Prophylactic cranial irradiation fails to improve overall survival in NSCLC


Dr Alex Sun.

An updated 10-year analysis of the RTOG 0214 trial showed that the use of prophylactic cranial irradiation (PCI) improved disease-free survival (DFS) and reduced brain metastases, but failed to improve overall survival (OS) in patients with locally advanced non-small-cell lung carcinoma (LA-NSCLC).

The results of the 10-year follow-up of this phase III study, done from September 2001 to August 2007 in 356 patients with stage III A/B LA-NSCLC (median age, 60), showed that PCI did not improve OS rate vs observation alone (17.6 percent vs 13.3 percent; hazard ratio [HR], 1.23; 95 percent confidence interval [CI], 0.95 to 1.59; p=0.124)  [Sun A, et al, WCLC 2018 abstract OA01.01]

Patients who underwent PCI, however, experienced better DFS (12.6 percent vs 7.5 percent; HR, 1.32; 95 percent CI, 1.03 to 1.69; p=0.0298) and less central nervous system (CNS) metastasis (16.7 percent vs 28.3 percent; HR, 2.33; 95 percent CI, 1.31 to 4.15; p=0.0298) vs those who were just observed.

“There was only 45 percent power to detect the hypothesized difference [HR=1.25], and if we were able to accrue the targeted number, there may have been a benefit in OS,” said study investigator Dr Alex Sun from the University of Toronto, Toronto, Ontario, Canada.

“As compared with previous trials, PCI employing delivery of 30 Gy in 15 fractions as used in the RTOG 0214 study might also be too low a dose to exert its desirable effects,” commented discussant Dr John Armstrong of St Luke’s Radiation Oncology Network, Dublin, Ireland. [Radiat Oncol 2016;11:67]

“However, a subgroup analysis among 225 patients who did not have surgery as primary treatment showed that patients who underwent PCI had better OS [p=0.026] and DFS [p=0.014] and a lower incidence of brain metastases [p=0.003],” said Sun.

Most patients in the study experienced grade 1 (14.6 percent) or grade 2 (35 percent) acute toxicities or grade 1 (12.7 percent) or grade 2 (8.7 percent) late toxicities, with neurocognitive-associated toxicities being the most commonly reported.

“The most probable reason why we do not do much PCI is due to concerns about its reported toxicities such as somnolence, cognitive disturbances, neuropathy, memory impairment and dizziness. It is difficult to convince patients to undergo a procedure which will unlikely alter their survival,” said Armstrong. [J Clin Oncol 2018;36:2366-2377]

A previous study in 113 cancer patients with brain metastases showed that hippocampus-sparing intensity-modulated radiation therapy (IMRT) is associated with a significantly lower decline in Hopkins Verbal Learning Test-Revised Delayed Recall scores vs historical controls (p<0.001). [J Clin Oncol 2014;32:3810-3816]

In the future, PCI in NSCLC is foreseen to involve identification of ultra-high-risk individuals and performance of research which can be used for profiling patients who will experience brain metastases. For these patients, aggressive surveillance with volumetric MRI and early intervention with stereotactic surgery should be performed.

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Gene Involved in Lung Tumor Growth Identified.


Lung cancer researchers at St. Joseph’s Hospital and Medical Center in Phoenix, Ariz., in collaboration with researchers at the Translational Genomics Research Institute and other institutions, have identified a gene that plays a role in the growth and spread of non-small cell lung cancer tumors, opening the door for potential new treatment options.

The study, titled “Elevated Expression of Fn14 in Non-Small Cell Lung Cancer Correlates with Activated EGFR and Promotes Tumor Cell Migration and Invasion,” was published in the May 2012 issue of The American Journal of Pathology. Landon J. Inge, PhD, is the lead scientist in the thoracic oncology laboratory at St. Joseph’s Center for Thoracic Disease and Transplantation and was a member of the study’s research team.

Lung cancer is the leading cause of cancer deaths worldwide, and approximately 85 percent of these cancers are non-small cell lung cancers (NSCLC). Patients with NSCLC frequently have tumors with mutations in the epidermal growth factor receptor (EGFR) gene. When activated, this mutated gene leads to tumor development and growth. By studying lung cancer samples from patients who had undergone tumor resection, the researchers discovered that many patients with EGFR mutations also exhibited higher than normal levels of the gene fibroblast growth factor-inducible 14 (Fn14). The researchers believe that activation of EGFR can lead to increased expression and activity of the Fn14 gene.

The research team also discovered that while over-expression of Fn14 enhances lung tumor formation and metastasis, suppression of Fn14 reduces metastasis in NSCLC.

“Our data suggest that Fn14 levels can contribute to NSCLC cell migration and invasion,” says Dr. Inge. “Thus, tumor suppression through the targeting of Fn14 may prove to be a therapeutic intervention in NSCLC and other tumor types.”

The Fn14 gene has been found to be elevated in other types of tumors, as well, including glioblastoma and certain types of breast cancer, suggesting that Fn14 may be a therapeutic target for multiple cancer therapies.

Source: http://www.sciencedaily.com

Scientists Detail Critical Role of Gene in Many Lung Cancer Cases.


Scientists from the Florida campus of The Scripps Research Institute (TSRI) have shown that a well-known cancer-causing gene implicated in a number of malignancies plays a far more critical role in non-small cell lung cancer, the most common form of the disease, than previously thought.

These findings establish the gene as a critical regulator of lung cancer tumor growth. This new information could turn out to be vital for the design of potentially new therapeutic strategies for a group of patients who represent almost half of non-small cell lung cancer cases.

In the study, published online ahead of print by the journal Cancer Research, the scientists found that presence of known oncogene Notch 1 is required for survival of cancer cells. In both cell and animal model studies, disabling Notch 1 leads to a rise in cancer cell death.

“While Notch signaling has emerged as an important target in many types of cancer, current methodologies that target that pathway affect all members of the Notch family, and this has been associated with toxicity,” said Joseph Kissil, a TSRI associate professor who led the study. “We were able to identify Notch 1 as the critical oncogene to target, at least in a common form of lung cancer.”

The new findings show that Notch1 is required for initial tumor growth, as it represses p53, a well-known tumor suppressor protein that has been called the genome’s guardian because of its role in preventing mutations. The p53 protein can repair damaged cells or force them to die through apoptosisprogrammed cell death.

