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Microscopic Vascular Invasion Emerging as a Powerful Prognosticator in Early Lung Cancer
CHICAGO - New data suggest that microscopic vascular invasion may be a more powerful prognosticator in early lung cancer than are the tumor size-based categories suggested in the new TNM staging system.
Italian researchers used histologic and immunohistochemical techniques to identify microscopic vascular invasion (MVI), or the presence of neoplastic structures inside the lumen of a vessel, in one-third (154) of 512 patients with resected, pathologically staged T1a to T3 node-negative non-small cell lung cancer (NSCLC). The 2009 edition of the tumor, node, metastasis (TNM) staging system for lung tumors was used.
MVI was significantly correlated with the presence of tumor-infiltrating lymphocytes (odds ratio 1.65, P value = .03), adenocarcinoma histology (OR 1.32, P = .003), and increased tumor size (OR 1.13, P = .009).
Five-year overall survival was significantly lower for patients with MVI at 50% vs. those without MVI at 66% (P = .001), Dr. Enrico Ruffini said at the Chicago Multidisciplinary Symposium in Thoracic Oncology.
The difference in survival remained significant even in those with squamous cell carcinoma (45% vs. 61%, P = .05), although it was more pronounced in those with adenocarcinoma (56% vs. 70%, P = .03).
"Microscopic vascular invasion is a significant independent negative prognostic factor," he said.
When patients with pT1a-T2b tumors were stratified by T-size category, the presence of MVI resulted in a one-category upstaging for each T category, said Dr. Ruffini of the division of thoracic surgery at the University of Torino (Italy). For example, T1a patients with MVI had a prognosis similar to that of patients with T1b tumors without MVI. The number of T3 cases was too small to stratify.
T size was prognostic of survival in the MVI-negative patients (P = .03) but was not a statistically significant factor in MVI-positive patients (P = .9), indicating that MVI is indeed a more powerful prognosticator, he said.
The 2009 TNM stresses the importance of tumor size as a major prognostic factor, but no TNM edition has so far included MVI as a major determinant in the staging of NSCLC.
In a multivariate survival analysis that included age, sex, histology, grading, T-size determinant, MVI, perineural invasion, and tumor-infiltrating lymphocytes, MVI was a stronger prognostic indicator (hazard ratio 1.43, P = .02) than T-size determinant (HR 1.06, P = .06), Dr. Ruffini said.
"The use of adjuvant chemotherapy in NSCLC patients with MVI may be considered," he said.
Invited discussant Dr. Mark Socinski pointed out that 88% of patients in the analysis had 5 cm or smaller tumors, a category of patients in which the role of adjuvant therapy has been discouraged. He highlighted the recent LACE meta-analysis of 4,584 NSCLC patients in five cisplatin-based adjuvant chemotherapy trials that showed an overall significant survival benefit of 4% at 5 years, but also a potentially negative effect in resected stage 1A (Ann. Oncol. 2010 Oct;21 Suppl. 7:vii196-vii198).
"We need to make sure [MVI] is easily reproducible amongst pathologists, and we also clearly need to demonstrate that adjuvant therapy can overcome the biologic impact of this histopathologic finding," said Dr. Socinski of the Lineberger Comprehensive Cancer Center at the University of North Carolina, Chapel Hill.
Dr. Ruffini acknowledged that bias could have been introduced into the study through its retrospective design, use of overall survival rather than disease-free survival as an outcome measure, and the long study period of January 1998 to August 2008. Prospective validation of MVI is underway using the prospective International Association for the Study of Lung Cancer database, he said.
The median tumor size among the 512 patients was 3.4 cm, with 164 classified as having T1a (less than 2 cm) tumors, 123 T1b (2-3 cm), 164 T2a (3-5 cm), 50 T2b (5-7 cm), and 11 T3 (greater than 7 cm) tumors.
The researchers and Dr. Socinski disclosed no relevant conflicts.
Subtle histologic markers have long been championed as a potential means to this ends, but historically gain little traction because essentially all are trumped by the presence of either metastic disease or regional lymph node involvement as important risks for recurrence. Consequently, the use of more sophisticated, but perhaps less reproduceable, pathologic markers is retricted to node-negative cancers, where T (of TNM) descriptors are important. This represents only about one-quarter of all lung cancers detected.
The authors have proposed microscopic vascular invasion (MVI) as an important factor that might be a reasonable addition to the T aspect of the new staging system. Their data demonstrate that MVI (found in a relatively small cohort of all node-negative patients in their study) appears to be an important risk for mortality. However, the road to the perfect staging system is paved with new histopathologic markers, and few are adopted because another one soon emerges and it is difficult for pathologists to keep up.
I think that molecular and radiologic characterization will eventually supplant all such subjective histopathologic markers and, within the next few years, will make the microscope something we'll be telling our grandkids about.
Subtle histologic markers have long been championed as a potential means to this ends, but historically gain little traction because essentially all are trumped by the presence of either metastic disease or regional lymph node involvement as important risks for recurrence. Consequently, the use of more sophisticated, but perhaps less reproduceable, pathologic markers is retricted to node-negative cancers, where T (of TNM) descriptors are important. This represents only about one-quarter of all lung cancers detected.
The authors have proposed microscopic vascular invasion (MVI) as an important factor that might be a reasonable addition to the T aspect of the new staging system. Their data demonstrate that MVI (found in a relatively small cohort of all node-negative patients in their study) appears to be an important risk for mortality. However, the road to the perfect staging system is paved with new histopathologic markers, and few are adopted because another one soon emerges and it is difficult for pathologists to keep up.
I think that molecular and radiologic characterization will eventually supplant all such subjective histopathologic markers and, within the next few years, will make the microscope something we'll be telling our grandkids about.
Subtle histologic markers have long been championed as a potential means to this ends, but historically gain little traction because essentially all are trumped by the presence of either metastic disease or regional lymph node involvement as important risks for recurrence. Consequently, the use of more sophisticated, but perhaps less reproduceable, pathologic markers is retricted to node-negative cancers, where T (of TNM) descriptors are important. This represents only about one-quarter of all lung cancers detected.
The authors have proposed microscopic vascular invasion (MVI) as an important factor that might be a reasonable addition to the T aspect of the new staging system. Their data demonstrate that MVI (found in a relatively small cohort of all node-negative patients in their study) appears to be an important risk for mortality. However, the road to the perfect staging system is paved with new histopathologic markers, and few are adopted because another one soon emerges and it is difficult for pathologists to keep up.
I think that molecular and radiologic characterization will eventually supplant all such subjective histopathologic markers and, within the next few years, will make the microscope something we'll be telling our grandkids about.
CHICAGO - New data suggest that microscopic vascular invasion may be a more powerful prognosticator in early lung cancer than are the tumor size-based categories suggested in the new TNM staging system.
Italian researchers used histologic and immunohistochemical techniques to identify microscopic vascular invasion (MVI), or the presence of neoplastic structures inside the lumen of a vessel, in one-third (154) of 512 patients with resected, pathologically staged T1a to T3 node-negative non-small cell lung cancer (NSCLC). The 2009 edition of the tumor, node, metastasis (TNM) staging system for lung tumors was used.
MVI was significantly correlated with the presence of tumor-infiltrating lymphocytes (odds ratio 1.65, P value = .03), adenocarcinoma histology (OR 1.32, P = .003), and increased tumor size (OR 1.13, P = .009).
Five-year overall survival was significantly lower for patients with MVI at 50% vs. those without MVI at 66% (P = .001), Dr. Enrico Ruffini said at the Chicago Multidisciplinary Symposium in Thoracic Oncology.
The difference in survival remained significant even in those with squamous cell carcinoma (45% vs. 61%, P = .05), although it was more pronounced in those with adenocarcinoma (56% vs. 70%, P = .03).
"Microscopic vascular invasion is a significant independent negative prognostic factor," he said.
When patients with pT1a-T2b tumors were stratified by T-size category, the presence of MVI resulted in a one-category upstaging for each T category, said Dr. Ruffini of the division of thoracic surgery at the University of Torino (Italy). For example, T1a patients with MVI had a prognosis similar to that of patients with T1b tumors without MVI. The number of T3 cases was too small to stratify.
T size was prognostic of survival in the MVI-negative patients (P = .03) but was not a statistically significant factor in MVI-positive patients (P = .9), indicating that MVI is indeed a more powerful prognosticator, he said.
The 2009 TNM stresses the importance of tumor size as a major prognostic factor, but no TNM edition has so far included MVI as a major determinant in the staging of NSCLC.
In a multivariate survival analysis that included age, sex, histology, grading, T-size determinant, MVI, perineural invasion, and tumor-infiltrating lymphocytes, MVI was a stronger prognostic indicator (hazard ratio 1.43, P = .02) than T-size determinant (HR 1.06, P = .06), Dr. Ruffini said.
"The use of adjuvant chemotherapy in NSCLC patients with MVI may be considered," he said.
Invited discussant Dr. Mark Socinski pointed out that 88% of patients in the analysis had 5 cm or smaller tumors, a category of patients in which the role of adjuvant therapy has been discouraged. He highlighted the recent LACE meta-analysis of 4,584 NSCLC patients in five cisplatin-based adjuvant chemotherapy trials that showed an overall significant survival benefit of 4% at 5 years, but also a potentially negative effect in resected stage 1A (Ann. Oncol. 2010 Oct;21 Suppl. 7:vii196-vii198).
"We need to make sure [MVI] is easily reproducible amongst pathologists, and we also clearly need to demonstrate that adjuvant therapy can overcome the biologic impact of this histopathologic finding," said Dr. Socinski of the Lineberger Comprehensive Cancer Center at the University of North Carolina, Chapel Hill.
Dr. Ruffini acknowledged that bias could have been introduced into the study through its retrospective design, use of overall survival rather than disease-free survival as an outcome measure, and the long study period of January 1998 to August 2008. Prospective validation of MVI is underway using the prospective International Association for the Study of Lung Cancer database, he said.
The median tumor size among the 512 patients was 3.4 cm, with 164 classified as having T1a (less than 2 cm) tumors, 123 T1b (2-3 cm), 164 T2a (3-5 cm), 50 T2b (5-7 cm), and 11 T3 (greater than 7 cm) tumors.
The researchers and Dr. Socinski disclosed no relevant conflicts.
CHICAGO - New data suggest that microscopic vascular invasion may be a more powerful prognosticator in early lung cancer than are the tumor size-based categories suggested in the new TNM staging system.
Italian researchers used histologic and immunohistochemical techniques to identify microscopic vascular invasion (MVI), or the presence of neoplastic structures inside the lumen of a vessel, in one-third (154) of 512 patients with resected, pathologically staged T1a to T3 node-negative non-small cell lung cancer (NSCLC). The 2009 edition of the tumor, node, metastasis (TNM) staging system for lung tumors was used.
MVI was significantly correlated with the presence of tumor-infiltrating lymphocytes (odds ratio 1.65, P value = .03), adenocarcinoma histology (OR 1.32, P = .003), and increased tumor size (OR 1.13, P = .009).
Five-year overall survival was significantly lower for patients with MVI at 50% vs. those without MVI at 66% (P = .001), Dr. Enrico Ruffini said at the Chicago Multidisciplinary Symposium in Thoracic Oncology.
The difference in survival remained significant even in those with squamous cell carcinoma (45% vs. 61%, P = .05), although it was more pronounced in those with adenocarcinoma (56% vs. 70%, P = .03).
"Microscopic vascular invasion is a significant independent negative prognostic factor," he said.
When patients with pT1a-T2b tumors were stratified by T-size category, the presence of MVI resulted in a one-category upstaging for each T category, said Dr. Ruffini of the division of thoracic surgery at the University of Torino (Italy). For example, T1a patients with MVI had a prognosis similar to that of patients with T1b tumors without MVI. The number of T3 cases was too small to stratify.
T size was prognostic of survival in the MVI-negative patients (P = .03) but was not a statistically significant factor in MVI-positive patients (P = .9), indicating that MVI is indeed a more powerful prognosticator, he said.
The 2009 TNM stresses the importance of tumor size as a major prognostic factor, but no TNM edition has so far included MVI as a major determinant in the staging of NSCLC.
In a multivariate survival analysis that included age, sex, histology, grading, T-size determinant, MVI, perineural invasion, and tumor-infiltrating lymphocytes, MVI was a stronger prognostic indicator (hazard ratio 1.43, P = .02) than T-size determinant (HR 1.06, P = .06), Dr. Ruffini said.
"The use of adjuvant chemotherapy in NSCLC patients with MVI may be considered," he said.
Invited discussant Dr. Mark Socinski pointed out that 88% of patients in the analysis had 5 cm or smaller tumors, a category of patients in which the role of adjuvant therapy has been discouraged. He highlighted the recent LACE meta-analysis of 4,584 NSCLC patients in five cisplatin-based adjuvant chemotherapy trials that showed an overall significant survival benefit of 4% at 5 years, but also a potentially negative effect in resected stage 1A (Ann. Oncol. 2010 Oct;21 Suppl. 7:vii196-vii198).
"We need to make sure [MVI] is easily reproducible amongst pathologists, and we also clearly need to demonstrate that adjuvant therapy can overcome the biologic impact of this histopathologic finding," said Dr. Socinski of the Lineberger Comprehensive Cancer Center at the University of North Carolina, Chapel Hill.
Dr. Ruffini acknowledged that bias could have been introduced into the study through its retrospective design, use of overall survival rather than disease-free survival as an outcome measure, and the long study period of January 1998 to August 2008. Prospective validation of MVI is underway using the prospective International Association for the Study of Lung Cancer database, he said.
The median tumor size among the 512 patients was 3.4 cm, with 164 classified as having T1a (less than 2 cm) tumors, 123 T1b (2-3 cm), 164 T2a (3-5 cm), 50 T2b (5-7 cm), and 11 T3 (greater than 7 cm) tumors.
