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  #1  
Old 03-02-2011, 09:21 PM
gdpawel gdpawel is offline
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Default Smart-pill alternative to PCI (prophylactic cranial irradiation)

"Smart Pill" is a euphemism for other preventative measures that are available for SCLC. It's called a smart-pill alternative.

The idea that systemic therapies can be as effective as PCI has been looked upon for a number of years now, with agents like Temodar and EGFR inhibitors (like Iressa and Tarceva) against brain metastases.

Being that SCLC is intrinsically sensitive to chemotherapy (although it is very aggressive and tends to grow fast), while NSCLC is not intrinsically sensitive to chemotherapy (although it is not as aggressive as SCLC), it would make sense to have the most "effective" chemotherapy from the start.

EGF is epidermal growth factor. EGF is a receptor on many normal tissues/cells, and also on many cancer cells. It is a growth hormone, locally secreted by cells. It attaches to a receptor on the cell membrane called EGFR (epidermal growth factor receptor).

It then activates signalling pathways withing the cell (a cascade of biochemical events). One type of enzyme which is involved in the pathway is called tyrosine kinase.

Targeted treatments like Iressa and Tarceva take advantage of the biologic differences between cancer cells and healthy cells by "targeting" faulty genes or proteins that contribute to the growth and development of cancer.

The brain is the most common site of metastatic spread of small cell lung cancer (SCLC). Accumulating evidence suggests that systemic chemotherapy may play an important role. There have been clinical observations of frequent brain metastasis responses with systemic chemotherapy.

With a brain metastasis indicated or not, small molecule intervention can be beneficial by dissolving through the capillary cell membranes and absorbed into the brain. A small molecule drug may be able to penetrate the blood-brain barrier (BBB). Systemic brain chemotherapy can also treat coexistent systemic disease.

Clinical data suggests that patients benefit both in terms of response and survival from drugs and drug combinations found to be "sensitive" to cancer cells rather than "resistant" to those cells.

The leading edge of research today is determing how a patient's tumor cells work and hitting those pathways with multiple drugs, simultaneously or sequentially, each chosen because it targets one of those growth, replication and angiogenesis pathways. Matching tumor type to drug.

Drugs like Temodar, Iressa and Tarceva are small molecule. Empirically, it has been shown to cross the BBB to affect cell death in circulating tumor cells. And exciting results have come from studies of "multitargeted" tyrosine kinase inhibitors, small molecules that act on multiple receptors in the cancerous cells, like Tykerb and Sutent.

The problem of penetration into the central nervous system (CNS) is not as nearly as severe for small-molecule drugs. Large molecules cannot permeate through the narrow spaces, however, fat soluble (lipophilic) molecules can dissolve through the capillary cell membranes and are absorbed into the brain. A few brain diseases consistently respond to lipid-soluble small molecules.

The problem with most large molecule drugs is that they do not have a convenient way of getting access to the large majority of cells. Plus, there is multicellular resistance, the drug affecting only the cells on the outside may not kill these cells if they are in contact with cells on the inside, which are protected from the drug. The cells may pass small molecules back and forth. Large molecule drugs cannot permeate the BBB to give added effects to the CNS where brain mets develop.

Although approximately 100% of large molecule drugs do not cross the BBB, the problem is not as nearly as severe for small molecule drugs (greater than 98% of small molecule drugs do not cross the BBB).

Despite this situation, no pharmaceutical company has a BBB drug-targeting program that I know of. Nevertheless, BBB drug targeting technology can be built around a knowledge base of the endogenous transporters within the brain capillary endothelium, which forms the BBB in vivo. The capillary endothelium are single pavement layer of cells, which line the surface of the entire vascular system and regulate the transport of macromolecules and blood components.

An assay for microvascular viability (M.V.V.) has discovered that endothelial cells are present in tumor microclusters and it appears that drug effect upon these cells can be assessed in the M.V.V. The M.V.V. assay is being offered as an adjunct to either a standard assay or a tyrosine kinase assay. The assay is able to test small molecule drugs like Iressa, Tarceva, Tykerb and Sutent.

High dose pulse Tarceva can be effective for central nervous system (CNS) disease, so long as resistance has not developed.