Using animal models, the study shows that inhibition of Notch1 signaling results in a dramatic decrease in initial tumor growth. Moreover, disruption of Notch 1 induces apoptosis by increasing p53 stability — substantially increasing its biological half-life, for example.

These findings provide important clinical insights into the correlation between Notch1 activity and the poor prognosis of non-small cell lung cancer patients who carry the non-mutated form of the p53 gene. “If you look at lung cancer patient populations, Notch signaling alone isn’t a prognostic indicator, but if you look at p53-positive patients it is,” Kissil said.

Source: http://www.sciencedaily.com

Icotinib versus gefitinib in previously treated advanced non-small-cell lung cancer (ICOGEN): a randomised, double-blind phase 3 non-inferiority trial.


Background

Icotinib, an oral EGFR tyrosine kinase inhibitor, had shown antitumour activity and favourable toxicity in early-phase clinical trials. We aimed to investigate whether icotinib is non-inferior to gefitinib in patients with non-small-cell lung cancer.

Methods

In this randomised, double-blind, phase 3 non-inferiority trial we enrolled patients with advanced non-small-cell lung cancer from 27 sites in China. Eligible patients were those aged 18—75 years who had not responded to one or more platinum-based chemotherapy regimen. Patients were randomly assigned (1:1), using minimisation methods, to receive icotinib (125 mg, three times per day) or gefitinib (250 mg, once per day) until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival, analysed in the full analysis set. We analysed EGFR status if tissue samples were available. All investigators, clinicians, and participants were masked to patient distribution. The non-inferiority margin was 1·14; non-inferiority would be established if the upper limit of the 95% CI for the hazard ratio (HR) of gefitinib versus icotinib was less than this margin. This study is registered with ClinicalTrials.gov, number NCT01040780, and the Chinese Clinical Trial Registry, number ChiCTR-TRC-09000506.

Findings

400 eligible patients were enrolled between Feb 26, 2009, and Nov 13, 2009; one patient was enrolled by mistake and removed from the study, 200 were assigned to icotinib and 199 to gefitinib. 395 patients were included in the full analysis set (icotinib, n=199; gefitinib, n=196). Icotinib was non-inferior to gefitinib in terms of progression-free survival (HR 0·84, 95% CI 0·67—1·05; median progression-free survival 4·6 months [95% CI 3·5—6·3] vs 3·4 months [2·3—3·8]; p=0·13). The most common adverse events were rash (81 [41%] of 200 patients in the icotinib group vs 98 [49%] of 199 patients in the gefitinib group) and diarrhoea (43 [22%] vs 58 [29%]). Patients given icotinib had less drug-related adverse events than did those given gefitinib (121 [61%] vs 140 [70%]; p=0·046), especially drug-related diarrhoea (37 [19%] vs 55 [28%]; p=0·033).

Interpretation

Icotinib could be a new treatment option for pretreated patients with advanced non-small-cell lung cancer.

Source: Lancet

 

Dual-Maintenance Therapy for Advanced Non–Small-Cell Lung Cancer.


Progression-free survival was superior with bevacizumab plus pemetrexed versus bevacizumab alone after induction with bevacizumab, cisplatin, and pemetrexed.
Maintenance therapy has been shown to improve survival in patients with non–small-cell lung cancer (NSCLC). Recently, maintenance with single-agent pemetrexed versus placebo was associated with improved progression-free survival (PFS) and overall survival . To test a dual-maintenance strategy in this setting, investigators conducted an industry-supported, phase III, multicenter, randomized, open-label trial (AVAPERL) of maintenance bevacizumab with or without pemetrexed.

A total of 376 patients with advanced, nonsquamous NSCLC received induction therapy with intravenous bevacizumab (7.5 mg/kg), cisplatin (75 mg/m2), and pemetrexed (500 mg/m2) every 3 weeks for 4 cycles. The 253 responding patients were randomized to maintenance bevacizumab every 3 weeks or combination bevacizumab (7.5 mg/kg) plus pemetrexed (500 mg/m2) every 3 weeks.

At a median follow-up of 8.1 months, PFS from time of randomization (the primary endpoint) was superior with combination bevacizumab plus pemetrexed versus bevacizumab alone (median, 7.4 vs. 3.7 months; hazard ratio, 0.48; P<0.0001), as was PFS from time of induction (10.2 vs. 6.6 months; HR, 0.50; P<0.001). OS favored combination therapy but did not reach statistical significance. No new safety signals were identified, but toxicity was greater with combination therapy.

COMMENT

At ASC0 2013, updated results from the AVAPERL trial (Abstract 8014) indicated that OS also failed to reach statistical significance (median OS from randomization, 17.1 vs. 13.2 months; HR 0.87; P=0.29 and median OS from induction, 19.8 vs. 15.9 months; HR 0.88; P=0.32). The AVAPERL trial thus suggests that adding pemetrexed to maintenance bevacizumab improves PFS with a trend towards OS benefit. However, other randomized, phase III data presented at ASCO 2013 (Abstract 8004) indicate that dual maintenance provides no OS benefit. At present, the issue of optimal maintenance therapy in unselected nonsquamous NSCLC patients remains unknown. Treatment decisions are currently based on eligibility for bevacizumab treatment and patient preference for toxicity profiles.

Source: NEJM

EU Okays Afatinib for NSCLC, Filgrastim and Defibrotide.


The European Committee for Medicinal Products for Human Use (CHMP) has recommended that the targeted agent afatinib (Giotrif, Boehringer Ingelheim) be approved for use in nonsmall-cell lung cancer (NSCLC) that tests positive for EGFRmutations.

Afatinib was recently approved for this indication in the United States under the trade name Gilotrif.

This is the third drug to target EGFR mutations in NSCLC; it joins erlotinib (Tarceva) and gefitinib (Iressa). Both are available in most countries in the world, with one notable exception — gefitinib is not available in the United States.

About 10% to 15% of NSCLC is positive for EGFR mutations in Western populations; in Asian populations, the incidence is higher.

Filgrastim Biosimilar

The CHMP also recommended approval for the growth factor filgrastim (Grastofil, Apotex) for the treatment of neutropenia, which is a biosimilar to Neupogen (Amgen). “Studies have shown Grastofil to have a comparable quality, safety, and efficacy profile to Neupogen,” the committee noted.