The researchers and Dr. Socinski disclosed no relevant conflicts.
Low-Dose Aspirin Cut Cancer Death Rates 30%-40%
LONDON - The daily, long-term use of low-dose aspirin cuts the risk of death from several types of cancer, according to a large meta-analysis.
In a meta-analysis of eight randomized clinical trials involving 25,570 patients, low-dose aspirin taken for 5 years or longer reduced mortality from esophageal, pancreatic, brain, stomach, colorectal, prostate, and even lung cancer, with doses as low as 75 mg/day having an effect.
This is the first time that low-dose aspirin has been linked to a reduction in cancer mortality other than colorectal cancer, said Dr. Peter M. Rothwell, who conceived and coordinated the research.
Dr. Rothwell of the John Radcliffe Hospital and the University of Oxford, United Kingdom, and his associates in October 2010 showed that low-dose aspirin reduced the 20-year risk of new colon cancer cases by approximately one-quarter and deaths by a third (Lancet 2010;376:1741-50).
The current study looked at all deaths from cancer that occurred during or after completion of eight randomized clinical trials that had been performed to look at the effects of daily aspirin vs. control for the primary or secondary prevention of vascular events (Lancet 2010 [doi:10.1016/S0140-6736(10)62110-1]).
Across all eight trials, 674 cancer deaths occurred in 25,570 patients, with aspirin treatment significantly reducing the risk of death, compared with no aspirin treatment (pooled odds ratio [OR] 0.79, 95% confidence interval [CI] 0.68-0.92, P = .003).
Using individual patient data available for seven of the trials and in which 657 cancer deaths occurred in 23,535 patients, the benefit of aspirin therapy was apparent only after 5 years or more of follow-up. The hazard ratio (HR) for death from all types of cancer was 0.66 (95% CI 0.50-0.87, P =.003), with a greater effect seen in patients with gastrointestinal tumors (HR 0.46, 95% CI 0.27-0.77, P =.003).
"We found that within the trials, while people were still on aspirin vs. no aspirin, the aspirin group had about a 30%-40% reduction in cancer deaths between year 5 and the end of the trial," Dr. Rothwell said at a press briefing.
To determine the longer-term effects of aspirin on cancer mortality, the team looked more closely at data from three of the trials. These had all been conducted in the United Kingdom and continued to collect information on cancer deaths via national death certification and cancer registration systems long after the trials had concluded.
In all, individual patient data were obtained on 1,634 cancer deaths that had occurred in 12,659 patients. Aspirin was found to reduce the 20-year risk of death from all solid cancers by 20% (HR 0.80, 95% CI 0.72-0.88, P less than .0001). Again, the effect on gastrointestinal cancer was greater (HR 0.65, 95% CI 0.54-0.78, P less than .0001), but there was no effect on hematologic malignancies.
At least 5 years of therapy were needed to reduce the risk of death from esophageal, pancreatic, brain, or lung cancer, with 10 years or more treatment required to see an effect on stomach and colorectal cancer death rates, and 15 years or more for prostate cancer. With regard to both lung and esophageal cancer, the effect of aspirin was limited to adenocarcinomas.
While the findings do not mean that everyone over the age of 40 years should now start taking daily aspirin to prevent cancer, given the increased risk of bleeding in some individuals, "We should probably stop taking people off aspirin unless they've got side effects," Dr. Rothwell said in an interview, adding "We probably shouldn't discourage those who want to take aspirin as actively as we have been doing."
"There is a fundamental difference between the treatment and the prevention of a disease," said Dr. Peter Elwood, professor of epidemiology at Cardiff University, Wales. Dr. Elwood suggested that deciding to take a daily dose of aspirin to prevent cancer could be another choice patients make once they have all the relevant facts, much as lifestyle changes are advised but not prescribed for cardiovascular disease prevention.
Dr. Rothwell has received honoraria from pharmaceutical companies with an interest in antiplatelet therapy, including AstraZeneca and Bayer.
LONDON - The daily, long-term use of low-dose aspirin cuts the risk of death from several types of cancer, according to a large meta-analysis.
In a meta-analysis of eight randomized clinical trials involving 25,570 patients, low-dose aspirin taken for 5 years or longer reduced mortality from esophageal, pancreatic, brain, stomach, colorectal, prostate, and even lung cancer, with doses as low as 75 mg/day having an effect.
This is the first time that low-dose aspirin has been linked to a reduction in cancer mortality other than colorectal cancer, said Dr. Peter M. Rothwell, who conceived and coordinated the research.
Dr. Rothwell of the John Radcliffe Hospital and the University of Oxford, United Kingdom, and his associates in October 2010 showed that low-dose aspirin reduced the 20-year risk of new colon cancer cases by approximately one-quarter and deaths by a third (Lancet 2010;376:1741-50).
The current study looked at all deaths from cancer that occurred during or after completion of eight randomized clinical trials that had been performed to look at the effects of daily aspirin vs. control for the primary or secondary prevention of vascular events (Lancet 2010 [doi:10.1016/S0140-6736(10)62110-1]).
Across all eight trials, 674 cancer deaths occurred in 25,570 patients, with aspirin treatment significantly reducing the risk of death, compared with no aspirin treatment (pooled odds ratio [OR] 0.79, 95% confidence interval [CI] 0.68-0.92, P = .003).
Using individual patient data available for seven of the trials and in which 657 cancer deaths occurred in 23,535 patients, the benefit of aspirin therapy was apparent only after 5 years or more of follow-up. The hazard ratio (HR) for death from all types of cancer was 0.66 (95% CI 0.50-0.87, P =.003), with a greater effect seen in patients with gastrointestinal tumors (HR 0.46, 95% CI 0.27-0.77, P =.003).
"We found that within the trials, while people were still on aspirin vs. no aspirin, the aspirin group had about a 30%-40% reduction in cancer deaths between year 5 and the end of the trial," Dr. Rothwell said at a press briefing.
To determine the longer-term effects of aspirin on cancer mortality, the team looked more closely at data from three of the trials. These had all been conducted in the United Kingdom and continued to collect information on cancer deaths via national death certification and cancer registration systems long after the trials had concluded.
In all, individual patient data were obtained on 1,634 cancer deaths that had occurred in 12,659 patients. Aspirin was found to reduce the 20-year risk of death from all solid cancers by 20% (HR 0.80, 95% CI 0.72-0.88, P less than .0001). Again, the effect on gastrointestinal cancer was greater (HR 0.65, 95% CI 0.54-0.78, P less than .0001), but there was no effect on hematologic malignancies.
At least 5 years of therapy were needed to reduce the risk of death from esophageal, pancreatic, brain, or lung cancer, with 10 years or more treatment required to see an effect on stomach and colorectal cancer death rates, and 15 years or more for prostate cancer. With regard to both lung and esophageal cancer, the effect of aspirin was limited to adenocarcinomas.
While the findings do not mean that everyone over the age of 40 years should now start taking daily aspirin to prevent cancer, given the increased risk of bleeding in some individuals, "We should probably stop taking people off aspirin unless they've got side effects," Dr. Rothwell said in an interview, adding "We probably shouldn't discourage those who want to take aspirin as actively as we have been doing."
"There is a fundamental difference between the treatment and the prevention of a disease," said Dr. Peter Elwood, professor of epidemiology at Cardiff University, Wales. Dr. Elwood suggested that deciding to take a daily dose of aspirin to prevent cancer could be another choice patients make once they have all the relevant facts, much as lifestyle changes are advised but not prescribed for cardiovascular disease prevention.
Dr. Rothwell has received honoraria from pharmaceutical companies with an interest in antiplatelet therapy, including AstraZeneca and Bayer.
LONDON - The daily, long-term use of low-dose aspirin cuts the risk of death from several types of cancer, according to a large meta-analysis.
In a meta-analysis of eight randomized clinical trials involving 25,570 patients, low-dose aspirin taken for 5 years or longer reduced mortality from esophageal, pancreatic, brain, stomach, colorectal, prostate, and even lung cancer, with doses as low as 75 mg/day having an effect.
This is the first time that low-dose aspirin has been linked to a reduction in cancer mortality other than colorectal cancer, said Dr. Peter M. Rothwell, who conceived and coordinated the research.
Dr. Rothwell of the John Radcliffe Hospital and the University of Oxford, United Kingdom, and his associates in October 2010 showed that low-dose aspirin reduced the 20-year risk of new colon cancer cases by approximately one-quarter and deaths by a third (Lancet 2010;376:1741-50).
The current study looked at all deaths from cancer that occurred during or after completion of eight randomized clinical trials that had been performed to look at the effects of daily aspirin vs. control for the primary or secondary prevention of vascular events (Lancet 2010 [doi:10.1016/S0140-6736(10)62110-1]).
Across all eight trials, 674 cancer deaths occurred in 25,570 patients, with aspirin treatment significantly reducing the risk of death, compared with no aspirin treatment (pooled odds ratio [OR] 0.79, 95% confidence interval [CI] 0.68-0.92, P = .003).
Using individual patient data available for seven of the trials and in which 657 cancer deaths occurred in 23,535 patients, the benefit of aspirin therapy was apparent only after 5 years or more of follow-up. The hazard ratio (HR) for death from all types of cancer was 0.66 (95% CI 0.50-0.87, P =.003), with a greater effect seen in patients with gastrointestinal tumors (HR 0.46, 95% CI 0.27-0.77, P =.003).
"We found that within the trials, while people were still on aspirin vs. no aspirin, the aspirin group had about a 30%-40% reduction in cancer deaths between year 5 and the end of the trial," Dr. Rothwell said at a press briefing.
To determine the longer-term effects of aspirin on cancer mortality, the team looked more closely at data from three of the trials. These had all been conducted in the United Kingdom and continued to collect information on cancer deaths via national death certification and cancer registration systems long after the trials had concluded.
In all, individual patient data were obtained on 1,634 cancer deaths that had occurred in 12,659 patients. Aspirin was found to reduce the 20-year risk of death from all solid cancers by 20% (HR 0.80, 95% CI 0.72-0.88, P less than .0001). Again, the effect on gastrointestinal cancer was greater (HR 0.65, 95% CI 0.54-0.78, P less than .0001), but there was no effect on hematologic malignancies.
At least 5 years of therapy were needed to reduce the risk of death from esophageal, pancreatic, brain, or lung cancer, with 10 years or more treatment required to see an effect on stomach and colorectal cancer death rates, and 15 years or more for prostate cancer. With regard to both lung and esophageal cancer, the effect of aspirin was limited to adenocarcinomas.
While the findings do not mean that everyone over the age of 40 years should now start taking daily aspirin to prevent cancer, given the increased risk of bleeding in some individuals, "We should probably stop taking people off aspirin unless they've got side effects," Dr. Rothwell said in an interview, adding "We probably shouldn't discourage those who want to take aspirin as actively as we have been doing."
"There is a fundamental difference between the treatment and the prevention of a disease," said Dr. Peter Elwood, professor of epidemiology at Cardiff University, Wales. Dr. Elwood suggested that deciding to take a daily dose of aspirin to prevent cancer could be another choice patients make once they have all the relevant facts, much as lifestyle changes are advised but not prescribed for cardiovascular disease prevention.
Dr. Rothwell has received honoraria from pharmaceutical companies with an interest in antiplatelet therapy, including AstraZeneca and Bayer.
First-Line Tarceva May Benefit NSCLC With EGFR Mutation
Genentech Inc. and partner OSI Pharmaceuticals Inc. are set to pursue a broader label for Tarceva (erlotinib) in the United States as a first-line treatment of advanced non-small cell lung cancer with epidermal growth factor receptor mutations, after reporting positive top-line results in that setting from a phase III European study.
Genentech announced that compared with platinum-based chemo-therapy, Tarceva, an EGFR inhibitor, improved progression-free survival in an interim analysis of the EURTAC study of 178 newly-diagnosed advanced NSCLC patients who had tested positive for the mutations. Safety was in line with Tarceva's profile. In light of the efficacy and safety results, the trial was halted early on the recommendation of its independent data monitoring committee.
Tarceva is currently approved in the United States and Europe as a maintenance and second-line treatment for advanced or metastatic NSCLC with and without EGFR activating mutations. An estimated 10% of NSCLC carries the EGFR mutations and according to Genentech a first-line indication would mean Tarceva could emerge as the first-choice for that sliver of the patient population, ahead of chemotherapy and other drugs approved for first-line NSCLC.
Genentech's parent company, Roche, had already submitted a bid to expand the drug's label to the European Medicines Agency in June 2010.
Then, in November 2010, Roche announced that it was sublicensing a diagnostic assay for EGFR mutations from Genzyme Corporation and collaborating with OSI on the development of a PCR- based companion diagnostic test to identify people with non-small cell lung cancer that harbors EGFR activating mutations.
Genentech and OSI plan to talk to the Food and Drug Administration about possibilities for a first-line indication in NSCLC and also for the companion diagnostic test in development, but timing on these discussions has not yet been decided.
It's unclear whether the drug would be submitted to the FDA simultaneously with a diagnostic test, which was the case in a recent approval of a new, narrow indication for Herceptin in a particular type of gastric cancer.
The test in development by Roche and OSI was not the same diagnostic used in the EURTAC study, which was designed and sponsored by the Spanish Lung Cancer Group. Genentech said it still needs to validate the test used in the EURTAC study using samples from the trial, prior to talks with FDA. It's also unclear at this time whether another study beyond EURTAC would be needed to expand the U.S. label.
Genentech did not disclose the magnitude of the benefit for progression-free survival - the primary end point - in the EURTAC trial. Secondary end points include overall survival, 1-year survival, objective response rate, and safety profile.
