Whole exome sequencing reveals intertumor heterogeneity and distinct genetic origins of sporadic synchronous colorectal cancer

Abstract

Sporadic synchronous colorectal cancer (CRC) refers to more than one primary tumor detected in a single patient at the time of the first diagnosis without predisposition of cancer development. Given the same genetic and microenvironment they raise, sporadic synchronous CRC is a unique model to study CRC tumorigenesis. We performed whole exome sequencing in 32 fresh frozen tumor lesions from 15 patients with sporadic synchronous CRC to compare their genetic alterations. This approach identified ubiquitously mutated genes in the range from 0.34% to 4.22% and from 0.8% to 7.0% in non-hypermutated tumors and hypermutated tumors, respectively, in a single patient. We show that both ubiquitously mutated genes and candidate cancer genes from different tumors in the same patient mutated at different sites. Consistently, obvious differences in somatic copy number variations (SCNV) were found in most patients with non-hypermutated tumor lesions, which had ubiquitous copy number amplification rates ranging from 0% to 8.8% and ubiquitous copy number deletion rates ranging from 0% to 8.2%. Hypermutated lesions were nearly diploid with 0% to 18.8% common copy number aberrations. Accordingly, clonal structures, altered signaling pathways, and druggable genes in a single patient with synchronous CRC varied significantly. Taken together, the disparate SCNVs and mutations in synchronous CRC supported the field effect theory of tumorigenesis. Moreover, the intertumor heterogeneity of synchronous CRCs implies that analysis of all tumor lesions from the same patient is necessary for appropriate clinical treatment decisions. This article is protected by copyright. All rights reserved.

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Whole exome sequencing reveals intertumor heterogeneity and distinct genetic origins of sporadic synchronous colorectal cancer

Abstract

Sporadic synchronous colorectal cancer (CRC) refers to more than one primary tumor detected in a single patient at the time of the first diagnosis without predisposition of cancer development. Given the same genetic and microenvironment they raise, sporadic synchronous CRC is a unique model to study CRC tumorigenesis. We performed whole exome sequencing in 32 fresh frozen tumor lesions from 15 patients with sporadic synchronous CRC to compare their genetic alterations. This approach identified ubiquitously mutated genes in the range from 0.34% to 4.22% and from 0.8% to 7.0% in non-hypermutated tumors and hypermutated tumors, respectively, in a single patient. We show that both ubiquitously mutated genes and candidate cancer genes from different tumors in the same patient mutated at different sites. Consistently, obvious differences in somatic copy number variations (SCNV) were found in most patients with non-hypermutated tumor lesions, which had ubiquitous copy number amplification rates ranging from 0% to 8.8% and ubiquitous copy number deletion rates ranging from 0% to 8.2%. Hypermutated lesions were nearly diploid with 0% to 18.8% common copy number aberrations. Accordingly, clonal structures, altered signaling pathways, and druggable genes in a single patient with synchronous CRC varied significantly. Taken together, the disparate SCNVs and mutations in synchronous CRC supported the field effect theory of tumorigenesis. Moreover, the intertumor heterogeneity of synchronous CRCs implies that analysis of all tumor lesions from the same patient is necessary for appropriate clinical treatment decisions. This article is protected by copyright. All rights reserved.

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Author Correction: Chemoprevention of Colorectal Cancer in High-Risk Patients: from Molecular Targets to Clinical Trials

Abstract

In the original version of this article, which published in Current Colorectal Cancer Reports, Volume 13, Issue 3, June 2017, the references in both Tables 1 and 2 were captured incorrectly. The tables provided are now correct.

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Early participant-reported symptoms as predictors of adherence to anastrozole in the International Breast Cancer Intervention Studies II

Abstract

Background

Anastrozole reduces breast cancer risk in women at high risk, but implementing preventive therapy in clinical practice is difficult. Here, we evaluate adherence to anastrozole in the International Breast Cancer Intervention Study (IBIS) II prevention and Ductal Carcinoma in Situ (DCIS) trials, and its association with early symptoms.

Patients and methods

In the prevention trial, 3864 postmenopausal women were randomized to placebo vs. anastrozole. 2980 postmenopausal women with DCIS were randomized to tamoxifen vs. anastrozole. Adherence to trial medication was calculated using the Kaplan-Meier method and all P-values were two-sided.