Filgrastim is a granulocyte colony-stimulating factor that regulates the production and release of functional neutrophils from the bone marrow. It is used in cancer patients to counteract the myelosuppressive effects of chemotherapy by reducing the duration of neutropenia and the incidence of febrile neutropenia.

Change of Mind on Defibrotide

In addition, in its July meeting, the CHMP recommended the approval of defibrotide (Defitelio, Gentium) for use in the treatment of severe hepatic veno-occlusive disease, also known as sinusoidal obstructive syndrome, related to hematopoietic stem cell transplantation. The product has orphan drug status for this indication.

The CHMP issued a negative opinion on this product in March 2012. But at the request of the company, the committee re-examined its stance. After that re-examination, it issued a positive opinion for the very narrow indication of severe veno-occlusive disease.

The mechanism of action of defibrotide has not been fully elucidated, the committee notes in its summary. The drug increases the breakdown of blood clots, and it might also protect cells lining the blood vessels, it notes. The most common adverse events are hemorrhage, hypotension, and coagulopathy.

Source: Medscape.com

The PD-1 Immune Checkpoint Emerges as a Promising Therapeutic Target in NSCLC.


Several new studies presented at the American Society of Clinical Oncology (ASCO) 2013 annual meeting provide additional support for the growing interest in programmed cell death 1 (PD-1), a key immune-checkpoint receptor, as a therapeutic target in NSCLC and other tumor types.

“We now have a new pillar of treatment for cancer patients,” said Padmanee Sharma, MD, PhD, of the MD Anderson Cancer Center in Houston, Texas, a discussant in the session on developmental immunotherapy. “We have standard chemotherapy, targeted therapies, radiation therapy, surgery—and I propose now that immune-checkpoint therapy is really here.”

Under normal physiologic conditions, immune checkpoints such as PD-1 maintain self-tolerance and prevent autoimmunity by limiting T cell effector functions within tissues. Tumor cells can upregulate various ligands for PD-1, including PD-L1 and PD-L2, as a mechanism of evading antitumor immune responses in the tumor microenvironment. Therapeutic strategies for targeting the PD-1 pathway to restore tumor-specific T cell immunity include direct inhibition of the PD-1 receptor and PD-L1 blockade.

Nivolumab is an anti-PD-1 antibody with activity in advanced solid tumors, including melanoma, NSCLC, and renal cell carcinoma (RCC). In a phase I study, treatment with intravenous nivolumab induced an overall response rate of 16% in 122 patients with heavily pretreated, advanced NSCLC, and was associated with a median overall survival of 9.6 months (Topalian SL et al.). In the total study population of 304 patients with melanoma, NSCLC, and RCC, 10 patients (3%) developed drug-related pneumonitis, resulting in 3 deaths. Additional grade 3-4 adverse events were reported in 15% of patients.

Additional phase I trials demonstrated the utility of nivolumab in previously treated patients with advanced NSCLC (Brahmer JR et al.) and in combination with platinum-based doublet chemotherapy in chemotherapy-naïve patients with stage IIIB/IV NSCLC (Rizvi NA et al.). Based on these promising results, nivolumab is currently being evaluated in two phase III trials versus docetaxel for the second-line treatment of NSCLC, as well as a phase II trial of third-line therapy in patients with squamous cell histology.

MPDL32802 is a human monoclonal anti-PD-L1 antibody that contains an engineered Fc-domain designed to optimize efficacy and safety. Treatment with MPDL32802 yielded a 21% response rate in a phase I study of 171 patients with locally advanced or metastatic tumors, including NSCLC, melanoma, colorectal cancer, gastric cancer, and RCC (Herbst RS et al.). The highest response rates were in patients with NSCLC and melanoma. Intravenous treatment with MPDL32802 every 3 weeks was well tolerated, with no dose-limiting toxicities and no pneumonitis-related deaths.

Biomarker studies show that higher levels of PD-L1 tumor expression predict better response rates to PD-1 checkpoint inhibitors (Herbst RS et al.Powderly JD et al.). The investigational PD-1 checkpoint inhibitors are being developed with companion diagnostic assays to measure tumor PD-L1 expression by immunohistochemistry (IHC). Each agent, however, uses a different antibody to detect PD-L1 expression and a different IHC staining threshold to define PD-L1 positivity. Although some ongoing trials will include patients with any PD-L1 IHC status, others will require PD-L1 positivity for enrollment.

“Selection by PD-L1 expression may enhance response, but there is activity seen in PD-L1-negative tumors,” saidNatasha B. Leighl, MD, MMSc, of the University of Toronto, Canada, a discussant in the session on new agents for metastatic NSCLC. “I think it is far too early to close the door on this group.”

Several other agents targeting the PD-1 checkpoint are currently under development. Other direct inhibitors of PD-1 include the humanized monoclonal antibodies pidilizumab (CT-011) and lembrolizumab (MK-3475), and AMP-224, a recombinant fusion protein. Investigational monoclonal antibodies targeting PD-L1 include BMS-936559, Medl-4736, and MPDL-3280A 

Source: The oncologist

 

ght:1K�p;# 0 d:white’>Because of the very low doses of pollutants used in the mixture, these findings may have strong implications in terms of understanding the potential role of environmental contaminants in food in the development of metabolic diseases.”

 

Endocrine-Disrupting Chemicals Likely to Cause Harm Even at Low ‘Safe’ Doses

The chemical contaminants used in the study were chosen not only because they’re pervasive in the food supply, but also because they’re known endocrine disruptors. The glands of your endocrine system and the hormones they release influence almost every cell, organ, and function of your body. It is instrumental in regulating mood, growth and development, tissue function, metabolism, as well as sexual function and reproductive processes.

Endocrine disrupters are substances or mixtures that alter the functions of your endocrine system and consequently cause adverse health effects, either in your body or in your offspring. These types of chemicals can exert their effects by:

  • Mimicking the biological activity of your hormones by binding to a cellular receptor. This can initiate your cell’s normal response to the naturally-occurring hormone at the wrong time or to an excessive extent (agonistic effect).
  • Binding to the receptor but not activating it. Instead the presence of the chemical on the receptor prevents binding of the natural hormone (antagonistic effect).
  • Binding to transport proteins in your blood, thus altering the amounts of natural hormones that are present in your blood circulation.
  • Interfering with the metabolic processes in your body, affecting the synthesis or breakdown rates of your natural hormones.

