Bill

Linus : I feel for you and the others like mammasbabygirl, and GDPawel et al. that have personally experienced the later stages of this condition. Based on input from other sources, including posts on this message board, I've seen and learned about much more advanced disease than my wife's current condition. I feel fortunate by comparison. The big BUT is not knowing where this thing is headed. Overall, data and opinion about this condition ( postradiation leukoencephalopathy ~ secondary to WBR ) points to further decline with time. My wife spent yesterday afternoon with a friend. This gave me an opportunity to compare notes. Her friend sees less change than I do. Probably not much of a surprise as I'm ultrasensitive to everything now. But, we agree on the following : Mentally, short-term memory is very poor and she seems " sluggish " in her thinking and actions. Also, and recognizing that personality change is a tough one to call because I know that my wife is miserable and has been depressed for quite awhile, I see a HARDENED, LESS CARING / LESS CONSIDERATE / DULLED attitude about everybody and everything recently. Not like her at all. I do know that personality change is one component in this group of mental changes that usually occur. Her walking ( both with and without her cane ) is not as steady as in the past. She stumbles enough that walking w/o her cane is no longer safe. Regarding your question about physician attitude and selection of WBR, I have several suspicions but I think that one of the big problems is that the subject isn't addressed early on because of the typically prolonged period of time before onset of L/T symptoms ( and dissipation of S/T symptoms ). The attitude is ' You need WBR now, keep the subject on a S/T level and we'll worry about the longer-term consequences later '. JMO and best wishes to ALL !

Eppie : I think that your doctor is incorrectly grouping together all levels of damage and severity of symptoms pertaining to postradiation leukoencephalopathy as if it's one all-or-nothing syndrome. Most of us discussing this condition in these WBR threads have been victimized by a demyelination of nerve fibers in the white matter of the brain. Usually an asymptomatic condition until some sort of a critical threshold of myelin deterioration is reached ( hence the prolonged delay in onset from ~ 6 months to 2 yrs. or more ) then symptoms start surfacing. Many of us, including my wife, are experiencing symptoms explainable by deterioration in nerve conductivity. No clinical evidence of any vascular involvement. My sources tell me that my wife's currrent condition is very common. There will always be variables that will influence severity from one patient to the next. This doesn't mean that vascular damage and symptoms aren't part of the bigger picture if the condition worsens. I'm already worrying about that myself and some people are posting post-WBR symptoms that clearly suggest vascular imvolvement. But, based on my knowledge of the condition, it can hardly be called rare. In fact, patients over age 50 have an ~ 80% chance of developing the condition. And, GDPawel has given us a detailed, full-spectrum overview of this condition and it's tx options. Whether the tx is worth the risk and effective or not is an entirely separate issue. As for me, my focus has been dealing with the sudden onset of my wife's neurological symptoms after such a long asymptomatic period. And, other than watching symptoms and monitoring brain MRIs nobody can tell me how to even quantify her condition and where it's headed good or bad.

This summarizes my message exactly. Add to that alot of foot dragging by some of the docs and HCPs ( late stage tx attitude ~ sort of reminds me of triage ). Situations like this can quickly turn into a meltdown. I'm currently watching and waiting. As previously stated, I most likely won't waste time scheduling appointments with any of her docs. When I've seen enough I will bring her directly to the ER and they can contact her docs and force them into immediate action. We had been looking towards her rad onc but given the fact that he performed the wbr and his surprisingly defensive attitude, and lack of concern, I'm thinking that I should insist that her neurosurgeon get involved. Once again, my poor wife is the proverbial hot potato. Nobody wants to get stuck with her. If I understand GDPawel and the rest of you folks that are knowledgeable about this terrible condition ( postradiation leukoencephalopathy ) HBOT is the tx of choice ? Please correct me if this isn't so or if there are other options. As some of you know, some of these docs don't know mud about some of these complications and we, the patient or caregiver, need to be ready to offer up tx recommendations, etc. Any additional input that can be offered to help me better prepare once I have seen enough and take action would be greatly appreciated. Thanks much.