Results

In the prevention trial, adherence was 65.8% (anastrozole (65.7%) vs. placebo (65.9%); HR = 0.97 (0.87-1.09), p=0.6). Adherence was lower for those reporting arthralgia in the placebo group (p=0.02) or gynecological symptoms in the anastrozole group (P=0.003), compared with those not reporting these symptoms at 6 months. In the DCIS study, adherence was 66.7% (anastrozole (67.5%) vs. tamoxifen (65.8%); HR = 1.06 (0.94-1.20), p=0.4). Hot flashes were associated with greater adherence in the anastrozole arm (p=0.02). In both studies, symptoms were mostly mild or moderately severe, and adherence decreased with increasing severity for most symptoms. Drop-outs were highest in the first 1.5 years of therapy in both trials.

Conclusions

In the IBIS-II prevention and DCIS trials, over two-thirds of women were adherent to therapy, with no differences by treatment groups. Participants who reported specific symptoms in the IBIS-II prevention trial had a small but significant effect on adherence, which strengthened as severity increased. Strategies to promote adherence should target the first year of preventive therapy.

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Impact of Neoadjuvant Chemoradiotherapy on Health Related Quality of Life In Long-Term Survivors of Esophageal or Junctional Cancer: Results from the Randomized Cross Trial

Abstract

Background

Neoadjuvant chemoradiotherapy (nCRT) plus surgery is a standard of care for patients with esophageal or junctional cancer, but the long-term impact of nCRT on health-related quality of life (HRQOL) is unknown. The purpose of this study is to compare very long-term HRQOL in long-term survivors of esophageal cancer who received nCRT plus surgery or surgery alone.

Patients and methods

Patients were randomly assigned to receive nCRT (carboplatin/paclitaxel with 41.4Gy radiotherapy) plus surgery or surgery alone. HRQOL was measured using EORTC-QLQ-C30, EORTC-QLQ-OES24 and K-BILD questionnaires after a minimum follow-up of 6 years. To allow for examination over time, EORTC-QLQ-C30 and QLQ-OES24 questionnaire scores were compared to pre-treatment and 12-months-postoperative questionnaire scores. Physical functioning (QLQ-C30), eating problems (QLQ-OES24) and respiratory problems (K-BILD) were predefined primary endpoints. Predefined secondary endpoints were global quality of life and fatigue (both QLQ-C30).

Results

After a median follow-up of 105 months, 123/368 included patients (33%) were still alive (70 nCRT plus surgery, 53 surgery alone). No statistically significant or clinically relevant differential effects in HRQOL-endpoints were found between both groups. Compared to one-year postoperative levels, eating problems, physical functioning, global quality of life and fatigue remained at the same level in both groups. Compared to pre-treatment levels, eating problems had improved (Cohen's d -0.37, p = 0.011) during long-term follow-up, whereas physical functioning and fatigue were not restored to pre-treatment levels in both groups (Cohen's d -0.56 and 0.51, resp., both p < 0.001).

Conclusion(s)

Although physical functioning and fatigue remain reduced after long-term follow-up, no adverse impact of nCRT is apparent on long-term HRQOL compared to patients who were treated with surgery alone. In addition to the earlier reported improvement in survival and the absence of impact on short-term HRQOL, these results support the view that nCRT according to CROSS can be considered as a standard of care.

CLINICAL TRIALS NUMBER

Trial registration number: Netherlands Trial Register NTR487

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Early participant-reported symptoms as predictors of adherence to anastrozole in the International Breast Cancer Intervention Studies II

Abstract

Background

Anastrozole reduces breast cancer risk in women at high risk, but implementing preventive therapy in clinical practice is difficult. Here, we evaluate adherence to anastrozole in the International Breast Cancer Intervention Study (IBIS) II prevention and Ductal Carcinoma in Situ (DCIS) trials, and its association with early symptoms.

Patients and methods

In the prevention trial, 3864 postmenopausal women were randomized to placebo vs. anastrozole. 2980 postmenopausal women with DCIS were randomized to tamoxifen vs. anastrozole. Adherence to trial medication was calculated using the Kaplan-Meier method and all P-values were two-sided.