[url]http://cancerfocus.org/forum/showthread.php?t=3920

What may be another alternative is high doses of two small molecule EGFR pathway drugs, Tarceva and Iressa, given together. It might cross the BBB and some patients may get a long-lived remission with these drugs. Iressa and Tarceva are very similar drugs, small molecule inhibitors of tyrosine kinase, a key intermediary in the EGF cascade pathway. They act on multiple receptors in the cancerous cells.

High-dose tamoxifen could then be given continuously as a potentiator and an anti-angiogenic effect. This suggestion comes from cell function analysis.

It makes me wonder, if they radiate just the whole brain but not the spinal cord, how does PCI benefit the patient? Any theoretical cancer cells in the spinal cord would eventually infiltrate the brain.

What does intrinsically sensitive mean?

Intrinsic just means belonging to the essential nature of a thing. Non-solid cancers are intrinsically "sensitive" to most any anticancer drug. That's why blood cancers are relatively easy to "cure" not just obtain remission. Testicular cancer, gestational choriocarcinoma, Hodgkin disease and high-grade lymphomas are routinely curative with chemotherapy.

The intrinsic properties of malignancies themselves, rather than the qualities of individual drugs or combination therapies, are primarily responsible for their curability with chemotherapy. Curability of these malignancies result from an intrinsic 'locked-in' state of sensitivity to pro-apoptotic (cell death) stresses in these cells.

A common property of such curable malignancies is that they arise from cells that undergo major genetic rearrangements or recombination as part of their normal physiology. The absence of further genetic and epigenetic changes in genes that regulate apoptosis, DNA repair and senescence allows these cells to maintain their intrinsic sensitivity to chemotherapy (Nature Clinical Practice Oncology, 6 (1). pp. 43-52. ISSN 1743-4254).

[url]http://publications.icr.ac.uk/7440/

Pulsatile High-dose Tarceva (erlotinib)

In a recent, small study on the efficacy of pulsatile high-dose Tarceva (median dose: 1500 mg once weekly) in nine patients with EGFR mutations and disease progression while on standard-dose Tarceva treatment, partial brain metastasis response was obtained in six out of nine patients (67%) with a median time to CNS progression of 2.7 months and an OS of 12 months (1).

The rationale for this study was derived from a previous report in which Clarke et al. demonstrated that a pulsatile Tarceva regimen was effective against leptomeningeal metastases in a patient with EGFR mutation who progressed during standard Tarceva treatment (2).

The Tarceva concentration required to inhibit the growth of EGFR-mutated cells by 50% is 100 nM. The standard dose of 150 mg allows a plasma concentration of 3000 nM of erlotinib, while the concentration reached in the cerebrospinal fluid is less than 1% of the plasma level, which is not sufficient to achieve an anti-tumoral effect against CNS metastases (3).

The administration of a high dose (e.g., 1500 mg) once a week is generally well tolerated and allows a concentration of 130 nM Tarceva to be reached in the cerebrospinal fluid (4). Further prospective studies are therefore required to confirm the efficacy of high-dose pulsatile Tarceva in the treatment of brain metastasis from NSCLC.

1. Grommes C, Oxnard GR, Kris MG et al. 'Pulsatile' high-dose weekly erlotinib for CNS metastases from EGFR mutant non-small cell lung cancer. Neuro Oncol. 13(12), 1364–1369(2011).

2. Clarke JL, Pao W, Wu N, Miller VA, Lassman AB. High dose weekly erlotinib achieves therapeutic concentrations in CSF and is effective in leptomeningeal metastases from epidermal growth factor receptor mutant lung cancer. J. Neurooncol. 99(2), 283–286(2010).

3. Jackman DM, Holmes AJ, Lindeman N et al. Response and resistance in a non-small-cell lung cancer patient with an epidermal growth factor receptor mutation and leptomeningeal metastases treated with high-dose gefitinib. J. Clin. Oncol. 24(27), 4517–4520(2006).

4. Milton DT, Azzoli CG, Heelan RT et al. A Phase I/II study of weekly high-dose erlotinib in previously treated patients with nonsmall cell lung cancer. Cancer 107(5), 1034–1041(2006).

Last edited by gdpawel : 03-20-2013 at 09:21 AM. Reason: corrected url address
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Old 03-02-2011, 09:23 PM
gdpawel gdpawel is offline
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Default Preventative Brain Radiation for Lung Cancer

What they did for SCLC (PCI), they tried to do for NSCLC. This clinical study showed it doesn't work. NSCLC patients who undergo PCI as a means to stop cancer from spreading to the brain does not increase survival and has not significant impact on quality of life.