In the SATURN trial of Tarceva as a maintenance therapy for NSCLC, the drug showed only a modest PFS benefit for NSCLC patients overall (12.3 weeks for the drug versus 11.1 weeks for placebo). Its use as a maintenance treatment has proven controversial since the FDA approved the indication despite a negative vote by an advisory committee.
However, SATURN showed dramatically better results for patients who had EGFR mutations. In this subgroup, which accounted for 11% of the total population, PFS was 44.6 weeks for the treated group versus the 11 weeks for placebo. Based on the data, some physician surveys have suggested more willingness to use Tarceva as a maintenance treatment in the case of EGFR mutations.
Elsevier Global Medical News and "The Pink Sheet" are published by Elsevier.
Genentech Inc. and partner OSI Pharmaceuticals Inc. are set to pursue a broader label for Tarceva (erlotinib) in the United States as a first-line treatment of advanced non-small cell lung cancer with epidermal growth factor receptor mutations, after reporting positive top-line results in that setting from a phase III European study.
Genentech announced that compared with platinum-based chemo-therapy, Tarceva, an EGFR inhibitor, improved progression-free survival in an interim analysis of the EURTAC study of 178 newly-diagnosed advanced NSCLC patients who had tested positive for the mutations. Safety was in line with Tarceva's profile. In light of the efficacy and safety results, the trial was halted early on the recommendation of its independent data monitoring committee.
Tarceva is currently approved in the United States and Europe as a maintenance and second-line treatment for advanced or metastatic NSCLC with and without EGFR activating mutations. An estimated 10% of NSCLC carries the EGFR mutations and according to Genentech a first-line indication would mean Tarceva could emerge as the first-choice for that sliver of the patient population, ahead of chemotherapy and other drugs approved for first-line NSCLC.
Genentech's parent company, Roche, had already submitted a bid to expand the drug's label to the European Medicines Agency in June 2010.
Then, in November 2010, Roche announced that it was sublicensing a diagnostic assay for EGFR mutations from Genzyme Corporation and collaborating with OSI on the development of a PCR- based companion diagnostic test to identify people with non-small cell lung cancer that harbors EGFR activating mutations.
Genentech and OSI plan to talk to the Food and Drug Administration about possibilities for a first-line indication in NSCLC and also for the companion diagnostic test in development, but timing on these discussions has not yet been decided.
It's unclear whether the drug would be submitted to the FDA simultaneously with a diagnostic test, which was the case in a recent approval of a new, narrow indication for Herceptin in a particular type of gastric cancer.
The test in development by Roche and OSI was not the same diagnostic used in the EURTAC study, which was designed and sponsored by the Spanish Lung Cancer Group. Genentech said it still needs to validate the test used in the EURTAC study using samples from the trial, prior to talks with FDA. It's also unclear at this time whether another study beyond EURTAC would be needed to expand the U.S. label.
Genentech did not disclose the magnitude of the benefit for progression-free survival - the primary end point - in the EURTAC trial. Secondary end points include overall survival, 1-year survival, objective response rate, and safety profile.
In the SATURN trial of Tarceva as a maintenance therapy for NSCLC, the drug showed only a modest PFS benefit for NSCLC patients overall (12.3 weeks for the drug versus 11.1 weeks for placebo). Its use as a maintenance treatment has proven controversial since the FDA approved the indication despite a negative vote by an advisory committee.
However, SATURN showed dramatically better results for patients who had EGFR mutations. In this subgroup, which accounted for 11% of the total population, PFS was 44.6 weeks for the treated group versus the 11 weeks for placebo. Based on the data, some physician surveys have suggested more willingness to use Tarceva as a maintenance treatment in the case of EGFR mutations.
Elsevier Global Medical News and "The Pink Sheet" are published by Elsevier.
Genentech Inc. and partner OSI Pharmaceuticals Inc. are set to pursue a broader label for Tarceva (erlotinib) in the United States as a first-line treatment of advanced non-small cell lung cancer with epidermal growth factor receptor mutations, after reporting positive top-line results in that setting from a phase III European study.
Genentech announced that compared with platinum-based chemo-therapy, Tarceva, an EGFR inhibitor, improved progression-free survival in an interim analysis of the EURTAC study of 178 newly-diagnosed advanced NSCLC patients who had tested positive for the mutations. Safety was in line with Tarceva's profile. In light of the efficacy and safety results, the trial was halted early on the recommendation of its independent data monitoring committee.
Tarceva is currently approved in the United States and Europe as a maintenance and second-line treatment for advanced or metastatic NSCLC with and without EGFR activating mutations. An estimated 10% of NSCLC carries the EGFR mutations and according to Genentech a first-line indication would mean Tarceva could emerge as the first-choice for that sliver of the patient population, ahead of chemotherapy and other drugs approved for first-line NSCLC.
Genentech's parent company, Roche, had already submitted a bid to expand the drug's label to the European Medicines Agency in June 2010.
Then, in November 2010, Roche announced that it was sublicensing a diagnostic assay for EGFR mutations from Genzyme Corporation and collaborating with OSI on the development of a PCR- based companion diagnostic test to identify people with non-small cell lung cancer that harbors EGFR activating mutations.
Genentech and OSI plan to talk to the Food and Drug Administration about possibilities for a first-line indication in NSCLC and also for the companion diagnostic test in development, but timing on these discussions has not yet been decided.
It's unclear whether the drug would be submitted to the FDA simultaneously with a diagnostic test, which was the case in a recent approval of a new, narrow indication for Herceptin in a particular type of gastric cancer.
The test in development by Roche and OSI was not the same diagnostic used in the EURTAC study, which was designed and sponsored by the Spanish Lung Cancer Group. Genentech said it still needs to validate the test used in the EURTAC study using samples from the trial, prior to talks with FDA. It's also unclear at this time whether another study beyond EURTAC would be needed to expand the U.S. label.
Genentech did not disclose the magnitude of the benefit for progression-free survival - the primary end point - in the EURTAC trial. Secondary end points include overall survival, 1-year survival, objective response rate, and safety profile.
In the SATURN trial of Tarceva as a maintenance therapy for NSCLC, the drug showed only a modest PFS benefit for NSCLC patients overall (12.3 weeks for the drug versus 11.1 weeks for placebo). Its use as a maintenance treatment has proven controversial since the FDA approved the indication despite a negative vote by an advisory committee.
However, SATURN showed dramatically better results for patients who had EGFR mutations. In this subgroup, which accounted for 11% of the total population, PFS was 44.6 weeks for the treated group versus the 11 weeks for placebo. Based on the data, some physician surveys have suggested more willingness to use Tarceva as a maintenance treatment in the case of EGFR mutations.
Elsevier Global Medical News and "The Pink Sheet" are published by Elsevier.
Lung Debris May Help Identify Surgical Margins
CHICAGO - A novel technique utilizing stapled lung debris could help determine adequate and inadequate surgical margins in resected non-small cell lung cancer, results of a prospective study suggest.
Researchers at Albany (N.Y.) Medical College and the Hospital of St. Raphael in New Haven, Conn., are using cytology to analyze lung tissue taken from spent staple cartridges used during sublobar resection. The staple cartridge is simply mixed with 30 cc of normal saline and serves as the cytologic margin, Dr. Thomas Fabian explained at the Chicago Multidisciplinary Symposium in Thoracic Oncology.
"People have [observed] that certain staples used through cancers can potentially contaminate new tissue planes, so that is how the idea was born," he said in an interview.
Dr. Fabian and his colleagues prospectively compared staple-line cytology with traditional histopathologic evaluation of surgical specimens taken from 97 patients undergoing diagnostic sublobar wedge resection between November 2007 and September 2009. Of the 98 specimens retrieved, 30 were benign and 68 were malignant.
Staple-line cytology was 100% accurate in the evaluation of benign lesions when compared with histology, he said.
In the 68 malignant nodules, initial blinded cytologic evaluation was positive in 7, surgical pathology was positive in 6, and both were positive in 4.
Subsequent unblinded review of both specimens changed the final pathologic interpretation in 4 (6%) of the 68 cases, said Dr. Fabian, chief of thoracic surgery at the Albany Medical Center. The interpretation changed from a negative margin to a positive margin in 3 surgical specimens (7%) and in 1 staple-line cytology specimen (2%).
According to analysis of the unblinded data, staple-line cytology demonstrated an overall accuracy of 96%, with 88% sensitivity, 97% specificity, 70% positive-predictive value, and 99% negative-predictive value.
Dr. Fabian described staple-line cytology as a simple technique that could serve as an adjunct to the gold standard of histopathology, which he said is prone to inaccuracies including both false positives and false negatives.
"We need to reevaluate the techniques that allow us to accurately assess surgical margins - particularly in the setting of sublobar resections, given the growing interest in this technique," according to Dr. Fabian.
"The cytologic technique appears to be sensitive, specific, and accurate, but it does need to be validated at other institutions and with additional studies," he added.
Dr. Fabian acknowledged that by design the study lacked clinical outcome data and said further evaluation is ongoing. The next step is to evaluate the technique in patients undergoing sublobar resection with curative intent.
Of the 68 malignant samples, 43 were diagnosed as adenocarcinoma, 7 as squamous cell carcinoma, 3 as large cell, 1 as small cell, 5 as carcinoid, and 9 as other histologies.
Dr. Fabian disclosed serving as a speaker for, and receiving research funding and honoraria from, Covidien. His coauthors reported no conflicts.
CHICAGO - A novel technique utilizing stapled lung debris could help determine adequate and inadequate surgical margins in resected non-small cell lung cancer, results of a prospective study suggest.
Researchers at Albany (N.Y.) Medical College and the Hospital of St. Raphael in New Haven, Conn., are using cytology to analyze lung tissue taken from spent staple cartridges used during sublobar resection. The staple cartridge is simply mixed with 30 cc of normal saline and serves as the cytologic margin, Dr. Thomas Fabian explained at the Chicago Multidisciplinary Symposium in Thoracic Oncology.
"People have [observed] that certain staples used through cancers can potentially contaminate new tissue planes, so that is how the idea was born," he said in an interview.
Dr. Fabian and his colleagues prospectively compared staple-line cytology with traditional histopathologic evaluation of surgical specimens taken from 97 patients undergoing diagnostic sublobar wedge resection between November 2007 and September 2009. Of the 98 specimens retrieved, 30 were benign and 68 were malignant.
Staple-line cytology was 100% accurate in the evaluation of benign lesions when compared with histology, he said.
In the 68 malignant nodules, initial blinded cytologic evaluation was positive in 7, surgical pathology was positive in 6, and both were positive in 4.
Subsequent unblinded review of both specimens changed the final pathologic interpretation in 4 (6%) of the 68 cases, said Dr. Fabian, chief of thoracic surgery at the Albany Medical Center. The interpretation changed from a negative margin to a positive margin in 3 surgical specimens (7%) and in 1 staple-line cytology specimen (2%).
According to analysis of the unblinded data, staple-line cytology demonstrated an overall accuracy of 96%, with 88% sensitivity, 97% specificity, 70% positive-predictive value, and 99% negative-predictive value.
Dr. Fabian described staple-line cytology as a simple technique that could serve as an adjunct to the gold standard of histopathology, which he said is prone to inaccuracies including both false positives and false negatives.
"We need to reevaluate the techniques that allow us to accurately assess surgical margins - particularly in the setting of sublobar resections, given the growing interest in this technique," according to Dr. Fabian.
"The cytologic technique appears to be sensitive, specific, and accurate, but it does need to be validated at other institutions and with additional studies," he added.
Dr. Fabian acknowledged that by design the study lacked clinical outcome data and said further evaluation is ongoing. The next step is to evaluate the technique in patients undergoing sublobar resection with curative intent.
Of the 68 malignant samples, 43 were diagnosed as adenocarcinoma, 7 as squamous cell carcinoma, 3 as large cell, 1 as small cell, 5 as carcinoid, and 9 as other histologies.
Dr. Fabian disclosed serving as a speaker for, and receiving research funding and honoraria from, Covidien. His coauthors reported no conflicts.
CHICAGO - A novel technique utilizing stapled lung debris could help determine adequate and inadequate surgical margins in resected non-small cell lung cancer, results of a prospective study suggest.
Researchers at Albany (N.Y.) Medical College and the Hospital of St. Raphael in New Haven, Conn., are using cytology to analyze lung tissue taken from spent staple cartridges used during sublobar resection. The staple cartridge is simply mixed with 30 cc of normal saline and serves as the cytologic margin, Dr. Thomas Fabian explained at the Chicago Multidisciplinary Symposium in Thoracic Oncology.
"People have [observed] that certain staples used through cancers can potentially contaminate new tissue planes, so that is how the idea was born," he said in an interview.
Dr. Fabian and his colleagues prospectively compared staple-line cytology with traditional histopathologic evaluation of surgical specimens taken from 97 patients undergoing diagnostic sublobar wedge resection between November 2007 and September 2009. Of the 98 specimens retrieved, 30 were benign and 68 were malignant.
Staple-line cytology was 100% accurate in the evaluation of benign lesions when compared with histology, he said.
In the 68 malignant nodules, initial blinded cytologic evaluation was positive in 7, surgical pathology was positive in 6, and both were positive in 4.
Subsequent unblinded review of both specimens changed the final pathologic interpretation in 4 (6%) of the 68 cases, said Dr. Fabian, chief of thoracic surgery at the Albany Medical Center. The interpretation changed from a negative margin to a positive margin in 3 surgical specimens (7%) and in 1 staple-line cytology specimen (2%).
According to analysis of the unblinded data, staple-line cytology demonstrated an overall accuracy of 96%, with 88% sensitivity, 97% specificity, 70% positive-predictive value, and 99% negative-predictive value.