I don't plan on scheduling any doctor's appointments re: this matter. If symptoms get much worse I will bring her to ER with her latest brain MRI films and rad report. They can notify her doctors then maybe somebody will be forced to take action. Based on input from those of you familiar with postradiation ( wbr ) leukoencephalopathy it looks like I should be asking about HBOT. My wife can no longer walk without losing her balance. Two days ago she was fine, even walking around the house w/o her cane. Now, w/o her cane she starts stumbling and falls after a couple of steps. Also, her S/T memory ( information recall ) is almost totally gone. IMO Sundrop1964 is right re: tx attitude, not just with wbr adverse effects but generally speaking, about late stage cancer patients. Many of you have spoke about the stigma of lung cancer patients because of it's association with smoking. I've observed directly and indirectly throughout my wife's experience a stigma or attitude of indifference to tx with late stage cancer patients, also. A far too common ' throw in the towel and make 'em comfortable ' mentality.

Fay A. Posted: Thu Dec 15, 2005 10:49 am Post subject: I am looking into the impact Tarceva may have on white matter. I'm curious about that, also. The research on wbr and leukoencephalopathy is very confusing which seems to be the norm for anything related to cancer. I've seen research blaming radiation, chemo plus radiation, and chemo with radiation being, by a large margin, the most likely culprit. I would also like to know how to quantify postradiation brain damage ( progression ) by looking at a brain MRI or series of MRIs over time. Do changes noted on a brain MRI correlate well with patient symptoms ? So far, the answer in my wife's case appears to be no. Perhaps with advanced damage involving severe neuromuscular impairment and vascular damage causing stroke maybe MRI changes are more evident and easier to correlate with symptoms. The oncs seem lost and are quick to defer to the radiologist. Another hot potato. My wife's rad onc wants to wait for one more brain MRI ( for comparison ) but he doesn't even know how long to wait for this next scan. And, he wants it performed at a specific facility that specializes in cyberknife radiosurgery. ( ? ) I recall GDPawel mentioning gamma knife surgery.

GDPawel : My wife's latest brain MRI radiology report states : " interval development of a diffuse abnormal signal intensity in the subcortical and deep white matter of the cerebral hemispheres which likely presents postradiation changes ( leukoencephalopathy ) . There is no evidence of acute infarction. " Based on your research, does the above-referenced terminology, esp. mentioning no evidence of acute infarction, suggest one particular sub-type of this condition as the likely culprit in my wife's case ? And, would this particular sub-type be considered, in your opinion, a candidate for HBOT ? She received WBR ( 11 treatments, don't know the rad dosage ) in late May ~ early June of 2004 for brain mets secondary to NSCLC. I'm estimating that noticeable mental deterioration, as outlined in one of my last posts, began appearing ~ 14 months post-WBR and appear to have stabilized over the last few weeks. Lastly, based on all of this, and if you conclude that she appears to be a candidate for HBOT, any educated guess as to why her rad onc, or rad onc's generally, wouldn't offer HBOT at this stage ? Thanks much. Bill

Here's an example of a very practical matter to think about. Imagine estate planning with a spouse that's NED that could outlive you but can no longer balance a check book. We thought that we had all contingencies covered in our estate planning after her cancer dx but because of her deteriorated mental condition we must revise the whole thing. Because my wife is no longer capable of competently handling even basic financial affairs in the event of my death, additional and complicated legal arrangements must be made for her care and thereafter. We have a very fragmented family which makes matters worse. Getting a safe and sound financial plan organized to cover this new twist has already proven to be one big headache. I strongly recommend that any cancer patient undergoing WBR organize their financial affairs to cover this possibility.

Unfortunately, I can't reveal this individual's name without obtaining permission which I haven't at this writing. But, this person, a board member known to most of us, had been doing extremely well, even what I'd classify as in remission territory. Around June of this year brain mets were discovered. WBR was performed and this individual now states to me that " I can’t walk, I can’t type, I can’t read, I can’t write, I can but it’s very minimal ". ( I think this was written to me by the spouse ). I'm mentioning this case becasue IMO too much emphasis is placed on the immediate or S/T transitory side effects of WBR or radiation generally. Longer term ( and permanent ) consequences of WBR such as postradiation leukoencephalopathy are unknown to many patients, seldom discussed or viewed as no cause for concern. My wife had barely any S/T side effects from WBR. Hair loss, loss of taste for a few days, some fatigue and that's all that I can remember. We walked away thinking that WBR was a piece of cake. As I stated in a previous post, WBR wasn't really that effective for my wife. It knocked out some very small suspect areas and modestly shrunk a couple of her larger brain tumors. As I also posted, up until starting Tarceva on 3/3/05 her four well-defined brain tumors hadn't significantly change in size or morphology. My wife's condition has currently stabilized at a diminished level of memory and intellect. She's easily confused and her soft personality has hardened somewhat. She claims to feel a little more unsteady on her feet but I can't tell any difference by watching her walk ( with a cane ). She has fallen twice in recent weeks.I am fully aware that postradiation leukoencephalopathy is considered a progressive disease so if her condition stabilizes at this level I will consider her very fortunate. BTW, thanks to gdpawel for the additional insight and info into WBR and leukoencephalopathy.

