one does it, it should begin at the age of 20 and continue monthly traffic. l y

thereafter. you start by standing and looking in the mirror, look for changes in size, shape, color, you look for things that are not good like dimpling, puckering, inverted nipple or nipple discharge and do that also in the position with your arms

raised above your head so you can take a good look under the arm pits where there is also breast tissue. the next step is lie flat and feel your breasts while-like lying down. use a firm smooth touch. you want to keep your fingers

flat and together. there are different ways, one is a circular motion, the most important thing, you want to follow a pattern and cover the whole breast. so you do this both lying down and standing up or sitting. i said the self breast exam is

an option. in 2002 the u.s. preventive service task force recommended against teaching self breast exams, based on evidence indicating that self breast exam did not reduce breast cancer the decision was largely based on one randomised clinical trial

indicating no difference in breast cancer mortality after ten years in shanghai factory workers randomly assigned to receive self breast examination versus controlled. most clinicians do still recommend the self breast exam.

i think it's a good way to pick up things in between your physician visits which for most people are annually or every three years if you're younger. that's the data from a study. as far as clinical exam, it should be performed by a doctor or trained nurse practitioner,

the exams have been shown to decrease mortality based on evidence from the canadian national breast screening study. so the clinical exam is recommended every 2 to 3 years between the age of 20 to 40, and annually for women over 40.

what are you looking for when doing your own exam, paying attention to yourself during the year? make sure there's no change in breast size, no pain or tenderness, although i have to point out most breast cancers there's no pain or tenderness,

it's often a painless lump. it may be picked up on also redness, change in nipple position, scaling around the nipples, sore breasts that don't heal, puckering, dimpling, retraction, nipple discharge, thickening of skin, lump or knot or retracted nipple.

mammograms can be used as a screening tool in women with no symptoms. they can be used to detect and diagnose breast disease in women experiencing symptoms such as lump, pain or nipple discharge. we know that breast cancer screening mammography reduces

mortality by 26% in women 50-74 and 17% in women 40-49. there's probably higher incidence rate of breast cancers in the 50-74 age group. other modalities of screening in high risk women, digital mammography, most institutions now do use digital mammography.

the advantage is that electronic image is stored as a computer file and image can be enhanced, magnified and manipulated to get a good look as compared to the old films people did. we also use mri, especially in women who have a greater breast density, which makes mammography

difficult. but so the mri has sensitivity, it's higher than mammograms. so it's more often causative in disease but the specificity is lower you end up with more false positives in the biopsiy, that's the down side. diagnosis, how do we diagnose

breast cancer? so biopsy is necessary to ascertain whether a lesion is benign or cancerous and involves removing a sample of breast tissue. there are several methods. the most appropriate method depends on certain

characteristics of the lesion, its size, location, appearance, and how it's accessible. so one of the most common ways is final needle aspiration done on a palpable lesion when you can feel it, where the needle is going to go into. it's a percutaneous using a fine

gauge needle, and you withdraw fluid from a cyst or it could take cells from a solid mass. another technique is the core and needle biopsy, it is done using mammography and ultrasound guidance. therefore it can be used on nonpalpable lesions, a hollow

spring loaded device is fired into the breast and you get one sample per firing. the poor patient is subjected to 10 to 20 samples from the different areas within the lesion, so it's 10 to 20 times they will have to fire the thing to get the sample.

then there is something called a vacuum biopsy, it's a mammotome biopsy, guided by ultrasound or stereo tactic, it's quick, there's no pain, it's actually more commonly done than the other procedures, three times more accurate than core biopsy for early breast cancer, the

reason for that is because it takes a wide area of tissue and allows for sampling of micro calcification often seen in early breast cancer. then there is the abbi method, which is automated stereo tactical surgical biopsy, and this canula takes a sufficient

amount of tissue in one pass through the lesion. and it's able to take -- the cylinder is large enough to sample the uninvolved area which is good and open surgical is done by a general surgeon in the operating room. which is also i guess a good

technique in that you're able to get the whole lesion and you're able to get normal tissue surrounding it. this is just a picture of a device for the vacuum assisted or mammotome biopsy. this is a picture showing you, like i said earlier, sometimes a

lesion is not palpable but they are picked up on mammogram and therefore the interventional radiologist who is going to do the biopsy will need ultrasound guidance in order to locate the lesion, and here you just see what the breast mass will look like on ultrasound and you seed

needle approaching for the biopsy. sometimes something on mammogram turns out to be a cyst. oftentimes mammograms are followed by ultrasound to see if it's a solid lesion, and here you see an ultrasound, how a cyst will look on ultrasound.

it's biopsied, and if the fluid that's withdrawn from the cyst is clear, it's most often benign, and cysts are most often benign. but if it's bloody then you have to be concerned for a malignancy but that's not often the case in breast cancer.

what are the types of breast cancer? so a pathologist will give a final pathological diagnosis. so ductal carcinoma in situ, d.c.is and lcis. d.c.is is the most common type of noninvasive, only in the duct and has not spread through the

wall of the duct into the tissue of the breast. nearly all women with cancer at this stage can be cured. it's the best form of early detection for this lesion, with a mammogram, because the d.c.is is nonpalpable, asymptomatic, routinely picked up if a woman

of woman has a routine mammogram, often these are the lesions that are the reason we're seeing increased incidence of breast cancer but we're picking them up early and they are curable and treatable. globular carcinoma in siti begins in the milk grands.

it's not a true cancer, it does increase your risk of developing a cancer later in life. it's important that women who do have lobular carcinoma in situ follow up with regular mammograms. okay. invasive breast cancer, you've

got invasible ofive breast cars name a, idc and ilc. idc is the second most common type of breast cancer accounting for 8 out of 10 invasive breast cancers. it starts in the duct and breaks through the duct wall and invades the tissue.

from there it may enter into the lymphatics and spread to other parts of the body. from the lobules it can go through the wall and into the breast tissue and enter the lymphatics, but ilc accounts for 1/10 of invasive cancers. we do see a lot of idc in the

community. inflammatory breast cancer is rare it accounts for 1 to 5% in the united states, the most aggressive form. symptoms diffuse erythema, or peau d' orange. oftentimes there is no palpable

mass. unfortunately this type of breast cancer has a significantly lower overall survival rate. compared with other types of breast cancer iminflammatory tends to be diagnosed at younger ages.

median age is 57 years compared to 62 for other types of breast it is more common and diagnosed at younger ages in african-american women. median age at diagnosis in the african-american population is 54. and that's compared with median

age of 58 in white females. inflammatory breast tumors are frequently hormone receptor negatives, hormone therapies are not affected, in these cancers. more common in obese women than women of normal weight. so what is the -- what causes inflammatory breast cancer?