Dr. Fabian described staple-line cytology as a simple technique that could serve as an adjunct to the gold standard of histopathology, which he said is prone to inaccuracies including both false positives and false negatives.
"We need to reevaluate the techniques that allow us to accurately assess surgical margins - particularly in the setting of sublobar resections, given the growing interest in this technique," according to Dr. Fabian.
"The cytologic technique appears to be sensitive, specific, and accurate, but it does need to be validated at other institutions and with additional studies," he added.
Dr. Fabian acknowledged that by design the study lacked clinical outcome data and said further evaluation is ongoing. The next step is to evaluate the technique in patients undergoing sublobar resection with curative intent.
Of the 68 malignant samples, 43 were diagnosed as adenocarcinoma, 7 as squamous cell carcinoma, 3 as large cell, 1 as small cell, 5 as carcinoid, and 9 as other histologies.
Dr. Fabian disclosed serving as a speaker for, and receiving research funding and honoraria from, Covidien. His coauthors reported no conflicts.
Microscopic Vascular Invasion Emerging as a Powerful Prognosticator in Early Lung Cancer
CHICAGO - New data suggest that microscopic vascular invasion may be a more powerful prognosticator in early lung cancer than are the tumor size-based categories suggested in the new TNM staging system.
Italian researchers used histologic and immunohistochemical techniques to identify microscopic vascular invasion (MVI), or the presence of neoplastic structures inside the lumen of a vessel, in one-third (154) of 512 patients with resected, pathologically staged T1a to T3 node-negative non-small cell lung cancer (NSCLC). The 2009 edition of the tumor, node, metastasis (TNM) staging system for lung tumors was used.
MVI was significantly correlated with the presence of tumor-infiltrating lymphocytes (odds ratio 1.65, P value = .03), adenocarcinoma histology (OR 1.32, P = .003), and increased tumor size (OR 1.13, P = .009).
Five-year overall survival was significantly lower for patients with MVI at 50% vs. those without MVI at 66% (P = .001), Dr. Enrico Ruffini said at the Chicago Multidisciplinary Symposium in Thoracic Oncology.
The difference in survival remained significant even in those with squamous cell carcinoma (45% vs. 61%, P = .05), although it was more pronounced in those with adenocarcinoma (56% vs. 70%, P = .03).
"Microscopic vascular invasion is a significant independent negative prognostic factor," he said.
When patients with pT1a-T2b tumors were stratified by T-size category, the presence of MVI resulted in a one-category upstaging for each T category, said Dr. Ruffini of the division of thoracic surgery at the University of Torino (Italy). For example, T1a patients with MVI had a prognosis similar to that of patients with T1b tumors without MVI. The number of T3 cases was too small to stratify.
T size was prognostic of survival in the MVI-negative patients (P = .03) but was not a statistically significant factor in MVI-positive patients (P = .9), indicating that MVI is indeed a more powerful prognosticator, he said.
The 2009 TNM stresses the importance of tumor size as a major prognostic factor, but no TNM edition has so far included MVI as a major determinant in the staging of NSCLC.
In a multivariate survival analysis that included age, sex, histology, grading, T-size determinant, MVI, perineural invasion, and tumor-infiltrating lymphocytes, MVI was a stronger prognostic indicator (hazard ratio 1.43, P = .02) than T-size determinant (HR 1.06, P = .06), Dr. Ruffini said.
"The use of adjuvant chemotherapy in NSCLC patients with MVI may be considered," he said.
Invited discussant Dr. Mark Socinski pointed out that 88% of patients in the analysis had 5 cm or smaller tumors, a category of patients in which the role of adjuvant therapy has been discouraged. He highlighted the recent LACE meta-analysis of 4,584 NSCLC patients in five cisplatin-based adjuvant chemotherapy trials that showed an overall significant survival benefit of 4% at 5 years, but also a potentially negative effect in resected stage 1A (Ann. Oncol. 2010 Oct;21 Suppl. 7:vii196-vii198).
"We need to make sure [MVI] is easily reproducible amongst pathologists, and we also clearly need to demonstrate that adjuvant therapy can overcome the biologic impact of this histopathologic finding," said Dr. Socinski of the Lineberger Comprehensive Cancer Center at the University of North Carolina, Chapel Hill.
Dr. Ruffini acknowledged that bias could have been introduced into the study through its retrospective design, use of overall survival rather than disease-free survival as an outcome measure, and the long study period of January 1998 to August 2008. Prospective validation of MVI is underway using the prospective International Association for the Study of Lung Cancer database, he said.
The median tumor size among the 512 patients was 3.4 cm, with 164 classified as having T1a (less than 2 cm) tumors, 123 T1b (2-3 cm), 164 T2a (3-5 cm), 50 T2b (5-7 cm), and 11 T3 (greater than 7 cm) tumors.
The researchers and Dr. Socinski disclosed no relevant conflicts.
Subtle histologic markers have long been championed as a potential means to this ends, but historically gain little traction because essentially all are trumped by the presence of either metastic disease or regional lymph node involvement as important risks for recurrence. Consequently, the use of more sophisticated, but perhaps less reproduceable, pathologic markers is retricted to node-negative cancers, where T (of TNM) descriptors are important. This represents only about one-quarter of all lung cancers detected.
The authors have proposed microscopic vascular invasion (MVI) as an important factor that might be a reasonable addition to the T aspect of the new staging system. Their data demonstrate that MVI (found in a relatively small cohort of all node-negative patients in their study) appears to be an important risk for mortality. However, the road to the perfect staging system is paved with new histopathologic markers, and few are adopted because another one soon emerges and it is difficult for pathologists to keep up.
I think that molecular and radiologic characterization will eventually supplant all such subjective histopathologic markers and, within the next few years, will make the microscope something we'll be telling our grandkids about.
Subtle histologic markers have long been championed as a potential means to this ends, but historically gain little traction because essentially all are trumped by the presence of either metastic disease or regional lymph node involvement as important risks for recurrence. Consequently, the use of more sophisticated, but perhaps less reproduceable, pathologic markers is retricted to node-negative cancers, where T (of TNM) descriptors are important. This represents only about one-quarter of all lung cancers detected.
The authors have proposed microscopic vascular invasion (MVI) as an important factor that might be a reasonable addition to the T aspect of the new staging system. Their data demonstrate that MVI (found in a relatively small cohort of all node-negative patients in their study) appears to be an important risk for mortality. However, the road to the perfect staging system is paved with new histopathologic markers, and few are adopted because another one soon emerges and it is difficult for pathologists to keep up.
I think that molecular and radiologic characterization will eventually supplant all such subjective histopathologic markers and, within the next few years, will make the microscope something we'll be telling our grandkids about.
Subtle histologic markers have long been championed as a potential means to this ends, but historically gain little traction because essentially all are trumped by the presence of either metastic disease or regional lymph node involvement as important risks for recurrence. Consequently, the use of more sophisticated, but perhaps less reproduceable, pathologic markers is retricted to node-negative cancers, where T (of TNM) descriptors are important. This represents only about one-quarter of all lung cancers detected.
The authors have proposed microscopic vascular invasion (MVI) as an important factor that might be a reasonable addition to the T aspect of the new staging system. Their data demonstrate that MVI (found in a relatively small cohort of all node-negative patients in their study) appears to be an important risk for mortality. However, the road to the perfect staging system is paved with new histopathologic markers, and few are adopted because another one soon emerges and it is difficult for pathologists to keep up.
I think that molecular and radiologic characterization will eventually supplant all such subjective histopathologic markers and, within the next few years, will make the microscope something we'll be telling our grandkids about.
CHICAGO - New data suggest that microscopic vascular invasion may be a more powerful prognosticator in early lung cancer than are the tumor size-based categories suggested in the new TNM staging system.
Italian researchers used histologic and immunohistochemical techniques to identify microscopic vascular invasion (MVI), or the presence of neoplastic structures inside the lumen of a vessel, in one-third (154) of 512 patients with resected, pathologically staged T1a to T3 node-negative non-small cell lung cancer (NSCLC). The 2009 edition of the tumor, node, metastasis (TNM) staging system for lung tumors was used.
MVI was significantly correlated with the presence of tumor-infiltrating lymphocytes (odds ratio 1.65, P value = .03), adenocarcinoma histology (OR 1.32, P = .003), and increased tumor size (OR 1.13, P = .009).
Five-year overall survival was significantly lower for patients with MVI at 50% vs. those without MVI at 66% (P = .001), Dr. Enrico Ruffini said at the Chicago Multidisciplinary Symposium in Thoracic Oncology.
The difference in survival remained significant even in those with squamous cell carcinoma (45% vs. 61%, P = .05), although it was more pronounced in those with adenocarcinoma (56% vs. 70%, P = .03).
"Microscopic vascular invasion is a significant independent negative prognostic factor," he said.
When patients with pT1a-T2b tumors were stratified by T-size category, the presence of MVI resulted in a one-category upstaging for each T category, said Dr. Ruffini of the division of thoracic surgery at the University of Torino (Italy). For example, T1a patients with MVI had a prognosis similar to that of patients with T1b tumors without MVI. The number of T3 cases was too small to stratify.
T size was prognostic of survival in the MVI-negative patients (P = .03) but was not a statistically significant factor in MVI-positive patients (P = .9), indicating that MVI is indeed a more powerful prognosticator, he said.
The 2009 TNM stresses the importance of tumor size as a major prognostic factor, but no TNM edition has so far included MVI as a major determinant in the staging of NSCLC.
In a multivariate survival analysis that included age, sex, histology, grading, T-size determinant, MVI, perineural invasion, and tumor-infiltrating lymphocytes, MVI was a stronger prognostic indicator (hazard ratio 1.43, P = .02) than T-size determinant (HR 1.06, P = .06), Dr. Ruffini said.
"The use of adjuvant chemotherapy in NSCLC patients with MVI may be considered," he said.
Invited discussant Dr. Mark Socinski pointed out that 88% of patients in the analysis had 5 cm or smaller tumors, a category of patients in which the role of adjuvant therapy has been discouraged. He highlighted the recent LACE meta-analysis of 4,584 NSCLC patients in five cisplatin-based adjuvant chemotherapy trials that showed an overall significant survival benefit of 4% at 5 years, but also a potentially negative effect in resected stage 1A (Ann. Oncol. 2010 Oct;21 Suppl. 7:vii196-vii198).
"We need to make sure [MVI] is easily reproducible amongst pathologists, and we also clearly need to demonstrate that adjuvant therapy can overcome the biologic impact of this histopathologic finding," said Dr. Socinski of the Lineberger Comprehensive Cancer Center at the University of North Carolina, Chapel Hill.
Dr. Ruffini acknowledged that bias could have been introduced into the study through its retrospective design, use of overall survival rather than disease-free survival as an outcome measure, and the long study period of January 1998 to August 2008. Prospective validation of MVI is underway using the prospective International Association for the Study of Lung Cancer database, he said.
The median tumor size among the 512 patients was 3.4 cm, with 164 classified as having T1a (less than 2 cm) tumors, 123 T1b (2-3 cm), 164 T2a (3-5 cm), 50 T2b (5-7 cm), and 11 T3 (greater than 7 cm) tumors.
The researchers and Dr. Socinski disclosed no relevant conflicts.
CHICAGO - New data suggest that microscopic vascular invasion may be a more powerful prognosticator in early lung cancer than are the tumor size-based categories suggested in the new TNM staging system.
Italian researchers used histologic and immunohistochemical techniques to identify microscopic vascular invasion (MVI), or the presence of neoplastic structures inside the lumen of a vessel, in one-third (154) of 512 patients with resected, pathologically staged T1a to T3 node-negative non-small cell lung cancer (NSCLC). The 2009 edition of the tumor, node, metastasis (TNM) staging system for lung tumors was used.
MVI was significantly correlated with the presence of tumor-infiltrating lymphocytes (odds ratio 1.65, P value = .03), adenocarcinoma histology (OR 1.32, P = .003), and increased tumor size (OR 1.13, P = .009).
Five-year overall survival was significantly lower for patients with MVI at 50% vs. those without MVI at 66% (P = .001), Dr. Enrico Ruffini said at the Chicago Multidisciplinary Symposium in Thoracic Oncology.
The difference in survival remained significant even in those with squamous cell carcinoma (45% vs. 61%, P = .05), although it was more pronounced in those with adenocarcinoma (56% vs. 70%, P = .03).
"Microscopic vascular invasion is a significant independent negative prognostic factor," he said.
When patients with pT1a-T2b tumors were stratified by T-size category, the presence of MVI resulted in a one-category upstaging for each T category, said Dr. Ruffini of the division of thoracic surgery at the University of Torino (Italy). For example, T1a patients with MVI had a prognosis similar to that of patients with T1b tumors without MVI. The number of T3 cases was too small to stratify.
T size was prognostic of survival in the MVI-negative patients (P = .03) but was not a statistically significant factor in MVI-positive patients (P = .9), indicating that MVI is indeed a more powerful prognosticator, he said.
The 2009 TNM stresses the importance of tumor size as a major prognostic factor, but no TNM edition has so far included MVI as a major determinant in the staging of NSCLC.
In a multivariate survival analysis that included age, sex, histology, grading, T-size determinant, MVI, perineural invasion, and tumor-infiltrating lymphocytes, MVI was a stronger prognostic indicator (hazard ratio 1.43, P = .02) than T-size determinant (HR 1.06, P = .06), Dr. Ruffini said.
"The use of adjuvant chemotherapy in NSCLC patients with MVI may be considered," he said.
Invited discussant Dr. Mark Socinski pointed out that 88% of patients in the analysis had 5 cm or smaller tumors, a category of patients in which the role of adjuvant therapy has been discouraged. He highlighted the recent LACE meta-analysis of 4,584 NSCLC patients in five cisplatin-based adjuvant chemotherapy trials that showed an overall significant survival benefit of 4% at 5 years, but also a potentially negative effect in resected stage 1A (Ann. Oncol. 2010 Oct;21 Suppl. 7:vii196-vii198).