I was asked by a fellow board member if I wouldn't mind posting separately the Tarceva / brain mets comments from my latest message that I posted on my WBR / postradiation leukoencephalopathy thread. She thought that with all of the Tarceva users on this board that it would be more helpful to post this news seperately thereby reducing the chance that it might be overlooked and unread by Tarceva users who haven't had, or have no interest in, WBR. Makes sense, so here's the relevant portion of that message and I hope that some other Tarceva responders with brain mets are equally fortunate : ( I've edited it some for added clarity and perspective ) P.S. There has been some clinical studies and speculation about Tarceva use in treating brain cancer and / or brain mets. One piece of good news that I can share with you is, at least in my wife's case, Tarceva IS effective against brain mets secondary to NSCLC ( and, therefore, does cross the BBB ). The four brain mets that she had prior to starting Tarceva on 3/3/05 were described as " completely resolved " on her latest brain MRI. These four tumors have always been the primary focus of all of my wife's MRI and CT brain scans. WBR cleared up some small suspect areas in her brain but only slightly shrunk a couple of these four remaining tumors. Basically, there was no significant change in size or morphology of these tumors throughout conventional chemo up to starting Tarceva.

P.S. There has been some clinical studies and speculation about Tarceva use in brain cancer and / or brain mets. One piece of good news that I can share with you is, at least in my wife's case, Tarceva IS effective against brain mets ( and therefore, does pass the BBB ). The four brain mets that she had prior to starting Tarceva in 3/3/05 were " completely resolved " on this latest brain MRI. As I stated in my initial post, she is NED head to toe but now has the postradiation leukoencephalopathy to battle. She's currently stabilized but the mental / emotional changes are noticeable to everyone. Karen335 : RE: your question, just do an on-line search of the term. There's plenty of info.

Just speaking for myself, a warning about the general risks associated with radiation and WBR were mentioned. And, I'm certain that additional risk details are buried deep in the pile of paperwork that my wife signed. Realistically speaking, the problem that most of us had is that the rad onc didn't level with us in plain terms up front as to the very high probability and severity associated with WBR and postradiation leukoencephalopathy. I honestly don't know if my wife had any other tx options available to her. We didn't bother to check because WBR was presented as a good and essential choice with an acceptable risk : reward ratio. If WBR was the only tx option, and the risks were properly spelled out, we most likely would have still gone with WBR. BUT, the risk of brain damage with WBR is so high that the rad onc owes it to the patients and caregivers to be up front and honest about it so that they can prepare and plan accordingly. For most of us, this condition suddenly surfaces as a complete surprise, blindside attack. JMO

Thanks to ALL of you for the kind words, suggestions, etc. I feel for the others reporting similar outcomes. I am sickened to my stomach to report that my wife's condition has further deteriorated. Nothing really new RE: neuromuscular, such as related to walking and falling, etc., but mentally she is in bad shape. I'm shocked at the rapidity of this decline. I can't care for her much longer if this decline doesn't stabilize soon. I'm writing tonight mainly because I finally received a phone call from my wife's rad onc. Here's some FWIW snippits of that conversation that I'm passing on to you just in case that something said can help someone else. Keep in mind that he was " got-caught " angry and very defensive throughout the entire conversation. He states that, simply put, WBR damages / kills healthy brain tissue. It's unavoidable. There are numerous patient-specific factors ( age being a big one ) and procedure variables that can influence the degree of damage. But, damage to healthy brain tissue to some degree is a 100% certainty with WBR. I stated in an earlier post that onset of postradiation leukoencephalopathy is delayed, ~ 6 months to ~ 2 years. He basically agreed with that but stated that onset can be even longer than 2 years. In my wife's case onset of symptoms appeared ~ 14 - 15 months post-WBR. He also stated that it's not uncommon for a radiologist reading a brain MRI to not report subtle white matter changes suggestive of leukoencephalopathy unless the RX was ordered by a rad onc and / or ordered as a " status post radiation therapy " report. ( He mentioned that dx of this condition is much more accurate with MRI than CT ). Additonally, he states that this condition is more common than most realize because of the delayed onset of the condition. Many times a WBR patient will have some degree of postradiation leukoencephalopathy but dies before this condition becomes evident enough to become a dominant issue. As far as why he chose to administer WBR to my wife, the only half-assed answer that I got from him was that she had too many brain tumors to treat it any other way. I feel ill. Sorry, gotta go !