we don't know what causes it but the appearance is caused by the rapidly accumulating malignant cells that infiltrate and clog the lymphatic vessels, the dermal lymphatics, the blockage causes the appearance of the swollen and dimpled skin and classic signs that we're seeing

in inflammatory breast cancer. what are the guidelines developed by an international panel of experts? so the minimum criteria for diagnosis is the following. a patient often sees -- this is the history you often get from them, a rapid onset of erythema

and swelling, and a peau d' orange appearance and/or abnormal breast warmth. sometimes they can feel a lump. most often not. and usually the symptoms last less than six months, or they have seen it for less than six months.

oftentimes the erythema can cover a third or more of the breast and the initial biopsy samples will often show invasive carcinoma. this is a picture of somebody with inflammatory breast cancer. it's an african-american female. you cannot appreciate the

erythema but you can see the peau d' orange that looks like an orange peel. very classic. these are inflammatory breast oftentimes it goes misdiagnosed because physicians, especially primary care physicians, seem to think it's mastitis.

i've seen too many unfortunate cases where patients will come in six months after having symptoms, after being treated by antibiotic after antibiotic for a mastitis. especially unfortunately in women who had a recent pregnancy and are, you know, nursing

babies, i think that a lot of physicians will think, well, it's mastitis, but sometimes breast cancers do show up post-pregnancy. you have to be thinking all the time, this is something not good. so what is the prognosis for

inflammatory breast cancer usually develops quickly and spreads aggressively to other women diagnosed with this disease in general do not survive unfortunately as long as those diagnosed with other types of breast cancer. the five year relative survival

for women with this, the statistics from 1988-2001 it was 34%. that's compared with a five-year relative survival of 87% with women diagnosed with other types of invasive breast cancer. most commonly the idc. all right.

so staging, once the cancer is diagnosed it has to be staged. staging is a way of describing a cancer such as the size of a tumor and if or where it has spread, it's the most important tool doctors have to determine a patient's prognosis, also the stage dictates treatment options

a patient has. just briefly i'll go through the staging. stage 0 is known as carcinoma in situ, the cancer has not spread past ducts or lobules, noninvasive. stage 1 less than or equal to 2 centimeters, if there's no

lymph node involvement stage 2-a less than or equal to two centimeters, up to three lymph nodes, between two and five centimeters but still has not spread to the lymph nodes. or you can see no lesion in the breast but you still could have one to three nodes, that's still

a stage 2a. 2b is going to be between 2 and 5 centimeters, but it has also spread to between 1 and 3 lymph nodes, or greater than 5 centimeters and no lymph node involvement. 3a, you can see nothing in the breast, or you can see any size

tumor, up to four to nine lymph node or tumor greater than five centimeters they are continually refining stages. 3b, any size but spread to the chest wall and/or skin of the breast causing swelling or alteration.

it may involve up to 9 lymph nodes. so inflammatory breast cancer is at least a stage 3b at stage 3c, you can see no evidence of any disease in the breast, or the tumor may be of any size and cancer may have spread to the skin or chest wall

causing alteration. you can also see 10 or more axillary lymph nodes or you can also see lymph nodes above or below the collarbone which is also known as the super top. stage 4 breast cancer, breast cancer can be any size but it

has spread to parts of the body and the more commonplaces for breast cancer to go are bones, lungs, liver, chest wall or brain. what is the lymphatic system? the lymphatic system is part of the circulatory system. and it comprise as network of

lymphatic vessels that carry lymph toward the heart and lymph nodes are part of the lymphatic system, act as filters and remove foreign materials such as bacteria and cancer cells. so here you can see a cancer cell, they are escaping into the lymphatics, they can travel

through the body. at the top you see a normal duct, then you see a noninvasive cancer and at the bottom you see an invasive cancer that has broken through the duct wall and is now getting into the lymphatic channels, into the lymph node.

so what are the lymph nodes commonly involved in breast this is a traditional proceed you're, involving removing 10 to 30 lymph nodes, it's a reliable determination where the cancer is spreading but the drawbacks

here, there's always drawbacks to everything, it could cause post surgical complications, nerve damage from surgery, lymphedema, when there's lymphedema that could result in infection and be cumbersome. let's talk about sentinel nodes. it's from the french word that

means to guard over or vigilance, the first node that lymphatic fluid passes through, the protective node that acts as first filter for harmful material. a sentinel biopsy is a less invasive method to determine if axillary nodes contain cancer

with fewer complications. during surgery, there is injection near the tumor or nipple. tracer and dye travel, sentinel node is removed and sent for pathological review, if cancer is present the surgeon will take out more lymph nodes.

if there's no cancer, no more lymph nodes are taken and the patient is spared the problems with the full dissection. we know that sent until lymph node die session accurately identified nodal metastasis of early breast cancer but it's not clear if you do further nodal

dissection is it better in the long run? does it affect survival? there was a randomised clinical trial done, it was conducted to determine the effects of complete nodal dissection on survival of patients with sentinel lymph node mets, open

at 115 sites from may 1999 to december of 2004. patients with invasive breast cancer, but no palpable adenopathy. so those who had sentinel lymph nodes mets were randomised to a full axillary dissection or no further treatment at all.

the primary end point of this trial was overall survival, the secondary end point was disease free survival. results showed that at a median follow-up of 6.3 years, five years overall survival was 91.8% with full axillary dissection and 92.5% with just the sentinel

the five year disease free survival was 82% with alnd and 8 approximate .9% with slnd. among patients with limited sentinel mets, breast cancer treated with the use of only taking the sentinel node alone compared with axillary dissection did not result in

inferior survival. it's okay just to spare the patient and just do the sentinel so prognosis, it is the likely outcome for a patient diagnosed with cancer and it is often viewed as the chance the cancer will be treated successfully and patient will cover.

many the factors can inclines a cancer prognosis including type and location. treating the cancer, these are the different things that we have to work with. so what are the basic factors that doctors will consider in planning breast cancer

treatments? they will look at the stage of the disease, pathological grade of a tumor, which can range from 1 to 3, 3 being more aggressive. hormone receptor status, they look at her2 status, age and general health, menopausal status and presence of known

mutations. so as far as treating early stage disease, for both d.c.is and early stage invasive doctors recommend surgery to remove the tumor, to ensure the entire tumor is removed the surgeon will also remove a small area of tissue around the tumor.