"We need to make sure [MVI] is easily reproducible amongst pathologists, and we also clearly need to demonstrate that adjuvant therapy can overcome the biologic impact of this histopathologic finding," said Dr. Socinski of the Lineberger Comprehensive Cancer Center at the University of North Carolina, Chapel Hill.
Dr. Ruffini acknowledged that bias could have been introduced into the study through its retrospective design, use of overall survival rather than disease-free survival as an outcome measure, and the long study period of January 1998 to August 2008. Prospective validation of MVI is underway using the prospective International Association for the Study of Lung Cancer database, he said.
The median tumor size among the 512 patients was 3.4 cm, with 164 classified as having T1a (less than 2 cm) tumors, 123 T1b (2-3 cm), 164 T2a (3-5 cm), 50 T2b (5-7 cm), and 11 T3 (greater than 7 cm) tumors.
The researchers and Dr. Socinski disclosed no relevant conflicts.
Low-Dose Aspirin Cut Cancer Death Rates 30%-40%
LONDON - The daily, long-term use of low-dose aspirin cuts the risk of death from several types of cancer, according to a large meta-analysis.
In a meta-analysis of eight randomized clinical trials involving 25,570 patients, low-dose aspirin taken for 5 years or longer reduced mortality from esophageal, pancreatic, brain, stomach, colorectal, prostate, and even lung cancer, with doses as low as 75 mg/day having an effect.
This is the first time that low-dose aspirin has been linked to a reduction in cancer mortality other than colorectal cancer, said Dr. Peter M. Rothwell, who conceived and coordinated the research.
Dr. Rothwell of the John Radcliffe Hospital and the University of Oxford, United Kingdom, and his associates in October 2010 showed that low-dose aspirin reduced the 20-year risk of new colon cancer cases by approximately one-quarter and deaths by a third (Lancet 2010;376:1741-50).
The current study looked at all deaths from cancer that occurred during or after completion of eight randomized clinical trials that had been performed to look at the effects of daily aspirin vs. control for the primary or secondary prevention of vascular events (Lancet 2010 [doi:10.1016/S0140-6736(10)62110-1]).
Across all eight trials, 674 cancer deaths occurred in 25,570 patients, with aspirin treatment significantly reducing the risk of death, compared with no aspirin treatment (pooled odds ratio [OR] 0.79, 95% confidence interval [CI] 0.68-0.92, P = .003).
Using individual patient data available for seven of the trials and in which 657 cancer deaths occurred in 23,535 patients, the benefit of aspirin therapy was apparent only after 5 years or more of follow-up. The hazard ratio (HR) for death from all types of cancer was 0.66 (95% CI 0.50-0.87, P =.003), with a greater effect seen in patients with gastrointestinal tumors (HR 0.46, 95% CI 0.27-0.77, P =.003).
"We found that within the trials, while people were still on aspirin vs. no aspirin, the aspirin group had about a 30%-40% reduction in cancer deaths between year 5 and the end of the trial," Dr. Rothwell said at a press briefing.
To determine the longer-term effects of aspirin on cancer mortality, the team looked more closely at data from three of the trials. These had all been conducted in the United Kingdom and continued to collect information on cancer deaths via national death certification and cancer registration systems long after the trials had concluded.
In all, individual patient data were obtained on 1,634 cancer deaths that had occurred in 12,659 patients. Aspirin was found to reduce the 20-year risk of death from all solid cancers by 20% (HR 0.80, 95% CI 0.72-0.88, P less than .0001). Again, the effect on gastrointestinal cancer was greater (HR 0.65, 95% CI 0.54-0.78, P less than .0001), but there was no effect on hematologic malignancies.
At least 5 years of therapy were needed to reduce the risk of death from esophageal, pancreatic, brain, or lung cancer, with 10 years or more treatment required to see an effect on stomach and colorectal cancer death rates, and 15 years or more for prostate cancer. With regard to both lung and esophageal cancer, the effect of aspirin was limited to adenocarcinomas.
While the findings do not mean that everyone over the age of 40 years should now start taking daily aspirin to prevent cancer, given the increased risk of bleeding in some individuals, "We should probably stop taking people off aspirin unless they've got side effects," Dr. Rothwell said in an interview, adding "We probably shouldn't discourage those who want to take aspirin as actively as we have been doing."
"There is a fundamental difference between the treatment and the prevention of a disease," said Dr. Peter Elwood, professor of epidemiology at Cardiff University, Wales. Dr. Elwood suggested that deciding to take a daily dose of aspirin to prevent cancer could be another choice patients make once they have all the relevant facts, much as lifestyle changes are advised but not prescribed for cardiovascular disease prevention.
Dr. Rothwell has received honoraria from pharmaceutical companies with an interest in antiplatelet therapy, including AstraZeneca and Bayer.
LONDON - The daily, long-term use of low-dose aspirin cuts the risk of death from several types of cancer, according to a large meta-analysis.
In a meta-analysis of eight randomized clinical trials involving 25,570 patients, low-dose aspirin taken for 5 years or longer reduced mortality from esophageal, pancreatic, brain, stomach, colorectal, prostate, and even lung cancer, with doses as low as 75 mg/day having an effect.
This is the first time that low-dose aspirin has been linked to a reduction in cancer mortality other than colorectal cancer, said Dr. Peter M. Rothwell, who conceived and coordinated the research.
Dr. Rothwell of the John Radcliffe Hospital and the University of Oxford, United Kingdom, and his associates in October 2010 showed that low-dose aspirin reduced the 20-year risk of new colon cancer cases by approximately one-quarter and deaths by a third (Lancet 2010;376:1741-50).
The current study looked at all deaths from cancer that occurred during or after completion of eight randomized clinical trials that had been performed to look at the effects of daily aspirin vs. control for the primary or secondary prevention of vascular events (Lancet 2010 [doi:10.1016/S0140-6736(10)62110-1]).
Across all eight trials, 674 cancer deaths occurred in 25,570 patients, with aspirin treatment significantly reducing the risk of death, compared with no aspirin treatment (pooled odds ratio [OR] 0.79, 95% confidence interval [CI] 0.68-0.92, P = .003).
Using individual patient data available for seven of the trials and in which 657 cancer deaths occurred in 23,535 patients, the benefit of aspirin therapy was apparent only after 5 years or more of follow-up. The hazard ratio (HR) for death from all types of cancer was 0.66 (95% CI 0.50-0.87, P =.003), with a greater effect seen in patients with gastrointestinal tumors (HR 0.46, 95% CI 0.27-0.77, P =.003).
"We found that within the trials, while people were still on aspirin vs. no aspirin, the aspirin group had about a 30%-40% reduction in cancer deaths between year 5 and the end of the trial," Dr. Rothwell said at a press briefing.
To determine the longer-term effects of aspirin on cancer mortality, the team looked more closely at data from three of the trials. These had all been conducted in the United Kingdom and continued to collect information on cancer deaths via national death certification and cancer registration systems long after the trials had concluded.
In all, individual patient data were obtained on 1,634 cancer deaths that had occurred in 12,659 patients. Aspirin was found to reduce the 20-year risk of death from all solid cancers by 20% (HR 0.80, 95% CI 0.72-0.88, P less than .0001). Again, the effect on gastrointestinal cancer was greater (HR 0.65, 95% CI 0.54-0.78, P less than .0001), but there was no effect on hematologic malignancies.
At least 5 years of therapy were needed to reduce the risk of death from esophageal, pancreatic, brain, or lung cancer, with 10 years or more treatment required to see an effect on stomach and colorectal cancer death rates, and 15 years or more for prostate cancer. With regard to both lung and esophageal cancer, the effect of aspirin was limited to adenocarcinomas.
While the findings do not mean that everyone over the age of 40 years should now start taking daily aspirin to prevent cancer, given the increased risk of bleeding in some individuals, "We should probably stop taking people off aspirin unless they've got side effects," Dr. Rothwell said in an interview, adding "We probably shouldn't discourage those who want to take aspirin as actively as we have been doing."
"There is a fundamental difference between the treatment and the prevention of a disease," said Dr. Peter Elwood, professor of epidemiology at Cardiff University, Wales. Dr. Elwood suggested that deciding to take a daily dose of aspirin to prevent cancer could be another choice patients make once they have all the relevant facts, much as lifestyle changes are advised but not prescribed for cardiovascular disease prevention.
Dr. Rothwell has received honoraria from pharmaceutical companies with an interest in antiplatelet therapy, including AstraZeneca and Bayer.
LONDON - The daily, long-term use of low-dose aspirin cuts the risk of death from several types of cancer, according to a large meta-analysis.
In a meta-analysis of eight randomized clinical trials involving 25,570 patients, low-dose aspirin taken for 5 years or longer reduced mortality from esophageal, pancreatic, brain, stomach, colorectal, prostate, and even lung cancer, with doses as low as 75 mg/day having an effect.
This is the first time that low-dose aspirin has been linked to a reduction in cancer mortality other than colorectal cancer, said Dr. Peter M. Rothwell, who conceived and coordinated the research.
Dr. Rothwell of the John Radcliffe Hospital and the University of Oxford, United Kingdom, and his associates in October 2010 showed that low-dose aspirin reduced the 20-year risk of new colon cancer cases by approximately one-quarter and deaths by a third (Lancet 2010;376:1741-50).
The current study looked at all deaths from cancer that occurred during or after completion of eight randomized clinical trials that had been performed to look at the effects of daily aspirin vs. control for the primary or secondary prevention of vascular events (Lancet 2010 [doi:10.1016/S0140-6736(10)62110-1]).
Across all eight trials, 674 cancer deaths occurred in 25,570 patients, with aspirin treatment significantly reducing the risk of death, compared with no aspirin treatment (pooled odds ratio [OR] 0.79, 95% confidence interval [CI] 0.68-0.92, P = .003).
Using individual patient data available for seven of the trials and in which 657 cancer deaths occurred in 23,535 patients, the benefit of aspirin therapy was apparent only after 5 years or more of follow-up. The hazard ratio (HR) for death from all types of cancer was 0.66 (95% CI 0.50-0.87, P =.003), with a greater effect seen in patients with gastrointestinal tumors (HR 0.46, 95% CI 0.27-0.77, P =.003).
"We found that within the trials, while people were still on aspirin vs. no aspirin, the aspirin group had about a 30%-40% reduction in cancer deaths between year 5 and the end of the trial," Dr. Rothwell said at a press briefing.
To determine the longer-term effects of aspirin on cancer mortality, the team looked more closely at data from three of the trials. These had all been conducted in the United Kingdom and continued to collect information on cancer deaths via national death certification and cancer registration systems long after the trials had concluded.
In all, individual patient data were obtained on 1,634 cancer deaths that had occurred in 12,659 patients. Aspirin was found to reduce the 20-year risk of death from all solid cancers by 20% (HR 0.80, 95% CI 0.72-0.88, P less than .0001). Again, the effect on gastrointestinal cancer was greater (HR 0.65, 95% CI 0.54-0.78, P less than .0001), but there was no effect on hematologic malignancies.
At least 5 years of therapy were needed to reduce the risk of death from esophageal, pancreatic, brain, or lung cancer, with 10 years or more treatment required to see an effect on stomach and colorectal cancer death rates, and 15 years or more for prostate cancer. With regard to both lung and esophageal cancer, the effect of aspirin was limited to adenocarcinomas.
While the findings do not mean that everyone over the age of 40 years should now start taking daily aspirin to prevent cancer, given the increased risk of bleeding in some individuals, "We should probably stop taking people off aspirin unless they've got side effects," Dr. Rothwell said in an interview, adding "We probably shouldn't discourage those who want to take aspirin as actively as we have been doing."
"There is a fundamental difference between the treatment and the prevention of a disease," said Dr. Peter Elwood, professor of epidemiology at Cardiff University, Wales. Dr. Elwood suggested that deciding to take a daily dose of aspirin to prevent cancer could be another choice patients make once they have all the relevant facts, much as lifestyle changes are advised but not prescribed for cardiovascular disease prevention.
Dr. Rothwell has received honoraria from pharmaceutical companies with an interest in antiplatelet therapy, including AstraZeneca and Bayer.
Drug Resistance Triggers Lung Cancer Transformation
CHICAGO - A small study provides compelling data that both the genotype and phenotype of non-small cell lung cancers can transform with acquired resistance to tyrosine kinase inhibitors.
Repeat tumor biopsies revealed that the histologic diagnosis of the tumor shifted from adenocarcinoma to small cell lung cancer (SCLC) in 14% of 37 consecutive patients with epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) and acquired tyrosine kinase inhibitor (TKI) resistance, Dr. Lecia Sequist said at the Multidisciplinary Syposium on Thoracic Oncology.
The L858R mutation or E 19 deletion was retained in all cases. In one patient, an additional PIK3CA mutation was seen only when the tumor shifted to SCLC.
Although other groups have documented sporadictransformation, Dr. Sequist called the 14% transformation rate remarkable. “I think this points to a broader conceptual model of acquired resistance, and we need to think very carefully about doing more repeat biopsies in patients,” she said.
EGFR-mutant NSCLC is highly sensitive to EGFR TKI therapy, but acquired resistance develops at about 9-12 months due to T790M mutations in half of patients and MET amplification in 10% to 15%, said Dr. Sequist of Massachusetts General Hospital Cancer Center, Boston.
Although re-biopsy is not common practice, invited discussant Dr. Mark Socinski said it should be on the clinician's radar because it can alter the therapeutic course of refractory disease and arguably the clinical benefit.