A new study is taking a closer look at the benefits versus risks for lung cancer patients to undergo preventative brain radiation therapy as a means to stop cancer from spreading to the brain.

Study results show that while preventative brain radiation for patients with non-small cell lung cancer – the most common form of lung cancer – does reduce the chance of developing brain metastases, it impacts some short-term and long-term memory.

The study also reveals that preventative brain radiation does not increase survival and has no significant impact on quality of life, says study co-investigator Benjamin Movsas, M.D., chair of the Department of Radiation Oncology at Henry Ford Hospital in Detroit.

“These findings offer a more complete perspective regarding this intervention for patients with non-small cell lung cancer,” Movsas says. “We now need to develop strategies to help shift the benefit-risk ratio for this treatment.”

Dr. Movsas presents study results Nov. 2 at the plenary session for the 51st annual American Society for Radiation Oncology (ASTRO) meeting. Out of nearly 1,000 abstracts submitted, only a handful of study abstracts, including the one from Henry Ford, were selected for the ASTRO plenary session.

The study is part of a national Radiation Therapy Oncology Group (RTOG) analysis of prophylactic cranial irradiation for patients with stage III non-small cell lung cancer.

Previous studies have found this preventative type of external beam radiation therapy that treats the entire brain – known as prophylactic cranial irradiation (PCI) – can reduce the risk of cancer spreading to the brain in patients with non-small cell lung cancer, as well as its sister disease, small-cell lung cancer. The risk of cancer developing in the brain increases as people with non-small cell lung cancer live longer with more effective treatments.

To learn more about how PCI impacts a patient’s quality of life and cognitive function, Dr. Movsas and his colleagues tracked the progress of 340 patients with stage III non-small cell lung cancer for one year after receiving PCI, a 10-minute treatment that occurs once a day for two to three weeks.

The study finds that patients with non-small cell lung cancer treated with PCI have a significantly decreased risk of developing brain metastases by 10 percent (from 18 percent to 8 percent), compared with those who did not receive the treatment.

Although there was no significant impact on quality of life, patients who underwent PCI had a greater decline in immediate memory recall and delayed memory recall than patients who did not have PCI.

“This study offers patients a look at both sides of the coin with this treatment, allowing them to make an informed decision about their care,” says Dr. Movsas. “Now that we have a more complete perspective and know the challenges, we need to move forward to develop strategies to reduce the risk of neurocognitive changes after brain radiation.”

Already a RTOG study is underway to test memantine, a medication approved for Alzheimer’s disease, to see if it may help improve memory following brain radiation.

Dr. Movsas notes the potential for exploring other strategies, such as using newer radiation technologies like intensity modulated radiation therapy, for a more precise treatment that will spare parts of the brain associated with memory.

About Non-Small Cell Lung Cancer

Non-small cell lung cancer is a disease in which cancer cells form in the tissues of the lung. With non-small cell lung cancer, cancer tends to spread in the earlier phase of the disease to other organs, including the brain.

According to the American Cancer Society, about eight to nine out of 10 cases of all lung cancers are the non-small cell type. There are three main sub-types of non-small cell: Squamous cell carcinoma, which make up about 25 percent to 30 percent of all lung cancers; adenocarcinoma, which accounts for about 40 percent of lung cancers and is usually found in the outer part of the lung; and large-cell carcinoma, which accounts for about 10 percent to 15 percent of lung cancers.

Smoking tobacco is the major risk factor for developing lung cancer. Possible signs of lung cancer include a cough that doesn't go away and/or shortness of breath, according to the National Cancer Institute.

Reference: “Phase III Study of Prophylactic Cranial Irradiation versus Observation in Patients with Stage III Non-Small Cell Lung Cancer: Neurocognitive and Quality of Life Analysis of RTOG 0214.” ASTRO 2009.

Last edited by gdpawel : 03-02-2011 at 09:31 PM.
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Old 03-02-2011, 09:38 PM
gdpawel gdpawel is offline
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Default Neurobehavioral sequelae of PCI in adults: review of radiation-induced encephalopathy

Neurobehavioral sequelae of cranial irradiation in adults: a review of radiation-induced encephalopathy

JR Crossen, D Garwood, E Glatstein and EA Neuwelt

Department of Medical Psychology, Oregon Health Sciences University, Portland 97201.