Results

In the prevention trial, adherence was 65.8% (anastrozole (65.7%) vs. placebo (65.9%); HR = 0.97 (0.87-1.09), p=0.6). Adherence was lower for those reporting arthralgia in the placebo group (p=0.02) or gynecological symptoms in the anastrozole group (P=0.003), compared with those not reporting these symptoms at 6 months. In the DCIS study, adherence was 66.7% (anastrozole (67.5%) vs. tamoxifen (65.8%); HR = 1.06 (0.94-1.20), p=0.4). Hot flashes were associated with greater adherence in the anastrozole arm (p=0.02). In both studies, symptoms were mostly mild or moderately severe, and adherence decreased with increasing severity for most symptoms. Drop-outs were highest in the first 1.5 years of therapy in both trials.

Conclusions

In the IBIS-II prevention and DCIS trials, over two-thirds of women were adherent to therapy, with no differences by treatment groups. Participants who reported specific symptoms in the IBIS-II prevention trial had a small but significant effect on adherence, which strengthened as severity increased. Strategies to promote adherence should target the first year of preventive therapy.

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Impact of Neoadjuvant Chemoradiotherapy on Health Related Quality of Life In Long-Term Survivors of Esophageal or Junctional Cancer: Results from the Randomized Cross Trial

Abstract

Background

Neoadjuvant chemoradiotherapy (nCRT) plus surgery is a standard of care for patients with esophageal or junctional cancer, but the long-term impact of nCRT on health-related quality of life (HRQOL) is unknown. The purpose of this study is to compare very long-term HRQOL in long-term survivors of esophageal cancer who received nCRT plus surgery or surgery alone.

Patients and methods

Patients were randomly assigned to receive nCRT (carboplatin/paclitaxel with 41.4Gy radiotherapy) plus surgery or surgery alone. HRQOL was measured using EORTC-QLQ-C30, EORTC-QLQ-OES24 and K-BILD questionnaires after a minimum follow-up of 6 years. To allow for examination over time, EORTC-QLQ-C30 and QLQ-OES24 questionnaire scores were compared to pre-treatment and 12-months-postoperative questionnaire scores. Physical functioning (QLQ-C30), eating problems (QLQ-OES24) and respiratory problems (K-BILD) were predefined primary endpoints. Predefined secondary endpoints were global quality of life and fatigue (both QLQ-C30).

Results

After a median follow-up of 105 months, 123/368 included patients (33%) were still alive (70 nCRT plus surgery, 53 surgery alone). No statistically significant or clinically relevant differential effects in HRQOL-endpoints were found between both groups. Compared to one-year postoperative levels, eating problems, physical functioning, global quality of life and fatigue remained at the same level in both groups. Compared to pre-treatment levels, eating problems had improved (Cohen's d -0.37, p = 0.011) during long-term follow-up, whereas physical functioning and fatigue were not restored to pre-treatment levels in both groups (Cohen's d -0.56 and 0.51, resp., both p < 0.001).

Conclusion(s)

Although physical functioning and fatigue remain reduced after long-term follow-up, no adverse impact of nCRT is apparent on long-term HRQOL compared to patients who were treated with surgery alone. In addition to the earlier reported improvement in survival and the absence of impact on short-term HRQOL, these results support the view that nCRT according to CROSS can be considered as a standard of care.

CLINICAL TRIALS NUMBER

Trial registration number: Netherlands Trial Register NTR487

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Rare Cancers and Social Media: Analysis of Twitter Metrics in the First 2 Years of a Rare-Disease Community for Myeloproliferative Neoplasms on Social Media—#MPNSM

Abstract

Purpose of review

The use of social media has now become a standard 13 means of communication for many individuals worldwide. 14 The use of one specific form of social media, Twitter, has 15 increased among healthcare providers, both as a means of 16 information gathering and as a conduit for original content 17 creation. Recently, major efforts by users have been put for- 18 ward to help streamline the unprecedented amount of infor- 19 mation that can be found on Twitter. These efforts have led to 20 the creation of diseasespecific hashtag (#) medical communi- 21 ties and have greatly enhanced the ability to understand and 22 better categorize the available data on Twitter. Specifically, for 23 those involved in rare cancer fields, adhering to organically 24 designed and consistently used hashtags has led to the rapid, 25 reliable dissemination of information and the ability to effi- 26 ciently discuss and debate topics of interest in the field. For the 27 field of myeloproliferative neoplasms (MPNs), the creation of #MPNSM (myeloproliferative neoplasms on social media) in 28 2015 has facilitated interactions among healthcare stake- 29 holders from all over the world in the MPN field.