The strongest evidence showing that exposure to these types of environmental chemicals can lead to disruption of endocrine function comes from the bizarre changes seen in a number of wildlife species, such as male fish transforming into females, frogs developing a variety of defects like multiple testes or ovaries, and hermaphrodite bears, just to name a few.  

Yet, it’s commonly stated that these chemicals are not dangerous to humans because they exist at such low levels, even as research suggests otherwise. For instance, of 115 published animal studies, 81 percent found significant effects from even low-level exposure to BPA.

And the latest study only adds to this undeniable knowledge:

“With this study, we have succeeded in providing proof-of-concept that low doses of contaminants, even at levels normally considered to be without health impacts in humans, do in fact affect humans when subjected to chronic exposure, and when the contaminants are combined with a high-calorie diet,” the researchers said.2

What Are the Long-Term Health Risks from Exposure to Common Food Contaminants?

A typical American comes in regular contact with some 6,000 chemicals and an untold number of potentially toxic substances on a less frequent basis. There are about 75,000 chemicals regularly manufactured and imported by US industries, so you could be exposed to any number of them. Disturbingly, many of them have never been fully tested for safety, and virtually none have been studied in combination with one another, which is how real-world exposure occurs and where their toxicities can be amplified exponentially.

Upwards of 20 environmental chemicals, most of them endocrine-disrupting chemicals, have been shown to cause weight gain when exposure occurs during fetal and infant development, although some are also linked to adult exposures. Others, including BPA, PCBs, phthalates and agricultural pesticides can lead to health problems including:

Non-descended testes in young males

Breast cancer in women

Prostate cancer in men

Developmental effects on the nervous system in children

Attention deficit hyperactivity in children

Thyroid cancer

 

According to a World Health Organization (WHO) and United Nations Environment Program (UNEP) report:3

“The diverse systems affected by endocrine-disrupting chemicals likely include all hormonal systems and range from those controlling development and function of reproductive organs to the tissues and organs regulating metabolism and satiety. Effects on these systems can lead to obesity, infertility or reduced fertility, learning and memory difficulties, adult-onset diabetes or cardiovascular disease, as well as a variety of other diseases.”

Specifically, health problems linked to some of the most common food contaminants include:

  • BPA: Plasticizing chemicals like BPA, found in plastics and canned food linings, disrupt embryonic development and are linked to heart disease and cancer. Beware that many manufacturers of ‘BPA-free’ products have simply replaced BPA with bisphenol-S (BPS), an equally toxic chemical. More recently, research has found that other bisphenols used in the production of consumer products, namely, bisphenols M, AP and P, are actually more toxic to DNA than BPA.4
  • Phthalates: Phthalates dysregulate gene expression and cause genital anomalies, especially in baby boys, that may pass down several generations. Phthalates are found in vinyl flooring, detergents, automotive plastics, soap, shampoo, deodorants, fragrances, hair spray, nail polish, plastic bags, food packaging, garden hoses, inflatable toys, blood-storage bags, and intravenous medical tubing.
  • Dioxins: Dioxins are a byproduct of industrial processes, such as chlorine bleaching of paper products and the manufacturing of some pesticides. Because they are persistent environmental pollutants, they accumulate in the food chain and more than 90 percent of human exposure is through foods like meat, dairy products and fish. According to WHO, “Dioxins are highly toxic and can cause reproductive and developmental problems, damage the immune system, interfere with hormones and also cause cancer.”5
  • PCBs: Like dioxins, PCBs are persistent organic pollutants (POPs) that persist in the environment and resist breaking down, accumulating in the food chain and posing serious risks to human health and the environment. For instance, even though PCBs have been banned in the US for decades, they are still present in your environment. PCBs and other POPs have caused birth defects and other abnormalities among wildlife, along with damage to virtually every human bodily system.

Tips for Finding the Purest Foods Possible

When it comes to staying healthy, avoiding processed foods and replacing them with fresh, whole foods is the “secret” you’ve been looking for. The more steps your food goes through before it reaches your plate, the greater your chances of contamination becomes. If you are able to get your food locally, you eliminate numerous routes that could expose your food to contamination with not only disease-causing pathogens but also with the chemical contaminants noted above, which often exist in food packaging.

It’s also important to choose your fresh foods wisely, as you’ll want to focus on those grown in non-polluted areas using organic farming methods. Whatever food you’re looking to eat, whether organic or locally grown, from either your local supermarket or a farmer’s market, the following are signs of a high-quality, healthy food. Most often, the best place to find these foods is from asustainable agricultural group in your area. You can also review my free nutrition plan to get started on a healthy eating program today:

It’s grown without pesticides and chemical fertilizers (organic foods fit this description, but so do some non-organic foods)

It’s not genetically engineered

It contains no added growth hormones, antibiotics, or other drugs

It does not contain artificial anything, nor any preservatives

It is fresh (if you have to choose between wilted organic produce or fresh conventional produce, the latter may still be the better option as freshness is important for optimal nutrient content)

It was not grown in a concentrated animal feeding operation (CAFO)

It is grown with the laws of nature in mind (meaning animals are fed their native diets, not a mix of grains and animal byproducts, and have free-range access to the outdoors)

It is grown in a sustainable way (using minimal amounts of water, protecting the soil from burnout, and turning animal wastes into natural fertilizers instead of environmental pollutants)

 

 

Source: mercola.com

Treatment With a Next-Generation ALK Inhibitor Results in High Response Rates Following Crizotinib Failure in Advanced, ALK-Positive NSCLC.


A majority of patients with advanced non-small cell lung cancer (NSCLC) whose tumors harbor mutations in the anaplastic lymphoma kinase (ALK) gene responded to treatment with a novel ALK inhibitor despite progressing on earlier ALK inhibitor therapy, according to new results from a phase I study (Shaw AT et al.). The trial highlights the potential role of second-line ALK-targeted therapy in the treatment of ALK-positive NSCLC.