“I think the message here is to consider re-biopsy more often in selected patients until we have a better understanding of this one disease we call non-small lung cancer that we realize is an incredibly heterogenous disease,” said Dr. Socinski, director of the thoracic oncology program at the Lineberger Comprehensive Cancer Center at the University of North Carolina-Chapel Hill.
Among the five patients whose cancer transformed, two maintained a slow, indolent course after SCLC transformation, while three had a change around the time of their biopsy to an explosive growth pattern more clinically reminiscent of SCLC, Dr. Sequist said. Four patients were treated with SCLC-like chemotherapy regimens, and three responded with marked partial responses.
Longitudinal data from fluorescent in situ hybridization analysis for MET and EGFR gene copy number suggest that the resistant tumor is distinct from the original tumor and that MET amplification lies in a distinct subpopulation of the cell and is selected out under pressure from TKI therapy, she said.
Multiple biopsies over time also identified a waxing and waning of genotypic and phenotypic findings in response to TKI therapy. This pattern was most pronounced in a case that transformed from EGFR TKI-sensitive adenocarcinoma to resistant SCLC while on erlotinib (Tarceva) for more than 1 year, switched back to TKI-sensitive adenocarcinoma following treatment with chemotherapy and radiation and a 9- to 10-month break from erlotinib, and then after a very successful, but short-lived re-response to erlotinib, shifted back to SCLC a second time upon clinical resistance.
“It's showing us that if you do repeat biopsies, it can direct patients towards clinical trials that they have a higher likelihood of benefiting from,” she said.
The population comprised 15 men and 22 women, median age 60 years. All had responded to either gefitinib (Iressa) or erlotinib, with a median of 18.4 months of initial EGFR TKI therapy. The majority (81%) remained on TKI at the time of repeat biopsy. Repeat biopsy showed T790m mutations in 49%, PIK3CA in 5%, MET amplification in 5%, and an unknown mechanism in 30%, reported Dr. Sequist.
Dr. Sequist and Dr. Socinski disclosed no relevant conflicts.
CHICAGO - A small study provides compelling data that both the genotype and phenotype of non-small cell lung cancers can transform with acquired resistance to tyrosine kinase inhibitors.
Repeat tumor biopsies revealed that the histologic diagnosis of the tumor shifted from adenocarcinoma to small cell lung cancer (SCLC) in 14% of 37 consecutive patients with epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) and acquired tyrosine kinase inhibitor (TKI) resistance, Dr. Lecia Sequist said at the Multidisciplinary Syposium on Thoracic Oncology.
The L858R mutation or E 19 deletion was retained in all cases. In one patient, an additional PIK3CA mutation was seen only when the tumor shifted to SCLC.
Although other groups have documented sporadictransformation, Dr. Sequist called the 14% transformation rate remarkable. “I think this points to a broader conceptual model of acquired resistance, and we need to think very carefully about doing more repeat biopsies in patients,” she said.
EGFR-mutant NSCLC is highly sensitive to EGFR TKI therapy, but acquired resistance develops at about 9-12 months due to T790M mutations in half of patients and MET amplification in 10% to 15%, said Dr. Sequist of Massachusetts General Hospital Cancer Center, Boston.
Although re-biopsy is not common practice, invited discussant Dr. Mark Socinski said it should be on the clinician's radar because it can alter the therapeutic course of refractory disease and arguably the clinical benefit.
“I think the message here is to consider re-biopsy more often in selected patients until we have a better understanding of this one disease we call non-small lung cancer that we realize is an incredibly heterogenous disease,” said Dr. Socinski, director of the thoracic oncology program at the Lineberger Comprehensive Cancer Center at the University of North Carolina-Chapel Hill.
Among the five patients whose cancer transformed, two maintained a slow, indolent course after SCLC transformation, while three had a change around the time of their biopsy to an explosive growth pattern more clinically reminiscent of SCLC, Dr. Sequist said. Four patients were treated with SCLC-like chemotherapy regimens, and three responded with marked partial responses.
Longitudinal data from fluorescent in situ hybridization analysis for MET and EGFR gene copy number suggest that the resistant tumor is distinct from the original tumor and that MET amplification lies in a distinct subpopulation of the cell and is selected out under pressure from TKI therapy, she said.
Multiple biopsies over time also identified a waxing and waning of genotypic and phenotypic findings in response to TKI therapy. This pattern was most pronounced in a case that transformed from EGFR TKI-sensitive adenocarcinoma to resistant SCLC while on erlotinib (Tarceva) for more than 1 year, switched back to TKI-sensitive adenocarcinoma following treatment with chemotherapy and radiation and a 9- to 10-month break from erlotinib, and then after a very successful, but short-lived re-response to erlotinib, shifted back to SCLC a second time upon clinical resistance.
“It's showing us that if you do repeat biopsies, it can direct patients towards clinical trials that they have a higher likelihood of benefiting from,” she said.
The population comprised 15 men and 22 women, median age 60 years. All had responded to either gefitinib (Iressa) or erlotinib, with a median of 18.4 months of initial EGFR TKI therapy. The majority (81%) remained on TKI at the time of repeat biopsy. Repeat biopsy showed T790m mutations in 49%, PIK3CA in 5%, MET amplification in 5%, and an unknown mechanism in 30%, reported Dr. Sequist.
Dr. Sequist and Dr. Socinski disclosed no relevant conflicts.
CHICAGO - A small study provides compelling data that both the genotype and phenotype of non-small cell lung cancers can transform with acquired resistance to tyrosine kinase inhibitors.
Repeat tumor biopsies revealed that the histologic diagnosis of the tumor shifted from adenocarcinoma to small cell lung cancer (SCLC) in 14% of 37 consecutive patients with epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) and acquired tyrosine kinase inhibitor (TKI) resistance, Dr. Lecia Sequist said at the Multidisciplinary Syposium on Thoracic Oncology.
The L858R mutation or E 19 deletion was retained in all cases. In one patient, an additional PIK3CA mutation was seen only when the tumor shifted to SCLC.
Although other groups have documented sporadictransformation, Dr. Sequist called the 14% transformation rate remarkable. “I think this points to a broader conceptual model of acquired resistance, and we need to think very carefully about doing more repeat biopsies in patients,” she said.
EGFR-mutant NSCLC is highly sensitive to EGFR TKI therapy, but acquired resistance develops at about 9-12 months due to T790M mutations in half of patients and MET amplification in 10% to 15%, said Dr. Sequist of Massachusetts General Hospital Cancer Center, Boston.
Although re-biopsy is not common practice, invited discussant Dr. Mark Socinski said it should be on the clinician's radar because it can alter the therapeutic course of refractory disease and arguably the clinical benefit.
“I think the message here is to consider re-biopsy more often in selected patients until we have a better understanding of this one disease we call non-small lung cancer that we realize is an incredibly heterogenous disease,” said Dr. Socinski, director of the thoracic oncology program at the Lineberger Comprehensive Cancer Center at the University of North Carolina-Chapel Hill.
Among the five patients whose cancer transformed, two maintained a slow, indolent course after SCLC transformation, while three had a change around the time of their biopsy to an explosive growth pattern more clinically reminiscent of SCLC, Dr. Sequist said. Four patients were treated with SCLC-like chemotherapy regimens, and three responded with marked partial responses.
Longitudinal data from fluorescent in situ hybridization analysis for MET and EGFR gene copy number suggest that the resistant tumor is distinct from the original tumor and that MET amplification lies in a distinct subpopulation of the cell and is selected out under pressure from TKI therapy, she said.
Multiple biopsies over time also identified a waxing and waning of genotypic and phenotypic findings in response to TKI therapy. This pattern was most pronounced in a case that transformed from EGFR TKI-sensitive adenocarcinoma to resistant SCLC while on erlotinib (Tarceva) for more than 1 year, switched back to TKI-sensitive adenocarcinoma following treatment with chemotherapy and radiation and a 9- to 10-month break from erlotinib, and then after a very successful, but short-lived re-response to erlotinib, shifted back to SCLC a second time upon clinical resistance.
“It's showing us that if you do repeat biopsies, it can direct patients towards clinical trials that they have a higher likelihood of benefiting from,” she said.
The population comprised 15 men and 22 women, median age 60 years. All had responded to either gefitinib (Iressa) or erlotinib, with a median of 18.4 months of initial EGFR TKI therapy. The majority (81%) remained on TKI at the time of repeat biopsy. Repeat biopsy showed T790m mutations in 49%, PIK3CA in 5%, MET amplification in 5%, and an unknown mechanism in 30%, reported Dr. Sequist.
Dr. Sequist and Dr. Socinski disclosed no relevant conflicts.
Nonsurgical Approaches to Perforation Are Rising
CHICAGO - Nonsurgical approaches are beginning to dominate the management of acute esophageal perforations.
An analysis of 81 consecutive acute esophageal perforation cases between June 1989 and March 2009 revealed that nonsurgical management jumped from 0% during the first 4 years of the study to 75% in the last 4 years.
The average length of stay declined significantly over the same period, from 26 days to 20 days , while complications trended downward, from 50% to 33%, Dr. Michal Hubka reported on behalf of lead author Dr. Madhan Kumar Kuppusamy and their colleagues at Virginia Mason Medical Center in Seattle.
In all, 33 patients were managed nonoperatively and 48 surgically. Primary repair was the most common surgical approach (34 cases). Nonsurgical treatments included endoscopic stenting (11 cases), drainage procedures including mediastinal drainage (13 cases), total parenteral nutrition (7 cases), Dobhoff feeding tube (5 cases), gastrostomy (5 cases), endoscopic repair with clips or glue (3 cases), and feeding jejunostomy (3 cases).
"Nonoperative treatment options are increasing and surgeons must be able to apply these techniques to improve outcomes,” Dr. Hubka said at the annual meeting of the Western Surgical Society.
Hybrid-type management was performed in 21% of patients and most often took the form of endoscopic stents or drainage at the time of open or thoracoscopic drainage or decortication.
The nonoperative group was less likely than the operative group to experience pneumonia (4 patients vs. 7 patients) and dysrhythmias (4 patients vs. 11 patients), but more likely to experience persistent leak at the 14th day (3 vs. 2), stent migration (3 vs. 0), sepsis (1 vs. 0), and renal failure (1 vs. 0), Dr. Hubka said. Deep vein thrombosis occurred in one patient in each group.
Two patients managed medically died vs. one treated surgically (6% vs. 2%), for an overall mortality rate of 3.7%. A historical comparison of nine other studies involving nonoperative management of esophageal perforations presented by Dr. Hubka showed mortality rates reaching a high of 24% between 1973 and 1993 and a low of 3.8% between 1990 and 2001.
One of those nine studies identified a stepwise increase in mortality as time from perforation to diagnosis increased, with 5% of 75 patients dying with an immediate diagnosis vs. 14% with a diagnosis within 24 hours and 44% if the diagnosis occurred after 24 hours (Eur. J. Cardiothorac. Surg. 2003;23:799-804).
In all, 57 patients in the current analysis were treated within 24 hours and 24 were treated after 24 hours. Length of stay was significantly shorter in the early-treatment group at 15.6 days vs. 29.4 days in the late-treatment group. In the early-treatment group, complications occurred in 20 and death in 1; in the late-treatment group, 11 had complications and 2 died, Dr. Hubka said.
"Time to diagnosis continues to be important; however, management in an experienced center facile with all current management techniques is the major issue affecting outcomes,” he said.
The percentage of cases referred to the tertiary referral center was 50% from 1989 to 1992 and 79% from 2005 to 2009. Referred patients were significantly more likely to be treated more than 24 hours after perforation.
The improvement in outcomes is likely related to increasing diversity of treatment techniques and management in specialty centers, Dr. Hubka said.
Invited discussant Dr. Jeffrey Peters from the University of Rochester (N.Y.) Medical Center, said, "What you heard was an increasing chorus of a paradigm change, if you will, that's sort of paradoxical to most of us - that someone with a hole in their esophagus does better if you don't operate on them. I still struggle trying not to do that when patients present in the emergency room with these issues.”
Still, he described the improvement in outcomes as true progress for patients. Dr. Peters noted that the etiology of acute perforations has changed over time, with most now iatrogenic, and thus the benefit of early treatment may not be as critical as in years past. He said referral to a tertiary center is important, but that the paper did not prove a causal effect.
Based on the findings, Dr. Peters asked when surgeons should operate, how the size of the injury and presence of underlying disease should be taken into account in treatment decisions, and when surgery should be considered if nonoperative therapy fails.
Dr. Hubka said patients with larger esophageal tears or injuries and moderate mediastinal pleural contamination who can tolerate surgery are the ones who proceed to the operating room. He suggested that the study's operative rate would likely have been higher if patients with perforations due to neoplasia or cancer had been included and that the presence of such underlying disease would surely push them toward operative management in clinical practice. Finally, if a patient becomes unstable or their level of contamination increases despite nonsurgical management, they would proceed to surgery and decontamination.
"A point of our study is that this management, whether it's endoscopic or operative, should be performed by surgeons because we have all the tools to manage all patients appropriately,” Dr. Hubka said.
The study authors and discussant said that they had no financial disclosures.
CHICAGO - Nonsurgical approaches are beginning to dominate the management of acute esophageal perforations.
An analysis of 81 consecutive acute esophageal perforation cases between June 1989 and March 2009 revealed that nonsurgical management jumped from 0% during the first 4 years of the study to 75% in the last 4 years.
The average length of stay declined significantly over the same period, from 26 days to 20 days , while complications trended downward, from 50% to 33%, Dr. Michal Hubka reported on behalf of lead author Dr. Madhan Kumar Kuppusamy and their colleagues at Virginia Mason Medical Center in Seattle.