surgery aims to remove all of the cancer, it is known many times microscopic cells can be left behind in the breast or elsewhere. so what is the next step in treatment after surgery? the next step in the management is to lower the risk of

recurrence and get rid of hidden cancer cells that remain, adjuvant therapy. adjuvant therapies include radiation, chemotherapy, hormone therapy and targeted therapy. the need for adjuvant therapy is determined based on chance of residual cancer, chance of

recurrence, adjuvant therapy lowers the risk of recurrence, it does not necessarily eliminate it. as far as inflammatory breast cancer, the treatment stems, i want to make mention it's a multi-modal approach. treated first with systemic

chemotherapy as opposed to normal routine of surgery followed by adjuvant therapy. in this case, we use systemic chemotherapy, followed with surgery to remove tumor followed by radiation therapy. and then we -- there's better chance for survival with this

approach. so metastatic breast cancer, what are the goals of treatment here? so as you know it is stage 4 cancer, noncurable at this point. so prolongation of survival is the goal.

we want to improve the quality of life for the patients and improve their symptoms. part of improving the quality of life is that you don't want to give medications that are so toxic that are more debilitating to the patients than the disease itself.

so in breast cancer we do have the option of hormonal therapy and if that is the case for patients that's what we prefer to do first. if chemotherapy is what we need to do, we prefer to use single agent therapy in metastatic disease as opposed to

combination chemotherapy. talk about hormone therapy. targeting the estrogen pathway, it's a well recognized growth factor for majority of breast cancers, that makes it a very lucrative preventive target, and for treatment as well. so estrogen pathway, you can use

drugs that work at the receptor, the selected estrogen receptor modulators including tamoxifen and receptamine. the aromatase inhibitors inhibit aromatase which is an enzyme found in peripheral tissues such as back, liver, muscle, brain,

aromatase will convert, eventually to estrodiol. tamoxifen will act as a receptor. tamoxifen is an agonist on the bone and uterus. and it's an antagonist at the breast.

so with the uterus you have to worry about if it's an agonist, you have to worry about uterine cancers, and that's the down side to treating with tamoxifen. reloxafine is used in treatment and prevention, an agonist on the bone, acts like an estrogen on the bone which is good, it

canning used for osteoporosis. but it's an antagonist on the breast and the uterus, which again is good for the uterus because you don't have to worry about developing uterine cancer with it. it's a good agent for prevention and for patients who want to

prevent osteoporosis and have a high risk family history of so i just want to make mention that at nci we developed a tool that weighs benefits and risks to prevent breast cancer. and although studies have though tamoxifen and raloxifene can both be used to reduce the risk,

they can also cause adverse side effects. blot clods, deep vain thrombosis, pulmonary embolism. researchers led a study developing a benefit risk index to guide decisions on whether postmenopausal women at

increased risk should take either drug. so the researchers who let the study used data from previous prevention studies and considered possible adverse effects, broken fractures, blood clots, stroke, endometrial anker

is, and invaseive and in situ breast cancer and calculated the probability a woman with a particular risk factor would have the outcome in five years with or without the medications. they created a color coded table for each drug, for each age group and five-year projected

risk of invasive cancer whether there is strong or moderate evidence the benefits outweigh the risks or that the risks outweigh the benefits for that particular patient. so this is being used clinically. this is just some data showing

you that tamoxifen definitely is beneficial. it does reduce the risk of reoccurence. let's talk about tamoxifen pharmaco genetics. we know the growth inhibitor effect is mediated by metabolites.

4-hydroxytamoxifen and endoxifen, catalyzed by the p450 and 2d6 enzyme. approximately 100 cyp 2dhave been identified. these manifest as distinct of four phenotypes. expensive, intermediatate, poor or ultra rapid.

formation of active metabolites influence therapeutic response. everybody is different in how they metabolize tamoxifen and respond to it. as far as aromatase inhibitors, there are three approved by the fda.

exemestane is an aromatase inhibitor, and they discovered it reduced risk of invasive breast cancer in postmenopausal woman at high risk of developing the disease. the map 3 trials randomly assigned them to the drug or

placebo, those who received the drug see 11 women developed invaseive breast cancer, those who received placebo, 32. the key points from the map 3 trial, women who took exemestane were 65% less likely to develop breast cancer, the largest reduction to date.

the trials did not reveal any serious side effects such as those for tamoxifen, and the follow-up for this trial is ongoing. they need a longer follow-up. it's still not actually fda approved as a preventive agent. systemic adjuvant chemo, so here

in the graph, so they are showing reduction in recurrence and mortality in the two age groups. and so both age groups do benefit from polychemotherapy but the greatest reduction in recurrence and mortality is seen in those that are less than 50

years old. so polychemotherapy is usually what we do as adjuvant chemotherapy when we're trying to go for a cure. it definitely has benefit over single agent therapy. so this is just looking at systemic chemotherapy and

showing that different types of breast cancer have different sensitivities to chemotherapy. we can see that those breast cancers that are endocrine dependent or hormone dependent are more chemotherapy resistant. if they are more hormone independent they are more

chemotherapy sensitive. all this is is taken into account when making a treatment. here i listed some chemotherapies. you can take a look at them. so her2 is a member of the membrane-spanning type 1

receptor, dimerizing. it is a definite therapeutic target. her-2 trastuzamab has high affinity and specificity, decreasing the potential for immunogenecity, approved for early stage breast cancer in 2005, when you add it to

chemotherapy it increases overall survival, when you add herceptin you increase survival in those that are her-2 positive. triple negative breast cancer does not express the genes for estrogen receptor, diagnosed in younger women,

african-americans, hispanics, women with brca1 mutations, characterized as more aggressive, less responsive to standard chemotherapy, associated with a poor overall prognosis. you can see from this graph that survival as compared to lunal-a,

survival drops after 60 months. so we're looking at -- these are just agents, we know platinum agents are more effective in triple negative breast cancer. ixabepilone. there's so few treatments with these patients unfortunately. we need better selection of

chemotherapy regimens to predict response to particular agents, we need a better selection of patients, we need to treat patients most likely to recur and who will therefore benefit from addition of chemotherapy. that brings us to the tailorx trial.

i'll talk about that in a second. neoadjuvant allows for assessment of tumor response because you're giving it before the lesion has actually been surgically removed through seeing if the chemotherapy is effective or not at reducing the

size of the lesion. we use this in clinical and research settings. recently last year, odac approved genentech's pertuzamab for early stage breast cancer. and this recommendation was based on two phase 2 studies,

and so actually it is on its way to becoming approved in the u.s., like 33% of the patients from the trials showed a pathological complete response with this agent. full approval is pending, data are expected in 2016 from a study that's ongoing.

an important question in breast cancer treatment, what is the likelihood of distant recurrence in patients with patients with no involved lymph nodes ines general receptor positive tumors? prognosis

is poorly defined. onco-typedx was developed for an assay for the expression of tumor related genes. gene expression was quantified, 250 candidate genes were selected from published literature, genomic databases and experiments based on dna

arrays done on frozen tissue, data was acknowledge liesed on 447 patients to test relationship between gene expression and recurrence of they used the results of the three studies to select a panel of 16 cancer-related genes, and five reference genes.