PURPOSE:

To examine behavioral dimensions of treatment outcomes for patients receiving cranial irradiation. Radiation encephalopathy is one of these and refers to significant cognitive and emotional dysfunction following radiation therapy to the brain. Issues of definition, estimated incidence, pathophysiologic mechanisms, and recommended research designs are reviewed in relationship to functional neurobehavioral outcomes.

PATIENTS AND METHODS:

Twenty-nine studies of adults receiving therapeutic cranial irradiation (TCI) involving 748 patients and 18 studies of prophylactic cranial irradiation (PCI) involving 368 patients are reviewed. Assessment of patient outcomes are summarized for research published since 1980, with specific attention to adverse changes in cognitive and emotional functioning.

RESULTS:

Analyses revealed that 213 TCI patients and 100 PCI patients showed encephalopathy attributed to radiation. Manifestations of the late delayed effects of radiotherapy on brain function are related to patient age, total dose of irradiation, fraction sizes, and timing of chemotherapy. Radiation encephalopathy appears to be more common than the pathologic tissue injury of radiation necrosis. Accurate diagnosis of these neurobehavioral sequelae can require follow-up over a period of years with sensitive assessment procedures.

CONCLUSIONS:

It is likely that the true incidence of treatment-related side effects of cranial irradiation in adults who survive more than 6 months without brain tumor growth or recurrence has been significantly underestimated. Research designs that include formal neuropsychologic assessment in conjunction with other neurodiagnostic tests can provide more comprehensive evaluation of long-term neurobehavioral outcomes.
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  #4  
Old 03-02-2011, 09:56 PM
gdpawel gdpawel is offline
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Default SCLC and Assay-directed Therapy

[SCLC is not a death sentence as some fear. Matching the right drug agents against the "individual" cancer cells, can produce a long term remission. David Hanbidge's surgeon sent tumor tissue for chemosensitivity testing. The results from assay test showed that Hanbidge's cancer cells were sensitive to several novel chemotherapy combinations. Hanbidge underwent assay-directed therapy and remains free of disease today. From the Rational Therapeutics Blog]

My name is David Hanbidge. I was diagnosed at 57 years old and I am proud to say that I am reaching the 11-year mark in my journey to be cured of small cell lung cancer. Here is my story:

I first noticed that something was wrong in the spring of 1999. I was having trouble breathing without wheezing and coughing. Initially, I just attributed my symptoms to my yearly allergy condition and thought nothing more of it. After a few months, I started coughing up traces of blood and decided to see my doctor. X-rays didn't show anything unusual but the doctor thought I might have had pneumonia recently. When the condition just persisted and the traces of blood became more apparent, I went to see a pulmonary specialist, Dr. Cameron Dick. He performed a bronchoscope procedure on my lungs and discovered evidence of cancerous cells. I'll never forget the day when the doctor took my wife and me to a small back office and told us the horrible news…I had the very worst kind of lung cancer - small cell lung cancer. I remember Dr. Dick had tears in his eyes when he told us the news. He had to tell us that the outlook of surviving this kind of cancer was very bleak. The news stunned us—nothing really prepares you to get this kind of death sentence.

The doctor told us that I needed to get under the care of an oncologist immediately and told us about a special one named Dr. Robert Nagourney, who practiced locally in Long Beach. He told us that he had a reputation of being a bit of a renegade in the way he treated cancer—using non-traditional approaches and chemotherapy medicines. However, he was earning some notoriety for the positive results that he was achieving. Dr. Dick told us that if he or his father were in the situation that I found myself in, that he would choose Dr. Nagourney for his physician. I'll never forget that we were so shaken by the news that we had just heard that neither my wife nor I could even enter Dr. Nagourney's phone number in my cell phone. Dr. Dick observed our shock and offered to make the call for us. We overheard him speaking on my behalf to Dr. Nagourney, persuading him to add a very difficult case to his already heavy patient load. My wife and I were praying in the next room that Dr. Nagourney would see me.

One of the luckiest days of my life was when Dr. Nagourney agreed to meet with me. He explained the basis for his approach to treating cancer was to obtain a sample of the cancerous tissue and test a wide variety of chemo medicines against it. The chemo(s) that responded the best to eliminating the cancer were then to be used to battle it. I was scheduled for surgery to obtain the tissue sample immediately. My cancer seemed to be isolated in one area of the lower left lobe of my lung, so the surgeon decided to remove the whole area. Dr. Nagourney's tissue testing resulted in some good news - my cancer tissue was apparently very sensitive to most types of chemo. Given this encouraging information that he had a wide range of chemo's to choose from, and knowing that I would undergo anything to stop this cancer, Dr. Nagourney went to work defining an aggressive treatment plan for me. We ended up with eleven sessions of chemo for five days at a stretch, three weeks apart. He also arranged for radiation twice a day for 30 days. The final component to my treatment plan was brain radiation to help eliminate the chance of the cancer spreading to my brain.