In all, 33 patients were managed nonoperatively and 48 surgically. Primary repair was the most common surgical approach (34 cases). Nonsurgical treatments included endoscopic stenting (11 cases), drainage procedures including mediastinal drainage (13 cases), total parenteral nutrition (7 cases), Dobhoff feeding tube (5 cases), gastrostomy (5 cases), endoscopic repair with clips or glue (3 cases), and feeding jejunostomy (3 cases).
"Nonoperative treatment options are increasing and surgeons must be able to apply these techniques to improve outcomes,” Dr. Hubka said at the annual meeting of the Western Surgical Society.
Hybrid-type management was performed in 21% of patients and most often took the form of endoscopic stents or drainage at the time of open or thoracoscopic drainage or decortication.
The nonoperative group was less likely than the operative group to experience pneumonia (4 patients vs. 7 patients) and dysrhythmias (4 patients vs. 11 patients), but more likely to experience persistent leak at the 14th day (3 vs. 2), stent migration (3 vs. 0), sepsis (1 vs. 0), and renal failure (1 vs. 0), Dr. Hubka said. Deep vein thrombosis occurred in one patient in each group.
Two patients managed medically died vs. one treated surgically (6% vs. 2%), for an overall mortality rate of 3.7%. A historical comparison of nine other studies involving nonoperative management of esophageal perforations presented by Dr. Hubka showed mortality rates reaching a high of 24% between 1973 and 1993 and a low of 3.8% between 1990 and 2001.
One of those nine studies identified a stepwise increase in mortality as time from perforation to diagnosis increased, with 5% of 75 patients dying with an immediate diagnosis vs. 14% with a diagnosis within 24 hours and 44% if the diagnosis occurred after 24 hours (Eur. J. Cardiothorac. Surg. 2003;23:799-804).
In all, 57 patients in the current analysis were treated within 24 hours and 24 were treated after 24 hours. Length of stay was significantly shorter in the early-treatment group at 15.6 days vs. 29.4 days in the late-treatment group. In the early-treatment group, complications occurred in 20 and death in 1; in the late-treatment group, 11 had complications and 2 died, Dr. Hubka said.
"Time to diagnosis continues to be important; however, management in an experienced center facile with all current management techniques is the major issue affecting outcomes,” he said.
The percentage of cases referred to the tertiary referral center was 50% from 1989 to 1992 and 79% from 2005 to 2009. Referred patients were significantly more likely to be treated more than 24 hours after perforation.
The improvement in outcomes is likely related to increasing diversity of treatment techniques and management in specialty centers, Dr. Hubka said.
Invited discussant Dr. Jeffrey Peters from the University of Rochester (N.Y.) Medical Center, said, "What you heard was an increasing chorus of a paradigm change, if you will, that's sort of paradoxical to most of us - that someone with a hole in their esophagus does better if you don't operate on them. I still struggle trying not to do that when patients present in the emergency room with these issues.”
Still, he described the improvement in outcomes as true progress for patients. Dr. Peters noted that the etiology of acute perforations has changed over time, with most now iatrogenic, and thus the benefit of early treatment may not be as critical as in years past. He said referral to a tertiary center is important, but that the paper did not prove a causal effect.
Based on the findings, Dr. Peters asked when surgeons should operate, how the size of the injury and presence of underlying disease should be taken into account in treatment decisions, and when surgery should be considered if nonoperative therapy fails.
Dr. Hubka said patients with larger esophageal tears or injuries and moderate mediastinal pleural contamination who can tolerate surgery are the ones who proceed to the operating room. He suggested that the study's operative rate would likely have been higher if patients with perforations due to neoplasia or cancer had been included and that the presence of such underlying disease would surely push them toward operative management in clinical practice. Finally, if a patient becomes unstable or their level of contamination increases despite nonsurgical management, they would proceed to surgery and decontamination.
"A point of our study is that this management, whether it's endoscopic or operative, should be performed by surgeons because we have all the tools to manage all patients appropriately,” Dr. Hubka said.
The study authors and discussant said that they had no financial disclosures.
CHICAGO - Nonsurgical approaches are beginning to dominate the management of acute esophageal perforations.
An analysis of 81 consecutive acute esophageal perforation cases between June 1989 and March 2009 revealed that nonsurgical management jumped from 0% during the first 4 years of the study to 75% in the last 4 years.
The average length of stay declined significantly over the same period, from 26 days to 20 days , while complications trended downward, from 50% to 33%, Dr. Michal Hubka reported on behalf of lead author Dr. Madhan Kumar Kuppusamy and their colleagues at Virginia Mason Medical Center in Seattle.
In all, 33 patients were managed nonoperatively and 48 surgically. Primary repair was the most common surgical approach (34 cases). Nonsurgical treatments included endoscopic stenting (11 cases), drainage procedures including mediastinal drainage (13 cases), total parenteral nutrition (7 cases), Dobhoff feeding tube (5 cases), gastrostomy (5 cases), endoscopic repair with clips or glue (3 cases), and feeding jejunostomy (3 cases).
"Nonoperative treatment options are increasing and surgeons must be able to apply these techniques to improve outcomes,” Dr. Hubka said at the annual meeting of the Western Surgical Society.
Hybrid-type management was performed in 21% of patients and most often took the form of endoscopic stents or drainage at the time of open or thoracoscopic drainage or decortication.
The nonoperative group was less likely than the operative group to experience pneumonia (4 patients vs. 7 patients) and dysrhythmias (4 patients vs. 11 patients), but more likely to experience persistent leak at the 14th day (3 vs. 2), stent migration (3 vs. 0), sepsis (1 vs. 0), and renal failure (1 vs. 0), Dr. Hubka said. Deep vein thrombosis occurred in one patient in each group.
Two patients managed medically died vs. one treated surgically (6% vs. 2%), for an overall mortality rate of 3.7%. A historical comparison of nine other studies involving nonoperative management of esophageal perforations presented by Dr. Hubka showed mortality rates reaching a high of 24% between 1973 and 1993 and a low of 3.8% between 1990 and 2001.
One of those nine studies identified a stepwise increase in mortality as time from perforation to diagnosis increased, with 5% of 75 patients dying with an immediate diagnosis vs. 14% with a diagnosis within 24 hours and 44% if the diagnosis occurred after 24 hours (Eur. J. Cardiothorac. Surg. 2003;23:799-804).
In all, 57 patients in the current analysis were treated within 24 hours and 24 were treated after 24 hours. Length of stay was significantly shorter in the early-treatment group at 15.6 days vs. 29.4 days in the late-treatment group. In the early-treatment group, complications occurred in 20 and death in 1; in the late-treatment group, 11 had complications and 2 died, Dr. Hubka said.
"Time to diagnosis continues to be important; however, management in an experienced center facile with all current management techniques is the major issue affecting outcomes,” he said.
The percentage of cases referred to the tertiary referral center was 50% from 1989 to 1992 and 79% from 2005 to 2009. Referred patients were significantly more likely to be treated more than 24 hours after perforation.
The improvement in outcomes is likely related to increasing diversity of treatment techniques and management in specialty centers, Dr. Hubka said.
Invited discussant Dr. Jeffrey Peters from the University of Rochester (N.Y.) Medical Center, said, "What you heard was an increasing chorus of a paradigm change, if you will, that's sort of paradoxical to most of us - that someone with a hole in their esophagus does better if you don't operate on them. I still struggle trying not to do that when patients present in the emergency room with these issues.”
Still, he described the improvement in outcomes as true progress for patients. Dr. Peters noted that the etiology of acute perforations has changed over time, with most now iatrogenic, and thus the benefit of early treatment may not be as critical as in years past. He said referral to a tertiary center is important, but that the paper did not prove a causal effect.
Based on the findings, Dr. Peters asked when surgeons should operate, how the size of the injury and presence of underlying disease should be taken into account in treatment decisions, and when surgery should be considered if nonoperative therapy fails.
Dr. Hubka said patients with larger esophageal tears or injuries and moderate mediastinal pleural contamination who can tolerate surgery are the ones who proceed to the operating room. He suggested that the study's operative rate would likely have been higher if patients with perforations due to neoplasia or cancer had been included and that the presence of such underlying disease would surely push them toward operative management in clinical practice. Finally, if a patient becomes unstable or their level of contamination increases despite nonsurgical management, they would proceed to surgery and decontamination.
"A point of our study is that this management, whether it's endoscopic or operative, should be performed by surgeons because we have all the tools to manage all patients appropriately,” Dr. Hubka said.
The study authors and discussant said that they had no financial disclosures.
Endosonography Plus Surgical Staging for NSCLC?
For patients with suspected non-small cell lung cancer, adding endosonography before surgical staging improves detection of mediastinal nodal metastases, thus reducing unnecessary thoracotomies by more than half, a study has shown.
In addition, because endosonography is minimally invasive, adding this step doesn't raise the rate of complications for staging procedures, said Dr. Jouke T. Annema of Leiden (the Netherlands) University Medical Center and associates.
The researchers compared surgical staging alone to endosonography followed by surgical staging because "at present it is not known whether initial mediastinal tissue staging of lung cancer by endosonography improves the detection of nodal metastases." Failure to detect such metastases during staging results in patients undergoing thoracotomy for tumor resection, only to have the thoracotomy aborted when unresectable or metastatic lung disease is discovered (JAMA 2010;304:2245-52).
The investigators randomized 241 patients suspected of having resectable NSCLC, who were treated at four tertiary referral centers in Belgium, the Netherlands, and the United Kingdom. Patients were assigned to surgical staging alone, which is the current standard of care (118 subjects), or to endosonography followed by surgical staging (123 subjects).
The sensitivity of surgical staging alone was 79%. This improved to 94% when endosonography was combined with surgical staging, Dr. Annema and colleagues said.
Mediastinal nodal metastases were found in 41 of 118 patients (35%) by surgical staging alone, compared with 62 of 123 patients (50%) by the combined approach. This means that there were 21 unnecessary thoracotomies with surgical staging alone, for a rate of 18%, compared with 9 with the combined approach, for a rate of 7%.
The complication rate was 6% for surgical staging, compared with 1% for endosonography.
These findings show that endosonography improves the sensitivity of surgical staging, halves the rate of unnecessary thoracotomy, and has a low complication rate. Because it also does not require general anesthesia and has been shown in previous studies to be cost effective as well as preferred by patients, "endosonography should be the first step for mediastinal nodal staging," the investigators said.
They added that all of the staging procedures in this study were performed in specialty centers by highly trained and experienced interventionists, so the applicability of the study findings to other settings is limited.
This study was supported in part by Hitachi Medical Systems, COOK, Olympus, the Zorgprogramma Oncologie Gent, the U.K. National Health Service R & D Health Technology Assessment Program, and the National Institute for Health Research Cambridge Biomedical Research Centre.
The main question raised by this study is not whether endosonography improves the sensitivity of surgical staging but whether the combined approach can be translated into a larger patient population and yield equivalent outcomes there, according to Dr. Mark D. Iannettoni. The level of expertise in endoscopic techniques was likely much higher at the referral centers in this study than it is at community hospitals where most thoracic surgery takes place. "This fact is extremely important because these modalities are highly operator dependent," he noted. "Until this modality can be reproduced at all centers where thoracic surgery is commonly performed, or until all of these patients are cared for at specialized centers, surgical staging must remain the gold standard for adequate preoperative evaluation," he said.
Mark D. Iannettoni, M.D., is in cardiothoracic surgery at the University of Iowa Heart and Vascular Center, Iowa City. He reported that he had no financial disclosures. These comments were taken from his editorial accompanying Dr. Annema's report (JAMA 2010;304:2296-7).
The main question raised by this study is not whether endosonography improves the sensitivity of surgical staging but whether the combined approach can be translated into a larger patient population and yield equivalent outcomes there, according to Dr. Mark D. Iannettoni. The level of expertise in endoscopic techniques was likely much higher at the referral centers in this study than it is at community hospitals where most thoracic surgery takes place. "This fact is extremely important because these modalities are highly operator dependent," he noted. "Until this modality can be reproduced at all centers where thoracic surgery is commonly performed, or until all of these patients are cared for at specialized centers, surgical staging must remain the gold standard for adequate preoperative evaluation," he said.
Mark D. Iannettoni, M.D., is in cardiothoracic surgery at the University of Iowa Heart and Vascular Center, Iowa City. He reported that he had no financial disclosures. These comments were taken from his editorial accompanying Dr. Annema's report (JAMA 2010;304:2296-7).
The main question raised by this study is not whether endosonography improves the sensitivity of surgical staging but whether the combined approach can be translated into a larger patient population and yield equivalent outcomes there, according to Dr. Mark D. Iannettoni. The level of expertise in endoscopic techniques was likely much higher at the referral centers in this study than it is at community hospitals where most thoracic surgery takes place. "This fact is extremely important because these modalities are highly operator dependent," he noted. "Until this modality can be reproduced at all centers where thoracic surgery is commonly performed, or until all of these patients are cared for at specialized centers, surgical staging must remain the gold standard for adequate preoperative evaluation," he said.
Mark D. Iannettoni, M.D., is in cardiothoracic surgery at the University of Iowa Heart and Vascular Center, Iowa City. He reported that he had no financial disclosures. These comments were taken from his editorial accompanying Dr. Annema's report (JAMA 2010;304:2296-7).
For patients with suspected non-small cell lung cancer, adding endosonography before surgical staging improves detection of mediastinal nodal metastases, thus reducing unnecessary thoracotomies by more than half, a study has shown.
In addition, because endosonography is minimally invasive, adding this step doesn't raise the rate of complications for staging procedures, said Dr. Jouke T. Annema of Leiden (the Netherlands) University Medical Center and associates.
The researchers compared surgical staging alone to endosonography followed by surgical staging because "at present it is not known whether initial mediastinal tissue staging of lung cancer by endosonography improves the detection of nodal metastases." Failure to detect such metastases during staging results in patients undergoing thoracotomy for tumor resection, only to have the thoracotomy aborted when unresectable or metastatic lung disease is discovered (JAMA 2010;304:2245-52).