Approximately 3% to 7% of patients with NSCLC have ALK rearrangements, which occur more commonly in nonsmokers, younger patients, and adenocarcinomas. ALK-mutated tumors become dependent on ALK signaling, and as a result, are highly susceptible to ALK inhibition. Crizotinib, a first-generation ALK inhibitor, can induce response rates of 60% in patients with advanced ALK-positive NSCLC, but most patients develop resistance to crizotinib within one to two years.

In general, ALK rearrangements do not overlap with other oncogenic drivers such as EGFR and KRAS mutations in patients with NSCLC (Gainor JF et al.). New options for ALK-targeted therapy, therefore, expand treatment options for patients who are not candidates for other targeted therapies, and for those who progress on current ALK inhibitor therapy.

Alice T. Shaw, MD, PhD, Assistant Professor at Harvard Medical School in Boston, presented findings from a multicenter, open-label, single-arm study of 122 patients with locally advanced or metastatic ALK-positive NSCLC. Of these, 63% had progressed on prior crizotinib therapy, and 31% were ALK-inhibitor naïve. All patients received LDK378, an oral next-generation ALK inhibitor that has shown 20-fold greater potency against ALK compared with crizotinib.

Response rates to LDK378 400-750 mg once daily were high in 114 evaluable patients, with 75% demonstrating some degree of tumor regression. The complete response rate was 58% for all patients, with no apparent differences between those with crizotinib resistance (57%) and those with no prior exposure to an ALK inhibitor (60%). Responses were durable, with a prolonged median duration of response (8.2 months) and median progression-free survival (8.6 months). Imaging studies also demonstrated the activity of LDK378 against central nervous system (CNS) metastases.

“CNS relapses are a major cause of morbidity and mortality in patients treated with crizotinib, so establishing the CNS activity of LDK378 is extremely important,” Dr. Shaw said.

Treatment with LDK378 was generally well tolerated. The most common adverse events included mild gastrointestinal symptoms in 58%-73% of patients. Grade ≥3 adverse events included elevated ALT (19%), elevated AST (10%), diarrhea (8%), and elevated lipase, hypokalemia, and nausea in 5% of patients. Three patients (2%) discontinued LDK378 due to adverse events. No treatment-related deaths were reported.

The current gold standard for detecting ALK rearrangements is fluorescence in situ hybridization (FISH). Many institutions, however, are exploring the use of immunohistochemistry screening with ALK-specific antibodies, reserving ALK FISH to confirm ALK positivity (Tsao MS et al.Lantuejoul S et al.).

Based on early findings from this trial, the FDA recently designated LDK378 as a breakthrough therapy, a designation intended to expedite the development and review of new therapies for serious or life-threatening conditions. LDK378 is currently under evaluation in phase II and III trials of patients with advanced NSCLC who have received prior chemotherapy and crizotinib and in patients who are crizotinib-naïve.

Another investigational ALK inhibitor, CH5424802, showed antitumor activity in in a phase I/II study of patients with ALK-positive NSCLC and no prior exposure to ALK-inhibitor therapy (Nakagawa K et al.). AP26113, a dual inhibitor of ALK and EGFR, is also under development for the treatment of ALK-positive NSCLC.

Source: The oncologist

 

 

ine-hei�j1.# 0 ground:white’>In females, there was a marked deterioration of glucose tolerance, which may be related to the 2-fold induction of estrogen sulfotransferase and reduced expression of estrogen receptor α (25%) and estrogen target genes (>34%).

 

Because of the very low doses of pollutants used in the mixture, these findings may have strong implications in terms of understanding the potential role of environmental contaminants in food in the development of metabolic diseases.”

Endocrine-Disrupting Chemicals Likely to Cause Harm Even at Low ‘Safe’ Doses

The chemical contaminants used in the study were chosen not only because they’re pervasive in the food supply, but also because they’re known endocrine disruptors. The glands of your endocrine system and the hormones they release influence almost every cell, organ, and function of your body. It is instrumental in regulating mood, growth and development, tissue function, metabolism, as well as sexual function and reproductive processes.

Endocrine disrupters are substances or mixtures that alter the functions of your endocrine system and consequently cause adverse health effects, either in your body or in your offspring. These types of chemicals can exert their effects by:

  • Mimicking the biological activity of your hormones by binding to a cellular receptor. This can initiate your cell’s normal response to the naturally-occurring hormone at the wrong time or to an excessive extent (agonistic effect).
  • Binding to the receptor but not activating it. Instead the presence of the chemical on the receptor prevents binding of the natural hormone (antagonistic effect).
  • Binding to transport proteins in your blood, thus altering the amounts of natural hormones that are present in your blood circulation.
  • Interfering with the metabolic processes in your body, affecting the synthesis or breakdown rates of your natural hormones.

The strongest evidence showing that exposure to these types of environmental chemicals can lead to disruption of endocrine function comes from the bizarre changes seen in a number of wildlife species, such as male fish transforming into females, frogs developing a variety of defects like multiple testes or ovaries, and hermaphrodite bears, just to name a few.

Yet, it’s commonly stated that these chemicals are not dangerous to humans because they exist at such low levels, even as research suggests otherwise. For instance, of 115 published animal studies, 81 percent found significant effects from even low-level exposure to BPA.

And the latest study only adds to this undeniable knowledge:

“With this study, we have succeeded in providing proof-of-concept that low doses of contaminants, even at levels normally considered to be without health impacts in humans, do in fact affect humans when subjected to chronic exposure, and when the contaminants are combined with a high-calorie diet,” the researchers said.2

What Are the Long-Term Health Risks from Exposure to Common Food Contaminants?

A typical American comes in regular contact with some 6,000 chemicals and an untold number of potentially toxic substances on a less frequent basis. There are about 75,000 chemicals regularly manufactured and imported by US industries, so you could be exposed to any number of them. Disturbingly, many of them have never been fully tested for safety, and virtually none have been studied in combination with one another, which is how real-world exposure occurs and where their toxicities can be amplified exponentially.