On a personal level, I embraced my cancer treatment like a life raft. Dr. Nagourney's philosophy that our cancer-afflicted tissue’s ability to fight cancer is almost as unique as our fingerprints rang so true. It makes sense that there is no "one size fits all" approach to cancer treatment. The success lies in matching the most formidable chemo against a particular cancer tissue. That fact was especially proved when it was determined that the application of chemos traditionally used to fight breast cancers and brain cancers were among the best weapons to fight my lung cancer.

I did lose my hair twice and experienced some nausea and weakness during treatments. But all the way through I maintained confidence in my doctor and hope for a cure, I prayed and took long walks in the nature center most days and was constantly reminded of how precious life and good health is. After 10 years of remission I am happy to report that I am cured of my cancer. To celebrate the end of my treatments, my wife and I took a life's dream vacation to New Zealand. While there, I decided to paraglide from a 1,000-foot mountain. Was I afraid? Not nearly as much as I was when I first leaned of my diagnosis. I hate to think how my life may have turned out differently had I not met Dr. Nagourney. I am encouraged for other people's chances of success in battling cancer when I hear how my doctor's philosophy of treatment is becoming more accepted and practiced by other oncologists. I am convinced, without a doubt, that I wouldn't be here today if that philosophy hadn't been practiced in my life.

[url]http://www.rationaltherapeutics.com/patient-stories/default.aspx?id=17

Last edited by gdpawel : 02-16-2012 at 08:54 PM. Reason: correct url address
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Old 03-02-2011, 09:58 PM
gdpawel gdpawel is offline
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Default Treatment for SCLC

Small cell lung cancer (SCLC) is caused by an uncontrolled growth of cells beginning on the surface of the lung's breathing tubes (called bronchi) and tends to spread widely through the body (growth rate of cancer cells is much faster than that of normal cells).

This is important because it means that surgery is rarely used as a treatment option. However, chemotherapy has a cytostatic period, called the dormant period. Perhaps post-chemo surgery would be more beneficial? If metastasis can be controlled by tumor dormancy therapy, surgery could be less invasive.

Chemotherapy is the most common treatment for SCLC. Most SCLC patients can only be treated with chemotherapy because most are undetected until the disease is at an advanced stage when it is too late for surgery.

Although SCLC is often responsive to first-line treatments, patients may relapse. While SCLC is intrinsically sensitive to chemotherapy, it is very aggressive, tends to metastasize readily and grow rapidly.

Recurrences are much more difficult to treat. Brain metastases are common, hence the supposed benefits of prophylactic whole brain radiation (PCI). PCI comes in safer doses than normal WBR, with fewer side effects. Whole brain radiation and PCI are "diffuse" therapy, while Gamma-Knife/Cyber-Knife is "focal" therapy. A most recent published study found that NSCLC patients who undergo PCI as a means to stop cancer from spreading to the brain does not increase survival and has not significant impact on quality of life (don't forget NSCLC is not as aggressive as SCLC).

Carboplatin and Etoposide is the combination having the optimal treatment for SCLC, based on population studies (randomized clinical trials). However, therapeutic protocols are limited in their effectiveness, because they are based on the results of these clinical trials conducted on a general population, yet no two patients are alike. There is a chance that this combination may be "resistant" to an individual's tumor cells. There is a chance that this combination may be synergistic (sensitive) to an individual's tumor cells.

Be mindful that if the drug combinatin happens to be resistant, a chemo-induced gene mutation can happen when the original chemo received does not work. The cancer comes back. When it does this, the cancer comes back more aggressively. The mutagenic effects (changes in form) of chemotherapy on a genetically-unstable tumor, drives the tumor into a state of more aggressive behavior. You might kill off a whole lot of cancer, only to cause a mutation in the remaining cancer, such that the remaining cancer behaves in a more aggressive fashion.

Patients would be much better served by receiving the most probable "active" treatment the first time around.