Recent findings

In order to 30 better understand the trends and topics of interest to Twitter 31 users of this novel medical community, we conducted the 32 present analysis which focuses on Twitter analytics from the 33 first two years of #MPNSM.

Summary

In this analysis, we observed a 34 sustained increase in the number of Twitter users, number of 35 tweets, number of impressions, and number of retweets over 36 time, demonstrating the feasibility of creating and maintaining 37 a disease-specific hashtag for a rare cancer over time.

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Rare Cancers and Social Media: Analysis of Twitter Metrics in the First 2 Years of a Rare-Disease Community for Myeloproliferative Neoplasms on Social Media—#MPNSM

Abstract

Purpose of review

The use of social media has now become a standard 13 means of communication for many individuals worldwide. 14 The use of one specific form of social media, Twitter, has 15 increased among healthcare providers, both as a means of 16 information gathering and as a conduit for original content 17 creation. Recently, major efforts by users have been put for- 18 ward to help streamline the unprecedented amount of infor- 19 mation that can be found on Twitter. These efforts have led to 20 the creation of diseasespecific hashtag (#) medical communi- 21 ties and have greatly enhanced the ability to understand and 22 better categorize the available data on Twitter. Specifically, for 23 those involved in rare cancer fields, adhering to organically 24 designed and consistently used hashtags has led to the rapid, 25 reliable dissemination of information and the ability to effi- 26 ciently discuss and debate topics of interest in the field. For the 27 field of myeloproliferative neoplasms (MPNs), the creation of #MPNSM (myeloproliferative neoplasms on social media) in 28 2015 has facilitated interactions among healthcare stake- 29 holders from all over the world in the MPN field.

Recent findings

In order to 30 better understand the trends and topics of interest to Twitter 31 users of this novel medical community, we conducted the 32 present analysis which focuses on Twitter analytics from the 33 first two years of #MPNSM.

Summary

In this analysis, we observed a 34 sustained increase in the number of Twitter users, number of 35 tweets, number of impressions, and number of retweets over 36 time, demonstrating the feasibility of creating and maintaining 37 a disease-specific hashtag for a rare cancer over time.

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Generational shift in melanoma incidence and mortality in Queensland, Australia, 1995-2014

Abstract

Public campaigns encouraging sun protection for skin cancer prevention began in Queensland, Australia, in the early 1980s. We examined recent trends to assess whether earlier evidence of stabilizing melanoma incidence in young people has persisted. Anonymised incidence and mortality data for in situ and invasive melanoma for the 20 years 1995-2014 were obtained from the Queensland Cancer Registry. Time trends were analysed using joinpoint regression. Birth cohort patterns were assessed using age-period-cohort models. Melanoma incidence in Queensland remains the highest recorded in the world (age-standardised incidence of invasive melanoma (2010-2014) = 72/100,000/annum). Over the 20-year period, incidence of in situ melanoma increased in all age groups. Incidence of both thin (≤1mm) and thick (>1mm) invasive melanoma was either stable or decreased in people under 60, while it increased in those aged 60 and above, particularly in men. Age-period-cohort analysis revealed decreasing age-specific incidence of invasive melanoma under 40 years of age, beginning with the birth cohort born around the mid-1960s, with steepest falls for those born around 1980 and later. Age-specific incidence was stable between 40-59 years of age from the 1945 birth cohort onwards. Melanoma mortality over the period was stable or decreased in all groups except in men aged 60 or over. These findings are evidence of real advances in the prevention and early detection of invasive melanoma in this very high-risk population. They make a compelling case for continued public health efforts to reduce the burden of melanoma in susceptible populations. This article is protected by copyright. All rights reserved.

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Generational shift in melanoma incidence and mortality in Queensland, Australia, 1995-2014