The investigators randomized 241 patients suspected of having resectable NSCLC, who were treated at four tertiary referral centers in Belgium, the Netherlands, and the United Kingdom. Patients were assigned to surgical staging alone, which is the current standard of care (118 subjects), or to endosonography followed by surgical staging (123 subjects).
The sensitivity of surgical staging alone was 79%. This improved to 94% when endosonography was combined with surgical staging, Dr. Annema and colleagues said.
Mediastinal nodal metastases were found in 41 of 118 patients (35%) by surgical staging alone, compared with 62 of 123 patients (50%) by the combined approach. This means that there were 21 unnecessary thoracotomies with surgical staging alone, for a rate of 18%, compared with 9 with the combined approach, for a rate of 7%.
The complication rate was 6% for surgical staging, compared with 1% for endosonography.
These findings show that endosonography improves the sensitivity of surgical staging, halves the rate of unnecessary thoracotomy, and has a low complication rate. Because it also does not require general anesthesia and has been shown in previous studies to be cost effective as well as preferred by patients, "endosonography should be the first step for mediastinal nodal staging," the investigators said.
They added that all of the staging procedures in this study were performed in specialty centers by highly trained and experienced interventionists, so the applicability of the study findings to other settings is limited.
This study was supported in part by Hitachi Medical Systems, COOK, Olympus, the Zorgprogramma Oncologie Gent, the U.K. National Health Service R & D Health Technology Assessment Program, and the National Institute for Health Research Cambridge Biomedical Research Centre.
For patients with suspected non-small cell lung cancer, adding endosonography before surgical staging improves detection of mediastinal nodal metastases, thus reducing unnecessary thoracotomies by more than half, a study has shown.
In addition, because endosonography is minimally invasive, adding this step doesn't raise the rate of complications for staging procedures, said Dr. Jouke T. Annema of Leiden (the Netherlands) University Medical Center and associates.
The researchers compared surgical staging alone to endosonography followed by surgical staging because "at present it is not known whether initial mediastinal tissue staging of lung cancer by endosonography improves the detection of nodal metastases." Failure to detect such metastases during staging results in patients undergoing thoracotomy for tumor resection, only to have the thoracotomy aborted when unresectable or metastatic lung disease is discovered (JAMA 2010;304:2245-52).
The investigators randomized 241 patients suspected of having resectable NSCLC, who were treated at four tertiary referral centers in Belgium, the Netherlands, and the United Kingdom. Patients were assigned to surgical staging alone, which is the current standard of care (118 subjects), or to endosonography followed by surgical staging (123 subjects).
The sensitivity of surgical staging alone was 79%. This improved to 94% when endosonography was combined with surgical staging, Dr. Annema and colleagues said.
Mediastinal nodal metastases were found in 41 of 118 patients (35%) by surgical staging alone, compared with 62 of 123 patients (50%) by the combined approach. This means that there were 21 unnecessary thoracotomies with surgical staging alone, for a rate of 18%, compared with 9 with the combined approach, for a rate of 7%.
The complication rate was 6% for surgical staging, compared with 1% for endosonography.
These findings show that endosonography improves the sensitivity of surgical staging, halves the rate of unnecessary thoracotomy, and has a low complication rate. Because it also does not require general anesthesia and has been shown in previous studies to be cost effective as well as preferred by patients, "endosonography should be the first step for mediastinal nodal staging," the investigators said.
They added that all of the staging procedures in this study were performed in specialty centers by highly trained and experienced interventionists, so the applicability of the study findings to other settings is limited.
This study was supported in part by Hitachi Medical Systems, COOK, Olympus, the Zorgprogramma Oncologie Gent, the U.K. National Health Service R & D Health Technology Assessment Program, and the National Institute for Health Research Cambridge Biomedical Research Centre.
Drug Resistance Triggers Lung Cancer Transformation
CHICAGO - A small study provides compelling data that both the genotype and phenotype of non-small cell lung cancers can transform with acquired resistance to tyrosine kinase inhibitors.
Repeat tumor biopsies revealed that the histologic diagnosis of the tumor shifted from adenocarcinoma to small cell lung cancer (SCLC) in 14% of 37 consecutive patients with epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) and acquired tyrosine kinase inhibitor (TKI) resistance, Dr. Lecia Sequist said at the Multidisciplinary Syposium on Thoracic Oncology.
The L858R mutation or E 19 deletion was retained in all cases. In one patient, an additional PIK3CA mutation was seen only when the tumor shifted to SCLC.
Although other groups have documented sporadictransformation, Dr. Sequist called the 14% transformation rate remarkable. “I think this points to a broader conceptual model of acquired resistance, and we need to think very carefully about doing more repeat biopsies in patients,” she said.
EGFR-mutant NSCLC is highly sensitive to EGFR TKI therapy, but acquired resistance develops at about 9-12 months due to T790M mutations in half of patients and MET amplification in 10% to 15%, said Dr. Sequist of Massachusetts General Hospital Cancer Center, Boston.
Although re-biopsy is not common practice, invited discussant Dr. Mark Socinski said it should be on the clinician's radar because it can alter the therapeutic course of refractory disease and arguably the clinical benefit.
“I think the message here is to consider re-biopsy more often in selected patients until we have a better understanding of this one disease we call non-small lung cancer that we realize is an incredibly heterogenous disease,” said Dr. Socinski, director of the thoracic oncology program at the Lineberger Comprehensive Cancer Center at the University of North Carolina-Chapel Hill.
Among the five patients whose cancer transformed, two maintained a slow, indolent course after SCLC transformation, while three had a change around the time of their biopsy to an explosive growth pattern more clinically reminiscent of SCLC, Dr. Sequist said. Four patients were treated with SCLC-like chemotherapy regimens, and three responded with marked partial responses.
Longitudinal data from fluorescent in situ hybridization analysis for MET and EGFR gene copy number suggest that the resistant tumor is distinct from the original tumor and that MET amplification lies in a distinct subpopulation of the cell and is selected out under pressure from TKI therapy, she said.
Multiple biopsies over time also identified a waxing and waning of genotypic and phenotypic findings in response to TKI therapy. This pattern was most pronounced in a case that transformed from EGFR TKI-sensitive adenocarcinoma to resistant SCLC while on erlotinib (Tarceva) for more than 1 year, switched back to TKI-sensitive adenocarcinoma following treatment with chemotherapy and radiation and a 9- to 10-month break from erlotinib, and then after a very successful, but short-lived re-response to erlotinib, shifted back to SCLC a second time upon clinical resistance.
“It's showing us that if you do repeat biopsies, it can direct patients towards clinical trials that they have a higher likelihood of benefiting from,” she said.
The population comprised 15 men and 22 women, median age 60 years. All had responded to either gefitinib (Iressa) or erlotinib, with a median of 18.4 months of initial EGFR TKI therapy. The majority (81%) remained on TKI at the time of repeat biopsy. Repeat biopsy showed T790m mutations in 49%, PIK3CA in 5%, MET amplification in 5%, and an unknown mechanism in 30%, reported Dr. Sequist.
Dr. Sequist and Dr. Socinski disclosed no relevant conflicts.
CHICAGO - A small study provides compelling data that both the genotype and phenotype of non-small cell lung cancers can transform with acquired resistance to tyrosine kinase inhibitors.
Repeat tumor biopsies revealed that the histologic diagnosis of the tumor shifted from adenocarcinoma to small cell lung cancer (SCLC) in 14% of 37 consecutive patients with epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) and acquired tyrosine kinase inhibitor (TKI) resistance, Dr. Lecia Sequist said at the Multidisciplinary Syposium on Thoracic Oncology.
The L858R mutation or E 19 deletion was retained in all cases. In one patient, an additional PIK3CA mutation was seen only when the tumor shifted to SCLC.
Although other groups have documented sporadictransformation, Dr. Sequist called the 14% transformation rate remarkable. “I think this points to a broader conceptual model of acquired resistance, and we need to think very carefully about doing more repeat biopsies in patients,” she said.
EGFR-mutant NSCLC is highly sensitive to EGFR TKI therapy, but acquired resistance develops at about 9-12 months due to T790M mutations in half of patients and MET amplification in 10% to 15%, said Dr. Sequist of Massachusetts General Hospital Cancer Center, Boston.
Although re-biopsy is not common practice, invited discussant Dr. Mark Socinski said it should be on the clinician's radar because it can alter the therapeutic course of refractory disease and arguably the clinical benefit.
“I think the message here is to consider re-biopsy more often in selected patients until we have a better understanding of this one disease we call non-small lung cancer that we realize is an incredibly heterogenous disease,” said Dr. Socinski, director of the thoracic oncology program at the Lineberger Comprehensive Cancer Center at the University of North Carolina-Chapel Hill.
Among the five patients whose cancer transformed, two maintained a slow, indolent course after SCLC transformation, while three had a change around the time of their biopsy to an explosive growth pattern more clinically reminiscent of SCLC, Dr. Sequist said. Four patients were treated with SCLC-like chemotherapy regimens, and three responded with marked partial responses.
Longitudinal data from fluorescent in situ hybridization analysis for MET and EGFR gene copy number suggest that the resistant tumor is distinct from the original tumor and that MET amplification lies in a distinct subpopulation of the cell and is selected out under pressure from TKI therapy, she said.
Multiple biopsies over time also identified a waxing and waning of genotypic and phenotypic findings in response to TKI therapy. This pattern was most pronounced in a case that transformed from EGFR TKI-sensitive adenocarcinoma to resistant SCLC while on erlotinib (Tarceva) for more than 1 year, switched back to TKI-sensitive adenocarcinoma following treatment with chemotherapy and radiation and a 9- to 10-month break from erlotinib, and then after a very successful, but short-lived re-response to erlotinib, shifted back to SCLC a second time upon clinical resistance.
“It's showing us that if you do repeat biopsies, it can direct patients towards clinical trials that they have a higher likelihood of benefiting from,” she said.
The population comprised 15 men and 22 women, median age 60 years. All had responded to either gefitinib (Iressa) or erlotinib, with a median of 18.4 months of initial EGFR TKI therapy. The majority (81%) remained on TKI at the time of repeat biopsy. Repeat biopsy showed T790m mutations in 49%, PIK3CA in 5%, MET amplification in 5%, and an unknown mechanism in 30%, reported Dr. Sequist.
Dr. Sequist and Dr. Socinski disclosed no relevant conflicts.
CHICAGO - A small study provides compelling data that both the genotype and phenotype of non-small cell lung cancers can transform with acquired resistance to tyrosine kinase inhibitors.
Repeat tumor biopsies revealed that the histologic diagnosis of the tumor shifted from adenocarcinoma to small cell lung cancer (SCLC) in 14% of 37 consecutive patients with epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) and acquired tyrosine kinase inhibitor (TKI) resistance, Dr. Lecia Sequist said at the Multidisciplinary Syposium on Thoracic Oncology.
The L858R mutation or E 19 deletion was retained in all cases. In one patient, an additional PIK3CA mutation was seen only when the tumor shifted to SCLC.
Although other groups have documented sporadictransformation, Dr. Sequist called the 14% transformation rate remarkable. “I think this points to a broader conceptual model of acquired resistance, and we need to think very carefully about doing more repeat biopsies in patients,” she said.
EGFR-mutant NSCLC is highly sensitive to EGFR TKI therapy, but acquired resistance develops at about 9-12 months due to T790M mutations in half of patients and MET amplification in 10% to 15%, said Dr. Sequist of Massachusetts General Hospital Cancer Center, Boston.
Although re-biopsy is not common practice, invited discussant Dr. Mark Socinski said it should be on the clinician's radar because it can alter the therapeutic course of refractory disease and arguably the clinical benefit.
“I think the message here is to consider re-biopsy more often in selected patients until we have a better understanding of this one disease we call non-small lung cancer that we realize is an incredibly heterogenous disease,” said Dr. Socinski, director of the thoracic oncology program at the Lineberger Comprehensive Cancer Center at the University of North Carolina-Chapel Hill.
Among the five patients whose cancer transformed, two maintained a slow, indolent course after SCLC transformation, while three had a change around the time of their biopsy to an explosive growth pattern more clinically reminiscent of SCLC, Dr. Sequist said. Four patients were treated with SCLC-like chemotherapy regimens, and three responded with marked partial responses.
Longitudinal data from fluorescent in situ hybridization analysis for MET and EGFR gene copy number suggest that the resistant tumor is distinct from the original tumor and that MET amplification lies in a distinct subpopulation of the cell and is selected out under pressure from TKI therapy, she said.
Multiple biopsies over time also identified a waxing and waning of genotypic and phenotypic findings in response to TKI therapy. This pattern was most pronounced in a case that transformed from EGFR TKI-sensitive adenocarcinoma to resistant SCLC while on erlotinib (Tarceva) for more than 1 year, switched back to TKI-sensitive adenocarcinoma following treatment with chemotherapy and radiation and a 9- to 10-month break from erlotinib, and then after a very successful, but short-lived re-response to erlotinib, shifted back to SCLC a second time upon clinical resistance.
“It's showing us that if you do repeat biopsies, it can direct patients towards clinical trials that they have a higher likelihood of benefiting from,” she said.
The population comprised 15 men and 22 women, median age 60 years. All had responded to either gefitinib (Iressa) or erlotinib, with a median of 18.4 months of initial EGFR TKI therapy. The majority (81%) remained on TKI at the time of repeat biopsy. Repeat biopsy showed T790m mutations in 49%, PIK3CA in 5%, MET amplification in 5%, and an unknown mechanism in 30%, reported Dr. Sequist.
Dr. Sequist and Dr. Socinski disclosed no relevant conflicts.