these were the ones with the best performance. they designed an algorithm and had to validate the test and use paraffin-embedded tissue samples from patients previously enrolled in the b-14 trials and used that to validate ability of the 21 gene rt-pcr assay and the

recurrence for algorithm to quantify likelihood the patients would recur distantly. the patients from the nsabp-b-14 were node negative, er positive, early stage breast cancer patients previously treated with tamoxifen. do we need to give them

chemotherapy or just hormonal therapy? that's the question. we see the risks for that was provided by the onco-typedx, when they looked at the patients from the b-14 trials they saw that those who were placed into a low risk category and they

followed these patients for ten years, those had a low rate of distant recurrence and those placed in a high risk category did have a high rate of distant reoccurence at 10-year follow-up. so based on this study the recurrence has been validated.

as quantifying the likelihood of distant recurrence in tamoxifen treated patients with node negative, er positive breast so patients with tumors that have a high recurrence for, have a large absolute benefit of chemotherapy, the more likely you to recur, you will have a

higher benefit from chemotherapy. that's clear. patients with tumors with low recurrence scores have minimal benefit if any from chemotherapy, and that's clear. so there's ongoing research using results from the onco-type

dx assay, taylorx as i mentioned before is trial assigning and there's another ongoing trial using data from the onco-type dx assay, the swog xr-ponder trial. so running out of time but tailorx is a landmark trial, representing the culmination of a major initiative to integrate

molecular diagnostic testing into clinical decision making, the primary objective is determine whether adjuvant therapy is not inferior to chemo-hormonal in women with a mid-range onco-dx score. what do you do with the patients who have an intermediate range,

chemo, not give them chemo? taylorx will answer some of these questions. they will create a tissue and specimen bank for patients in this trial, including tumor specimens, tissue microarrays, plasma, nci is using onco-typedx to identify and assign treatment

to more than 10,000 breast cancer patients from 1500 sites in the u.s., canada and peru, and the research is ongoing and results should be around the corner in 2015. this is the scheme for the tailorx. the key points, it's going to

examine whether genes tsat are frequently associated with recurrence for women with early stage breast cancer can be used to assign patients to the most appropriate and effective can genes predict treatment? the results of this trial could spare men women the unnecessary

toxicity of chemotherapy. we really don't know what to do with the certain group of patients who are in the mid-range. most of them do end up getting and so it is one of the first trials to examine a methodology to personalize cancer treatment.

and this is the other trial that's ongoing right now. it's a key trial. it's evaluating the use of adjuvant endocrine therapy, this is going to look at women with recurrence scores from the onco-type dx assay less than or equal to 25, 1 to 3 positive

do they need chemotherapy? 9400 patients will be screened to randomize 4000, it's ongoing. we're still waiting for answers. the m-pact trial, i want to let you know what we're doing. our clinic launched a trial in january of 2014, the purpose is to assess whether assigning

treatment based on specific gene mutations can provide benefit to patients with metastatic solid tumors. during the screening process samples of tumors from patients with various cancers will be genetically expensed to look for 391 mutations in 20 greens, if

mutations of interest are determined those patients will be enrolled in the trial and assigned to one of two treatment arms. one arm is going to get a targeted treatment, particular to their gene mutation, and the other treatment arm is going to

get another nontargeted therapy, a good choice therapy but not targeted to the mutation. patients who progress on armb are allowed to cross over to a. what we don't know is whether using this approach is really effective at providing clinical benefit.

most tumors as you know have multiple mutations and it is often not clear which one is -- you need to target to achieve the maximal benefit. once a gene is mutated it can lead to the activation of multiple pathways, so the trial that we're doing in our clinic,

the m-pact trial will determine whether people will develop from targeted interventions and if they lead to better outcome. do i have time to finish the last four slides? being with a few slides, what are the goals in breast cancer research?

i want to finish with that. we'll use our rapidly increasing knowledge in the fields of cancer genomics and cell biology to develop more effective and less toxic treatments for breast cancer and improve our ability to identify cancers that are more likely to reoccur.

this is exemplified by the onco-typedx assay. we'll use this knowledge to tai tailor breast cancer treatment, focus youing on targeted therapy. for example, gene expression analysis has led to

identification of five subtypes in response to chemo. this knowledge can be exploited from the development of treatment strategy based on the specific characteristics of a particular woman's tumor. not tumors in general but a specific woman's tumor.

and then this is exemplified by the tailorx trial i talked about a minute ago. so a patient's response to chemo is influenced by genetic characteristics and the inherited variations that affect the body's ability to absorb and metabolize and severe adverse

events, specifically to each patient. different patients metabolize drugs in different ways, and when we know the variations, we will know which patients are better responders than others. this is exemplified by studies on endoxifen.

we'll use our knowledge to enhance the body's ability to recognize and destroy cancer cells. and i guess i'm done. but that was almost my last slide. i want to say that we will strive to understand, address

and eliminate factors that contribute to the higher mortality expressed by african-american females because i think there are several slides that i showed you that disparities greatly exist. we would like to understand more about that.

thank you. [applause] [off mic] unfortunately that's a reality with cardio toxicity but you have to look at the benefits and risks of treatment and patients i guess who need a treatment i think you have no choice.

but some of the studies that are being done right now i think there is a need to eliminate chemotherapy in the mid-range group where patients could possibly do as well, overall survival without using it is of concern. there's a lot of studies being

done on exercise and other things that can be done to help women maintain strong heart function. >> we'll be moving on. the next speaker is andra krauze, medical degree from the university of alberta and did a residency there and came to nci

as clinical fellow, she's a staff clinician and will talk about radiation oncology. >> can everybody hear me okay? we're just loading it up. it will be a few seconds here. so i'm a staff clinician in radiation oncology. i'll be talking about the role

of radiation oncology in cancer treatment, and some of the details about how radiation oncology plays a role and how it is being administered and a little bit of the science behind it. i'll try and get to my slides fairly efficiently.