Abstract

Public campaigns encouraging sun protection for skin cancer prevention began in Queensland, Australia, in the early 1980s. We examined recent trends to assess whether earlier evidence of stabilizing melanoma incidence in young people has persisted. Anonymised incidence and mortality data for in situ and invasive melanoma for the 20 years 1995-2014 were obtained from the Queensland Cancer Registry. Time trends were analysed using joinpoint regression. Birth cohort patterns were assessed using age-period-cohort models. Melanoma incidence in Queensland remains the highest recorded in the world (age-standardised incidence of invasive melanoma (2010-2014) = 72/100,000/annum). Over the 20-year period, incidence of in situ melanoma increased in all age groups. Incidence of both thin (≤1mm) and thick (>1mm) invasive melanoma was either stable or decreased in people under 60, while it increased in those aged 60 and above, particularly in men. Age-period-cohort analysis revealed decreasing age-specific incidence of invasive melanoma under 40 years of age, beginning with the birth cohort born around the mid-1960s, with steepest falls for those born around 1980 and later. Age-specific incidence was stable between 40-59 years of age from the 1945 birth cohort onwards. Melanoma mortality over the period was stable or decreased in all groups except in men aged 60 or over. These findings are evidence of real advances in the prevention and early detection of invasive melanoma in this very high-risk population. They make a compelling case for continued public health efforts to reduce the burden of melanoma in susceptible populations. This article is protected by copyright. All rights reserved.

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Five-year relative survival for human papillomavirus-associated cancer sites

BACKGROUND

Human papillomavirus (HPV) vaccines can potentially prevent greater than 90% of cervical and anal cancers as well as a substantial proportion of vulvar, vaginal, penile, and oropharyngeal cancers caused by certain HPV types. Because more than 38,000 HPV-associated cancers are diagnosed annually in the United States, current studies are needed to understand how relative survival varies for each of these cancers by certain demographic characteristics, such as race and age.

METHODS

The authors examined high-quality data from 27 population-based cancer registries covering approximately 59% of the US population. The analyses were limited to invasive cancers that were diagnosed during 2001 through 2011 and followed through 2011 and met specified histologic criteria for HPV-associated cancers. Five-year relative survival was calculated from diagnosis until death for these cancers by age, race, and sex.

RESULTS

The 5-year age-standardized relative survival rate was 64.2% for cervical carcinomas, 52.8% for vaginal squamous cell carcinomas (SCCs), 66% for vulvar SCCs, 47.4% for penile SCCs, 65.9% for anal SCCs, 56.2% for rectal SCCs, and 51.2% for oropharyngeal SCCs. Five-year relative survival was consistently higher among white patients compared with black patients for all HPV-associated cancers across all age groups; the greatest differences by race were observed for oropharyngeal SCCs among those aged <60 years and for penile SCCs among those ages 40 to 49 years compared with other age groups.

CONCLUSIONS

There are large disparities in relative survival among patients with HPV-associated cancers by sex, race, and age. HPV vaccination and improved access to screening (of cancers for which screening tests are available) and treatment, especially among groups that experience higher incidence and lower survival, may reduce disparities in survival from HPV-associated cancers. Cancer 2017. Published 2017. This article is a U.S. Government work and is in the public domain in the USA.

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Survival of human papillomavirus-associated cancers: Filling in the gaps

Human papillomavirus-associated cancers contribute to the total cancer burden in the United States. Although they are mostly preventable, 5-year relative survival rates can be as low as 47% for penile cancer and as high as 66% for vulvar cancer. See also pages 000-000.

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Five-year relative survival for human papillomavirus-associated cancer sites

BACKGROUND

Human papillomavirus (HPV) vaccines can potentially prevent greater than 90% of cervical and anal cancers as well as a substantial proportion of vulvar, vaginal, penile, and oropharyngeal cancers caused by certain HPV types. Because more than 38,000 HPV-associated cancers are diagnosed annually in the United States, current studies are needed to understand how relative survival varies for each of these cancers by certain demographic characteristics, such as race and age.

METHODS

The authors examined high-quality data from 27 population-based cancer registries covering approximately 59% of the US population. The analyses were limited to invasive cancers that were diagnosed during 2001 through 2011 and followed through 2011 and met specified histologic criteria for HPV-associated cancers. Five-year relative survival was calculated from diagnosis until death for these cancers by age, race, and sex.

RESULTS

The 5-year age-standardized relative survival rate was 64.2% for cervical carcinomas, 52.8% for vaginal squamous cell carcinomas (SCCs), 66% for vulvar SCCs, 47.4% for penile SCCs, 65.9% for anal SCCs, 56.2% for rectal SCCs, and 51.2% for oropharyngeal SCCs. Five-year relative survival was consistently higher among white patients compared with black patients for all HPV-associated cancers across all age groups; the greatest differences by race were observed for oropharyngeal SCCs among those aged <60 years and for penile SCCs among those ages 40 to 49 years compared with other age groups.