I have received several messages asking me about my wife's ( WBR ) postradiation leukoencephalopathy symptoms and leukoencephalopathy symptoms in general. If you do an on-line search of the condition the cause and symptoms are clearly and accurately outlined.In my wife's case the symptomatology is right on. Balance and related issues are a prominent feature along with mental changes. But, in my wife's case, as she has had two spine surgeries and already walks in a slow and guarded manner with a cane, hunched over, the balance related symptoms are harder to identify. But, I am noticing more unsteadiness and use of the cane to correct it. She has fallen once and I was stunned to hear her scream like a little child. Her mental deterioration, esp. loss of memory, loss of intellect and confusion are significant. All of this just sudddenly hit at about 14 - 15 months post WBR. Initially, we couldn't figure out what suddenlly happened until the brain MRI revealed the diffuse white matter damage. It doesn't appear that she has gotten worse in the last couple of weeks but in her current condition she can no longer safely take care of herself. There has already been two kitchen ( grease ) fires and she's the mental and emotional equivalent of a young child wandering around. We are aware of a gentlemen cancer patient in his mid 50s that's ~ 3 + years post-WBR. He has no balance or ability to walk w/o falling. I'm estimating that it took ~ 2 1/2 years for him to reach this point. He has just received an electric wheel chair but hates it, therefore, he is bedridden. He has no bladder / bowel control and is also mentally child like. My wife hasn't lost bladder / bowel control yet but she has had several " accidents " which indicate a borderline situation. The Alzheimer comparison that others have mentioned is pretty accurate. My big fear now is that with further deterioration vascular damage will cause my wife to have a stroke. Bye for now.

Thanks to all for the kind words. To answer MBG's question, this is an oversimplification but, IMO, there is a basket of interrelated terms and conditions, including radiation necrosis, that reflect different stages, severity, etc. of the same general malady. I say this because in my wife's brain MRI radiology report the radiologist diagnoses her with postradiation leukoencephalopathy and, for instance, adds that he sees no evidence of vascular defect " at this time ". This tells me that the vascular-related issues ( with stroke as a major threat ) are potentially part of the same process at some point with further progression and deterioration. This is a horrible outcome. To beat cancer, at least in the short-term, only to be struck with a disabling treatment-induced neurological condition that has already greatly diminished my wife's quality of life. At this rate if the deterioration doesn't stop now I feel like she will be bedridden and totally helpless within 6 months. Thanks again for the kind words.

My wife is NED but has developed diffuse postradiation ( WBR ) leukoencephalopathy. No point in second guessing WBR vs. alternative tx options. This is just a friendly warning to you that postradiation leukoencephalopathy is a delayed onset adverse effect of WBR ( as well as focal brain tx ). It can happen with or w/o chemo ( some studies blame rad + chemo ) and the incidence is very high. Upwards of 80% in patients in their 50's. A real sleeper that suddenly pops up with symptoms ( confirmed by brain MRI ) usually ~ 6 months to 2 years after WBR or focal brain tx. The symptoms can be numerous, progressive and devastating. Basically proportional to the amount of brain irradiated. Many patients, including my wife, aren't warned of this risk, or at least the magnitude, at the time of tx. Like I said, I'm not second-guessing the decision to use WBR in my wife's case. There are apparently some less destructive tx options to WBR but discussing the qualifying tx criteria for these alternatives is beyond my knowledge and the scope of this post. My wife's usually very accessible rad onc has suddenly become " unavailable " for comment. Good luck.

If it's any consolation you aren't alone if your PET / CT fusion results left you with more questions than answers. My wife just had a PET scan / CT fusion at supposedly the #1 ranked facility in SO CA and read by their most experienced PET / CT radiologist. He basically threw my wife's entire dx ( and therefore tx ) into question with some of his findings. I have appointments lined up with ALL 5 of my wife's treating physicians starting Friday to see how this thing shakes out. Get a consensus opinion and see what, if anything, can be done about this mess. Needless to say, my wife has been thru alot, including ( as some of you may recall ) near death earlier this year. She is stunned by these results and questions the integrity and reliability of the whole dx thru tx process right now. I can't blame her. I'm second guessing alot of things myself and will be demanding substantative proof to back opinions at these upcoming RE-evaluation appointments. I don't care whose egos get bruised ! BTW, here's a PET tip for you. The radiologist that read my wife's PET / CT told me that measuring ( the size of ) a lesion on a PET scan is highly unreliable / inaccurate and a waste of time. He, therefore, provides no such measurements in his reports. Just comparative SUVs. No peaceful weekend for us ! Good luck to ALL !

