Protein and microRNA expression patterns correlated with improved survival on regorafenib among patients with sorafenib-pretreated hepatocellular carcinoma, researchers reported.

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“In the absence of established or predefined biomarkers for regorafenib, we performed a broad exploratory biomarker analyses at the DNA, RNA, and protein level that represents a much more comprehensive approach than previous studies of regorafenib or sorafenib,” wrote Michael Teufel, PhD, of Bayer Healthcare Pharmaceuticals in Whippany, N.J., and his associates. The preplanned, retrospective analysis of data from the phase 3 RESOURCE trial was reported in Gastroenterology.

The randomized trial included 567 patients whose hepatocellular carcinoma had progressed on sorafenib. Regorafenib significantly outperformed placebo with regard to overall survival (OS). Dr. Teufel and his associates performed next-generation sequencing on 17 archived tumor samples containing sufficient tissue (all from regorafenib recipients). They also performed immune profiling on 46 tumor samples (32 from regorafenib recipients and 14 from placebo recipients), protein analysis on 499 plasma samples (332 from regorafenib recipients and 167 from placebo recipients), and microRNA analysis on 343 plasma samples (234 regorafenib recipients and 109 placebo recipients).

Among 266 proteins tested, decreased levels of 5 proteins correlated with significantly longer OS on regorafenib therapy. These proteins are involved in inflammation or hepatocellular carcinogenesis, the researchers noted. Importantly, none were associated with survival independent of treatment. These five proteins included angiopoietin 1 (hazard ratio for OS, 0.53; 95% confidence interval, 0.38-0.73), cystatin B (hazard ratio, 0.47; 95% CI, 0.34-0.64); the latency-associated peptide of transforming growth factor beta (HR, 0.46; 95% CI, 0.33-0.64), oxidized low-density lipoprotein receptor 1 (HR, 0.54; 95% CI, 0.41-0.72), and C-C motif chemokine ligand 3 (HR, 0.54; 95% CI, 0.39-0.74).

Additionally, baseline concentrations of 47 of the 266 proteins correlated with a time to progression (TPP) benefit on regorafenib therapy (adjusted P less than or equal to .05 for each). The 47 proteins included all 5 that predicted an OS benefit. All but two proteins (calbindin and gelsolin) showed the same directional effect as for OS (that is, low expression predicted response).

Nine plasma microRNA’s levels correlated with improved OS on regorafenib (adjusted P less than or equal to .05): MIR30A, MIR122, MIR125B, MIR200A, MIR374B, MIR15B, MIR107, MIR320, and MIR645. Notably, expression was linked to longer OS specifically among patients with the Hoshida S3 subtype of hepatocellular carcinoma. Next-generation sequencing of tumor samples also identified 49 variants in 27 oncogenes or tumor-suppressor genes. Mutations in CTNNB1 were found in 3 of 10 patients who progressed on regorafenib, and VEGFA amplification was found in 1 of 7 regorafenib responders.

“Thus far, rational biomarker selection has been unsuccessful in identifying predictive markers for regorafenib in colorectal cancer and gastrointestinal stromal tumors,” the researchers commented. “The broader approach used in this study is not only biologically warranted considering the heterogeneity of hepatocellular carcinoma tumors, but is also needed due to the multiple targets and pathways affected by MKIs such as regorafenib. Levels of these circulating biomarkers and genetic features of tumors might be used to identify patients with hepatocellular carcinoma most likely to respond to regorafenib.”

Bayer funded the study, provided the study drug, and was involved in all aspects of the study. Dr. Teufel and three coinvestigators are Bayer employees. Dr. Teufel and two coinvestigators own stock in Bayer. Three other coinvestigators disclosed ties to Bayer and other pharmaceutical companies.

SOURCE: Teufel M et al. Gastroenterology. 2019 Jan 30. doi: 10.1053/j.gastro.2019.01.261.

Protein and microRNA expression patterns correlated with improved survival on regorafenib among patients with sorafenib-pretreated hepatocellular carcinoma, researchers reported.

copyright Eraxion/Thinkstock

“In the absence of established or predefined biomarkers for regorafenib, we performed a broad exploratory biomarker analyses at the DNA, RNA, and protein level that represents a much more comprehensive approach than previous studies of regorafenib or sorafenib,” wrote Michael Teufel, PhD, of Bayer Healthcare Pharmaceuticals in Whippany, N.J., and his associates. The preplanned, retrospective analysis of data from the phase 3 RESOURCE trial was reported in Gastroenterology.

The randomized trial included 567 patients whose hepatocellular carcinoma had progressed on sorafenib. Regorafenib significantly outperformed placebo with regard to overall survival (OS). Dr. Teufel and his associates performed next-generation sequencing on 17 archived tumor samples containing sufficient tissue (all from regorafenib recipients). They also performed immune profiling on 46 tumor samples (32 from regorafenib recipients and 14 from placebo recipients), protein analysis on 499 plasma samples (332 from regorafenib recipients and 167 from placebo recipients), and microRNA analysis on 343 plasma samples (234 regorafenib recipients and 109 placebo recipients).

Among 266 proteins tested, decreased levels of 5 proteins correlated with significantly longer OS on regorafenib therapy. These proteins are involved in inflammation or hepatocellular carcinogenesis, the researchers noted. Importantly, none were associated with survival independent of treatment. These five proteins included angiopoietin 1 (hazard ratio for OS, 0.53; 95% confidence interval, 0.38-0.73), cystatin B (hazard ratio, 0.47; 95% CI, 0.34-0.64); the latency-associated peptide of transforming growth factor beta (HR, 0.46; 95% CI, 0.33-0.64), oxidized low-density lipoprotein receptor 1 (HR, 0.54; 95% CI, 0.41-0.72), and C-C motif chemokine ligand 3 (HR, 0.54; 95% CI, 0.39-0.74).

Additionally, baseline concentrations of 47 of the 266 proteins correlated with a time to progression (TPP) benefit on regorafenib therapy (adjusted P less than or equal to .05 for each). The 47 proteins included all 5 that predicted an OS benefit. All but two proteins (calbindin and gelsolin) showed the same directional effect as for OS (that is, low expression predicted response).

Nine plasma microRNA’s levels correlated with improved OS on regorafenib (adjusted P less than or equal to .05): MIR30A, MIR122, MIR125B, MIR200A, MIR374B, MIR15B, MIR107, MIR320, and MIR645. Notably, expression was linked to longer OS specifically among patients with the Hoshida S3 subtype of hepatocellular carcinoma. Next-generation sequencing of tumor samples also identified 49 variants in 27 oncogenes or tumor-suppressor genes. Mutations in CTNNB1 were found in 3 of 10 patients who progressed on regorafenib, and VEGFA amplification was found in 1 of 7 regorafenib responders.

“Thus far, rational biomarker selection has been unsuccessful in identifying predictive markers for regorafenib in colorectal cancer and gastrointestinal stromal tumors,” the researchers commented. “The broader approach used in this study is not only biologically warranted considering the heterogeneity of hepatocellular carcinoma tumors, but is also needed due to the multiple targets and pathways affected by MKIs such as regorafenib. Levels of these circulating biomarkers and genetic features of tumors might be used to identify patients with hepatocellular carcinoma most likely to respond to regorafenib.”

Bayer funded the study, provided the study drug, and was involved in all aspects of the study. Dr. Teufel and three coinvestigators are Bayer employees. Dr. Teufel and two coinvestigators own stock in Bayer. Three other coinvestigators disclosed ties to Bayer and other pharmaceutical companies.

SOURCE: Teufel M et al. Gastroenterology. 2019 Jan 30. doi: 10.1053/j.gastro.2019.01.261.

Protein and microRNA expression patterns correlated with improved survival on regorafenib among patients with sorafenib-pretreated hepatocellular carcinoma, researchers reported.

copyright Eraxion/Thinkstock

“In the absence of established or predefined biomarkers for regorafenib, we performed a broad exploratory biomarker analyses at the DNA, RNA, and protein level that represents a much more comprehensive approach than previous studies of regorafenib or sorafenib,” wrote Michael Teufel, PhD, of Bayer Healthcare Pharmaceuticals in Whippany, N.J., and his associates. The preplanned, retrospective analysis of data from the phase 3 RESOURCE trial was reported in Gastroenterology.

The randomized trial included 567 patients whose hepatocellular carcinoma had progressed on sorafenib. Regorafenib significantly outperformed placebo with regard to overall survival (OS). Dr. Teufel and his associates performed next-generation sequencing on 17 archived tumor samples containing sufficient tissue (all from regorafenib recipients). They also performed immune profiling on 46 tumor samples (32 from regorafenib recipients and 14 from placebo recipients), protein analysis on 499 plasma samples (332 from regorafenib recipients and 167 from placebo recipients), and microRNA analysis on 343 plasma samples (234 regorafenib recipients and 109 placebo recipients).

Among 266 proteins tested, decreased levels of 5 proteins correlated with significantly longer OS on regorafenib therapy. These proteins are involved in inflammation or hepatocellular carcinogenesis, the researchers noted. Importantly, none were associated with survival independent of treatment. These five proteins included angiopoietin 1 (hazard ratio for OS, 0.53; 95% confidence interval, 0.38-0.73), cystatin B (hazard ratio, 0.47; 95% CI, 0.34-0.64); the latency-associated peptide of transforming growth factor beta (HR, 0.46; 95% CI, 0.33-0.64), oxidized low-density lipoprotein receptor 1 (HR, 0.54; 95% CI, 0.41-0.72), and C-C motif chemokine ligand 3 (HR, 0.54; 95% CI, 0.39-0.74).

Additionally, baseline concentrations of 47 of the 266 proteins correlated with a time to progression (TPP) benefit on regorafenib therapy (adjusted P less than or equal to .05 for each). The 47 proteins included all 5 that predicted an OS benefit. All but two proteins (calbindin and gelsolin) showed the same directional effect as for OS (that is, low expression predicted response).

Nine plasma microRNA’s levels correlated with improved OS on regorafenib (adjusted P less than or equal to .05): MIR30A, MIR122, MIR125B, MIR200A, MIR374B, MIR15B, MIR107, MIR320, and MIR645. Notably, expression was linked to longer OS specifically among patients with the Hoshida S3 subtype of hepatocellular carcinoma. Next-generation sequencing of tumor samples also identified 49 variants in 27 oncogenes or tumor-suppressor genes. Mutations in CTNNB1 were found in 3 of 10 patients who progressed on regorafenib, and VEGFA amplification was found in 1 of 7 regorafenib responders.

“Thus far, rational biomarker selection has been unsuccessful in identifying predictive markers for regorafenib in colorectal cancer and gastrointestinal stromal tumors,” the researchers commented. “The broader approach used in this study is not only biologically warranted considering the heterogeneity of hepatocellular carcinoma tumors, but is also needed due to the multiple targets and pathways affected by MKIs such as regorafenib. Levels of these circulating biomarkers and genetic features of tumors might be used to identify patients with hepatocellular carcinoma most likely to respond to regorafenib.”

Bayer funded the study, provided the study drug, and was involved in all aspects of the study. Dr. Teufel and three coinvestigators are Bayer employees. Dr. Teufel and two coinvestigators own stock in Bayer. Three other coinvestigators disclosed ties to Bayer and other pharmaceutical companies.

SOURCE: Teufel M et al. Gastroenterology. 2019 Jan 30. doi: 10.1053/j.gastro.2019.01.261.

The PROBE (Patient Reported Outcomes Burdens and Experience) questionnaire was found to be a valid instrument to evaluate health status in patients with hemophilia in an cross‐cultural context, according to an international study.

PeopleImages/gettyimages

“This study [aimed] to investigate the variation in the PROBE questionnaire–driven measurements across four broad geographical regions,” wrote Chatree Chai‐Adisaksopha, MD, of McMaster University in Hamilton, Ontario, and his colleagues. The results of the study were published in Haemophilia.

The researchers analyzed data from 862 study participants who resided in various geographical regions, including North America, South America, Europe, and the Western Pacific. The majority of participants were male and had greater than 12 years of education.

The team assessed common characteristics of participants through collection of demographic data, including age, gender, years of education, among others. With respect to hemophilia, they evaluated patient‐reported outcome measures across these four regions.

“Outcome measurement in haemophilia has been developed to capture clinically relevant outcomes like bleeding rates, pharmacokinetics, joint pain, joint function scores, radiologic changes and mortality rates,” the researchers wrote.

After analysis, Dr. Chai‐Adisaksopha and his colleagues found that the PROBE questionnaire showed low variability when used on a multinational, cross‐cultural level. In particular, limited variation was found with respect to years of education and geographical region in all subcategories, with the exception of mobility score. In contrast, diagnosis and age had the highest levels of variation.

Region contributed 0.26% of variance in the PROBE score. Similarly, education level contributed 0.34% of the variance. However, age contributed 3.42% and diagnosis contributed 22.42% of the variance in the PROBE score.

The authors acknowledged a key limitation of the study was the inability to include all geographical regions, largely due to an inadequate number of participants in certain areas, such as Africa.

“Despite being used in disparate groups of patients, in 14 countries, in four regions and in 20 languages, the tool produced comparable results, suggesting it can be reliably used across these groups,” the researchers wrote.

The study was funded by Baxalta, Bayer, Bioverativ, CSL Behring, Novo Nordisk, Roche, and Sobi, with additional support from the U.S. National Hemophilia Foundation. Co-author Mark W. Skinner is the principal investigator and no other investigators reported relevant conflicts of interest.

SOURCE: Chai-Adisaksopha C et al. Haemophilia. 2019 Mar 12. doi: 10.1111/hae.13703 .

The PROBE (Patient Reported Outcomes Burdens and Experience) questionnaire was found to be a valid instrument to evaluate health status in patients with hemophilia in an cross‐cultural context, according to an international study.

PeopleImages/gettyimages

“This study [aimed] to investigate the variation in the PROBE questionnaire–driven measurements across four broad geographical regions,” wrote Chatree Chai‐Adisaksopha, MD, of McMaster University in Hamilton, Ontario, and his colleagues. The results of the study were published in Haemophilia.

The researchers analyzed data from 862 study participants who resided in various geographical regions, including North America, South America, Europe, and the Western Pacific. The majority of participants were male and had greater than 12 years of education.