Large-molecule drugs do not cross the blood-brain barrier (BBB), their concentration in the central nervous system (CNS) is very low. The concentration of radiolabeled large-molecule drugs in the CNS is found to be significantly lower than in other organs, and thus undetectable in the brain, in the spinal cord or in any other site of the CNS. If they do not penetrate well into the CNS, it may represent a tumor "sanctuary" site for these regimens.

My wonder is if they radiate just the whole brain but not the spinal cord, how does PCI benefit the patient? Any theoretical cancer cells in the spinal cord would eventually infiltrate the brain. The problem of penetration into the CNS is not as nearly as severe for small-molecule drugs. Fat soluble (lipophilic) molecules can dissolve through the capillary cell membranes and absorbed into the brain. A few brain diseases consistently respond to lipid-soluble small molecules.

Accumulating evidence suggests that systemic chemotherapy may play an important role. There have been clinical observations of frequent brain metastasis responses with systemic chemotherapy. Agents like Temodar and EGFR inhibitors could be used against any potential brain metastases.

Again, a particular drug may be beneficial for one type of patient, but not for another. I personally wouldn't want to try "trial-and-error." Clinical data suggests that patients benefit both in terms of response and survival from drugs and drug combinations found to be "sensitive" to cancer cells rather than "resistant" to those cells.

With a brain metastasis indicated or not, small molecule intervention can be beneficial by dissolving through the capillary cell membranes and absorbed into the brain. Systemic brain chemotherapy can also treat coexistent systemic disease.

Source: Cell Function Analysis
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Old 03-09-2011, 08:42 AM
gdpawel gdpawel is offline
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Default Prophylactic Cranial Irradiation (PCI) for Lung Cancer?

I've asked this question to Dr. West on the Grace forum. "If they radiate just the whole brain but not the spinal cord, how does it benefit that patient? Any theoretical cancer cells in the spinal cord would eventually infiltrate the brain." This was in regards the SCLC.

His answer was "the benefit of PCI is that the vast majority of CNS occurrences are in the brain rather than the meninges, so while there is some theoretical benefit to treating the spinal cord, there is also greater risk, and the volume at risk is probably low enough that it isn't worth the added risk."

One of his colleagues, Dr. Goldberg, stated that "PCI doesn't include the whole spine because it doesn't need to do that. So, while theoretically true that all disease in the brain could contaminate the spinal length, it doesn't seem to do that in reality very often, and certainly not often enough to warrent the widespread use of craniospinal radiation for brain mets or PCI."

What I gathered from both of them is that the larger the volume treated, the greater the "effect" from radiation. The patterns of recurrence along the spine do not support it. It doesn't seem to recur there very often (on average). So why do it, even if it could contaminate the spine? Still doesn't make a lot of sense.

Whether SCLC or NSCLC, if they prophylactically irradiated just the whole brain but not the spinal cord, how does it benefit that patient? Any theoretical cancer cells in the spinal cord would eventually infiltrate the brain.

West and Goldberg gave their respective reasons that the larger the volume treated, the greater the effect from radiation. The patterns of recurrence along the spine do not support it. It doesn't seem to recur there very often (on average). But it does happen.

In regards to NSCLC, Dr. West said "there is no proven value of PCI for NSCLC yet." He agreed that the question of whether systemic therapies can be as effective as PCI with a more favorable side effect profile is an interesting one, and one that might be done if the value of agents like Temodar and/or EGFR inhibitors against brain metastases can be established more clearly.

I think they can be established more clearly, if you "test the tumor first" with cell function analysis. The leading edge of research today is determing how a patient's tumor cells work and hitting those pathways with multiple drugs, simultaneously or sequentially, each chosen because it targets one of those growth, replication and angiogenesis pathways. Matching tumor type to drug.
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Old 03-11-2011, 03:05 PM
gdpawel gdpawel is offline
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Default Prophylactic Cranial Irradiation Fails to Improve NSCLC Survival

Prophylactic Cranial Irradiation Fails to Improve NSCLC Survival
IMNG Medical Media. 2012 Sept 7, M E. Tucker

(OncologySTAT) Prophylactic cranial irradiation reduced the 5-year rate of brain metastases, but did not improve overall survival in a randomized trial that evaluated 340 patients without disease progression following potentially curative treatment for locally advanced non-small cell lung cancer.