Upwards of 20 environmental chemicals, most of them endocrine-disrupting chemicals, have been shown to cause weight gain when exposure occurs during fetal and infant development, although some are also linked to adult exposures. Others, including BPA, PCBs, phthalates and agricultural pesticides can lead to health problems including:

Non-descended testes in young males Breast cancer in women Prostate cancer in men
Developmental effects on the nervous system in children Attention deficit hyperactivity in children Thyroid cancer

 

According to a World Health Organization (WHO) and United Nations Environment Program (UNEP) report:3

“The diverse systems affected by endocrine-disrupting chemicals likely include all hormonal systems and range from those controlling development and function of reproductive organs to the tissues and organs regulating metabolism and satiety. Effects on these systems can lead to obesity, infertility or reduced fertility, learning and memory difficulties, adult-onset diabetes or cardiovascular disease, as well as a variety of other diseases.”

Specifically, health problems linked to some of the most common food contaminants include:

  • BPA: Plasticizing chemicals like BPA, found in plastics and canned food linings, disrupt embryonic development and are linked to heart disease and cancer. Beware that many manufacturers of ‘BPA-free’ products have simply replaced BPA with bisphenol-S (BPS), an equally toxic chemical. More recently, research has found that other bisphenols used in the production of consumer products, namely, bisphenols M, AP and P, are actually more toxic to DNA than BPA.4
  • Phthalates: Phthalates dysregulate gene expression and cause genital anomalies, especially in baby boys, that may pass down several generations. Phthalates are found in vinyl flooring, detergents, automotive plastics, soap, shampoo, deodorants, fragrances, hair spray, nail polish, plastic bags, food packaging, garden hoses, inflatable toys, blood-storage bags, and intravenous medical tubing.
  • Dioxins: Dioxins are a byproduct of industrial processes, such as chlorine bleaching of paper products and the manufacturing of some pesticides. Because they are persistent environmental pollutants, they accumulate in the food chain and more than 90 percent of human exposure is through foods like meat, dairy products and fish. According to WHO, “Dioxins are highly toxic and can cause reproductive and developmental problems, damage the immune system, interfere with hormones and also cause cancer.”5
  • PCBs: Like dioxins, PCBs are persistent organic pollutants (POPs) that persist in the environment and resist breaking down, accumulating in the food chain and posing serious risks to human health and the environment. For instance, even though PCBs have been banned in the US for decades, they are still present in your environment. PCBs and other POPs have caused birth defects and other abnormalities among wildlife, along with damage to virtually every human bodily system.

Tips for Finding the Purest Foods Possible

When it comes to staying healthy, avoiding processed foods and replacing them with fresh, whole foods is the “secret” you’ve been looking for. The more steps your food goes through before it reaches your plate, the greater your chances of contamination becomes. If you are able to get your food locally, you eliminate numerous routes that could expose your food to contamination with not only disease-causing pathogens but also with the chemical contaminants noted above, which often exist in food packaging.

It’s also important to choose your fresh foods wisely, as you’ll want to focus on those grown in non-polluted areas using organic farming methods. Whatever food you’re looking to eat, whether organic or locally grown, from either your local supermarket or a farmer’s market, the following are signs of a high-quality, healthy food. Most often, the best place to find these foods is from asustainable agricultural group in your area. You can also review my free nutrition plan to get started on a healthy eating program today:

It’s grown without pesticides and chemical fertilizers (organic foods fit this description, but so do some non-organic foods) It’s not genetically engineered It contains no added growth hormones, antibiotics, or other drugs
It does not contain artificial anything, nor any preservatives It is fresh (if you have to choose between wilted organic produce or fresh conventional produce, the latter may still be the better option as freshness is important for optimal nutrient content) It was not grown in a concentrated animal feeding operation (CAFO)
It is grown with the laws of nature in mind (meaning animals are fed their native diets, not a mix of grains and animal byproducts, and have free-range access to the outdoors) It is grown in a sustainable way (using minimal amounts of water, protecting the soil from burnout, and turning animal wastes into natural fertilizers instead of environmental pollutants)  

 

Source: mercola.com

Targeted Drug Benefits Some Patients with Advanced Lung Cancer.


The drug crizotinib (Xalkori) substantially lengthens the amount of time some patients with advanced lung cancer live without their disease progressing, according to findings from the first large clinical trial to test the targeted therapy.

Initial results from the trial were presented Sunday at the European Society for Medical Oncology Congress(ESMO) in Vienna, Austria.

The Food and Drug Administration (FDA) approved crizotinib last year to treat patients with advanced non-small cell lung cancer (NSCLC) whose tumors have a specific genetic mutation. The approval was based on smaller, nonrandomized trials that showed crizotinib could shrink tumors in many patients with the mutation—a genetic rearrangement involving the ALK gene.

Until now, crizotinib had not been shown to prolong progression-free or overall survival compared with standard chemotherapy.

“The results from the phase I and phase II trials were pretty remarkable,” said lead investigator, Dr. Alice Shaw of Massachusetts General Hospital. “We had high tumor response rates, which were impressive for just a single agent.”

A large randomized trial was necessary, Dr. Shaw explained, to confirm that the tumor responses translated into meaningful outcomes and to answer questions about whether patients whose tumors had this genetic mutation were more sensitive to any therapy, not just crizotinib.

The results from the phase I and phase II trials were pretty remarkable. We had high tumor response rates, which were impressive for just a single agent.

—Dr. Alice Shaw

“Patients who received crizotinib did significantly better,” she said. Progression-free survival was more than twice as long in patients treated with crizotinib compared with those who received chemotherapy—docetaxel (Taxotere) or pemetrexed (Alimta)—7.7 months versus 3 months.

Nearly 350 patients were enrolled in the trial, which involved 105 centers in 21 countries and was funded by the drug’s manufacturer, Pfizer. Patients in the trial had advanced NSCLC that had returned after their initial treatment and their tumors had the ALK gene rearrangement. A number of studies have shown that tumors in about 4 to 5 percent of patients with NSCLC have the mutation.

The results may be enough to support a change in the drug’s regulatory status. The FDA’s earlier approval was an accelerated approval, meaning the drug was likely to benefit patients and address an unmet clinical need.

With such approvals, however, the agency requires data from larger trials to confirm that the drug has a clinical benefit and to ensure that unanticipated side effects do not outweigh any clinical improvements. Pfizer has notified the FDA of the trial results, the company said, and will provide the agency with the complete data when available.

Questions about Overall Survival

The ultimate goal of treatment, of course, is to lengthen overall survival. At this point, the trial has not shown that treatment with crizotinib does that any better than standard chemotherapy. And in large part because of the trial’s design, there’s a good chance that it won’t be able to show an improvement, according to several researchers.