The team assessed common characteristics of participants through collection of demographic data, including age, gender, years of education, among others. With respect to hemophilia, they evaluated patient‐reported outcome measures across these four regions.

“Outcome measurement in haemophilia has been developed to capture clinically relevant outcomes like bleeding rates, pharmacokinetics, joint pain, joint function scores, radiologic changes and mortality rates,” the researchers wrote.

After analysis, Dr. Chai‐Adisaksopha and his colleagues found that the PROBE questionnaire showed low variability when used on a multinational, cross‐cultural level. In particular, limited variation was found with respect to years of education and geographical region in all subcategories, with the exception of mobility score. In contrast, diagnosis and age had the highest levels of variation.

Region contributed 0.26% of variance in the PROBE score. Similarly, education level contributed 0.34% of the variance. However, age contributed 3.42% and diagnosis contributed 22.42% of the variance in the PROBE score.

The authors acknowledged a key limitation of the study was the inability to include all geographical regions, largely due to an inadequate number of participants in certain areas, such as Africa.

“Despite being used in disparate groups of patients, in 14 countries, in four regions and in 20 languages, the tool produced comparable results, suggesting it can be reliably used across these groups,” the researchers wrote.

The study was funded by Baxalta, Bayer, Bioverativ, CSL Behring, Novo Nordisk, Roche, and Sobi, with additional support from the U.S. National Hemophilia Foundation. Co-author Mark W. Skinner is the principal investigator and no other investigators reported relevant conflicts of interest.

SOURCE: Chai-Adisaksopha C et al. Haemophilia. 2019 Mar 12. doi: 10.1111/hae.13703 .

The PROBE (Patient Reported Outcomes Burdens and Experience) questionnaire was found to be a valid instrument to evaluate health status in patients with hemophilia in an cross‐cultural context, according to an international study.

PeopleImages/gettyimages

“This study [aimed] to investigate the variation in the PROBE questionnaire–driven measurements across four broad geographical regions,” wrote Chatree Chai‐Adisaksopha, MD, of McMaster University in Hamilton, Ontario, and his colleagues. The results of the study were published in Haemophilia.

The researchers analyzed data from 862 study participants who resided in various geographical regions, including North America, South America, Europe, and the Western Pacific. The majority of participants were male and had greater than 12 years of education.

The team assessed common characteristics of participants through collection of demographic data, including age, gender, years of education, among others. With respect to hemophilia, they evaluated patient‐reported outcome measures across these four regions.

“Outcome measurement in haemophilia has been developed to capture clinically relevant outcomes like bleeding rates, pharmacokinetics, joint pain, joint function scores, radiologic changes and mortality rates,” the researchers wrote.

After analysis, Dr. Chai‐Adisaksopha and his colleagues found that the PROBE questionnaire showed low variability when used on a multinational, cross‐cultural level. In particular, limited variation was found with respect to years of education and geographical region in all subcategories, with the exception of mobility score. In contrast, diagnosis and age had the highest levels of variation.

Region contributed 0.26% of variance in the PROBE score. Similarly, education level contributed 0.34% of the variance. However, age contributed 3.42% and diagnosis contributed 22.42% of the variance in the PROBE score.

The authors acknowledged a key limitation of the study was the inability to include all geographical regions, largely due to an inadequate number of participants in certain areas, such as Africa.

“Despite being used in disparate groups of patients, in 14 countries, in four regions and in 20 languages, the tool produced comparable results, suggesting it can be reliably used across these groups,” the researchers wrote.

The study was funded by Baxalta, Bayer, Bioverativ, CSL Behring, Novo Nordisk, Roche, and Sobi, with additional support from the U.S. National Hemophilia Foundation. Co-author Mark W. Skinner is the principal investigator and no other investigators reported relevant conflicts of interest.

SOURCE: Chai-Adisaksopha C et al. Haemophilia. 2019 Mar 12. doi: 10.1111/hae.13703 .

For women with metastatic hormone receptor–positive breast cancer, the addition of the selective estrogen receptor modifier fulvestrant (Faslodex) to the aromatase inhibitor anastrozole (Arimidex and generics) resulted in a small but significant improvement in overall survival, according to final results from a randomized phase 3 trial.

Among 694 patients randomized for whom data were available, the hazard ratio for death with the combination when compared with anastrozole alone was 0.82 (P = .03), reported Rita S. Mehta, MD, from the University of California (Irvine) Medical Center and her colleagues.

The benefit of the combination was highest for patients without prior exposure to adjuvant endocrine therapy.

“Furthermore, sequential therapy with anastrozole and fulvestrant (45% of patients crossed over to fulvestrant alone) did not negate the significance of the long-term overall survival benefit with the combination therapy as compared with anastrozole,” the investigators wrote in The New England Journal of Medicine.

The current report is the final survival analysis of the trial. The primary results were reported in 2012 (N Engl J Med. 2012; 367:435-44). A total of 707 postmenopausal women with previously untreated metastatic disease were randomly assigned to receive either 1 mg of anastrozole orally every day with crossover to fulvestrant alone strongly encouraged if the disease progressed or to anastrozole and fulvestrant in combination. Randomization was stratified according to prior adjuvant tamoxifen use. A total of 694 women had data available for analysis.

The primary analysis, conducted at a median follow-up of 35 months, showed a median progression-free survival (PFS) with anastrozole alone of 13.5 months, compared with 15.0 months for anastrozole/fulvestrant (HR for progression or death 0.80; P = .007). Respective median overall survival was 41.3 months and 47.7 months (HR for death 0.81; P = .05).

The current, final analysis, conducted at a median follow-up of 7 years in patients who did not have disease progression, showed 261 deaths among 345 women (76%) in the anastrozole-only group, compared with 247 deaths among 349 women (71%) in the combination group (HR for death 0.82; P = .03).

Overall survival was longer for those women who had not previously received tamoxifen who were treated with the combination, at a median of 52.2 months versus 40.3 months for women not previously treated with tamoxifen who received anastrozole alone (hazard ratio, 0.73; 95% confidence interval, 0.58-0.92). In contrast, there was no significant difference in OS between the two treatment groups in women who had previously received tamoxifen.

Approximately 45% of patients initially randomized to anastrozole alone were crossed over to fulvestrant.

The incidence of long-term toxic effects and treatment-related deaths was similar between the groups. Previously reported treatment-related deaths with the combination included pulmonary emboli in two patients and a cerebrovascular ischemic event in one patients.

At the time of data cutoff for the final report, 15% of patients in the combination-therapy group and 13% in the anastrozole-only group had experienced grade 3 toxicities.

The study was supported by National Cancer Institute grants and by AstraZeneca. Dr. Mehta reported institutional and personal grants from AstraZeneca and others. Multiple coauthors reported similar relationships.

SOURCE: Mehta RS et al. N Engl J Med. 2019;380:1226-34.

For women with metastatic hormone receptor–positive breast cancer, the addition of the selective estrogen receptor modifier fulvestrant (Faslodex) to the aromatase inhibitor anastrozole (Arimidex and generics) resulted in a small but significant improvement in overall survival, according to final results from a randomized phase 3 trial.

Among 694 patients randomized for whom data were available, the hazard ratio for death with the combination when compared with anastrozole alone was 0.82 (P = .03), reported Rita S. Mehta, MD, from the University of California (Irvine) Medical Center and her colleagues.

The benefit of the combination was highest for patients without prior exposure to adjuvant endocrine therapy.

“Furthermore, sequential therapy with anastrozole and fulvestrant (45% of patients crossed over to fulvestrant alone) did not negate the significance of the long-term overall survival benefit with the combination therapy as compared with anastrozole,” the investigators wrote in The New England Journal of Medicine.

The current report is the final survival analysis of the trial. The primary results were reported in 2012 (N Engl J Med. 2012; 367:435-44). A total of 707 postmenopausal women with previously untreated metastatic disease were randomly assigned to receive either 1 mg of anastrozole orally every day with crossover to fulvestrant alone strongly encouraged if the disease progressed or to anastrozole and fulvestrant in combination. Randomization was stratified according to prior adjuvant tamoxifen use. A total of 694 women had data available for analysis.

The primary analysis, conducted at a median follow-up of 35 months, showed a median progression-free survival (PFS) with anastrozole alone of 13.5 months, compared with 15.0 months for anastrozole/fulvestrant (HR for progression or death 0.80; P = .007). Respective median overall survival was 41.3 months and 47.7 months (HR for death 0.81; P = .05).

The current, final analysis, conducted at a median follow-up of 7 years in patients who did not have disease progression, showed 261 deaths among 345 women (76%) in the anastrozole-only group, compared with 247 deaths among 349 women (71%) in the combination group (HR for death 0.82; P = .03).

Overall survival was longer for those women who had not previously received tamoxifen who were treated with the combination, at a median of 52.2 months versus 40.3 months for women not previously treated with tamoxifen who received anastrozole alone (hazard ratio, 0.73; 95% confidence interval, 0.58-0.92). In contrast, there was no significant difference in OS between the two treatment groups in women who had previously received tamoxifen.

Approximately 45% of patients initially randomized to anastrozole alone were crossed over to fulvestrant.

The incidence of long-term toxic effects and treatment-related deaths was similar between the groups. Previously reported treatment-related deaths with the combination included pulmonary emboli in two patients and a cerebrovascular ischemic event in one patients.

At the time of data cutoff for the final report, 15% of patients in the combination-therapy group and 13% in the anastrozole-only group had experienced grade 3 toxicities.

The study was supported by National Cancer Institute grants and by AstraZeneca. Dr. Mehta reported institutional and personal grants from AstraZeneca and others. Multiple coauthors reported similar relationships.

SOURCE: Mehta RS et al. N Engl J Med. 2019;380:1226-34.

For women with metastatic hormone receptor–positive breast cancer, the addition of the selective estrogen receptor modifier fulvestrant (Faslodex) to the aromatase inhibitor anastrozole (Arimidex and generics) resulted in a small but significant improvement in overall survival, according to final results from a randomized phase 3 trial.

Among 694 patients randomized for whom data were available, the hazard ratio for death with the combination when compared with anastrozole alone was 0.82 (P = .03), reported Rita S. Mehta, MD, from the University of California (Irvine) Medical Center and her colleagues.

The benefit of the combination was highest for patients without prior exposure to adjuvant endocrine therapy.

“Furthermore, sequential therapy with anastrozole and fulvestrant (45% of patients crossed over to fulvestrant alone) did not negate the significance of the long-term overall survival benefit with the combination therapy as compared with anastrozole,” the investigators wrote in The New England Journal of Medicine.

The current report is the final survival analysis of the trial. The primary results were reported in 2012 (N Engl J Med. 2012; 367:435-44). A total of 707 postmenopausal women with previously untreated metastatic disease were randomly assigned to receive either 1 mg of anastrozole orally every day with crossover to fulvestrant alone strongly encouraged if the disease progressed or to anastrozole and fulvestrant in combination. Randomization was stratified according to prior adjuvant tamoxifen use. A total of 694 women had data available for analysis.

The primary analysis, conducted at a median follow-up of 35 months, showed a median progression-free survival (PFS) with anastrozole alone of 13.5 months, compared with 15.0 months for anastrozole/fulvestrant (HR for progression or death 0.80; P = .007). Respective median overall survival was 41.3 months and 47.7 months (HR for death 0.81; P = .05).

The current, final analysis, conducted at a median follow-up of 7 years in patients who did not have disease progression, showed 261 deaths among 345 women (76%) in the anastrozole-only group, compared with 247 deaths among 349 women (71%) in the combination group (HR for death 0.82; P = .03).

Overall survival was longer for those women who had not previously received tamoxifen who were treated with the combination, at a median of 52.2 months versus 40.3 months for women not previously treated with tamoxifen who received anastrozole alone (hazard ratio, 0.73; 95% confidence interval, 0.58-0.92). In contrast, there was no significant difference in OS between the two treatment groups in women who had previously received tamoxifen.

Approximately 45% of patients initially randomized to anastrozole alone were crossed over to fulvestrant.

The incidence of long-term toxic effects and treatment-related deaths was similar between the groups. Previously reported treatment-related deaths with the combination included pulmonary emboli in two patients and a cerebrovascular ischemic event in one patients.

At the time of data cutoff for the final report, 15% of patients in the combination-therapy group and 13% in the anastrozole-only group had experienced grade 3 toxicities.

The study was supported by National Cancer Institute grants and by AstraZeneca. Dr. Mehta reported institutional and personal grants from AstraZeneca and others. Multiple coauthors reported similar relationships.

SOURCE: Mehta RS et al. N Engl J Med. 2019;380:1226-34.

A balloon catheter system that measures mucosal impedance contour immediately distinguished gastroesophageal reflux disease (GERD), eosinophilic esophagitis, and non-GERD (normal findings), according to the findings of a prospective study of 69 adults.

Source: American Gastroenterological Association

Each group showed a significantly different (P less than .01) pattern of mucosal impedance (MI), or disruption of mucosal integrity, along the esophageal axis, wrote Dhyanesh A. Patel, MD, of Vanderbilt University Medical Center in Nashville, Tenn., and his associates. Patients without GERD had higher MI values along all esophageal segments, while GERD was characterized by below-normal values in the distal esophagus only, and eosinophilic esophagitis led to low values throughout the esophagus.

The findings were validated in a separate patient cohort, and the only reported adverse event was an episode of mild chest pain. “This contour heatmap could easily be employed to establish a diagnosis during endoscopy, independent of biopsy or pH monitoring,” the investigators wrote in Gastroenterology. They cautioned that the balloon catheter cannot be safely used in patients with severe fibrostenotic disease.

Current definitive diagnostics for GERD leave much to be desired. Transnasal probes are imprecise and uncomfortable, and they can be insensitive if discomfort causes patients to vary normal activity or skip meals. Wireless ambulatory pH monitoring is more tolerable but unreliable and measures only acidity of refluxed material at a single point along the esophagus. These tests also “fail to account for day-to-day variability of reflux, as they only provide a 24- to 48-hour snapshot of a disease process that is chronic in nature,” the researchers wrote. Eosinophilic esophagitis is becoming more common and usually requires proximal and distal biopsies for diagnosis.