The findings provide important confirmatory information regarding the effectiveness of prophylactic cranial irradiation (PCI) in decreasing the rate of brain failures, Dr. Elizabeth Gore said in a press briefing from the Chicago Multidisciplinary Symposium in Thoracic Oncology.

The trial closed early because of slow patient accrual, however, and did not enroll enough patients to answer the primary question: whether PCI improves overall survival in patients with stage III NSCLC.

"I'd like to emphasize the need for participation in clinical trials. This is particularly important in lung cancer, which is understudied" despite its being the leading cause of cancer death in the United States, said Dr. Gore, professor of radiation oncology at the Medical College of Wisconsin, Milwaukee.

Over a median follow-up of 24.2 months for all patients and 58.6 months for living patients, the 5-year rates of brain metastases were 17.3% for those randomized to receive PCI delivered to 30 Gy in 15 fractions, compared with 26.8% for patients randomized to observation. That difference was statistically significant (P = .009).

However, there were no significant differences in the 5-year rates of survival, (26.1% for PCI and 24.6% for observation), or disease-free survival (18.5% and 14.9%, respectively).

Of the patients with treatment failures, 10% of those receiving PCI and 23% in the observation group experienced failure in the brain initially. Brain metastases (BM) were the only component of first failure in 9.1% and 21.5% of patients with and without PCI, respectively.

On multivariate analysis, PCI was significantly associated with decreased BM, whereas nonsquamous histology was associated with an increased risk of BM. The overall rate of BM in this trial was insufficient for reliable subset analyses by histology, Dr. Gore noted.

"Brain metastasis has a profound impact on patients with lung cancer in terms of quality of life. We need more information to determine which patients are most likely to derive a survival benefit from prophylactic cranial irradiation before this can become a part of standard management," she said.

The Chicago Multidisciplinary Symposium in Thoracic Oncology is sponsored by the American Society of Clinical Oncology, the American Society for Radiation Oncology, the International Association for the Study of Lung Cancer, and the University of Chicago.

Dr. Gore and her associates reported no financial disclosures.
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Last edited by gdpawel : 09-10-2012 at 06:46 PM. Reason: additional info
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Old 03-26-2011, 05:09 PM
gdpawel gdpawel is offline
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Default Cerebral Atrophy follows prophylactic cranial irradiation

NEUROLOGY and GENERAL MEDICINE
Michael J. Aminoff
25 Neurological Complications of Chemotherapy and Radiation Therapy
Lisa M. DeAngeli Jean-Yves Delattre Jerome B. Posner

Cerebral Atrophy

Cerebral atrophy often follows whole-brain irradiation. The atrophy may occur in patients who are irradiated prophylactically or in patients harboring brain tumors in whom irradiation has eradicated the tumor. It usually begins 6 to 12 months after radiation therapy. The patient may be asymptomatic but, more commonly, suffers memory loss and, in some instances, severe cognitive dysfunction. Some patients have gait abnormalities and urgency incontinence, suggesting normal-pressure hydrocephalus. MRI of virtually all patients receiving whole-brain irradiation in excess of 3,000 cGy shows cerebral atrophy with enlarged sulci and ventricles; there may also be symmetric periventricular white matter hyperintense signals on T2-weighted or FLAIR (fluid-attenuated inversion recovery) images. Symptomatic patients appear to have greater degrees of cerebral atrophy and ventricular dilatation than asymptomatic patients. In some instances, the ventricular dilatation is out of proportion to the sulcal atrophy; when such patients are symptomatic with dementia, gait apraxia, and incontinence, they may respond to ventriculoperitoneal shunt. Cerebral atrophy also occurs in children receiving prophylactic brain irradiation for acute leukemia. The atrophy is associated with learning disability.

The pathogenesis of the cerebral atrophy is not clear. In some instances, true communicating hydrocephalus, perhaps from radiation-induced arachnoiditis or obliteration of pacchionian granulations, appears to be causal. In other instances, there is simply loss of cerebral substance. Pathology reveals spongiosis of the white matter, but no vascular changes such as those seen with radiation necrosis. Except in patients who respond to shunting, there is no treatment for the cerebral atrophy.
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Old 09-23-2011, 03:35 PM
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Default Small-cell lung cancer: an unusual therapeutic approach - surgery

Small-cell lung cancer: an unusual therapeutic approach with more than 10-year overall survival. Case report and review of the literature.

Samelis GF, Ekmektzoglou KA, Xanthos T, Zografos GC.