Patients in the trial who were randomly assigned to receive either docetaxel or pemetrexed and whose disease began to progress were allowed to cross over to treatment with crizotinib. The crossover rate, Dr. Shaw noted, was 87 percent.

It’s still early in the trial, so nothing definitive about overall survival can be said yet. But with that extent of crossover, “really, the chemo arm is just like the crizotinib arm,” Dr. Shaw added.

The failure to show an overall survival benefit should not dampen enthusiasm for crizotinib with these patients, stressed Dr. Ramaswamy Govindan of Siteman Cancer Center in St. Louis. It’s “entirely possible” that overall survival is improved with crizotinib, Dr. Govindan continued, but the crossover may make it impossible to see in this trial. “Unfortunately, that’s just the way things are,” he said.

No new concerns about the drug’s safety were raised in the trial. Consistent with earlier trials of crizotinib, visual disturbances—often described as floating streams of light in patients’ peripheral vision—were the most common side effect, along with diarrhea and nausea. But more patients who received chemotherapy stopped treatment due to side effects.

“At every level, crizotinib was superior to chemotherapy,” Dr. Shaw said, including improvements in symptoms, delay in the onset of new symptoms, and general quality of life.

“From an oncologists’ standpoint, it’s really gratifying to see patients reporting a better quality of life in what is essentially an incurable disease,” she said.

Overcoming Resistance

Historically, even following dramatic tumor reductions with crizotinib treatment—including complete tumor eradication—the disease almost always returns.

The situation closely parallels what has been seen in patients with advanced NSCLC whose tumors have mutations in the EGFR gene. Many of these patients initially have excellent responses to gefitinib (Iressa) or erlotinib (Tarceva), but the tumors almost always come back, explained Dr. Giuseppe Giaccone of NCI’s Center for Cancer Research.

One potential escape route for tumors may be the development of additional mutations in the ALK gene that interfere with crizotinib’s ability to bind to its target. “But that doesn’t seem to be the major mechanism,” Dr. Giaccone said. Alterations in other key genes that can fuel cancer cell proliferation, including EGFR and MET, also appear to allow tumors to resume growing, he added.

Ways to potentially overcome this resistance are already being studied in human trials.

Data from early stage trials of second-generation ALK-targeted drugs, for example, were also presented at the ESMO meeting. In a small phase I trial testing the experimental drug LDK378, tumor responses were seen in 81 percent of NSCLC patients whose tumors had the ALK mutation and whose disease had returned after crizotinib treatment.

Crizotinib’s rapid ascent from the lab to the clinic is ‘a great model for modern drug development.’

—Dr. Ramaswamy Govindan

Other approaches include targeting ALK and EGFR, either with a single drug that inhibits both targets or combinations of drugs. For example, Dr. Giaccone and his CCR colleagues are part of a phase I trial testing the combination of crizotinib and the experimental agent dacomitinib in patients with advanced lung cancer, including patients with EGFR and ALK mutations. Dacomitinib inhibits EGFR and other members of the same growth factor family. Early findings from the phase I trial were presented at ESMO.

Combining targeted drugs and further subdividing patients into molecularly defined subgroups will only increase from this point on, Dr. Giaccone stressed.

Dr. Govindan called crizotinib’s rapid ascent from the lab to the clinic “a great model for modern drug development.” It demonstrates that “patient selection is critical,” he said.

NCI cooperative group trials are already being planned to test crizotinib as the first-line therapuytreatment in patients with metastatic NSCLC with ALK mutations, he said. Pfizer has also initiated a phase III trial, PROFILE 1014, testing crizotinib as a first-line treatment in patients with ALK rearrangements.

 

 

Beyond ALK and EGFR

Patients with a different gene rearrangement may also benefit from crizotinib, according to another early-phase study presented at the ESMO meeting. In the trial, patients with advanced NSCLC whose tumors had rearrangements in the ROS1 gene, which occur in less than 2 percent of patients, also had substantial tumor responses.

Crizotinib “has remarkable activity [in these patients], nearly identical to what’s been seen in patients with ALK rearrangements,” explained Dr. Shaw, who was also an investigator on the trial.

Another gene, KRAS, is among the most frequently mutated genes in patients with the most common type of NSCLC, adenocarcinoma, and some studies suggest that KRAS mutations are associated with a poor prognosis. Results from the phase II GALAXY trial, also presented at the ESMO meeting, suggested that the drug ganetespib may have greater efficacy than standard chemotherapy in patients with adenocarcinoma and in patients with KRAS mutations whose disease has returned following initial treatment.

Ganetespib targets heat-shock protein (HSP) 90, a “chaperone” protein that helps other proteins carry out their functions. The drug is a second-generation HSP90 inhibitor that does not appear to have the toxicity issues of the first-generation HSP90 inhibitors, said the trial’s lead investigator, Dr. Suresh Ramalingam of the Winship Cancer Institute in Atlanta.

Further follow-up is needed before investigators can confirm a benefit, Dr. Ramalingam cautioned. Earlier this year, results from a clinical trial of another targeted therapy, selumetinib, also suggested it may improve survival in NSCLC patients with KRAS mutations.

Both trials offer some much-needed hope. “This is the biggest molecular subset of lung cancer patients,” Dr. Ramalingam said. “They’re in serious need of good treatment options.”

Source: NCI.

 

Lung Cancer Genome Surveys Find Many Potential Drug Targets.


Five new studies have identified genetic and epigenetic alterations in hundreds of lung tumors, including many changes that could be targeted by drugs that are already available or in clinical testing.

The reports, all published this month, included genomic information on more than 400 lung tumors. In addition to confirming genetic alterations previously tied to lung cancer, the studies identified other changes that may play a role in the disease. (Links to the study abstracts appear in the sidebar below.)

“These five papers are the first major salvo of genome-wide studies using all of the newest technologies to analyze a large number of lung cancers,” said Dr. John Minna, a clinician and lung cancer researcher at the University of Texas Southwestern Medical Center, who co-authored one of the studies.

Collectively, the studies covered the main forms of the disease—lung adenocarcinomas, squamous cell cancers of the lung, and small cell lung cancers.

Although preliminary, the findings could be used to develop molecular markers for identifying patients who are candidates for certain targeted drugs. At the same time, researchers in the lab can now evaluate the newly discovered changes to identify novel potential therapeutic targets.