Mucosal impedance contour pattern testing is based on the fact that both GERD and eosinophilic esophagitis involve increased distance between esophageal epithelial cells. The amount of intercellular dilatation correlates inversely with MI values. In proof-of-concept studies, individuals with GERD, non-GERD, eosinophilic esophagitis, and achalasia had distinct MI patterns. However, these studies tested a single-channel catheter system that took only point measurements and was subject to interoperator variability. To improve on this concept, Dr. Patel and his associates mounted radial and axial sensors on a balloon catheter to measure MI at 180-degree intervals along a 10-cm esophageal segment.

They tested the new device prospectively in 69 patients undergoing esophagogastroduodenoscopy with or without pH monitoring (which was used as the standard). In all, 24 patients had GERD, 21 had eosinophilic esophagitis, and 24 had normal findings. By using the intercept and slope of the balloon MI measurements, the researchers detected GERD with an area under the receiver operating characteristic curve (AUC) of 0.67, eosinophilic esophagitis with an AUC of 0.84, and non-GERD with an AUC of 0.83.

These findings held up in a separate validation cohort of 36 patients (28 with GERD and eight with eosinophilic esophagitis) from three tertiary care centers. The probability of eosinophilic esophagitis was highest in patients with low distal MI values (that is, a low intercept) and a low slope (showing that MI values remained low proximally). A low distal MI intercept with a steeper positive slope suggested GERD, while a higher distal MI intercept with a steep slope signified non-GERD.

The system “potentially obviates the need for 24- to 48-hour ambulatory wireless pH monitoring or esophageal biopsies for histopathology,” the researchers concluded. “This can help reduce diagnostic and treatment latency and might allow for monitoring disease activity over time.”

The National Institutes of Health funded the external validation analysis. Diversatek Healthcare, which patented the device together with Vanderbilt University, gave research funding to four coinvestigators, including the senior author. Dr. Patel and the other five coinvestigators reported having no conflicts of interest.

SOURCE: Patel DA et al. Gastroenterology. 2019 Jan 31. doi: 10.1053/j.gastro.2019.01.253.

A balloon catheter system that measures mucosal impedance contour immediately distinguished gastroesophageal reflux disease (GERD), eosinophilic esophagitis, and non-GERD (normal findings), according to the findings of a prospective study of 69 adults.

Source: American Gastroenterological Association

Each group showed a significantly different (P less than .01) pattern of mucosal impedance (MI), or disruption of mucosal integrity, along the esophageal axis, wrote Dhyanesh A. Patel, MD, of Vanderbilt University Medical Center in Nashville, Tenn., and his associates. Patients without GERD had higher MI values along all esophageal segments, while GERD was characterized by below-normal values in the distal esophagus only, and eosinophilic esophagitis led to low values throughout the esophagus.

The findings were validated in a separate patient cohort, and the only reported adverse event was an episode of mild chest pain. “This contour heatmap could easily be employed to establish a diagnosis during endoscopy, independent of biopsy or pH monitoring,” the investigators wrote in Gastroenterology. They cautioned that the balloon catheter cannot be safely used in patients with severe fibrostenotic disease.

Current definitive diagnostics for GERD leave much to be desired. Transnasal probes are imprecise and uncomfortable, and they can be insensitive if discomfort causes patients to vary normal activity or skip meals. Wireless ambulatory pH monitoring is more tolerable but unreliable and measures only acidity of refluxed material at a single point along the esophagus. These tests also “fail to account for day-to-day variability of reflux, as they only provide a 24- to 48-hour snapshot of a disease process that is chronic in nature,” the researchers wrote. Eosinophilic esophagitis is becoming more common and usually requires proximal and distal biopsies for diagnosis.

Mucosal impedance contour pattern testing is based on the fact that both GERD and eosinophilic esophagitis involve increased distance between esophageal epithelial cells. The amount of intercellular dilatation correlates inversely with MI values. In proof-of-concept studies, individuals with GERD, non-GERD, eosinophilic esophagitis, and achalasia had distinct MI patterns. However, these studies tested a single-channel catheter system that took only point measurements and was subject to interoperator variability. To improve on this concept, Dr. Patel and his associates mounted radial and axial sensors on a balloon catheter to measure MI at 180-degree intervals along a 10-cm esophageal segment.

They tested the new device prospectively in 69 patients undergoing esophagogastroduodenoscopy with or without pH monitoring (which was used as the standard). In all, 24 patients had GERD, 21 had eosinophilic esophagitis, and 24 had normal findings. By using the intercept and slope of the balloon MI measurements, the researchers detected GERD with an area under the receiver operating characteristic curve (AUC) of 0.67, eosinophilic esophagitis with an AUC of 0.84, and non-GERD with an AUC of 0.83.

These findings held up in a separate validation cohort of 36 patients (28 with GERD and eight with eosinophilic esophagitis) from three tertiary care centers. The probability of eosinophilic esophagitis was highest in patients with low distal MI values (that is, a low intercept) and a low slope (showing that MI values remained low proximally). A low distal MI intercept with a steeper positive slope suggested GERD, while a higher distal MI intercept with a steep slope signified non-GERD.

The system “potentially obviates the need for 24- to 48-hour ambulatory wireless pH monitoring or esophageal biopsies for histopathology,” the researchers concluded. “This can help reduce diagnostic and treatment latency and might allow for monitoring disease activity over time.”

The National Institutes of Health funded the external validation analysis. Diversatek Healthcare, which patented the device together with Vanderbilt University, gave research funding to four coinvestigators, including the senior author. Dr. Patel and the other five coinvestigators reported having no conflicts of interest.

SOURCE: Patel DA et al. Gastroenterology. 2019 Jan 31. doi: 10.1053/j.gastro.2019.01.253.

A balloon catheter system that measures mucosal impedance contour immediately distinguished gastroesophageal reflux disease (GERD), eosinophilic esophagitis, and non-GERD (normal findings), according to the findings of a prospective study of 69 adults.

Source: American Gastroenterological Association

Each group showed a significantly different (P less than .01) pattern of mucosal impedance (MI), or disruption of mucosal integrity, along the esophageal axis, wrote Dhyanesh A. Patel, MD, of Vanderbilt University Medical Center in Nashville, Tenn., and his associates. Patients without GERD had higher MI values along all esophageal segments, while GERD was characterized by below-normal values in the distal esophagus only, and eosinophilic esophagitis led to low values throughout the esophagus.

The findings were validated in a separate patient cohort, and the only reported adverse event was an episode of mild chest pain. “This contour heatmap could easily be employed to establish a diagnosis during endoscopy, independent of biopsy or pH monitoring,” the investigators wrote in Gastroenterology. They cautioned that the balloon catheter cannot be safely used in patients with severe fibrostenotic disease.

Current definitive diagnostics for GERD leave much to be desired. Transnasal probes are imprecise and uncomfortable, and they can be insensitive if discomfort causes patients to vary normal activity or skip meals. Wireless ambulatory pH monitoring is more tolerable but unreliable and measures only acidity of refluxed material at a single point along the esophagus. These tests also “fail to account for day-to-day variability of reflux, as they only provide a 24- to 48-hour snapshot of a disease process that is chronic in nature,” the researchers wrote. Eosinophilic esophagitis is becoming more common and usually requires proximal and distal biopsies for diagnosis.

Mucosal impedance contour pattern testing is based on the fact that both GERD and eosinophilic esophagitis involve increased distance between esophageal epithelial cells. The amount of intercellular dilatation correlates inversely with MI values. In proof-of-concept studies, individuals with GERD, non-GERD, eosinophilic esophagitis, and achalasia had distinct MI patterns. However, these studies tested a single-channel catheter system that took only point measurements and was subject to interoperator variability. To improve on this concept, Dr. Patel and his associates mounted radial and axial sensors on a balloon catheter to measure MI at 180-degree intervals along a 10-cm esophageal segment.

They tested the new device prospectively in 69 patients undergoing esophagogastroduodenoscopy with or without pH monitoring (which was used as the standard). In all, 24 patients had GERD, 21 had eosinophilic esophagitis, and 24 had normal findings. By using the intercept and slope of the balloon MI measurements, the researchers detected GERD with an area under the receiver operating characteristic curve (AUC) of 0.67, eosinophilic esophagitis with an AUC of 0.84, and non-GERD with an AUC of 0.83.

These findings held up in a separate validation cohort of 36 patients (28 with GERD and eight with eosinophilic esophagitis) from three tertiary care centers. The probability of eosinophilic esophagitis was highest in patients with low distal MI values (that is, a low intercept) and a low slope (showing that MI values remained low proximally). A low distal MI intercept with a steeper positive slope suggested GERD, while a higher distal MI intercept with a steep slope signified non-GERD.

The system “potentially obviates the need for 24- to 48-hour ambulatory wireless pH monitoring or esophageal biopsies for histopathology,” the researchers concluded. “This can help reduce diagnostic and treatment latency and might allow for monitoring disease activity over time.”

The National Institutes of Health funded the external validation analysis. Diversatek Healthcare, which patented the device together with Vanderbilt University, gave research funding to four coinvestigators, including the senior author. Dr. Patel and the other five coinvestigators reported having no conflicts of interest.

SOURCE: Patel DA et al. Gastroenterology. 2019 Jan 31. doi: 10.1053/j.gastro.2019.01.253.

Early Results Find Olaratumab Combo With Doxorubicin Plus Ifosfamide Safe

Initial results of the phase 1b study of olaratumab plus doxorubicin and ifosfamide have shown the combination to be safe, reported Sebastian Bauer, MD, of the West German Cancer Center, University of Duisburg-Essen, Essen, Germany, and his colleagues at CTOS 2018.

The phase 1 trial (NCT03283696) enrolled 16 patients with advanced or metastatic soft tissue sarcomas. Patients had received no prior lines of systemic therapy and had an ECOG performance status of 0-1. Adequate follow-up data were available for 10 patients.

Olaratumab (Lartruvo), which binds platelet-derived growth factor receptor alpha (PDGFRα), was given at 15 mg/kg in combination with doxorubicin (75 mg/m2 on days 1-3) and ifosfamide (10 g/m2 on days 1-4). This was followed by mandatory granulocyte-colony-stimulating factor therapy in cycles 1-6 on a 21-day cycle. Doxorubicin could be administered by continuous infusion or bolus administration and with cardiac protection. Mesna dosing was at least 60% of the ifosfamide dose.

Two of the 10 patients had dose-limiting toxicities; one had grade 4 febrile neutropenia and the other had grade 3 febrile neutropenia and grade 3 mucositis. Common related adverse events occurring in over 30% of patients included fatigue, anemia, neutropenia, thrombocytopenia, constipation, and nausea. One patient discontinued study treatment due to progressive disease, and all others were on study treatment as of the data cutoff. Among 7 patients evaluated for tumor response, 3 patients had a partial response according to RECIST and 3 other patients had stabilized disease as best overall response, for a disease control rate of 86%.

Given that 8 of 10 evaluable patients have completed the dose-limiting toxicity period without dose-limiting toxicities at the 15 mg/kg dose level of olaratumab, the study has proceeded to the next cohort. In those patients, an olaratumab loading dose of 20 mg/kg will be evaluated in cycle 1, followed by 15 mg/kg of olaratumab in subsequent cycles with the same doses of doxorubicin plus ifosfamide, the researchers wrote in their abstract.

NOTE: Since CTOS 2018, olaratumab plus doxorubicin did not meet its phase 3 endpoint of overall survival (OS) advantage in the full study population or in the leiomyosarcoma subpopulation compared to doxorubicin alone.

Anthracycline-Based Regimen Excels in FIGO-1 Uterine Leiomyosarcoma

Patients with uterine leiomyosarcomas treated with anthracycline-based regimens experienced longer disease-free survival compared to patients treated with gemcitabine and docetaxel, according to a retrospective analysis reported at CTOS 2018.

Roberta Sanfilippo, MD, of Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy, and her colleagues reviewed all patients with FIGO stage I uterine leiomyosarcomas at two Italian centers who underwent hysterectomy with or without oophorectomy and were then treated with adjuvant chemotherapy with anthracycline-based or gemcitabine-based regimens.

Of 145 patients, 97 were treated with an anthracycline-based regimen and 48 with gemcitabine and docetaxel. The median number of cycles of anthracycline-based therapy patients received was 4 (range 2-6) and the median number of cycles with gemcitabine and docetaxel was 5 (range 3-7). Disease-free survival was 31 months in patients treated with anthracycline-based chemotherapy and 19 months in patients treated with gemcitabine and docetaxel.

These results suggest that future trials to assess the efficacy of adjuvant chemotherapy in uterine leiomyosarcoma should incorporate anthracyclines, the investigators maintain.

Trabectedin and Concurrent Low-Dose Radiotherapy Feasible

Trabectedin concurrent with lowdose radiotherapy is being examined as an option for patients with pulmonary metastatic soft tissue sarcoma (NCT02275286).

In a phase 1 study, long-lasting dimensional responses were seen in 71% of the irradiated lesions. Based on those results, trabectedin (Yondelis) at 1.5 mg/m2 will be the recommended dose for phase 2, according to Javier Martín-Broto, MD, of the Institute of Biomedicine Research (IBIS)-University Hospital Virgen del Rocio/CSIC/University of Seville, Spain, and his colleagues, reporting at CTOS 2018.

For the study, trabectedin was given along with radiotherapy (30 Gy) in 10 fractions (3 Gy/fraction). Three dose levels of trabectedin were administered: -1 (1.1 mg/m2), 1 (1.3 mg/m2), and 2 (1.5 mg/m2). Dose-limiting toxicity was defined as grade 3 or greater events excluding grade 3/4 neutropenia lasting less than 5 days, grade 3 transaminitis if it did not lead to trabectedin delay, and grade 3/4 nausea/vomiting due to inadequate prophylaxis.

Ten of the 18 patients enrolled had synovial sarcoma; 3 had undifferentiated pleomorphic sarcomas, and the other patients had either myxoid liposarcoma, dedifferentiated liposarcoma, G3 not otherwise specified sarcoma, leiomyosarcoma, or malignant peripheral nerve sheath tumor.