CONCLUSIONS

There are large disparities in relative survival among patients with HPV-associated cancers by sex, race, and age. HPV vaccination and improved access to screening (of cancers for which screening tests are available) and treatment, especially among groups that experience higher incidence and lower survival, may reduce disparities in survival from HPV-associated cancers. Cancer 2017. Published 2017. This article is a U.S. Government work and is in the public domain in the USA.

http://ift.tt/2lV03l1

Survival of human papillomavirus-associated cancers: Filling in the gaps

Human papillomavirus-associated cancers contribute to the total cancer burden in the United States. Although they are mostly preventable, 5-year relative survival rates can be as low as 47% for penile cancer and as high as 66% for vulvar cancer. See also pages 000-000.

http://ift.tt/2yzCUdD

What’s New in Imaging for Gynecologic Cancer?

Abstract

Magnetic resonance imaging (MRI) is the optimal modality for local staging of gynecological tumors. Advances in functional MRI with diffusion-weighted and dynamic contrast-enhanced sequences provide more detailed information regarding tumor cellularity, vascularity, and viability. Fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) now has an established role in imaging for gynecological cancers, particularly staging of locally advanced cervical cancers and pre-salvage exenterative therapy in relapsed gynecologic tumors. Novel PET tracers, targeting other aspects of tumor biology, are being evaluated although none are currently in routine clinical use. New PET/MR scanners have the potential to combine the strengths of both modalities in one sitting. This review covers advances in gynecologic imaging concentrating on cervical, endometrial, and ovarian cancers.

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What’s New in Imaging for Gynecologic Cancer?

Abstract

Magnetic resonance imaging (MRI) is the optimal modality for local staging of gynecological tumors. Advances in functional MRI with diffusion-weighted and dynamic contrast-enhanced sequences provide more detailed information regarding tumor cellularity, vascularity, and viability. Fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) now has an established role in imaging for gynecological cancers, particularly staging of locally advanced cervical cancers and pre-salvage exenterative therapy in relapsed gynecologic tumors. Novel PET tracers, targeting other aspects of tumor biology, are being evaluated although none are currently in routine clinical use. New PET/MR scanners have the potential to combine the strengths of both modalities in one sitting. This review covers advances in gynecologic imaging concentrating on cervical, endometrial, and ovarian cancers.

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Scrotal calcinosis: two case reports

Scrotal calcinosis is a rare and benign condition. It usually gives rise to few symptoms, and the impact is mainly functional and aesthetic. It is considered part of dystrophic calcinosis cutis. Surgical manag...

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To prep or not to prep - that is the question: A randomized trial on the use of anti-flatulent medication as part of bowel preparation for patients having image-guided external-beam radiotherapy to the prostate

Publication date: Available online 4 November 2017
Source:Practical Radiation Oncology
Author(s): Merrylee McGuffin, Naila Devji, Lyann Kehoe, Anne Carty, Steve Russell, Lisa Di Prospero, Carlo DeAngelis, Alex Kiss, Danny Vesprini, Andrew Loblaw, Laura D'Alimonte
IntroductionRadiation therapy is a standard treatment option for prostate cancer. With growing use of escalated doses and tighter margins, procedures to limit rectal size variation are needed to reduce prostate motion, increase treatment accuracy and minimize rectal toxicity. This prospective study was done to determine whether the introduction of an anti-flatulent medication would decrease rectal distention at CT simulation and throughout a course of radiation therapy.Methods and MaterialsPatients undergoing a radical course of radiotherapy to the prostate/prostate bed were eligible to participate. Participants were randomly assigned to the intervention arm (anti-flatulent medication) or the control arm (no medication). For each participant, the number of CT simulation rescans was recorded. Rectal diameters were measured on CT simulation and treatment CBCT scans. Acute rectal toxicities were assessed at baseline and weekly using NCI CTCAE v4.0. Chi-square analysis was used to compare the number of participants requiring a rescan in each study arm. Change in rectal diameter over time was assessed using repeated measures ANOVA.ResultsA total of 78 patients participated, with equal numbers assigned to each study arm. There was no significant difference between arms in the number of participants requiring a CT simulation rescan (p=0.5551). There was no significant variation in rectal diameter between arms (p=0.8999). However, there was a significant effect of time (p=0.0017) and a significant interaction effect between study arm and time on rectal diameter (p=0.0141). No acute rectal toxicities above grade 2 were reported.ConclusionsThe addition of anti-flatulent medication did not affect the frequency of CT simulation rescans. Both time and the interaction between study arm and time had a statistically significant effect on rectal diameter, though neither finding was clinically significant. Instead, standardized bowel preparation education developed for this study may have been sufficient to limit rectal size variation.