and if at any point in time you have a question please raise your hand and let me know. you can wait until the end alternatively. you have a handout, and there's one mistake. it's on your last slide it should say the patient is not

radioactive. that's an important point to note on the back. briefly, i think to make the most of our time i think if you walk away with a general understanding of what the radiation oncology process is, and the important

co-disciplines, we're a specialty that deals with radiation physics and radiation biology. i'll give you an overview of terminology and the role of radiation in cancer. i broke it up into three parts. the first part is a process of

how radiation therapy is being administered, so you have an idea what happens. and then the next part is the science behind it, the last part is the role in cancer. briefly there's a few questions on your handout which i don't expect you to know the answer to

but in reading them you may think about some details that surround our specially and hopefully as i explain to you some of these it will, make a bit more sense. i'll go back to these at the end, and see if you guys understand a little bit better

what we're about. so radiation treatment planning software which i'll have a few slides on is in great part responsible for how we plan and treat patients. once you see plans i'll go back to the questions. i'd like you to remember the

term imrt, it's an important term in radiation oncology because a great portion of treatments do occur using this technique and i'll show you what entails. i'll go into discussion about how we split up the radiation dose in order to treat our

patients. and explain what hypo fractionation is and we'll go through some techniques at the end. the process of administration radiation to a patient, you have an understanding, there's a number of professions that are

involved in radiation oncology. they involve radiation therapists, dosimetrists. you'll have medical training, that may come in a few different types, medical, surgical or transitional, and a residency four years long and then you have a fellowship which as you

can see there can be in different subsites that you might treat, especially the ones that are procedural in nature, you have board exams, board certification. in some countries, radiation oncologists are trained in both radiation oncology and medical

oncology, in other words they can also prescribe chemotherapy but generally in cancer in the united states it tends to be just radiation oncology by so what happens when a patient is referred to radiation oncology? you see them in consult.

you see them in the clinic, examine them, take a history, and then you go on to take -- to review imaging and scan them to plan their treatment. and then you evaluate the plan, ensure the plan is going to be administered appropriately and then you start them on

and subsequently you follow them up. the consult, this is when the patient comes to the clinic, so you do a history and physical exam, you look at all the imaging they have had to date, all the treatments they have had to date, very important for us

is whether they have had prior radiation therapy to the air you're asked to treat which is important because there is dose tolerance, and how long ago, that's important. this is why that always requires records. sometimes that may be difficult

to obtain or may be incomplete but it's very important to have. there are also certain conditions that preclude administration of radiation such as you can see on inflammatory bowel disease or dna repair syndromes, that's important because radiation

therapy interferes with repair of dna. that is a great portion of how we achieve effects. so if the patient already has a dna repair syndrome, then that would of course increase the effect of radiation therapy and cause significant toxicity.

so we look at organ safety, that means if you're going to treat lungs you must make sure the lung is operating properly. if you treated kidney, you must make sure that both kidneys are working and if one is not working you must make sure you spare the one they do have that

is working. then you consent the patient for treatment, it look likes this depending on the institution, stipulating side effects of treatment and they are broken down into two categories, what happens during treatment and what happens long term.

you can see i'll try and show you here. on the slide here you can see what happens during treatment and here what may happen a month, two years later. that's a good framework in terms of radiation treatment, side effects, which i'll go into more

detail in a second. what we also need, i think, is one of the cornerstones of administration therapy, you must make sure the patient has indeed this sounds obvious but there are situations when you may be able to forgo having tissue diagnosis of cancer or by and

large most radiation oncologists will not treat without tissue diagnosis of malignancy. this case was treated in canada, full brain radiation treatment the patient did not have cancer and there was a big lawsuit. so abnormalities in the brain look like they could be

metastatic disease, the assumption was made the patient had lung cancer but the patient did not have lung cancer, they had a different condition for which radiation therapy would not be administered, they would have had a different treatment and had the side effects of

radiation therapy associated, which the patient didn't need to have. that means in more practical terms when we suspect cancer we get a biopsy and prove they have so how do we plan a treatment? what does that mean? you bring the patient in, do a

ct scan. you acquire images and then you plan based on the ct scan that you have just acquired. i'll show you pictures in a you can see on the right-hand side a mask that looks like a hockey goalie mask to immobilize the head and neck, you must make

sure the patient does not move, that would obviate the need for very accurate treatment if you have a lot of leeway in terms of patient movement. you can also see here this blue device here, you can suck the air out of to conform to the patient's shape to keep them in

the form for treatment. what happens is you image the patient and now we're in a day and age with the ct scan that can be done sometimes with contrast, depending on what structures you intend to treat, and if you treat an area or a structure that is likely to

move, you may obtain a 4d cd scan with movement in realtime and use that to incorporate it into your treatment findings. so the planning, first and foremost what's important here when you plan a patient's treatment is to decide is this patient being treated with the

intent to cure or palliate? are you trying to treat in order to make a symptom better such as pain or having obstruction, or are you treating them in order to cure? that's important because the doses are different, and sometimes it's the level of

sophistication that you're going to use in your planning may be different also. and fractionation means how you divide up your dose. so that is important because if you are treating with the intent to cure, your treatment course may be more prolonged, you're

going to give less dose in each treatment package. now if the patient you think you're treating with palliative intent and they have weeks or months to live, in that situation you are more likely to use a shorter treatment course, a higher dose in each treatment.

with the understanding that there's a possibility they may have have higher toxicity which they are not going to live to experience that toxicity. this is important, the treatment, that is very important. the radiation type you're going

to use depends on whether the area that you treat is deep or superficial. and i'll show you some more data on that in a second as to how you decide. ultimately you have to determine what volume or what area are you going to treat and what is

important to spare. there's different types of particles you can use in if you're going to treat a skin lesion, something that's superficial, you can use electrons or ortho voltage. i don't want to go into detail but the idea is different

particles will deposit differently in tissue. tumors that are superficial require them to be deposited at the skin surface or immediately in the skin surface. electrons will do no good if the tumor is it deep, there will be no dose, it will be deposited at

the surface. you have to be able to select the energy of the particles that you use in such a way that you can reach the lesion and and treat it with some margin to the lesion itself. so what do we actually do as radiation oncologists other than

see the patient or physical exam? you need to contour. you are going to -- on the ct scan you've acquired in conjunction with imaging, you will now contour what you perceive the tumor to be and where you think the tumor might

be or subclinical extent of the disease you don't yet see but based on your knowledge of oncology where you may think the disease might spread. and you also need to control or draw what is normal. and that is done in order to attempt to spare as much as you

can. something called the gtv, growth tumor volume, that's the tumor you can actually physically see or palpate. if you have the patient in front of you, they have a tumor on their arm, you can feel it, that would be already part of your

gtv growth tumor volume you'll have a scene, the next step is to determine where will the tumor spread, to the lymph nodes? what tissue planes? that determines your clinical tumor volume. gtv by and large is to most

people if you see a scanner, a patient, you're able to examine them and see the tumor or see it on scan you will know that gtv is largely easy to appreciate what it is. so a lot of radiation oncologists may explain to you the reason that we exist, what

we are paid for is the ctv, the gtv is very obvious. the ctv, what is the behavior of this malignancy and what do we need to include so the tumor doesn't feel immediately adjacent. on top of that you have the ptv, planning target volume that

accounts for motion and variability in the treatment. when you plan, it used to be that planning used to be done in 2d. that's no longer the case. 2.5d came after this and then came 3d. this is what we have now, 3d.