Patients received a median of 1 prior line of chemotherapy (range: 0-3). Twelve patients received trabectedin at dose level 1 and 6 patients at dose level 2. Grade 3/4 adverse events were neutropenia, seen in 8 patients; alanine aminotransferase (ALT) elevation, seen in 2 patients; gamma-glutamyl transferase (GGT) elevation, seen in 2 patients; anemia, seen in 2 patients; febrile neutropenia, seen in 1 patient; and pneumonitis, seen in 1 patient.

There were two dose-limiting toxicities: transient grade 4 ALT elevation at the level 1 dose and grade 4 neutropenia for more than 5 days at the level 2 dose.

Based on central radiological review of 17 evaluable patients, 2 patients achieved complete response, 3 had partial responses, 6 had stable disease, and 6 had progressive disease. The local review reported complete responses in 2 patients, partial responses in 5, stable disease in 4, and progressive disease in 6.

Of the irradiated lesions, 71% had long-lasting dimensional responses: 4 completely responded, 8 responded partially, 4 were stable, and 1 progressed.

With a median follow-up of 18 months, median progression-free survival was 2.83 months (95%CI: 2.3-3.3 months). Thirteen patients have died, with a median overall survival of 8.77 months (95%CI: 3.6-13.9) and a 12-month overall survival rate of 48%.

The investigators concluded trabectedin with concurrent radiotherapy was feasible in patients with pulmonary metastatic soft tissue sarcoma regardless of their histologic subtype.

Early Results Find Olaratumab Combo With Doxorubicin Plus Ifosfamide Safe

Initial results of the phase 1b study of olaratumab plus doxorubicin and ifosfamide have shown the combination to be safe, reported Sebastian Bauer, MD, of the West German Cancer Center, University of Duisburg-Essen, Essen, Germany, and his colleagues at CTOS 2018.

The phase 1 trial (NCT03283696) enrolled 16 patients with advanced or metastatic soft tissue sarcomas. Patients had received no prior lines of systemic therapy and had an ECOG performance status of 0-1. Adequate follow-up data were available for 10 patients.

Olaratumab (Lartruvo), which binds platelet-derived growth factor receptor alpha (PDGFRα), was given at 15 mg/kg in combination with doxorubicin (75 mg/m2 on days 1-3) and ifosfamide (10 g/m2 on days 1-4). This was followed by mandatory granulocyte-colony-stimulating factor therapy in cycles 1-6 on a 21-day cycle. Doxorubicin could be administered by continuous infusion or bolus administration and with cardiac protection. Mesna dosing was at least 60% of the ifosfamide dose.

Two of the 10 patients had dose-limiting toxicities; one had grade 4 febrile neutropenia and the other had grade 3 febrile neutropenia and grade 3 mucositis. Common related adverse events occurring in over 30% of patients included fatigue, anemia, neutropenia, thrombocytopenia, constipation, and nausea. One patient discontinued study treatment due to progressive disease, and all others were on study treatment as of the data cutoff. Among 7 patients evaluated for tumor response, 3 patients had a partial response according to RECIST and 3 other patients had stabilized disease as best overall response, for a disease control rate of 86%.

Given that 8 of 10 evaluable patients have completed the dose-limiting toxicity period without dose-limiting toxicities at the 15 mg/kg dose level of olaratumab, the study has proceeded to the next cohort. In those patients, an olaratumab loading dose of 20 mg/kg will be evaluated in cycle 1, followed by 15 mg/kg of olaratumab in subsequent cycles with the same doses of doxorubicin plus ifosfamide, the researchers wrote in their abstract.

NOTE: Since CTOS 2018, olaratumab plus doxorubicin did not meet its phase 3 endpoint of overall survival (OS) advantage in the full study population or in the leiomyosarcoma subpopulation compared to doxorubicin alone.

Anthracycline-Based Regimen Excels in FIGO-1 Uterine Leiomyosarcoma

Patients with uterine leiomyosarcomas treated with anthracycline-based regimens experienced longer disease-free survival compared to patients treated with gemcitabine and docetaxel, according to a retrospective analysis reported at CTOS 2018.

Roberta Sanfilippo, MD, of Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy, and her colleagues reviewed all patients with FIGO stage I uterine leiomyosarcomas at two Italian centers who underwent hysterectomy with or without oophorectomy and were then treated with adjuvant chemotherapy with anthracycline-based or gemcitabine-based regimens.

Of 145 patients, 97 were treated with an anthracycline-based regimen and 48 with gemcitabine and docetaxel. The median number of cycles of anthracycline-based therapy patients received was 4 (range 2-6) and the median number of cycles with gemcitabine and docetaxel was 5 (range 3-7). Disease-free survival was 31 months in patients treated with anthracycline-based chemotherapy and 19 months in patients treated with gemcitabine and docetaxel.

These results suggest that future trials to assess the efficacy of adjuvant chemotherapy in uterine leiomyosarcoma should incorporate anthracyclines, the investigators maintain.

Trabectedin and Concurrent Low-Dose Radiotherapy Feasible

Trabectedin concurrent with lowdose radiotherapy is being examined as an option for patients with pulmonary metastatic soft tissue sarcoma (NCT02275286).

In a phase 1 study, long-lasting dimensional responses were seen in 71% of the irradiated lesions. Based on those results, trabectedin (Yondelis) at 1.5 mg/m2 will be the recommended dose for phase 2, according to Javier Martín-Broto, MD, of the Institute of Biomedicine Research (IBIS)-University Hospital Virgen del Rocio/CSIC/University of Seville, Spain, and his colleagues, reporting at CTOS 2018.

For the study, trabectedin was given along with radiotherapy (30 Gy) in 10 fractions (3 Gy/fraction). Three dose levels of trabectedin were administered: -1 (1.1 mg/m2), 1 (1.3 mg/m2), and 2 (1.5 mg/m2). Dose-limiting toxicity was defined as grade 3 or greater events excluding grade 3/4 neutropenia lasting less than 5 days, grade 3 transaminitis if it did not lead to trabectedin delay, and grade 3/4 nausea/vomiting due to inadequate prophylaxis.

Ten of the 18 patients enrolled had synovial sarcoma; 3 had undifferentiated pleomorphic sarcomas, and the other patients had either myxoid liposarcoma, dedifferentiated liposarcoma, G3 not otherwise specified sarcoma, leiomyosarcoma, or malignant peripheral nerve sheath tumor.

Patients received a median of 1 prior line of chemotherapy (range: 0-3). Twelve patients received trabectedin at dose level 1 and 6 patients at dose level 2. Grade 3/4 adverse events were neutropenia, seen in 8 patients; alanine aminotransferase (ALT) elevation, seen in 2 patients; gamma-glutamyl transferase (GGT) elevation, seen in 2 patients; anemia, seen in 2 patients; febrile neutropenia, seen in 1 patient; and pneumonitis, seen in 1 patient.

There were two dose-limiting toxicities: transient grade 4 ALT elevation at the level 1 dose and grade 4 neutropenia for more than 5 days at the level 2 dose.

Based on central radiological review of 17 evaluable patients, 2 patients achieved complete response, 3 had partial responses, 6 had stable disease, and 6 had progressive disease. The local review reported complete responses in 2 patients, partial responses in 5, stable disease in 4, and progressive disease in 6.

Of the irradiated lesions, 71% had long-lasting dimensional responses: 4 completely responded, 8 responded partially, 4 were stable, and 1 progressed.

With a median follow-up of 18 months, median progression-free survival was 2.83 months (95%CI: 2.3-3.3 months). Thirteen patients have died, with a median overall survival of 8.77 months (95%CI: 3.6-13.9) and a 12-month overall survival rate of 48%.

The investigators concluded trabectedin with concurrent radiotherapy was feasible in patients with pulmonary metastatic soft tissue sarcoma regardless of their histologic subtype.

Early Results Find Olaratumab Combo With Doxorubicin Plus Ifosfamide Safe

Initial results of the phase 1b study of olaratumab plus doxorubicin and ifosfamide have shown the combination to be safe, reported Sebastian Bauer, MD, of the West German Cancer Center, University of Duisburg-Essen, Essen, Germany, and his colleagues at CTOS 2018.

The phase 1 trial (NCT03283696) enrolled 16 patients with advanced or metastatic soft tissue sarcomas. Patients had received no prior lines of systemic therapy and had an ECOG performance status of 0-1. Adequate follow-up data were available for 10 patients.

Olaratumab (Lartruvo), which binds platelet-derived growth factor receptor alpha (PDGFRα), was given at 15 mg/kg in combination with doxorubicin (75 mg/m2 on days 1-3) and ifosfamide (10 g/m2 on days 1-4). This was followed by mandatory granulocyte-colony-stimulating factor therapy in cycles 1-6 on a 21-day cycle. Doxorubicin could be administered by continuous infusion or bolus administration and with cardiac protection. Mesna dosing was at least 60% of the ifosfamide dose.

Two of the 10 patients had dose-limiting toxicities; one had grade 4 febrile neutropenia and the other had grade 3 febrile neutropenia and grade 3 mucositis. Common related adverse events occurring in over 30% of patients included fatigue, anemia, neutropenia, thrombocytopenia, constipation, and nausea. One patient discontinued study treatment due to progressive disease, and all others were on study treatment as of the data cutoff. Among 7 patients evaluated for tumor response, 3 patients had a partial response according to RECIST and 3 other patients had stabilized disease as best overall response, for a disease control rate of 86%.

Given that 8 of 10 evaluable patients have completed the dose-limiting toxicity period without dose-limiting toxicities at the 15 mg/kg dose level of olaratumab, the study has proceeded to the next cohort. In those patients, an olaratumab loading dose of 20 mg/kg will be evaluated in cycle 1, followed by 15 mg/kg of olaratumab in subsequent cycles with the same doses of doxorubicin plus ifosfamide, the researchers wrote in their abstract.

NOTE: Since CTOS 2018, olaratumab plus doxorubicin did not meet its phase 3 endpoint of overall survival (OS) advantage in the full study population or in the leiomyosarcoma subpopulation compared to doxorubicin alone.

Anthracycline-Based Regimen Excels in FIGO-1 Uterine Leiomyosarcoma

Patients with uterine leiomyosarcomas treated with anthracycline-based regimens experienced longer disease-free survival compared to patients treated with gemcitabine and docetaxel, according to a retrospective analysis reported at CTOS 2018.

Roberta Sanfilippo, MD, of Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy, and her colleagues reviewed all patients with FIGO stage I uterine leiomyosarcomas at two Italian centers who underwent hysterectomy with or without oophorectomy and were then treated with adjuvant chemotherapy with anthracycline-based or gemcitabine-based regimens.

Of 145 patients, 97 were treated with an anthracycline-based regimen and 48 with gemcitabine and docetaxel. The median number of cycles of anthracycline-based therapy patients received was 4 (range 2-6) and the median number of cycles with gemcitabine and docetaxel was 5 (range 3-7). Disease-free survival was 31 months in patients treated with anthracycline-based chemotherapy and 19 months in patients treated with gemcitabine and docetaxel.

These results suggest that future trials to assess the efficacy of adjuvant chemotherapy in uterine leiomyosarcoma should incorporate anthracyclines, the investigators maintain.

Trabectedin and Concurrent Low-Dose Radiotherapy Feasible

Trabectedin concurrent with lowdose radiotherapy is being examined as an option for patients with pulmonary metastatic soft tissue sarcoma (NCT02275286).

In a phase 1 study, long-lasting dimensional responses were seen in 71% of the irradiated lesions. Based on those results, trabectedin (Yondelis) at 1.5 mg/m2 will be the recommended dose for phase 2, according to Javier Martín-Broto, MD, of the Institute of Biomedicine Research (IBIS)-University Hospital Virgen del Rocio/CSIC/University of Seville, Spain, and his colleagues, reporting at CTOS 2018.

For the study, trabectedin was given along with radiotherapy (30 Gy) in 10 fractions (3 Gy/fraction). Three dose levels of trabectedin were administered: -1 (1.1 mg/m2), 1 (1.3 mg/m2), and 2 (1.5 mg/m2). Dose-limiting toxicity was defined as grade 3 or greater events excluding grade 3/4 neutropenia lasting less than 5 days, grade 3 transaminitis if it did not lead to trabectedin delay, and grade 3/4 nausea/vomiting due to inadequate prophylaxis.

Ten of the 18 patients enrolled had synovial sarcoma; 3 had undifferentiated pleomorphic sarcomas, and the other patients had either myxoid liposarcoma, dedifferentiated liposarcoma, G3 not otherwise specified sarcoma, leiomyosarcoma, or malignant peripheral nerve sheath tumor.

Patients received a median of 1 prior line of chemotherapy (range: 0-3). Twelve patients received trabectedin at dose level 1 and 6 patients at dose level 2. Grade 3/4 adverse events were neutropenia, seen in 8 patients; alanine aminotransferase (ALT) elevation, seen in 2 patients; gamma-glutamyl transferase (GGT) elevation, seen in 2 patients; anemia, seen in 2 patients; febrile neutropenia, seen in 1 patient; and pneumonitis, seen in 1 patient.

There were two dose-limiting toxicities: transient grade 4 ALT elevation at the level 1 dose and grade 4 neutropenia for more than 5 days at the level 2 dose.

Based on central radiological review of 17 evaluable patients, 2 patients achieved complete response, 3 had partial responses, 6 had stable disease, and 6 had progressive disease. The local review reported complete responses in 2 patients, partial responses in 5, stable disease in 4, and progressive disease in 6.

Of the irradiated lesions, 71% had long-lasting dimensional responses: 4 completely responded, 8 responded partially, 4 were stable, and 1 progressed.

With a median follow-up of 18 months, median progression-free survival was 2.83 months (95%CI: 2.3-3.3 months). Thirteen patients have died, with a median overall survival of 8.77 months (95%CI: 3.6-13.9) and a 12-month overall survival rate of 48%.

The investigators concluded trabectedin with concurrent radiotherapy was feasible in patients with pulmonary metastatic soft tissue sarcoma regardless of their histologic subtype.

For women, sexual health involves both body and mind. Conditions that compromise a woman’s sexual health interfere with intimacy and ultimately impact all areas of her well-being. Hypoactive sexual desire disorder (HSDD) is the most common of the female sexual dysfunctions. HSDD occurs in women of all ages but is continuously underdiagnosed and undermanaged.