“All of these studies say that lung cancers are genomically complex and genomically diverse,” said Dr. Matthew Meyerson of Harvard Medical School and the Dana-Farber Cancer Institute, who co-led several of the studies, including a large-scale analysis of squamous cell lung cancer by The Cancer Genome Atlas (TCGA) Research Network.

Some genes, Dr. Meyerson noted, were inactivated through different mechanisms in different tumors. He cautioned that little is known about alterations in DNA sequences that do not encode genes, which is most of the human genome.

Squamous Cell Tumors

The TCGA investigators sequenced the genomes or exomes (the protein-coding regions of DNA) of tumor samples from 178 patients with squamous cell lung cancer. In more than half of the tumors examined, the researchers found a change to a gene or a signaling pathway that is targeted by a drug that exists or is in development. The findings were reported in Nature on September 9.

“This gives us an enormous opportunity for progress in this disease,” said Dr. Meyerson.

The TCGA model integrates genomic data for squamous cell lung cancers with clinical information, when available, and with other tumor characteristics, such as gene expression, epigenetic changes to cells, and alterations in the number of gene copies.

“The framework for these five studies was built on a convergence of new technologies and the need to better understand the biology of lung cancers as it relates to new therapies for our patients,” said Dr. Paul Paik, who treats patients with lung cancer at Memorial Sloan-Kettering Cancer Center and was part of the clinical team involved in TCGA.

Small studies (for example, here and here) have provided hints that certain signaling pathways are important in squamous cell lung cancers, leading to new trials of targeted drugs. “Now, with the publication of the TCGA study, we know that squamous cell lung cancers have a myriad of potentially targetable changes,” Dr. Paik noted.

An unexpected finding was the presence of mutations in the EGFR gene in about 1 percent of squamous cell tumors. These tumors might respond to available drugs that block signals through the EGFR pathway.

The researchers also found evidence of genetic changes that may help lung cancer cells evade surveillance by the immune system.

The Five Studies

Testing Lung Tumors

Any therapeutic targets to emerge from the new reports would need to be incorporated into molecular tests that can identify candidates for certain drugs. A leader in this work is the Lung Cancer Mutation Consortium, which has been building knowledge of the mutations associated with the disease and testing for these changes.

Many patients with lung adenocarcinomas have benefited from targeted drugs. Crizotinib (Xalkori), for instance, has elicited some dramatic responses in patients whose tumors harbor a particular gene fusion. Some medical centers now routinely test tumors before selecting treatment for patients with lung adenocarcinomas.

“If you look at lung cancer as a whole, the big therapeutic targets were first identified in adenocarcinomas,” Dr. Minna explained. “Now there are new targeted therapies that could make an impact on squamous cell lung cancer.”

At Memorial Sloan-Kettering, all patients with squamous cell lung cancer have their tumors tested for drug targets using various techniques, including DNA sequencing. Among 28 of these patients evaluated recently, more than 60 percent had tumors that contained a potential target.

Dr. Paik noted that his group will use the TCGA results to expand their testing. “In a sense, the future potential of this new work is being realized now,” he said. “That’s pretty exciting.”

Small Cell Lung Cancer

Two new reports describe genetic changes in small cell lung cancers, which tend to be aggressive and about which little has been known. The research teams conducted exome or whole-genome sequencing on a total of 82 samples of such tumors.

“This study gave us a host of new targets to explore,” said Dr. Charles Rudin of the Johns Hopkins Kimmel Cancer Center, who led one study. The next steps will be to validate which targets are driving the growth of tumors and are “druggable,” he added.

The researchers found that a gene called SOX2, which plays a role in normal development, may contribute to some small cell lung cancers, as well as other cancers, and could be targeted.

Small cell lung cancers have been challenging to study because most are not treated surgically, so tumor samples are rare. What’s more, these tumors have high rates of genetic mutations due to tobacco smoke, yet only some mutations are driving the disease, noted Dr. Roman Thomas of the University of Cologne in Germany, who led the other study.

Using statistical “filters,” his group found that genes involved in modifying histone proteins, which help package DNA within a cell, were frequently mutated in the disease.

“These cancers are extraordinarily complex, so as researchers our steps forward are incremental—but, still, they are steps,” Dr. Thomas noted. “No one would have imagined that lung cancer would be the prototypical disease for targeted medicine.”

Comparing Tumors in Smokers and Nonsmokers

Non-small cell lung cancers were the focus of two additional studies, which appeared in Cell. One group sequenced the exomes or genomes of 183 tumor samples, and the other conducted whole-genome sequencing of tumor tissues from 17 smokers and nonsmokers.

“We found a substantially lower number of mutations in the genomes of tumors from nonsmokers compared to the smokers,” said Dr. Ramaswamy Govindan of the Washington University School of Medicine in St. Louis, MO, who led the study. Five study participants who had never smoked had a mutation that could be targeted by an existing drug.

All these studies show how diverse and how complicated the cancer genome is. But we now have a panoramic view of the genomic landscape, and this is important for moving forward in this disease.

—Dr. Ramaswamy Govindan

In all, the study authors found 54 genes with potentially targetable alterations in the 17 patients.

“The days of large clinical trials for lung cancer are over,” Dr. Govindan said, noting that patients need to be selected for specific treatments based on the characteristics of their tumors. “We also need to develop clinical trials that move targeted therapies to earlier stages of lung cancer, where we have a better chance of a cure.”

Future clinical trials, he predicted, would look for relatively large effects of drugs in selected patients. Dr. Minna agreed, saying, “If the effects are not there, we will move on to the next target and the next drug.”

The new results are really a teaser for what’s coming. TCGA plans to sequence a total of 500 adenocarcinomas and 500 squamous cells tumors. These results could help shed light on issues such as epigenetic changes in lung cancer, mechanisms of drug resistance, and how tumors are influenced by the surrounding tumor microenvironment.

“All these studies published back to back show how diverse and how complicated the cancer genome is,” Dr. Govindan said. “But we now have a panoramic view of the genomic landscape, and this is important for moving forward in this disease.”

Dr. Minna added, “After treating thousands of patients with lung cancer and not doing too well, I am very excited about the new results.”

Source: NCI

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