i'll show you pictures. i alerted you to intensity modulated radiation therapy, that will be done on ct scan and require complex planning technique. arc therapy and brachytherapy, treatment administered at short distance with the use of

needles, probes, devices placed into or adjacent to the tumor you make a plan, evaluate the plan, you replan, if you feel that you have not adequately covered your tumor, or administered too much dose to what you perceive are organs at risk in the field that you don't

want to administer such a high dose to. this is head and neck plan, head and neck primary, you can see outlined in blue. and then the other lines that you can see here are isodose lines, lines of equal dose. this shows you that the plan you

created for this patient will administer 90% of the dose in this area here with the cyan color. it covers the volume you intend to treat. usually what you want is for your dose to cover at least 95% of the volume, or your target.

but as you can see, the cells are star shaped, if you appreciate here, 20% lines, it's almost star shaped. this defines the irt plan, there's multiple fieldses, generally an odd number, five or seven. each one itself is modulated to

treat the tumor and spare what is normal around it. hence intensity modulated radiation therapy. you evaluate the plan, it's covered by dosage you intend to give. and then you obtain what's called a dose volume histogram

showing you what percentage of what structure you have con toured, like i explained, you tell the computer what you want to treat and spare, what percentage of the doses it receives. there's of course numbers we stick to that we have literature

on and evidence as to how much we can get away with before we can cause toxicity. we do not know for sure, the data is not great but we have certain lines in the sand that we stick to in order to avoid causing the patient significant toxicity.

ultimately what we do next is quality assurance, this is a complex and long process and it is complex in the case of imrt. this requires physicists, therapists. this is called a phantom. this is being used by the physicist in order to run

through the plan as if you were treating a person but you're not and to see where you would deposit those, to ensure what you have planned is indeed what you would administer. you start the treatment. while the patient is on treatment you acquire imaging in

order to make sure you are treating them in the position that you intended them to treat in so that nothing is changed, if the patient is treated for head and neck cancer you're still treating what you intended to treat and you're not putting additional dose and structures

that you want to spare. so this is the treatment here, the treatment table, the table moves as you can see from the arrows, the gantry moves as well, it will move to administer the radiation treatment, depending on the field. and this is the imaging that i

was alluding to. so you can acquire on the treatment machine, you don't only treat, you treat but you can acquire images. and the imaging can come in different kinds, depending on the machine you have. the simplest is x-ray, 2d, and

you can then super-impose the image prior to treatment with the one where the position that the patient is in at that moment in time and you see how here they are superimposed, you can move this across toggle back and forth to make sure they are superimposed correctly.

for more complex plans you acquire a ct scan, so this is the image from the treatment machine itself, it's superimposed for our treatment plan and you can see whether the area you intended to treat which you can see are these multi-colored outlines here,

where they are superimposed where the patient is positioned that day. if the patient loses weight, you may be putting additional doses to the spinal cord that you want to spare. you can see this is being spared and you recalculate.

this is why we image the side effects, i think the simplest way to remember radiation therapy side effects is that the side effects are generally localized where you treat. so there's one exception to that which is fatigue.

when you radiate, no matter what body part you radiate, doesn't have to be brain, it could be an arm, a leg, what have you, the patient will be feeling more tired. it's not maybe week one or week two but as the dose accumulates that will happen.

the rest of the toxicities are localized to where you treat, a localized treatment. when people say hair loss, it means hair loss in the treatment area, not all over as you would see with say gene therapy. where you treat you might see skin redness, warmth,

occasionally itching, it never opens up and weeps. very, very rarely. sometimes there's skin folds with higher doses in a more obese patient but generally not. other fallacies, it will cause bleeding. it does not cause bleeding.

or dementia after whole brain radiation treatment is also not the case. again, other fallacies, if you treated neck and head cancer you may cause swelling causing the patient to have a tracheostomy, that also doesn't happen, ultimately that causes second

malignancy outside the radiation field, radiation therapy can cause another cancer in the treatment field, in an adult the likelihood is remote, 1 to 2 per thousand. but if it does occur, it is a different histology or different type of cancer than what you

were treating but it would be in the field of what you were treating, and it would have to be sufficient time from the time you have administered your radiation treatment. if it occurs within six months that's not a secondary malignancy.

that's probably just bad luck. if it occurs five, ten years later it's in the field, it's something different than the original malignancy that could be radiation related. so briefly physics, where we treat -- if you look at the electromagnetic spectrum we

would be here under x-rays. gamma rays are a by-product of x-ray production, so we do guard against that with our shielding but it is not where we treat. different types of radiation treatment which i briefly alluded to earlier, i think the important part to understand is

that depending on the particle that you are treating with, the ability to penetrate tissue varies. here you see for example the alpha particle is stopped by a piece of paper, beta is stopped by aluminum, gamma ray is only stopped by concrete.

so what we use by and large, what's being used is photons. this is artificially produced x-rays, linear accelerator, accelerate electrons against the target, produce x-rays which comes out this little door which is being targeted or modulated by these devices here which i

have a picture of in a second. you can also of course treat with electrons for superficial lesions, for example. by and large when people say they are using external beem radiation treatment, it's photons.

just like i explained using photons, you can see where it came out, where they come out here. i wanted to show you this is the aperture where the the beamwould be coming out. this is how you can modulate or adjust the beam, the leaves move

in and out and you can block the beam where you don't want it to go. i went through this a little bit in terms of electron therapy which i explained, photon therapy deposits those deeper, when you're not sure what might work for your lesion you'll

probably use photons rather than electrons if it's deeper. and then there's particle therapy, requires a specialized facility, protons, carbons, there's proton centers in the united states, i think there are ten at this point in time. they are expensive facilities,

proton doses differently. the advantage over photons, they we'll deposit the dose and then we'll exit without anything, as much dose. photons will have a relatively lower dose at skin surface but will slowly peak, deposit dose in tissue and subsequently taper

off. what you see here actually at the top these are electron curves. you see they deposit quite a higher dose at the surface, that's the intent for superficial lesion. deposit the dose, drop off and

eventually taper off, at the energy increases the area where they deposit those is larger. briefly, how do we measure? people ask me a lot. we measure when you administer radiation therapy for cancer, or in general, it's measuring great.