Department of Medical Oncology, Hippocratio General Hospital, Athens, Greece.

Abstract

Small-cell lung cancer is the most aggressive lung cancer, with a dismal prognosis. The authors present a case report of a patient with limited-stage small-cell lung cancer who underwent a thoracotomy for diagnostic purposes, with the diagnosis being made after surgical excision. Combination chemotherapy remains the cornerstone of treatment for both limited and extensive disease. Radiotherapy has been established as an adjunct to chemotherapy in limited-stage disease, while in extensive-stage disease it is mostly reserved for the treatment of brain metastases. As for surgery, the potential benefits of resection are predominantly seen in patients who present with a solitary pulmonary nodule. Since small-cell lung cancer becomes highly resistant to chemotherapy, second-line chemotherapeutic schemes are used for disease progression, with topotecan being the highlighted agent. Despite the unusual therapeutic approach, where surgery was preferred over the standard diagnostic and staging procedures, the patient's more than ten years' survival makes this case presentation a very interesting one.

Tumori. 2008 Jul-Aug;94(4):612-6. PMID:18822705[PubMed - indexed for MEDLINE]

[url]http://www.tumorionline.it/allegati/00371_2008_04/fulltext/30%20-%20Samelis%20%28612-616%29.pdf
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Old 02-02-2013, 04:42 PM
gdpawel gdpawel is offline
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Default Memantine Protects Cognitive Function After Whole Brain Irradiation

Namenda (memantine), a drug normally prescribed for slowing cognitive decline in Alzheimer's disease, can help to preserve cognitive function in cancer patients who have undergone whole brain irradiation, a study showed.

In a phase III trial, patients with brain metastases were randomly assigned to take 20 mg memantine (Namenda) or placebo daily for 24 weeks after whole brain radiation therapy (WBRT). The memantine cohort had a 17% relative reduction in cognitive decline compared with patients who got a placebo, Dr. Nadia N. Laack reported at the annual meeting of the American Society for Radiation Oncology.

The finding teetered on the edge of statistical significance (P = .059), however, because only one-third of patients (32%) completed the 24 weeks of drug therapy, due to death (survival was poorer than expected), disease progression, or noncompliance, said Dr. Laack. a radiation oncologist at the Mayo Clinic in Rochester, Minn.

"Overall, we feel that the weight of evidence supports our conclusion that memantine helps to preserve cognitive function after whole brain radiotherapy in patients with brain metastases," Dr. Laack said at a briefing prior to presenting the data at a plenary session.

WBRT is associated with cognitive impairment in a majority of patients who receive it, Dr. Laack said, noting that at 4 months post radiation, 60% of patients will have declines in one or more cognitive domains.

Because the mechanism of decline is similar to that seen with Alzheimer's and vascular dementias, and because memantine has been shown to modestly improve mild to moderate cognition in both dementia types, Dr. Laack and his colleagues hypothesized that it might protect brains exposed to therapeutic doses of radiation.

A total of 508 patients were tested at baseline and at 8, 16, 24, and 52 weeks after radiation with 37.5 Gy in 15 fractions. They were evaluated with MRI and cognitive assessment; domains of memory, processing speed, executive function, global function, self-reported cognitive function, and quality of life were evaluated. Median overall follow-up was 12.4 months.

There were no differences between the treatment groups in overall survival at a median of 6 months or in progression-free survival at 5 months.

Among 149 patients available for analysis at 24 weeks, patients who took memantine had a significantly longer time to memory decline than did those on placebo (P = .02), and had a trend toward less decline in the primary end point, the Hopkins Verbal Learning Test-Revised delayed recall instrument (median decline of 0 standard deviation, vs. -2 standard deviations for patients on placebo).

For the secondary objective of cognitive function decline/failure, defined as a change greater than reversible cognitive impairment or 2 standard deviations decline from baseline on any domain of brain function, the hazard ratio for memantine at 24 weeks was 0.784 (P = .01), indicating a significant reduction in the incidence of cognitive dysfunction.

"Although memantine was discontinued at 6 months, the effect on cognitive function was maintained for the duration of the trial, suggesting that memantine may be preventing radiation injury rather than simply treating cognitive dysfunction," Dr. Laack said.

The trial was sponsored by grants from the National Cancer Institute and Forest Pharmaceuticals. Dr. Laack reported no relevant financial disclosures.

IMNG Medical Media. 2012 Oct 30, N Osterweil
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