I stumbled across this comment recently while doing some on-line PET research. Thought that this might be of interest to those of you with BAC sub-type : " Even with the use of SUVs there can still be false positives when it comes to lung cancer. Some pathologies that may cause false positives include: infectious and inflammatory lesions and aggressive neurofibromas. One very important false negative is bronchioalveolar carcinoma. This carcinoma is on the low end of metabolic activity. " http://www.mcg.edu/radscape/CaseStudies ... ngMass.htm

Public release date: 18-Sep-2005 Study finds Tarceva benefits older lung cancer patients Drug should be tested as front-line therapy, say researchers COPENHAGEN--The tyrosine kinase inhibitor erlotinib (Tarceva®) showed encouraging activity with relatively tolerable side effects in elderly, previously untreated patients with advanced non-small cell lung cancer (NSCLC), reports a team led by investigators from Dana-Farber Cancer Institute in Boston. The uncontrolled, Phase II results are sufficiently promising to merit a Phase III trial comparing erlotinib with single-agent navelbine in this population, the researchers say. The findings will be presented at the 15th Annual Congress of the European Respiratory Society in Copenhagen, Denmark. "While further research is needed, our findings suggest that it may be beneficial to use erlotinib, a relatively non-toxic targeted agent, to initially treat patients with advanced lung cancer, rather than use conventional chemotherapy regimens," said Dana-Farber's Bruce Johnson, MD, who headed the research. Erlotinib is designed to specifically and potently block an overactive growth-signaling molecule (EGFR) in cancer cells. Earlier studies have shown that erlotinib produced promising activity in NSCLC patients for whom chemotherapy has failed. The single-center Phase 2 study being reported now is the first assessment of erlotinib in patients who have not received chemotherapy. David M. Jackman, MD, is the first author of the abstract, and Pasi A. Janne, MD, PhD, is the senior author. The 80 patients in the study were treated with erlotinib between 2003 and 2005 at Dana-Farber. All had Stage IIIB or IV disease; half were male; median age was 75, and all but five were current or former smokers. All patients were evaluated for survival and toxicity; 69 were evaluated for best response. Ten patients were discontinued from the study because of toxicity, and there was one treatment-related death from pneumonitis. Rashes (74 percent of patients) and diarrhea (60 percent) were the most common side effects. There were no complete responses to the drug, but 60 percent of the patients experienced either a partial response or had stable disease. Eight patients had partial responses, 33 had stable disease and 28 had progressive disease. The median survival was 46 weeks, and the median duration of partial response and stable disease was 65 weeks and 24 weeks, respectively. The researchers conclude that erlotinib "appears to be relatively well-tolerated and demonstrates encouraging activity and median survival" in previously untreated patients 70 years or older with NSCLC. In addition to Jackman, Janne and Johnson, the study's other authors are Joan Lucca, RN, Michael Rabin, MD, and Arthur Skarin, MD, of Dana-Farber; and Thomas Lynch, MD, Patricia Ostler, RN, Jennifer Temel, MD, and Panagiotis Fidias, MD, of the Massachusetts General Hospital.

Gail : IMO there isn't a clinically significant relationship b/w Tarceva tx and loss of appetite / weight loss. However, I can see a possible indirect cause for this with Tarceva if G.I. symptoms, esp. diarrhea, were severe and persistent. In my wife's case, she has gained ~ 10 to 12 lbs. since starting Tarceva in March ' 05. Her G.I. symptoms are negligible but when she does have a bout of diarrhea her weight will quickly drop a couple of pounds then she gains it back over the following few days. Also, as you may know, the cancer process itself, particularly in the later stages, can cause weight loss ( cachexin / tumor necrosis factor ), RE: impact on blood values, based on my wife's hematology reports and collateral data, I don't see any Tarceva-induced abnormalities other than a modest elevation in a couple of liver function values. Overall, Tarceva has been easier on my wife's blood than her previous chemo regimen ( Gemzar / Carboplatin ). Hope this helps.