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Multiple myeloma and a mischievous pacemaker: A teaching case involving irradiation of a cardiovascular implantable electronic device

Publication date: Available online 4 November 2017
Source:Practical Radiation Oncology
Author(s): Shane Lloyd, Olivier Morin, Isaac Whitman, David Raleigh, Shannon Fogh, Paul Menzel




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Clinical log data analysis for assessing the accuracy of the CyberKnife fiducial-free lung tumor tracking system

Publication date: Available online 4 November 2017
Source:Practical Radiation Oncology
Author(s): Masao Nakayama, Hideki Nishimura, Hiroshi Mayahara, Masaki Nakamura, Kazuyuki Uehara, Shinji Tsudou, Aya Harada, Hiroaki Akasaka, Ryohei Sasaki
PurposeThe CyberKnife Xsight Lung Tracking (XLT) and 1-View tracking systems can synchronize beam targeting to a visible lung tumor with respiratory motion during irradiation without requiring internal fiducial markers. The systems utilize a correlation model that relates external marker positions to tumor positions as well as a prediction model that predicts the target's future position. In this study, the correlation and prediction model uncertainties related to the CyberKnife fiducial-free tumor tracking system were evaluated using clinical log data.Methods and materialsData from 211 fractions in 42 patients with lung tumors were analyzed. Log files produced by the CyberKnife Synchrony system were acquired after each treatment; the mean correlation and prediction errors for each patient were calculated. Additionally, we examined the tracking tumor-related parameters and analyzed the relationships between the model errors and tracking tumor-related parameters.ResultsThe overall means ± standard deviations (SDs) of the correlation errors were 0.70±0.43mm, 0.36±0.16mm, 0.44±0.22mm, and 0.95±0.43mm for the superior–inferior (SI), left–right (LR), anterior–posterior (AP), and radial directions, respectively. The overall means ± SDs of the prediction errors were 0.13±0.11mm, 0.03±0.02mm, 0.03±0.02mm, and 0.14±0.11mm for the SI, LR, AP, and radial directions, respectively. There were no significant differences in these errors between the XLT and 1-View tracking methods. The tumor motion amplitude was moderately associated with the correlation error and strongly related to the prediction error in the SI and radial directions.ConclusionsClinical log data analysis can be used to determine the necessary margin sizes in treatment plans to compensate for correlation and prediction errors in the CyberKnife fiducial-free lung tumor tracking system. The tumor motion amplitude may facilitate margin determination.



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Towards consensus reporting of radiation-induced liver toxicity in the treatment of primary liver malignancies: defining clinically relevant endpoints

Publication date: Available online 4 November 2017
Source:Practical Radiation Oncology
Author(s): Tobias R. Chapman, Stephen R. Bowen, Stephanie K. Schaub, Rosanna H. Yeung, Sharon W. Kwan, James O. Park, Lei Yu, William P. Harris, Guy E. Johnson, Iris W. Liou, Matthew J. Nyflot, Smith Apisarnthanarax
Background and PurposeTo define the most clinically relevant "non-classic" radiation-induced liver disease (ncRILD) endpoints in cirrhotic patients receiving stereotactic body radiotherapy (SBRT) or proton beam therapy (PBT) for primary liver cancer.Material and MethodsWe retrospectively collected pre-treatment, detailed toxicity (≤6 months post-treatment), and outcomes data from 48 patients. Deaths were examined for association with RILD. Univariate (UA) and multivariate (MA) Cox models defined significant predictors of overall survival (OS)/RILD-specific survival (RILD-SS).ResultsWith median follow-up of 13 months, 23 patients (48%) had an increase in CP score (≥2, 25%) and three (6%) had ≥G3 transaminase elevation. Of 18 deaths, 6 were potentially ascribed to RILD. On UA, CP score increases of ≥1, ≥2 and CP class change predicted OS, as did ≥G3 AST elevation and ≥1 CTCAE AST toxicity grade change. On MA, CP score increase of ≥2 and ≥1 CTCAE AST toxicity grade change were the strongest independent ncRILD predictors of OS. For RILD-SS, CP score increases of ≥2, ≥G3 CTCAE ALT and ≥G2 bilirubin elevations were predictive.ConclusionsIncreased CP score of ≥2 strongly predicts of both OS and RILD-SS, and should be reported in future studies along with transaminase elevations, which are also predictive of outcomes.