The articles in this CME journal supplement comprehensively address the areas of concern that inhibit women’s healthcare clinicians in effectively addressing HSDD—namely patient communications, diagnostic strategies, and therapeutic modalities for treating HSDD. The information presented will allow these healthcare providers to implement strategies that will improve the sexual health of their patients presenting with HSDD, with the intent of improving these patients’ overall sense of well-being.

Click here to read the supplement. 

To access the posttest and evaluation and claim credit, visit: www.omniaeducation.com/hsdd 

For women, sexual health involves both body and mind. Conditions that compromise a woman’s sexual health interfere with intimacy and ultimately impact all areas of her well-being. Hypoactive sexual desire disorder (HSDD) is the most common of the female sexual dysfunctions. HSDD occurs in women of all ages but is continuously underdiagnosed and undermanaged.

The articles in this CME journal supplement comprehensively address the areas of concern that inhibit women’s healthcare clinicians in effectively addressing HSDD—namely patient communications, diagnostic strategies, and therapeutic modalities for treating HSDD. The information presented will allow these healthcare providers to implement strategies that will improve the sexual health of their patients presenting with HSDD, with the intent of improving these patients’ overall sense of well-being.

Click here to read the supplement. 

To access the posttest and evaluation and claim credit, visit: www.omniaeducation.com/hsdd 

For women, sexual health involves both body and mind. Conditions that compromise a woman’s sexual health interfere with intimacy and ultimately impact all areas of her well-being. Hypoactive sexual desire disorder (HSDD) is the most common of the female sexual dysfunctions. HSDD occurs in women of all ages but is continuously underdiagnosed and undermanaged.

The articles in this CME journal supplement comprehensively address the areas of concern that inhibit women’s healthcare clinicians in effectively addressing HSDD—namely patient communications, diagnostic strategies, and therapeutic modalities for treating HSDD. The information presented will allow these healthcare providers to implement strategies that will improve the sexual health of their patients presenting with HSDD, with the intent of improving these patients’ overall sense of well-being.

Click here to read the supplement. 

To access the posttest and evaluation and claim credit, visit: www.omniaeducation.com/hsdd 

Introduction

Soft tissue sarcomas (STS) are a heterogeneous group of cancerous tumors, comprised of more than 50 histological subtypes that develop from soft tissues of the body (eg, fat, muscles, nerve tissue, deep skin tissue, visceral nonepithelial tissue). Due to many factors, not limited to the heterogeneity of this set of diseases and lack of screening tests, reaching a diagnosis of STS is challenging for the general practitioner as well as for the oncologist. Sarcomas may present with nonspecific and often indolent symptomology, depending on the specific histological subtype. According to the American Cancer Society, the signs and symptoms of a sarcoma include a new or growing lump, worsening abdominal pain, blood in stool or vomit, and black stools (due to abdominal bleeding).¹ Unfortunately, these symptoms could be indicative of any number of other health conditions and are nonspecific to sarcoma.

As with many cancers, the early detection of disease when it may be completely resected could lead to a cure, whereas diagnosis when the disease is no longer amenable to surgery will impact patient survival. Among all forms of STS, early diagnosis when the patient has only localized disease is associated with an 80.8% five-year survival rate, which decreases to 16.4% for patients whose disease has already metastasized to other parts of the body at the time of diagnosis.²

Previous work has evaluated the relationship between duration of symptoms that may lead to a diagnosis of sarcoma and cancer outcomes. A retrospective analysis of a cohort of adults with bone or STS found no correlation between patient recall of duration of prediagnosis symptoms and survival or metastatic disease at diagnosis.^3,4 Little other research was identified that examined the challenges of identifying a potential sarcoma. Despite the gap in knowledge, advocacy and patient-centered organizations emphasize the risk of delayed diagnosis and report high levels of stress and frustration among patients by the time an accurate diagnosis is obtained.⁵ The objective of this study was to quantify the health care experience and misdiagnoses that occurred prior to a sarcoma diagnosis compared to a cohort of matched controls.

Methods

A retrospective observational database study was conducted using detailed resource utilization and cost data from the Truven MarketScan claims database. Truven MarketScan^® is a HIPAA-compliant, fully integrated patient-level database containing inpatient, outpatient, drug, lab, health risk assessment, and benefit design information from commercial and Medicare supplemental insurance plans. Additionally, the Health and Productivity Management (HPM) database, containing workplace absence, short-term disability, long-term disability, and worker’s compensation data, is linked at the individual patient level. The linkage of the claims and HPM database was used for this study.

Patients were eligible for inclusion in the cohort of a sarcoma if they had at least two ICD-9 codes of 171.x on two different days between July 1, 2004, and March 30, 2014. The date of the first eligible code was considered the index date. Patients were required to have at least 6 months of health care plan enrollment prior to the first eligible ICD-9 code to allow for prediagnosis activity to be identified in the database. Patients were also required to be 18 years of age or older on the first eligible ICD-9 code date. Patients were excluded who had evidence suggesting a diagnosis of osteosarcoma, Kaposi’s sarcoma, or gastrointestinal stromal tumors (treatment with methotrexate, ICD-9 codes of 176.x, 171.x, or 238.1), a history of any cancer before the eligible sarcoma ICD-9 code, or history of systemic anticancer therapy during the 6-month pre-index period. All patients meeting eligibility criteria were included in the matching algorithm to identify the control cohort.

The matched control cohort was required to have at least the same duration of follow-up at the case level as the matched sarcoma patient, could not have any evidence of any malignancy at any time in the database, nor could have received any systemic anticancer therapy at any time. Controls were randomly selected from the more than 100 million individual patient cases in the MarketScan database to be matched to the eligible sarcoma patient cohort exactly on age, geographic region of residence, health insurance plan type, gender, noncancer comorbid conditions (measured by Charlson Comorbidity Index items), and employment status. All factors were exact matched at the sarcoma cohort index diagnosis date. In the case of missing variables, patients were matched on missingness (eg, a case with missing employment status would be matched to a control with missing employment status).

The eligible time period for the index date of the possible sarcoma cohort and matched controls was between July 1, 2004, and March 30, 2014, which allowed for a minimum of 1-year follow-up through the end of the database available at the time of analysis.

All ICD-9 diagnostic and procedure codes present in the matched 6-month time period pre-index diagnosis were compared to explore factors that may be more likely to be present in the sarcoma cohort compared to matched controls. Univariate analysis was conducted for each prediagnosis variable. Analyses were conducted using T test for continuous variables, and Chi-square or Fisher’s exact test was used for categorical variables.

Number of physician visits, inpatient hospital stays, surgical procedures, and emergency room visits were compared between those in the sarcoma cohort and matched controls during the matched 6-month pre-index period. The post-index diagnosis employment status was also compared between groups using the HPM database. Comparisons between the sarcoma cohort and control cohort were made among the actively employed patients at baseline related to the proportion of patients who continued active employment, the proportion who permanently discontinued work, and the proportion who initially discontinued work and then returned to work at a later time. No adjustments were made for multiple comparisons.

Results

A total of 7826 controls were each matched to patients in the sarcoma cohort. The baseline characteristics of the study cohorts are provided in Table 1. 

During the 6-month period before the sarcoma diagnosis (prediagnosis period), patients had significantly greater frequency of diagnoses identified than controls for uncertain neoplasms, limb pain, and hypertension (all P<.001, Table 2). 

Similarly, the majority of health care resource utilization factors evaluated showed statistically higher health care use among patients later suspected of having sarcoma than matched controls (Table 3). 

Discussion

The symptoms experienced by patients that were recorded in claims were significantly higher across multiple categories than matched controls. However, the rates were relatively low, demonstrating the wide variability in the presentation of sarcoma. Patients had a variety of recorded problems, not limited to a lump or pain, but including hematologic, gastric, and cardiac concerns, that differed from those who had no suspected sarcoma. These factors highlight the challenges that may be facing patients who have an undetected sarcoma.

An expected finding was the difference in duration of follow-up between cohorts. This could be due to longer survival of those without a sarcoma diagnosis or due to insurance changes among those who had a sarcoma diagnosis. The absence of death data did not allow for further exploration of this finding within this study. Future research may wish to identify more comprehensive datasets to allow for the objective evaluation of the differences in time to diagnosis and stage of disease and survival, which would be the ultimate goal in order to develop potential strategies to improve patient outcomes.

This study was limited in that the sarcoma diagnosis could not be verified in a clinical record due to the de-identified nature of the claims data used for this study. Prior work has shown that the ICD coding for sarcoma is incomplete^6,7; therefore it is likely there are many other patients in the claims dataset who had a suspected sarcoma but who did not have a 171.x code recorded. Hence, this study is limited to a comparison of a cohort for whom the provider specified a sarcoma code in their billing records. While there are gaps in the ability to identify the entire population of sarcoma patients, the patients with ICD codes used in this study are likely true sarcoma cases. Prior work has demonstrated that the presence of these codes accurately reflects a true sarcoma diagnosis.⁷ However, given the concerns with ICD coding, two sarcoma codes were required on unique days to reduce the risk of single rule-out codes or data entry error. Patients diagnosed with sarcoma demonstrate significantly greater health care resource use across variables as matched controls during the 6-month period leading to diagnosis, supporting the observations within advocacy and patient reports of the challenges faced during the process to reach an accurate diagnosis. This work may provide the initial basis for the development of strategies to more rapidly identify a potential sarcoma. Future research could also evaluate more than 6 months prior to diagnosis, to quantify the duration of time during which these differences versus controls may exist. Additionally, the cost of care may be of interest to future research to better quantify the burden of misdiagnosis on the health care system.

Acknowledgement
The authors would like to acknowledge Yun Fang, MS, for her support in the SAS coding for the analysis of this study.

Corresponding Author
Lisa M. Hess, PhD, Eli Lilly and Company. [email protected]

Disclosures
No funding was received or exchanged in the conceptualization, conduct, data collection, analysis, interpretation, or writing related to this study. This unfunded study was conducted by employees of Eli Lilly and Company.

Introduction

Soft tissue sarcomas (STS) are a heterogeneous group of cancerous tumors, comprised of more than 50 histological subtypes that develop from soft tissues of the body (eg, fat, muscles, nerve tissue, deep skin tissue, visceral nonepithelial tissue). Due to many factors, not limited to the heterogeneity of this set of diseases and lack of screening tests, reaching a diagnosis of STS is challenging for the general practitioner as well as for the oncologist. Sarcomas may present with nonspecific and often indolent symptomology, depending on the specific histological subtype. According to the American Cancer Society, the signs and symptoms of a sarcoma include a new or growing lump, worsening abdominal pain, blood in stool or vomit, and black stools (due to abdominal bleeding).¹ Unfortunately, these symptoms could be indicative of any number of other health conditions and are nonspecific to sarcoma.

As with many cancers, the early detection of disease when it may be completely resected could lead to a cure, whereas diagnosis when the disease is no longer amenable to surgery will impact patient survival. Among all forms of STS, early diagnosis when the patient has only localized disease is associated with an 80.8% five-year survival rate, which decreases to 16.4% for patients whose disease has already metastasized to other parts of the body at the time of diagnosis.²

Previous work has evaluated the relationship between duration of symptoms that may lead to a diagnosis of sarcoma and cancer outcomes. A retrospective analysis of a cohort of adults with bone or STS found no correlation between patient recall of duration of prediagnosis symptoms and survival or metastatic disease at diagnosis.^3,4 Little other research was identified that examined the challenges of identifying a potential sarcoma. Despite the gap in knowledge, advocacy and patient-centered organizations emphasize the risk of delayed diagnosis and report high levels of stress and frustration among patients by the time an accurate diagnosis is obtained.⁵ The objective of this study was to quantify the health care experience and misdiagnoses that occurred prior to a sarcoma diagnosis compared to a cohort of matched controls.

Methods

A retrospective observational database study was conducted using detailed resource utilization and cost data from the Truven MarketScan claims database. Truven MarketScan^® is a HIPAA-compliant, fully integrated patient-level database containing inpatient, outpatient, drug, lab, health risk assessment, and benefit design information from commercial and Medicare supplemental insurance plans. Additionally, the Health and Productivity Management (HPM) database, containing workplace absence, short-term disability, long-term disability, and worker’s compensation data, is linked at the individual patient level. The linkage of the claims and HPM database was used for this study.

Patients were eligible for inclusion in the cohort of a sarcoma if they had at least two ICD-9 codes of 171.x on two different days between July 1, 2004, and March 30, 2014. The date of the first eligible code was considered the index date. Patients were required to have at least 6 months of health care plan enrollment prior to the first eligible ICD-9 code to allow for prediagnosis activity to be identified in the database. Patients were also required to be 18 years of age or older on the first eligible ICD-9 code date. Patients were excluded who had evidence suggesting a diagnosis of osteosarcoma, Kaposi’s sarcoma, or gastrointestinal stromal tumors (treatment with methotrexate, ICD-9 codes of 176.x, 171.x, or 238.1), a history of any cancer before the eligible sarcoma ICD-9 code, or history of systemic anticancer therapy during the 6-month pre-index period. All patients meeting eligibility criteria were included in the matching algorithm to identify the control cohort.

The matched control cohort was required to have at least the same duration of follow-up at the case level as the matched sarcoma patient, could not have any evidence of any malignancy at any time in the database, nor could have received any systemic anticancer therapy at any time. Controls were randomly selected from the more than 100 million individual patient cases in the MarketScan database to be matched to the eligible sarcoma patient cohort exactly on age, geographic region of residence, health insurance plan type, gender, noncancer comorbid conditions (measured by Charlson Comorbidity Index items), and employment status. All factors were exact matched at the sarcoma cohort index diagnosis date. In the case of missing variables, patients were matched on missingness (eg, a case with missing employment status would be matched to a control with missing employment status).

The eligible time period for the index date of the possible sarcoma cohort and matched controls was between July 1, 2004, and March 30, 2014, which allowed for a minimum of 1-year follow-up through the end of the database available at the time of analysis.