Jen : Are you aware of any clinical trials for tx of Crohn's Disease in your area ? If not, I know of a physician currently recruiting patients with Crohn's disease for testing of an investigational drug. Even though he's not local for you his office may be able to direct you to participating physicians in your area. Here's his info : David B. Stanton, M.D. Medical Director Community Clinical Trials 505 S. Main St., # 1030 Orange, CA 92668 phone : ( 714 ) 835-1719 Good luck.

Addie : Yes, I read your post. Congrats on recognizing the problem AND taking the initiative to get it fixed. Just another good example of why the patient ( or caregiver ) MUST play an active role in managing his or her own healthcare. B

I've read some posts re: dexamethasone ( Decadron ) vs, prednisone and adverse effects so I thought that I'd add my 2 cents. IMO if administered in equivalent mg. for mg. oral therapeutic dosages ( prednisone dosage = ~ 6 x dexamethasone dosage ) the S/T and L/T adverse effects profiles of these two drugs are comparable. As far as tx effectiveness, either drug is fine for general ( antiinflammatory ) use but dexamethasone is preferred for use in the brain. However, the clinical significance of this is debatable. Overall, prescribers tend to favor dexamethasone. IMO more out of habit. But, with dexamethasone, lower dosing and available dosage forms simplifies maintenance. I would urge anyone that is on L/T steroidal tx to discuss dosing and adverse effects with their prescribing physician in order to be satisfied that the minimal effective tx dosage is being administered. IMO it is fairly common for prescribed dosages to be higher than necessary. JMO

Sunday, August 14, 2005 Patients forced to rely on their own resources Left to research and coordinate their own care, many find modern medicine to be lonely, scary and overwhelming. By JAN HOFFMAN The New York Times Nothing Meg Gaines endured had prepared her for this moment. Not the six rounds of chemotherapy for ovarian cancer that had metastasized to her liver. Not the doctor who told her, after Gaines was prepped for surgery, that he could not operate: a last-minute scan revealed too many tumors. "Go home and think about the quality, not the quantity, of your days," he said. Not the innumerable specialists whom Gaines, then 39 and the mother of two toddlers, had already mowed through in her terrified but unswerving effort to save her own life. Not the Internet research and clinical trial reports, all citing the grimmest of statistics. Not the fierce, frantic journey she made, leaving home in Wisconsin to visit cancer centers in Texas and California. Now, just about out of options, Gaines faced an excruciating decision. Her last-ditch chemotherapy regimen did seem to be working. Three medical oncologists thought she should stick with it. But two surgical oncologists thought she should first try cryosurgery, injecting liquid nitrogen in the tumors to shrink as many as possible, and then following up with chemotherapy, allowing it to be more effective. The catch? Gaines' chances of even surviving the procedure were uncertain. "Who will decide?" she asked a surgeon from Los Angeles. The doctor then recited what has become the maddening litany of medical correctness: "We're in the outer regions of medical knowledge," he said, "and none of us knows what you should do. So you have to make the decision, based on your values." Gaines, bald, tumor-ridden and exhausted from chemotherapy, was reeling. "I'm not a doctor!" she shouted. "I'm a criminal defense lawyer! How am I supposed to know?" A generation ago, patients argued for more information, more choice and more say about treatment. To a great extent, that is exactly what they have received: a superabundance of information, often several treatment options and the right to choose among them. As this new responsibility dawns on patients, some embrace it with a sense of pride and furious determination. But many find the job of being a modern patient, with its slog through medical uncertainty, to be lonely, frightening and overwhelming. Many prostate-cancer patients can choose a passive treatment, like watchful waiting, or a more aggressive therapy, like radiation or surgery; each has differing risks and different patterns of side effects. Women with breast cancer often hear conflicting advice from the experts: lumpectomy or mastectomy? Some patients with heart disease can be told by one doctor that they need a bypass, by another that they need angioplasty and by a third that drugs would be just fine. The job of being a modern patient includes not only decision-making, but often coordinating doctors, medical records and procedures, as well as