not in rads. it's not rads anymore. if you hear a dose of say 2005, that means 2000 and 5 fractions. you have an idea of the doses being given for different conditions. and this alludes to the point i made at the beginning as to

whether you're treating with intent to cure or intent to palliate? you can see a significant difference in how much dose you would be giving. significantly higher dose with curative intend, more likely to accept toxicity but less likely

in a palliative case. briefly, radiobiology, so radiobiology is the science that governs how we think of tissue response to radiation therapy. what it means, we want to maximize effect of radiation in terms of cancer killing and minimize effect of radiation in

terms of how it affects normal the way we do that is by dividing the radiation dose into low packages or fraction for you don't give all your dose all at once in one treatment. that would cause significant you may achieve dose response to the tumor itself but you would

also kill the patient. so what you need to do is walk the line between treating tumor and killing tumor and sparing normal tissue. what this shows here, the idea is to explain as we set off the dose in packages we can move this curve over and in so doing

spare normal tissue. what we want is exploit differential between what is responding quickly such as tumor or early responding tissue and late responding tissue such as same idea here. this is what i want -- actually what i want to show here, when

you use heavier particles you may see a dose response like this. the advantage of being able to do this is that they may deposit dose in tissue differently. in other words, less normal tissue will see radiation. four important things,

radiobiology if you want to reduce it, it would be the four rs, repair, reassortment, reoxygenation and repopulation. this means you want to allow normal tissue to repair and take advantage of the deficiency. reassortment, as you kill cancer cells they move to a cell cycle

and reasort or redistribute which we'll get to in a second into phases. cell cycle more radiosensitive or more likely to respond to and then reoxygenation which is the idea that as you radiate and kill some cells, some were previously hypoxic are moving

into areas more oxygenated. and they increase the ability to repopulate. so this is what i was alluding to with repair. radiations causes two types of damage. it causes single strand breaks and double strand breaks, it's

the double strand that you want, least likely to be repaired. particles cause significant damage, what we call bulky adduct, difficult to repair which is why they are effective. this is the redistribution point i mentioned.

so we understand that cancer cells are more likely to be susceptible to radiation treatment in certain phases, specifically the most radiosensitive in g 2 and m. i have this on the next slide. what you want, so this is -- they are most sensitive in m

than g2 and least or most radioresistant in s-phase. so as you exert an effect with radiation therapy on cancer cells, they may continue to divide for some time. but they get stuck. so when they get stuck in g2 or

m and you radiate again you are more likely to achieve cell killing. reoxygenation, as you may know one of the hallmarks of cancer, the cancer cells proliferate, develop areas of hypoxia, areas that did not previously have access to oxygen will now have

access to oxygen. this is something you want. this is supposed to illustrate the interplay between various agents that could be used to manipulate tumor cascades. where radiation therapy comes in, it has as you have seen in previously slides, it has

implication in terms of its ability to impair dna repair. it will also impair proliferation and cause cell death. a lot of these agents have overlapping effects. there are four, the idea is if you combine cytotoxic agents,

you may achieve a better response than either entity by i alluded to this, i want you to focus on the pictures themselves, the easiest way to understand. so you can see here on the right-hand side this is how we used to plan radiation therapy.

you would acquire an x-ray and say i want to treat from here to here, here and there, and block everything else. we no longer do this. the next step was to acquire an image but plot what the dose would go, even by hand. now we acquire a ct scan and in

three dimensions determine what we want to treat and what we want to spare and it looks like you can see the tumor and you can see how the beams would be treating this tumor and it has different aperture at each angle. intensity modulated radiation

therapy is an important concept, it will become increasingly used. this technique requires a lot of work both, it requires a lot of quality assurance, a lot of volume to be contoured or drawn. you use a number of beams, each is modulated or adjusted to

conform to a volume. this picture i think illustrates that quite well. you can see this beam here, for example, would have this outline. this one is different and they change in realtime, as you treat the person.

in so doing you can envelop your tumor in a dose cloud which means you can spare things that may be around the tumor that you do not want to put those in or you can put less dose in as a result. example is treated tumor to 50 gray but keep the bladder dose

at 20. if the tumor is next to the bladder without imrt that may not be possible. imrt is not always the best it is expensive. it is as you mentioned very complex. you now instead of having two

beams might have five, or seven. so it comes at a cost. these techniques here cyberknife therapy and gamma knife represent forms of imrt. i know it can be confusing but the idea behind them is the same. rx therapy is another example

of -- arc therapy is another example of imrt. you deposit the dose as the machine rotates in an arc. brachytherapy is different. up until this point what i mentioned was all external beams, the beam coming from the outside.

brachytherapy is different, you place the radiational source next to the tumor, within the tumor or in a body cavity. so gynecology, cervix, endometrium, vagina, or head and neck cancer. you place the source right

within the tumor and treat it from the inside as opposed to from the outside. the other examples, this is an example of plaque treatment for the back of the eye. the alternative is removing the eye so this was a great advancement and the outcome can

be quite good. this is a prostate implant. prostate gland implanted with radioactive seeds. what is important? well, when you treat with external beam treatment the patient is not radioactive. cannot be.

radiation goes in and out, it's done. when you treat with brachytherapy, the patient actually is radioactive because you put the radioactive source in the patient. over the course of the half-life the patient will be radioactive.

i think that's an important distinction to make. newer modalities you understand the difference but tomotherapy is analagous to how do you a ct scan, rotational move, administer as the gantry rotates. cyberknife is a robotic arm

moving around the patient even as the tumor moves. proton beam is a particle treatment that can be used at specialized centers, this is the one i explained has an advantage on how it deposits. gamma knife looks like this, a helmet with multiple apertures,

and you can plan as to which apertures you're going to use and administer your beam to contour your dose around the tumor. and radiopharmaceutical therapy for certain malignancy or metastatic disease with multiple areas of disease like for

example prostate cancer. very briefly, fractionation, this means how you divide your hypo fractionation means that you are going to administer larger doses for fractions. conventional fractionation, 1.8. the opposite is hyper. so you are now giving less dose

per fraction but you are giving more fractions. other terms you might hear that people can be confused about are igrt, image guided radiation treatment, you're imaging while you're treating to ensure you're administering appropriately. srs, stereotactic, high dose in

large fraction. when you say radiotherapy, three to five. fsrt, this treats a small area to high dose in a few treatments. here you can see a comparison between treatments that are 3d, how we used to treat and still

do in certain situations and in comparison to imrt where you have multiple beams with dose cloud that envelops the tumor that looks like a star. you want to move the curves as far down this way as possible to spare any organs in the field that are not cancer, that you

want to give as also toxicity as possible. what imrt will do for you, will enable you to envelope in a dose cloud while sparing larynx, mandible, and these lines here represent other organs that are adjacent to your target that you are now giving less dose to in

comparison to a 3d conventional i mentioned a form of imrt, the star-shape drugs, proton, the two lower pictures represent proton beams. i tried to explain that the point of proton therapy is that it deposits those in tissue differently.