All ICD-9 diagnostic and procedure codes present in the matched 6-month time period pre-index diagnosis were compared to explore factors that may be more likely to be present in the sarcoma cohort compared to matched controls. Univariate analysis was conducted for each prediagnosis variable. Analyses were conducted using T test for continuous variables, and Chi-square or Fisher’s exact test was used for categorical variables.

Number of physician visits, inpatient hospital stays, surgical procedures, and emergency room visits were compared between those in the sarcoma cohort and matched controls during the matched 6-month pre-index period. The post-index diagnosis employment status was also compared between groups using the HPM database. Comparisons between the sarcoma cohort and control cohort were made among the actively employed patients at baseline related to the proportion of patients who continued active employment, the proportion who permanently discontinued work, and the proportion who initially discontinued work and then returned to work at a later time. No adjustments were made for multiple comparisons.

Results

A total of 7826 controls were each matched to patients in the sarcoma cohort. The baseline characteristics of the study cohorts are provided in Table 1. 

During the 6-month period before the sarcoma diagnosis (prediagnosis period), patients had significantly greater frequency of diagnoses identified than controls for uncertain neoplasms, limb pain, and hypertension (all P<.001, Table 2). 

Similarly, the majority of health care resource utilization factors evaluated showed statistically higher health care use among patients later suspected of having sarcoma than matched controls (Table 3). 

Discussion

The symptoms experienced by patients that were recorded in claims were significantly higher across multiple categories than matched controls. However, the rates were relatively low, demonstrating the wide variability in the presentation of sarcoma. Patients had a variety of recorded problems, not limited to a lump or pain, but including hematologic, gastric, and cardiac concerns, that differed from those who had no suspected sarcoma. These factors highlight the challenges that may be facing patients who have an undetected sarcoma.

An expected finding was the difference in duration of follow-up between cohorts. This could be due to longer survival of those without a sarcoma diagnosis or due to insurance changes among those who had a sarcoma diagnosis. The absence of death data did not allow for further exploration of this finding within this study. Future research may wish to identify more comprehensive datasets to allow for the objective evaluation of the differences in time to diagnosis and stage of disease and survival, which would be the ultimate goal in order to develop potential strategies to improve patient outcomes.

This study was limited in that the sarcoma diagnosis could not be verified in a clinical record due to the de-identified nature of the claims data used for this study. Prior work has shown that the ICD coding for sarcoma is incomplete^6,7; therefore it is likely there are many other patients in the claims dataset who had a suspected sarcoma but who did not have a 171.x code recorded. Hence, this study is limited to a comparison of a cohort for whom the provider specified a sarcoma code in their billing records. While there are gaps in the ability to identify the entire population of sarcoma patients, the patients with ICD codes used in this study are likely true sarcoma cases. Prior work has demonstrated that the presence of these codes accurately reflects a true sarcoma diagnosis.⁷ However, given the concerns with ICD coding, two sarcoma codes were required on unique days to reduce the risk of single rule-out codes or data entry error. Patients diagnosed with sarcoma demonstrate significantly greater health care resource use across variables as matched controls during the 6-month period leading to diagnosis, supporting the observations within advocacy and patient reports of the challenges faced during the process to reach an accurate diagnosis. This work may provide the initial basis for the development of strategies to more rapidly identify a potential sarcoma. Future research could also evaluate more than 6 months prior to diagnosis, to quantify the duration of time during which these differences versus controls may exist. Additionally, the cost of care may be of interest to future research to better quantify the burden of misdiagnosis on the health care system.

Acknowledgement
The authors would like to acknowledge Yun Fang, MS, for her support in the SAS coding for the analysis of this study.

Corresponding Author
Lisa M. Hess, PhD, Eli Lilly and Company. [email protected]

Disclosures
No funding was received or exchanged in the conceptualization, conduct, data collection, analysis, interpretation, or writing related to this study. This unfunded study was conducted by employees of Eli Lilly and Company.

Introduction

Soft tissue sarcomas (STS) are a heterogeneous group of cancerous tumors, comprised of more than 50 histological subtypes that develop from soft tissues of the body (eg, fat, muscles, nerve tissue, deep skin tissue, visceral nonepithelial tissue). Due to many factors, not limited to the heterogeneity of this set of diseases and lack of screening tests, reaching a diagnosis of STS is challenging for the general practitioner as well as for the oncologist. Sarcomas may present with nonspecific and often indolent symptomology, depending on the specific histological subtype. According to the American Cancer Society, the signs and symptoms of a sarcoma include a new or growing lump, worsening abdominal pain, blood in stool or vomit, and black stools (due to abdominal bleeding).¹ Unfortunately, these symptoms could be indicative of any number of other health conditions and are nonspecific to sarcoma.

As with many cancers, the early detection of disease when it may be completely resected could lead to a cure, whereas diagnosis when the disease is no longer amenable to surgery will impact patient survival. Among all forms of STS, early diagnosis when the patient has only localized disease is associated with an 80.8% five-year survival rate, which decreases to 16.4% for patients whose disease has already metastasized to other parts of the body at the time of diagnosis.²

Previous work has evaluated the relationship between duration of symptoms that may lead to a diagnosis of sarcoma and cancer outcomes. A retrospective analysis of a cohort of adults with bone or STS found no correlation between patient recall of duration of prediagnosis symptoms and survival or metastatic disease at diagnosis.^3,4 Little other research was identified that examined the challenges of identifying a potential sarcoma. Despite the gap in knowledge, advocacy and patient-centered organizations emphasize the risk of delayed diagnosis and report high levels of stress and frustration among patients by the time an accurate diagnosis is obtained.⁵ The objective of this study was to quantify the health care experience and misdiagnoses that occurred prior to a sarcoma diagnosis compared to a cohort of matched controls.

Methods

A retrospective observational database study was conducted using detailed resource utilization and cost data from the Truven MarketScan claims database. Truven MarketScan^® is a HIPAA-compliant, fully integrated patient-level database containing inpatient, outpatient, drug, lab, health risk assessment, and benefit design information from commercial and Medicare supplemental insurance plans. Additionally, the Health and Productivity Management (HPM) database, containing workplace absence, short-term disability, long-term disability, and worker’s compensation data, is linked at the individual patient level. The linkage of the claims and HPM database was used for this study.

Patients were eligible for inclusion in the cohort of a sarcoma if they had at least two ICD-9 codes of 171.x on two different days between July 1, 2004, and March 30, 2014. The date of the first eligible code was considered the index date. Patients were required to have at least 6 months of health care plan enrollment prior to the first eligible ICD-9 code to allow for prediagnosis activity to be identified in the database. Patients were also required to be 18 years of age or older on the first eligible ICD-9 code date. Patients were excluded who had evidence suggesting a diagnosis of osteosarcoma, Kaposi’s sarcoma, or gastrointestinal stromal tumors (treatment with methotrexate, ICD-9 codes of 176.x, 171.x, or 238.1), a history of any cancer before the eligible sarcoma ICD-9 code, or history of systemic anticancer therapy during the 6-month pre-index period. All patients meeting eligibility criteria were included in the matching algorithm to identify the control cohort.

The matched control cohort was required to have at least the same duration of follow-up at the case level as the matched sarcoma patient, could not have any evidence of any malignancy at any time in the database, nor could have received any systemic anticancer therapy at any time. Controls were randomly selected from the more than 100 million individual patient cases in the MarketScan database to be matched to the eligible sarcoma patient cohort exactly on age, geographic region of residence, health insurance plan type, gender, noncancer comorbid conditions (measured by Charlson Comorbidity Index items), and employment status. All factors were exact matched at the sarcoma cohort index diagnosis date. In the case of missing variables, patients were matched on missingness (eg, a case with missing employment status would be matched to a control with missing employment status).

The eligible time period for the index date of the possible sarcoma cohort and matched controls was between July 1, 2004, and March 30, 2014, which allowed for a minimum of 1-year follow-up through the end of the database available at the time of analysis.

All ICD-9 diagnostic and procedure codes present in the matched 6-month time period pre-index diagnosis were compared to explore factors that may be more likely to be present in the sarcoma cohort compared to matched controls. Univariate analysis was conducted for each prediagnosis variable. Analyses were conducted using T test for continuous variables, and Chi-square or Fisher’s exact test was used for categorical variables.

Number of physician visits, inpatient hospital stays, surgical procedures, and emergency room visits were compared between those in the sarcoma cohort and matched controls during the matched 6-month pre-index period. The post-index diagnosis employment status was also compared between groups using the HPM database. Comparisons between the sarcoma cohort and control cohort were made among the actively employed patients at baseline related to the proportion of patients who continued active employment, the proportion who permanently discontinued work, and the proportion who initially discontinued work and then returned to work at a later time. No adjustments were made for multiple comparisons.

Results

A total of 7826 controls were each matched to patients in the sarcoma cohort. The baseline characteristics of the study cohorts are provided in Table 1. 

During the 6-month period before the sarcoma diagnosis (prediagnosis period), patients had significantly greater frequency of diagnoses identified than controls for uncertain neoplasms, limb pain, and hypertension (all P<.001, Table 2). 

Similarly, the majority of health care resource utilization factors evaluated showed statistically higher health care use among patients later suspected of having sarcoma than matched controls (Table 3). 

Discussion

The symptoms experienced by patients that were recorded in claims were significantly higher across multiple categories than matched controls. However, the rates were relatively low, demonstrating the wide variability in the presentation of sarcoma. Patients had a variety of recorded problems, not limited to a lump or pain, but including hematologic, gastric, and cardiac concerns, that differed from those who had no suspected sarcoma. These factors highlight the challenges that may be facing patients who have an undetected sarcoma.

An expected finding was the difference in duration of follow-up between cohorts. This could be due to longer survival of those without a sarcoma diagnosis or due to insurance changes among those who had a sarcoma diagnosis. The absence of death data did not allow for further exploration of this finding within this study. Future research may wish to identify more comprehensive datasets to allow for the objective evaluation of the differences in time to diagnosis and stage of disease and survival, which would be the ultimate goal in order to develop potential strategies to improve patient outcomes.

This study was limited in that the sarcoma diagnosis could not be verified in a clinical record due to the de-identified nature of the claims data used for this study. Prior work has shown that the ICD coding for sarcoma is incomplete^6,7; therefore it is likely there are many other patients in the claims dataset who had a suspected sarcoma but who did not have a 171.x code recorded. Hence, this study is limited to a comparison of a cohort for whom the provider specified a sarcoma code in their billing records. While there are gaps in the ability to identify the entire population of sarcoma patients, the patients with ICD codes used in this study are likely true sarcoma cases. Prior work has demonstrated that the presence of these codes accurately reflects a true sarcoma diagnosis.⁷ However, given the concerns with ICD coding, two sarcoma codes were required on unique days to reduce the risk of single rule-out codes or data entry error. Patients diagnosed with sarcoma demonstrate significantly greater health care resource use across variables as matched controls during the 6-month period leading to diagnosis, supporting the observations within advocacy and patient reports of the challenges faced during the process to reach an accurate diagnosis. This work may provide the initial basis for the development of strategies to more rapidly identify a potential sarcoma. Future research could also evaluate more than 6 months prior to diagnosis, to quantify the duration of time during which these differences versus controls may exist. Additionally, the cost of care may be of interest to future research to better quantify the burden of misdiagnosis on the health care system.

Acknowledgement
The authors would like to acknowledge Yun Fang, MS, for her support in the SAS coding for the analysis of this study.

Corresponding Author
Lisa M. Hess, PhD, Eli Lilly and Company. [email protected]

Disclosures
No funding was received or exchanged in the conceptualization, conduct, data collection, analysis, interpretation, or writing related to this study. This unfunded study was conducted by employees of Eli Lilly and Company.

We begin this second full year publishing The Sarcoma Journal—Official Journal of the Sarcoma Foundation of America^TM—with renewed energy and dedication to its founding principle of communicating authoritative and comprehensive scientific information on the diagnosis and treatment of sarcomas and sarcoma subtypes.

Despite advances in treatment and management options for our patients, the need still exists for more effective treatment strategies, new treatment paradigms, and improved understanding of disease biology. This journal, along with its online platform, plays an important role in the dissemination of reliable, peer-reviewed content to the sarcoma community and aims to bridge the gap between bench and bedside.

To this end, we have again recruited an outstanding advisory board, many of whom have long-standing affiliations with the Sarcoma Foundation of America. With their help, the editorial staff and I will continue to build the journal and make it the number one academic and practice resource for the sarcoma community.

We invite you and your colleagues to submit original research, review articles, case reports, opinion pieces, and meeting summaries for publication. In this way we will create the robust forum we all desire.

We begin this second full year publishing The Sarcoma Journal—Official Journal of the Sarcoma Foundation of America^TM—with renewed energy and dedication to its founding principle of communicating authoritative and comprehensive scientific information on the diagnosis and treatment of sarcomas and sarcoma subtypes.

Despite advances in treatment and management options for our patients, the need still exists for more effective treatment strategies, new treatment paradigms, and improved understanding of disease biology. This journal, along with its online platform, plays an important role in the dissemination of reliable, peer-reviewed content to the sarcoma community and aims to bridge the gap between bench and bedside.

To this end, we have again recruited an outstanding advisory board, many of whom have long-standing affiliations with the Sarcoma Foundation of America. With their help, the editorial staff and I will continue to build the journal and make it the number one academic and practice resource for the sarcoma community.

We invite you and your colleagues to submit original research, review articles, case reports, opinion pieces, and meeting summaries for publication. In this way we will create the robust forum we all desire.

We begin this second full year publishing The Sarcoma Journal—Official Journal of the Sarcoma Foundation of America^TM—with renewed energy and dedication to its founding principle of communicating authoritative and comprehensive scientific information on the diagnosis and treatment of sarcomas and sarcoma subtypes.

Despite advances in treatment and management options for our patients, the need still exists for more effective treatment strategies, new treatment paradigms, and improved understanding of disease biology. This journal, along with its online platform, plays an important role in the dissemination of reliable, peer-reviewed content to the sarcoma community and aims to bridge the gap between bench and bedside.

To this end, we have again recruited an outstanding advisory board, many of whom have long-standing affiliations with the Sarcoma Foundation of America. With their help, the editorial staff and I will continue to build the journal and make it the number one academic and practice resource for the sarcoma community.