negotiating with insurance companies, which are often the ultimate arbiters over which treatment options will be covered. As Gaines was being treated for cancer she had to wage such a battle. Before she had her diagnosis, her HMO gynecologist laparoscopically removed what appeared to be a cyst on her ovary. But during the procedure, the cyst, which turned out to be a malignant tumor, burst, sending cancer cells into her abdomen. She then wanted to be treated by a specialist, but her insurance plan did not have a gynecological oncologist on its roster. So Gaines spent months fighting to transfer her care to an out-of-network doctor. Finally the insurers relented, but only after the specialist agreed to perform her surgery at the HMO's regional hospital, not his own. Like many patients, Gaines did not turn to a primary-care doctor to help coordinate her care or aid with decisions. Increasingly, that soul-healing, doctor-patient relationship has become harder to sustain. Whipsawed by insurance plans, patients frequently switch physicians. Pressed by diminishing reimbursements, those doctors are building ever larger, more unwieldy practices, with less time for each patient. Gaines was out of time. She had to make a decision. She felt the chill of mortality and the full weight of nearly a year of drastic surgeries, blood clots, a punctured lung, chemotherapy, research, traveling, countless specialists and unanswerable questions bearing down on her. "Who's in charge here?" she thought that night, wishing someone would just issue her marching orders. "Oh. I am." A generation ago, most of the diagnostic tests that monitored Gaines' cancer did not exist. Nor did the range of treatments. After the cancer had been found, most likely her primary-care doctor or local oncologist would have told her what to do. And Gaines would have obeyed. Until the late 1960s, patients perceived doctors, then almost exclusively white men, as unassailable figures of authority. They knew best. But during the social and cultural upheaval that ushered in the women's-rights, civil-rights and consumer-rights movements, the paternalistic authority of the physician became deeply suspect. With the introduction of Medicaid and Medicare in 1965, health care began to be seen as a right, not a privilege. Patients repositioned themselves as consumers of health care, entitled to as much information as possible. Support groups sought to empower patients with booklets and questions for doctors. The eruption of pharmaceutical advertising introduced millions to medical conditions that were once discussed only in the privacy of a consultation and to the promises of new approved treatments. And inevitably following these promises was the prompt: "Ask your doctor." By the 1980s, opinion-seeking could even turn into doctor-shopping for specific procedures. Within the past decade, the shift in the doctor-patient conversation - from, "This is what's wrong with you, here's what to do," to "Here are your options, what do you want to do?" - became all but complete. "People want to feel a part of their health care," said David Mechanic, a medical sociologist at Rutgers University. "But they don't want to be abandoned to making decisions all on their own. When a doctor says, 'Here are your options,' without offering expert help and judgment, that is a form of abandonment. " In the 11 years since Rick Sommers received a diagnosis of multiple sclerosis, medical advancements have raised and dashed his hopes. Sommers, 45, a former marathon runner and New York DJ, went through the shock that many patients experience, after two neurologists determined the cause of his numbness and tingling. "The doctors are trying to map out exactly what is wrong with you," he said, "and they're giving it to you in sophisticated neurologic terms. It's like being in a foreign country: you don't speak the language, and you're trying to find directions." In the years since the disease was diagnosed in him, multiple sclerosis patients have gained access to more information, more specialists and more treatment options. In addition to a phalanx of alternative remedies, at least five drugs that try to prevent exacerbations are on the market. Sommers receives an electronic newsletter from the National Multiple Sclerosis Society, a patient support group, and sets his computer's stock watch for advisories on companies researching drugs. Early detection for MS has improved, which means that more patients are seeking treatment. Clinics are filling rapidly. Sommers had to make appointments four months in advance. "There are a lot more hoops to jump through before you can get to the doctor," he said. "I got more personal care 11 years ago."