there's almost no exit dose in comparison, to this plan here which is 3d where you see all this dose here that's going all the way out even here, 20% of the dose. protons have one major advantage, they give less dose to normal tissue, they have less

integral dose. you want to use protons for pediatric malignancies, children especially general are curative intent for treatment, very important, they will be around a long time, any area where you put dose could develop a secondary malignancy.

that's important in a child. important in adults as well but adults, especially as we age, in theory we have less lifetime to develop a secondary malignancy, so it's very important in children or tumors in bad places by organs that cannot receive a high dose.

so i've alluded to this a few times on the left-hand side, can you see sites that are being treated with intention to cure such as prostate, breast cancer, lung cancer, all of the entities on the left-hand side can also be treated with palliative intent if you have now

metastatic disease and a patient with lung cancer, maybe a role to palliate with radiation bone pain, shortness of breath, neurologic symptoms or pain from a space occupying lesion. there are some radiation oncology emergencies, not many such as cord compression when a

tumor will suppress on the spinal cord, or pressing on a nerve, cauda equina syndrome, pressure on the vessel, swelling, shortness of breath, organ compromise potentially or airway obstruction, bleeding. and the following conditions so here this picture is supposed

to illustrate for you, this is a tumor here pressing on the spinal cord, you can see that a situation like this could be managed surgically in some situations, if surgery is possible you would want for this patient to have surgery but that would be followed with radiation

in the event the patient cannot have surgery or unable to undergo anesthetic ors that multiple lesions you could treat with radiation to take pressure off the nerve and prevent neurology compromise. here you can see a big mass causing obstruction of the vena

cava, this patient is likely to present with swelling, vessel prominence, shortness of breath. this can be an emergency. it can be treated possibly by stenting this area, as an alternative with radiation metastatic disease of the bones can cause pain, fracture, so

this can also be an area where radiation therapy has a role with palliative can see here with obstruction, the tumor is compressing causing shortness of breath, further growth could cause collapse of this lung and oxygen dependency so this can again be treated

with palliation intent or potentially curative, depending on extent of disease. i think an important take home point is that radiation therapy has evolved significantly, even in just the last two years, we moved from using a very simple collumator where the beam is

now it is this type of collimator. this is a really big deal and can significantly help target and give the beautiful dose cloud where you can give the dose where you want and spare as much around as possible. this is the type of blocking

that used to be used that they used to cut. you use a ct scan in order to determine what dose is being administered to the structures in your field. and finally, here i think i explained about imrt, but i

wanted you to draw your attention to this. i think possibly where the future may lead us, functional imaging where you can now image the biology over targets. ultimately, depending on what statistics, 2/3 of patients that have cancer receive radiation

treatment at some point in their most of the treatments patients receive are external. there is of course i explained about brachytherapy, generally the patient is not radioactive, if you implant a radioactive such as for cancer therapy they are radioactive.

a lot of cancers require multi-disciplinary approach. radiation therapy, there are conditions where you administer alone but increasingsly a combination. it's an evolving field with physics and radio biology heavily involved.

thank you to these doctors for slides and i'll be happy to take any questions. [off mic] >> okay. so there are several aspects within that question. so difficult to treat, a brain tumor is difficult to treat

because it tends to be adjacent to organs you can't put much in, such as optic nerve. it's difficult to treat and plan, putting 60 gray into the tumor while putting as little as possible into the adjacent structures. we have constraints where for

example the brain stem that's right next to the tumor cannot go over 60 gray either. optic nerves 54 or 55 gray. now you have to tell your planning system whether you use imrt or conventional planning that you are now going to treat this area to 60 gray while

sparing everything else or trying to minimize the dose in other areas. we have to modulate our beams in such a way that we achieve that objective. that's one aspect of your question but the other aspect is that -- which is more important,

you achieve your 60 gray and constraints, but your tumor fails, because it does. we tell the patient this is curative intent but we know this is not going to be curative intent. we do not by and large cure neuroblastoma.

they might live a long time, they might go to multiple surgeries, multiple interventions but that 60 gray did not cure the tumor. it is the biology that we have yet to get to the bottom of in order to achieve that superior response where the tumor does

not fail in the field. when i say fail in field it means literally the tumor more than 95% of time neuroblastoma will fail in the field or edge of the field. in your high dose area you achieve your objective of putting the dose there but you

did not achieve your objective of curing your patient. and that is because presumably there's multiple mechanisms of radioresistance. there's also a significant hetrogeneity in terms of the biology of these tumors. and that's true for most tumors,

not just neuroblastoma but that's one entity we believe there's multiple different entities within that category. some of which may be more radioresistant, others more radiosensitive. incidentally, radiation therapy is combined can chemotherapy in

that particular instance, and that has been shown, the combination has been shown to include survival. you achieve that synergy that i mentioned to you guys in terms of combining the effect of radiation therapy over another agent.

but it is unfortunately not sufficient to produce a cure. the multi-factorial problem. of which the planning i think is the least problematic at this the actual nitty-gritty of planning and administration is not really the problem, it's the biology we have to solve.

>> yeah, that's a great question. so first of all it depends what sort of -- what radioactive source have you used, what is the half-life of it, where have you put it? so in the case of prostate cancer like the picture you saw

with the seeds in the prostate gland you provide the patient with an entireness of recommendation as to what they can and cannot do. that will mean seeds can migrate, we may see one of the seeds, they look like a pencil lead in the lung, they get stuck

in tiny blood vessels in the lung which is why you do a test a month after the seed implant. for seed migration you don't do anything. you tell the patient we think we see a seed there. it hasn't been associated with increased malignancy of the

lung. other precaution, discuss with them to not be around -- the most radiation is susceptible people, pregnant women, children, not keep the grandchild on their lap, because these are developing children that are more susceptible.

they are able to share a bed with a life partner. if they sleep one meter apart, while the patient has the seed implant present, the partner will receive as much radiation as flying from new york to paris, so really because flying i think you know is associated

with exposure to ionizing radiation. this is how much the partner would receive. in other words, it's not a big issue but you do counsel the person. if they have intercourse they are going to have to use a

condom because there's a risk of seed migration, we don't want them to deposit the seed into the partner. those are some of the issues. of course, you have to counsel them, god forbid they die and they have an autopsy performed, that tends to be a big issue for

of course the pathologist, because there's now radiation exposure, so they have to have lead protection and there's a long list of precautions. if you give somebody radioactive iodine for thyroid cancer there's an entire said of precautions depending on the

dose. for some you have to keep them admitted for 24-48, times 72 hours until they are no longer -- or the level of radioactivity is sufficient that you can release them. if you release them home they have to have their own room, so

toilets used only by that person, they can not share food, cutlery or body fluids with another person for at least seven days. it's complex but it's toldly dependent on the half-life of the isotope and where you put it.