We invite you and your colleagues to submit original research, review articles, case reports, opinion pieces, and meeting summaries for publication. In this way we will create the robust forum we all desire.

Gastrointestinal stromal tumor (GIST) is the most common soft tissue sarcoma of the gastrointestinal tract, usually arising from the interstitial cells of Cajal or similar cells in the outer wall of the gastrointestinal tract.^1,2 Most GISTs have an activating mutation in KIT or platelet-derived growth factor receptor alpha (PDGFRα). Tumor size, mitotic rate, and anatomic site are the most common pathological features used to risk stratify GIST tumors.^3-10 It is important to note when using such risk calculators that preoperative imatinib before determining tumor characteristics (such as mitoses per 50 high-power fields [hpf]) often changes the relevant parameters so that the same risk calculations may not apply. Tumors with a mitotic rate ≤5 mitoses per 50 hpf and a size ≤5 cm in greatest dimension have a lower recurrence rate after resection than tumors with a mitotic rate >5 mitoses per 50 hpf and a size >10 cm, and larger tumors can have a recurrence rate of up to 86%.^11,12 Findings from a large observational study have suggested that the prognosis of gastric GIST in Korea and Japan may be more favorable compared with that in Western countries.¹³

The primary treatment of a localized primary GIST is surgical excision, but a cure is limited by recurrence.^14,15 Imatinib is useful in the treatment of metastatic or recurrent GIST, and adjuvant treatment with imatinib after surgery has been shown to improve progression-free and overall survival in some cases.^3,16-18 Responses to adjuvant imatinib depend on tumor sensitivity to the drug and the risk of recurrence. Drug sensitivity is largely dependent on the presence of mutations in KIT or PDGFRα.^3,18 Recurrence risk is highly dependent on tumor size, tumor site, tumor rupture, and mitotic index.^{1,3,5,6,8,9,18,19} Findings on the use of gene expression patterns to predict recurrence risk have also been reported.^20-27 However, recurrence risk is poorly understood for categories in which there are few cases with known outcomes, such as very small gastric GIST with a high mitotic index. For example, few cases of gastric GIST have been reported with a tumor size ≤2 cm, a mitotic rate >5 mitoses per 50 hpf, and adequate clinical follow-up. In such cases, it is difficult to assess the risk of recurrence.⁶ We report here the long-term outcome of a patient with a 1.8-cm gastric GIST with a mitotic index of 36 mitoses per 50 hpf and a KIT exon 11 mutation.

Case Presentation and Summary

A 69-year-old man presented with periumbilical and epigastric pain of 6-month duration. His medical history was notable for hyperlipidemia, hypertension, coronary angioplasty, and spinal surgery. He had a 40 pack-year smoking history and consumed 2 to 4 alcoholic drinks per day. The results of a physical examination were unremarkable. A computed tomographic (CT) scan showed no abnormalities. An esophagogastroduodenoscopy (EGD) revealed gastric ulcers. He was treated successfully with omeprazole 20 mg by mouth daily.

A month later, a follow-up EGD revealed a 1.8 x 1.5-cm submucosal mass 3 cm from the gastroesophageal junction. The patient underwent a fundus wedge resection, and a submucosal mass 1.8 cm in greatest dimension was removed. Pathologic examination revealed a GIST, spindle cell type, with a mitotic rate of 36 mitoses per 50 hpf with negative margins. Immunohistochemistry was positive for CD117. An exon 11 deletion (KVV558-560NV) was present in KIT. The patient’s risk of recurrence was unclear, and his follow-up included CT scans of the abdomen and pelvis every 3 to 4 months for the first 2 years, then every 6 months for the next 2.5 years.

A CT scan about 3.5 years after primary resection revealed small nonspecific liver hypodensities that became more prominent during the next year. About 5 years after primary resection, magnetic resonance imaging (MRI) revealed several liver lesions, the largest of which measured 1.3 cm in greatest dimension. The patient’s liver metastases were readily identified by MRI (Figure 1) and CT imaging (Figure 2A). 

Discussion

Small gastric GISTs are sometimes found by endoscopy performed for unrelated reasons. Recent data suggest that the incidence of gastric GIST may be higher than previously thought. In a Japanese study of patients with gastric cancer in which 100 stomachs were systematically examined pathologically, 50 microscopic GISTs were found in 35 patients.²⁸ Most small gastric GISTs have a low mitotic index. Few cases have been described with a high mitotic index. In a study of 1765 cases of GIST of the stomach, 8 patients had a tumor size less than 2 cm and a mitotic index greater than 5. Of those, only 6 patients had long-term follow-up, and 3 were alive without disease at 2, 17, and 20 years of follow-up.⁷ These limited data make it impossible to predict outcomes in patients with small gastric GIST with a high mitotic index.

For patients who are at high risk of recurrence after surgery, 3 years of adjuvant imatinib treatment compared with 1 year has been shown to improve overall survival and is the current standard of care.^10,17 A study comparing 5 and 3 years of imatinib is ongoing to establish whether a longer period of adjuvant treatment is warranted. In patients with metastatic GIST, lifelong imatinib until lack of benefit is considered optimal treatment.¹⁰ All patients should undergo KIT mutation analysis. Those with the PDGFRα D842V mutation, SDH (succinate dehydrogenase) deficiency, or neurofibromatosis-related GIST should not receive adjuvant imatinib.

This case has several unusual features. The small tumor size with a very high mitotic rate is rare. Such cases have not been reported in large numbers and have therefore not been reliably incorporated into risk prediction algorithms. In addition, despite a high mitotic index, the tumor was not FDG avid on PET imaging. The diagnosis of GIST is strongly supported by the KIT mutation and response to imatinib. This particular KIT mutation in larger GISTs is associated with aggressive disease. The present case adds to the data on the biology of small gastric GISTs with a high mitotic index and suggests the mitotic index in these tumors may be a more important predictor than size. TSJ

Acknowlegement
The authors thank Michael Franklin, MS, for editorial assistance, and Sabrina Porter for media edits.

^aDepartment of Medicine, University of Minnesota Medical School; ^bDepartment of Laboratory Medicine and Pathology, University of Minnesota Medical School; and ^cMasonic Cancer Center, University of Minnesota Medical School, Minneapolis, Minnesota.

Disclosures
The authors report no disclosures or conflicts of interest. This article was originally published in The Journal of Community and Supportive Oncology JCSO. 2018;16(3):e163-e166. ©Frontline Medical Communications. doi:10.12788/jcso.0402. It is reproduced with permission from the copyright owner. Further reproduction prohibited without permission.

Gastrointestinal stromal tumor (GIST) is the most common soft tissue sarcoma of the gastrointestinal tract, usually arising from the interstitial cells of Cajal or similar cells in the outer wall of the gastrointestinal tract.^1,2 Most GISTs have an activating mutation in KIT or platelet-derived growth factor receptor alpha (PDGFRα). Tumor size, mitotic rate, and anatomic site are the most common pathological features used to risk stratify GIST tumors.^3-10 It is important to note when using such risk calculators that preoperative imatinib before determining tumor characteristics (such as mitoses per 50 high-power fields [hpf]) often changes the relevant parameters so that the same risk calculations may not apply. Tumors with a mitotic rate ≤5 mitoses per 50 hpf and a size ≤5 cm in greatest dimension have a lower recurrence rate after resection than tumors with a mitotic rate >5 mitoses per 50 hpf and a size >10 cm, and larger tumors can have a recurrence rate of up to 86%.^11,12 Findings from a large observational study have suggested that the prognosis of gastric GIST in Korea and Japan may be more favorable compared with that in Western countries.¹³

The primary treatment of a localized primary GIST is surgical excision, but a cure is limited by recurrence.^14,15 Imatinib is useful in the treatment of metastatic or recurrent GIST, and adjuvant treatment with imatinib after surgery has been shown to improve progression-free and overall survival in some cases.^3,16-18 Responses to adjuvant imatinib depend on tumor sensitivity to the drug and the risk of recurrence. Drug sensitivity is largely dependent on the presence of mutations in KIT or PDGFRα.^3,18 Recurrence risk is highly dependent on tumor size, tumor site, tumor rupture, and mitotic index.^{1,3,5,6,8,9,18,19} Findings on the use of gene expression patterns to predict recurrence risk have also been reported.^20-27 However, recurrence risk is poorly understood for categories in which there are few cases with known outcomes, such as very small gastric GIST with a high mitotic index. For example, few cases of gastric GIST have been reported with a tumor size ≤2 cm, a mitotic rate >5 mitoses per 50 hpf, and adequate clinical follow-up. In such cases, it is difficult to assess the risk of recurrence.⁶ We report here the long-term outcome of a patient with a 1.8-cm gastric GIST with a mitotic index of 36 mitoses per 50 hpf and a KIT exon 11 mutation.

Case Presentation and Summary

A 69-year-old man presented with periumbilical and epigastric pain of 6-month duration. His medical history was notable for hyperlipidemia, hypertension, coronary angioplasty, and spinal surgery. He had a 40 pack-year smoking history and consumed 2 to 4 alcoholic drinks per day. The results of a physical examination were unremarkable. A computed tomographic (CT) scan showed no abnormalities. An esophagogastroduodenoscopy (EGD) revealed gastric ulcers. He was treated successfully with omeprazole 20 mg by mouth daily.

A month later, a follow-up EGD revealed a 1.8 x 1.5-cm submucosal mass 3 cm from the gastroesophageal junction. The patient underwent a fundus wedge resection, and a submucosal mass 1.8 cm in greatest dimension was removed. Pathologic examination revealed a GIST, spindle cell type, with a mitotic rate of 36 mitoses per 50 hpf with negative margins. Immunohistochemistry was positive for CD117. An exon 11 deletion (KVV558-560NV) was present in KIT. The patient’s risk of recurrence was unclear, and his follow-up included CT scans of the abdomen and pelvis every 3 to 4 months for the first 2 years, then every 6 months for the next 2.5 years.

A CT scan about 3.5 years after primary resection revealed small nonspecific liver hypodensities that became more prominent during the next year. About 5 years after primary resection, magnetic resonance imaging (MRI) revealed several liver lesions, the largest of which measured 1.3 cm in greatest dimension. The patient’s liver metastases were readily identified by MRI (Figure 1) and CT imaging (Figure 2A). 

Discussion

Small gastric GISTs are sometimes found by endoscopy performed for unrelated reasons. Recent data suggest that the incidence of gastric GIST may be higher than previously thought. In a Japanese study of patients with gastric cancer in which 100 stomachs were systematically examined pathologically, 50 microscopic GISTs were found in 35 patients.²⁸ Most small gastric GISTs have a low mitotic index. Few cases have been described with a high mitotic index. In a study of 1765 cases of GIST of the stomach, 8 patients had a tumor size less than 2 cm and a mitotic index greater than 5. Of those, only 6 patients had long-term follow-up, and 3 were alive without disease at 2, 17, and 20 years of follow-up.⁷ These limited data make it impossible to predict outcomes in patients with small gastric GIST with a high mitotic index.

For patients who are at high risk of recurrence after surgery, 3 years of adjuvant imatinib treatment compared with 1 year has been shown to improve overall survival and is the current standard of care.^10,17 A study comparing 5 and 3 years of imatinib is ongoing to establish whether a longer period of adjuvant treatment is warranted. In patients with metastatic GIST, lifelong imatinib until lack of benefit is considered optimal treatment.¹⁰ All patients should undergo KIT mutation analysis. Those with the PDGFRα D842V mutation, SDH (succinate dehydrogenase) deficiency, or neurofibromatosis-related GIST should not receive adjuvant imatinib.

This case has several unusual features. The small tumor size with a very high mitotic rate is rare. Such cases have not been reported in large numbers and have therefore not been reliably incorporated into risk prediction algorithms. In addition, despite a high mitotic index, the tumor was not FDG avid on PET imaging. The diagnosis of GIST is strongly supported by the KIT mutation and response to imatinib. This particular KIT mutation in larger GISTs is associated with aggressive disease. The present case adds to the data on the biology of small gastric GISTs with a high mitotic index and suggests the mitotic index in these tumors may be a more important predictor than size. TSJ

Acknowlegement
The authors thank Michael Franklin, MS, for editorial assistance, and Sabrina Porter for media edits.

^aDepartment of Medicine, University of Minnesota Medical School; ^bDepartment of Laboratory Medicine and Pathology, University of Minnesota Medical School; and ^cMasonic Cancer Center, University of Minnesota Medical School, Minneapolis, Minnesota.

Disclosures
The authors report no disclosures or conflicts of interest. This article was originally published in The Journal of Community and Supportive Oncology JCSO. 2018;16(3):e163-e166. ©Frontline Medical Communications. doi:10.12788/jcso.0402. It is reproduced with permission from the copyright owner. Further reproduction prohibited without permission.

Gastrointestinal stromal tumor (GIST) is the most common soft tissue sarcoma of the gastrointestinal tract, usually arising from the interstitial cells of Cajal or similar cells in the outer wall of the gastrointestinal tract.^1,2 Most GISTs have an activating mutation in KIT or platelet-derived growth factor receptor alpha (PDGFRα). Tumor size, mitotic rate, and anatomic site are the most common pathological features used to risk stratify GIST tumors.^3-10 It is important to note when using such risk calculators that preoperative imatinib before determining tumor characteristics (such as mitoses per 50 high-power fields [hpf]) often changes the relevant parameters so that the same risk calculations may not apply. Tumors with a mitotic rate ≤5 mitoses per 50 hpf and a size ≤5 cm in greatest dimension have a lower recurrence rate after resection than tumors with a mitotic rate >5 mitoses per 50 hpf and a size >10 cm, and larger tumors can have a recurrence rate of up to 86%.^11,12 Findings from a large observational study have suggested that the prognosis of gastric GIST in Korea and Japan may be more favorable compared with that in Western countries.¹³

The primary treatment of a localized primary GIST is surgical excision, but a cure is limited by recurrence.^14,15 Imatinib is useful in the treatment of metastatic or recurrent GIST, and adjuvant treatment with imatinib after surgery has been shown to improve progression-free and overall survival in some cases.^3,16-18 Responses to adjuvant imatinib depend on tumor sensitivity to the drug and the risk of recurrence. Drug sensitivity is largely dependent on the presence of mutations in KIT or PDGFRα.^3,18 Recurrence risk is highly dependent on tumor size, tumor site, tumor rupture, and mitotic index.^{1,3,5,6,8,9,18,19} Findings on the use of gene expression patterns to predict recurrence risk have also been reported.^20-27 However, recurrence risk is poorly understood for categories in which there are few cases with known outcomes, such as very small gastric GIST with a high mitotic index. For example, few cases of gastric GIST have been reported with a tumor size ≤2 cm, a mitotic rate >5 mitoses per 50 hpf, and adequate clinical follow-up. In such cases, it is difficult to assess the risk of recurrence.⁶ We report here the long-term outcome of a patient with a 1.8-cm gastric GIST with a mitotic index of 36 mitoses per 50 hpf and a KIT exon 11 mutation.