Study identifies which patients will not respond to treatment with targeted cancer drug LOS ANGELES (August 8, 2005; 5:00 p.m., EDT) – By the time the human genome was mapped, cancer researchers had already begun investigating the proteins that were encoded by these newly identified genes. As the molecular engines that control all functions of the body, scientists wanted to find out how proteins work to promote health, or malfunction to cause disease. Subsequently, their discoveries have led to the development of a whole new arsenal of therapies designed to target proteins in cancer cells. But not all patients respond to treatment with these targeted drugs, prompting researchers to look for molecular clues within tumor cells that cause resistance to treatment. Now, cancer researchers at Cedars-Sinai Medical Center have identified a protein called EMP-1 that is present in the tumors of patients who fail to respond to treatment with gefitinib, or IressaTM, a drug that has limited success in the treatment of patients with non small-cell lung cancer – the most common and deadly form of lung cancer. The study, conducted in both laboratory tests and patients with advanced non small-cell lung cancer who were treated with gefitinib, is published on-line during the week of August 8 – 12, in an "Early Edition" of the Proceedings of the National Academy of Sciences, and may ultimately help physicians identify patients who would benefit from treatment with gefitinib. "Our results show that the EMP-1 protein is a biomarker for resistance to treatment with gefitinib and may enable us to identify patients who won't respond to the drug," said David Agus, M.D., senior author of the study and Research Director at the Louis Warschaw Prostate Cancer Center at the Samuel Oschin Comprehensive Cancer Institute at Cedars-Sinai Medical Center. "If we know who won't respond, we can explore other treatment options sooner and use gefitinib, when patients will benefit. This means we will be able to maximize use of this drug and treat more patients effectively." Gefitinib is a drug approved by the Food and Drug Administration to treat patients with NSCLC only after conventional treatment with chemotherapy has failed. It is taken in pill form and works by blocking the action of a key growth-signaling pathway in a protein called the epidermal growth factor receptor (EGFR). But gefitinib shrinks tumors in only about 11 percent of patients with non small-cell lung cancer, and most of these patients eventually develop resistance to the drug. Given the limitations of gefitinib, scientists began looking for proteins within non small-cell lung cancer tumor cells that might indicate who would be most responsive to the drug. The first of their efforts resulted in two important studies published early last year that identified specific mutations within the EGFR pathway linked to patient response to gefitinib. However, these mutations correlated only with a partial or complete response to gefitinib in NSCLC patients, while 30 percent or more of the patients receiving the treatment reported stable disease. "While these observations are very important, they still pose vast imprecision in predicting which patients would benefit from treatment with gefitinib, and emphasize the need for understanding the mechanisms responsible for gefitinib resistance," said Anjali Jain, Ph.D., the first author of the study and a research scientist at Cedars-Sinai Medical Center. To identify the proteins involved in resistance to gefitinib, the researchers first developed a resistant tumor model in the laboratory. This was done by implanting a type of prostate cancer in mice that was "androgen-independent," or that was resistant to treatment with hormone blocking drugs and grew independently of testosterone production. The researchers chose prostate cancer tumors for this study because, similar to non small-cell lung cancer, prostate cancer tumors become resistant to treatment, have the same EGFR protein-signaling pathway and have been found to respond to treatment with gefitinib in early clinical trials and laboratory studies. The mice were then treated with 100 mg/kg of gefitinib for five days per week. Every three weeks thereafter the tumors were removed and implanted in other mice until a gefitinib resistant tumor had been generated. The investigators then compared the resistant tumors to those tumors that were newly implanted and had not yet acquired resistance to the drug (gefitinib-sensitive). They found that a particular gene, EMP-1, was significantly expressed in the gefitinib-resistant tumors, whereas it was not expressed in the gefitinib-sensitive model. "This tumor model was generated in such a way that it closely mimicked acquired resistance to gefitinib and EMP-1 was identified as a surface biomarker whose expression correlated with the development of resistance to gefitinib," Agus said. "Molecular diagnostics, such as this, are extremely important as we attempt to personalize cancer treatments in the next decade." To confirm whether or not EMP-1 was present in patients with non small-cell lung cancer who were being treated with gefitinib in clinical trials, the investigators examined tumor samples from 39 patients. They found that none of the patients who responded to treatment with gefitinib expressed EMP-1. Alternatively, EMP-1 was present in 14 patients (28 percent) who had non small-cell lung cancer that had either stabilized or progressed. Importantly, however, one patient who initially did not express EMP-1 and had responded to treatment with gefitinib, later acquired resistance to the drug, and EMP-1 was significantly expressed when the cancer recurred. "This tells us that the absence of EMP-1 does not completely predict whether a person won't stop responding to gefitinib. However, it appears that testing for the presence of EMP-1 at the outset of treatment may help physicians predict which patients won't benefit from the drug," Jain explained. "Importantly, we found that EMP-1 is not only a marker for patients who won't respond to gefitinib, but also for those who will later develop resistance to the drug." To confirm that EMP-1 was also present in patients with types of non small-cell lung cancer that do not respond to gefitinib, the investigators examined tumor samples from patients with adenocarcinoma and squamous cell carcinoma. They found that EMP-1 was expressed in 66 percent of the squamous cell carcinomas and 40.9 percent of those with adenocarcinoma, confirming that the presence of EMP-1 is directly linked to Iressa-resistance. "This is an important new tool in the treatment of lung cancer which needs to be confirmed in ongoing large clinical trials," said Ronald Natale, M.D., an oncologist at the Cedars-Sinai Outpatient Cancer Center at the Samuel Oschin Comprehensive Cancer Institute and a principal investigator on clinical trials with gefitinib, including the Iressa Dose Evaluation in Advanced Lung Cancer Trial 2 (IDEAL 2) that provided the basis for the initial approval of Iressa by the FDA.