Case Presentation and Summary

A 69-year-old man presented with periumbilical and epigastric pain of 6-month duration. His medical history was notable for hyperlipidemia, hypertension, coronary angioplasty, and spinal surgery. He had a 40 pack-year smoking history and consumed 2 to 4 alcoholic drinks per day. The results of a physical examination were unremarkable. A computed tomographic (CT) scan showed no abnormalities. An esophagogastroduodenoscopy (EGD) revealed gastric ulcers. He was treated successfully with omeprazole 20 mg by mouth daily.

A month later, a follow-up EGD revealed a 1.8 x 1.5-cm submucosal mass 3 cm from the gastroesophageal junction. The patient underwent a fundus wedge resection, and a submucosal mass 1.8 cm in greatest dimension was removed. Pathologic examination revealed a GIST, spindle cell type, with a mitotic rate of 36 mitoses per 50 hpf with negative margins. Immunohistochemistry was positive for CD117. An exon 11 deletion (KVV558-560NV) was present in KIT. The patient’s risk of recurrence was unclear, and his follow-up included CT scans of the abdomen and pelvis every 3 to 4 months for the first 2 years, then every 6 months for the next 2.5 years.

A CT scan about 3.5 years after primary resection revealed small nonspecific liver hypodensities that became more prominent during the next year. About 5 years after primary resection, magnetic resonance imaging (MRI) revealed several liver lesions, the largest of which measured 1.3 cm in greatest dimension. The patient’s liver metastases were readily identified by MRI (Figure 1) and CT imaging (Figure 2A). 

Discussion

Small gastric GISTs are sometimes found by endoscopy performed for unrelated reasons. Recent data suggest that the incidence of gastric GIST may be higher than previously thought. In a Japanese study of patients with gastric cancer in which 100 stomachs were systematically examined pathologically, 50 microscopic GISTs were found in 35 patients.²⁸ Most small gastric GISTs have a low mitotic index. Few cases have been described with a high mitotic index. In a study of 1765 cases of GIST of the stomach, 8 patients had a tumor size less than 2 cm and a mitotic index greater than 5. Of those, only 6 patients had long-term follow-up, and 3 were alive without disease at 2, 17, and 20 years of follow-up.⁷ These limited data make it impossible to predict outcomes in patients with small gastric GIST with a high mitotic index.

For patients who are at high risk of recurrence after surgery, 3 years of adjuvant imatinib treatment compared with 1 year has been shown to improve overall survival and is the current standard of care.^10,17 A study comparing 5 and 3 years of imatinib is ongoing to establish whether a longer period of adjuvant treatment is warranted. In patients with metastatic GIST, lifelong imatinib until lack of benefit is considered optimal treatment.¹⁰ All patients should undergo KIT mutation analysis. Those with the PDGFRα D842V mutation, SDH (succinate dehydrogenase) deficiency, or neurofibromatosis-related GIST should not receive adjuvant imatinib.

This case has several unusual features. The small tumor size with a very high mitotic rate is rare. Such cases have not been reported in large numbers and have therefore not been reliably incorporated into risk prediction algorithms. In addition, despite a high mitotic index, the tumor was not FDG avid on PET imaging. The diagnosis of GIST is strongly supported by the KIT mutation and response to imatinib. This particular KIT mutation in larger GISTs is associated with aggressive disease. The present case adds to the data on the biology of small gastric GISTs with a high mitotic index and suggests the mitotic index in these tumors may be a more important predictor than size. TSJ

Acknowlegement
The authors thank Michael Franklin, MS, for editorial assistance, and Sabrina Porter for media edits.

^aDepartment of Medicine, University of Minnesota Medical School; ^bDepartment of Laboratory Medicine and Pathology, University of Minnesota Medical School; and ^cMasonic Cancer Center, University of Minnesota Medical School, Minneapolis, Minnesota.

Disclosures
The authors report no disclosures or conflicts of interest. This article was originally published in The Journal of Community and Supportive Oncology JCSO. 2018;16(3):e163-e166. ©Frontline Medical Communications. doi:10.12788/jcso.0402. It is reproduced with permission from the copyright owner. Further reproduction prohibited without permission.

PHILADELPHIA – The minimally invasive peroral endoscopic myotomy (POEM) approach has matured as a treatment for achalasia, with “outstanding” 2- to 5-year outcomes now reported, Stavros N. Stavropoulos, MD, said at a meeting jointly provided by Rutgers and Global Academy for Medical Education.

“POEM represents a first-line treatment option for achalasia that has equivalent or superior efficacy to Heller [myotomy],” said Dr. Stavropoulos, MD, director of the program in advanced GI endoscopy at NYU Winthrop Hospital, Mineola, N.Y.

Although POEM is associated with more gastrointestinal reflux disease (GERD) than laparoscopic Heller myotomy, there is some evidence that the advantage of Heller in this respect may decrease over time, he told attendees.

“GERD after POEM is easily treatable with proton pump inhibitors (PPIs), with good patient satisfaction and no significant long-term GERD complications,” Dr. Stavropoulos said in a presentation on minimally invasive approaches to esophageal disorders.

NYU Winthrop Hospital was the site of the first human POEM outside of Japan, performed in 2009 by Dr. Stavropoulos, who along with colleagues recently published what he said is the largest single-operator POEM series in the Western hemisphere.

That report in Gastrointestinal Endoscopy (2018 Apr;87[4]:972-85) was based on 318 consecutive POEMs performed through October 2016. Dr. Stavropoulos and colleagues reported that over a median follow-up of 28 months they had a 95.7% clinical success rate, defined as a Eckardt score of 3 or more and no further treatment needed.

Those results suggested POEM should be a “treatment of choice” for challenging cases managed at centers who have a high level of experience with the procedure, the investigators said at the time.

Dr. Stavropoulos presented his center’s updated experience including 515 patients undergoing POEM, with a median follow-up of 37 months. About 50% of the patients were previously treated, including 73 (14% who underwent Heller myotomy).

Mean Eckardt scores were 7.7 preprocedure and 0.5 post procedure, while on timed barium swallow, emptying of 50% or greater at 5 minutes was seen in 96% of patients, and 100% emptying at 5 minutes was seen in 68%, according to data Dr. Stavropoulos presented.

Disease-free probability was 99% at 1 year and 90% at 5 years, he added.

There were no deaths, leaks, aborted procedures, or need for drains in this series, according to the investigator. Three percent of patients had a hospitalization exceeding 5 days, while 1% were readmitted because of minor adverse events related to POEM, such as dehydration, Dr. Stavropoulos reported.

In 2017, the American Gastroenterological Association published a clinical practice update “legitimizing” POEM as a first-line achalasia treatment, Dr. Stavropoulos said. That update said POEM should be performed in high-volume centers by experienced physicians.

Patients who experience GERD after POEM can be effectively treated with standard, once-daily PPI therapy, according to the expert.

“The absolute difference in GERD rates between laparoscopic Heller myotomy and POEM is 20%-25% at 1 year, but may decrease with time, and may be associated with inferior dysphagia relief in LHM patients,” Dr. Stavropoulos told attendees.

Dr. Stavropoulos disclosed that he is a consultant for Boston Scientific and ERBE.

Global Academy and this news organization are owned by the same company.

PHILADELPHIA – The minimally invasive peroral endoscopic myotomy (POEM) approach has matured as a treatment for achalasia, with “outstanding” 2- to 5-year outcomes now reported, Stavros N. Stavropoulos, MD, said at a meeting jointly provided by Rutgers and Global Academy for Medical Education.

“POEM represents a first-line treatment option for achalasia that has equivalent or superior efficacy to Heller [myotomy],” said Dr. Stavropoulos, MD, director of the program in advanced GI endoscopy at NYU Winthrop Hospital, Mineola, N.Y.

Although POEM is associated with more gastrointestinal reflux disease (GERD) than laparoscopic Heller myotomy, there is some evidence that the advantage of Heller in this respect may decrease over time, he told attendees.

“GERD after POEM is easily treatable with proton pump inhibitors (PPIs), with good patient satisfaction and no significant long-term GERD complications,” Dr. Stavropoulos said in a presentation on minimally invasive approaches to esophageal disorders.

NYU Winthrop Hospital was the site of the first human POEM outside of Japan, performed in 2009 by Dr. Stavropoulos, who along with colleagues recently published what he said is the largest single-operator POEM series in the Western hemisphere.

That report in Gastrointestinal Endoscopy (2018 Apr;87[4]:972-85) was based on 318 consecutive POEMs performed through October 2016. Dr. Stavropoulos and colleagues reported that over a median follow-up of 28 months they had a 95.7% clinical success rate, defined as a Eckardt score of 3 or more and no further treatment needed.

Those results suggested POEM should be a “treatment of choice” for challenging cases managed at centers who have a high level of experience with the procedure, the investigators said at the time.

Dr. Stavropoulos presented his center’s updated experience including 515 patients undergoing POEM, with a median follow-up of 37 months. About 50% of the patients were previously treated, including 73 (14% who underwent Heller myotomy).

Mean Eckardt scores were 7.7 preprocedure and 0.5 post procedure, while on timed barium swallow, emptying of 50% or greater at 5 minutes was seen in 96% of patients, and 100% emptying at 5 minutes was seen in 68%, according to data Dr. Stavropoulos presented.

Disease-free probability was 99% at 1 year and 90% at 5 years, he added.

There were no deaths, leaks, aborted procedures, or need for drains in this series, according to the investigator. Three percent of patients had a hospitalization exceeding 5 days, while 1% were readmitted because of minor adverse events related to POEM, such as dehydration, Dr. Stavropoulos reported.

In 2017, the American Gastroenterological Association published a clinical practice update “legitimizing” POEM as a first-line achalasia treatment, Dr. Stavropoulos said. That update said POEM should be performed in high-volume centers by experienced physicians.

Patients who experience GERD after POEM can be effectively treated with standard, once-daily PPI therapy, according to the expert.

“The absolute difference in GERD rates between laparoscopic Heller myotomy and POEM is 20%-25% at 1 year, but may decrease with time, and may be associated with inferior dysphagia relief in LHM patients,” Dr. Stavropoulos told attendees.

Dr. Stavropoulos disclosed that he is a consultant for Boston Scientific and ERBE.

Global Academy and this news organization are owned by the same company.

PHILADELPHIA – The minimally invasive peroral endoscopic myotomy (POEM) approach has matured as a treatment for achalasia, with “outstanding” 2- to 5-year outcomes now reported, Stavros N. Stavropoulos, MD, said at a meeting jointly provided by Rutgers and Global Academy for Medical Education.

“POEM represents a first-line treatment option for achalasia that has equivalent or superior efficacy to Heller [myotomy],” said Dr. Stavropoulos, MD, director of the program in advanced GI endoscopy at NYU Winthrop Hospital, Mineola, N.Y.

Although POEM is associated with more gastrointestinal reflux disease (GERD) than laparoscopic Heller myotomy, there is some evidence that the advantage of Heller in this respect may decrease over time, he told attendees.

“GERD after POEM is easily treatable with proton pump inhibitors (PPIs), with good patient satisfaction and no significant long-term GERD complications,” Dr. Stavropoulos said in a presentation on minimally invasive approaches to esophageal disorders.

NYU Winthrop Hospital was the site of the first human POEM outside of Japan, performed in 2009 by Dr. Stavropoulos, who along with colleagues recently published what he said is the largest single-operator POEM series in the Western hemisphere.

That report in Gastrointestinal Endoscopy (2018 Apr;87[4]:972-85) was based on 318 consecutive POEMs performed through October 2016. Dr. Stavropoulos and colleagues reported that over a median follow-up of 28 months they had a 95.7% clinical success rate, defined as a Eckardt score of 3 or more and no further treatment needed.

Those results suggested POEM should be a “treatment of choice” for challenging cases managed at centers who have a high level of experience with the procedure, the investigators said at the time.

Dr. Stavropoulos presented his center’s updated experience including 515 patients undergoing POEM, with a median follow-up of 37 months. About 50% of the patients were previously treated, including 73 (14% who underwent Heller myotomy).

Mean Eckardt scores were 7.7 preprocedure and 0.5 post procedure, while on timed barium swallow, emptying of 50% or greater at 5 minutes was seen in 96% of patients, and 100% emptying at 5 minutes was seen in 68%, according to data Dr. Stavropoulos presented.

Disease-free probability was 99% at 1 year and 90% at 5 years, he added.

There were no deaths, leaks, aborted procedures, or need for drains in this series, according to the investigator. Three percent of patients had a hospitalization exceeding 5 days, while 1% were readmitted because of minor adverse events related to POEM, such as dehydration, Dr. Stavropoulos reported.

In 2017, the American Gastroenterological Association published a clinical practice update “legitimizing” POEM as a first-line achalasia treatment, Dr. Stavropoulos said. That update said POEM should be performed in high-volume centers by experienced physicians.

Patients who experience GERD after POEM can be effectively treated with standard, once-daily PPI therapy, according to the expert.

“The absolute difference in GERD rates between laparoscopic Heller myotomy and POEM is 20%-25% at 1 year, but may decrease with time, and may be associated with inferior dysphagia relief in LHM patients,” Dr. Stavropoulos told attendees.

Dr. Stavropoulos disclosed that he is a consultant for Boston Scientific and ERBE.

Global Academy and this news organization are owned by the same company.