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Circle of Gratitude

Publication date: Available online 4 November 2017
Source:Practical Radiation Oncology
Author(s): Christian Molerin




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Bowel and urinary quality of life after whole-pelvic versus prostate-only volumetric-modulated arc therapy for localized prostate cancer

Publication date: Available online 5 November 2017
Source:Practical Radiation Oncology
Author(s): Kentaro Ishii, Toshiko Yamanaga, Ryo Ogino, Yukinari Hosokawa, Shun Kishimoto, Ryuta Nakahara, Chiaki Shimada, Ryu Kawamorita, Takuhito Tada, Yoshiki Hayashi, Toshifumi Nakajima
PurposeThis study aimed to compare bowel and urinary health-related quality of life (HRQOL) between prostate-only (PO) volumetric-modulated arc therapy (VMAT) and whole-pelvic (WP) VMAT in patients with localized prostate cancer.Methods and MaterialsA total of 234 patients treated with definitive VMAT to 78Gy in 39 fractions were enrolled. Of these, 108 patients received PO-VMAT, and 126 patients received initial WP-VMAT to 46.8Gy in 26 fractions using a simultaneous integrated boost technique. HRQOL was prospectively assessed before radiotherapy (baseline), and 3, 6, 12, and 24months after treatment using the Expanded Prostate Cancer Index Composite (EPIC).ResultsBaseline HRQOL scores did not differ significantly between the two groups. No significant between-group differences in HRQOL change from baseline were observed for all bowel and urinary EPIC domains. The proportion of patients showing a clinically relevant decrease in bowel and urinary HRQOL scores from baseline was similar between the groups throughout the follow-up period. An analysis of individual HRQOL items showed that patients undergoing WP-VMAT were more likely to report moderate/big problems with bloody stools (P=.039) and overall bowel problems (P=.008) than those undergoing PO-VMAT at 12months. However, there was no significant between-group difference in any individual items at 24months.ConclusionsBowel and urinary HRQOL is largely similar for patients receiving PO-VMAT and WP-VMAT during 24months of follow-up, with the only differences seen in responses to specific bowel HRQOL items at 12months.



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Radiation-Induced Undifferentiated Pleomorphic Sarcoma of the Heart: A Case Report

Publication date: Available online 4 November 2017
Source:Practical Radiation Oncology
Author(s): Alexander K. Tsai, Melissa AL. Vyfhuis, Martha Francis, Fikru Merechi, Allen P. Burke, William F. Regine




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LAMPs: Shedding Light on Cancer Biology

Publication date: Available online 4 November 2017
Source:Seminars in Oncology
Author(s): Federica Alessandrini, Laura Pezzè, Yari Ciribilli
Lysosomes are important cytoplasmic organelles whose critical functions in cells are increasingly being understood. In particular, despite the long-standing accepted concept about the role of lysosomes as cellular machineries solely assigned to degradation, it has been demonstrated that they play active roles in homeostasis and even in cancer biology. Indeed, it is now well documented that during the process of cellular transformation and cancer progression lysosomes are changing localization, composition and volume and, through the release of their enzymes, lysosomes can also enhance cancer aggressiveness. LAMPs, Lysosome Associated Membrane Proteins, represent a family of glycosylated proteins present predominantly on the membrane of lysosomes whose expression can vary among different tissues, suggesting a separation of functions. In this review we focus on the functions and roles of the different LAMP family members with a particular emphasis on cancer progression and metastatic spread. LAMP proteins are involved in many different aspects of cell biology and can influence cellular processes such as phagocytosis, autophagy, lipid transport and aging. Interestingly, for all the five members identified so far, LAMP1, LAMP2, LAMP3, CD68/Macrosialin/LAMP4 and BAD-LAMP/LAMP5, a role in cancer has been suggested. While this is well documented for LAMP1 and LAMP2, the involvement of the other three proteins in cancer progression and aggressiveness has recently been proposed and remains to be elucidated. Here we present different examples about how LAMP proteins can influence and support tumor growth and metastatic spread, emphasizing the impact of each single member of the family.



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To prep or not to prep - that is the question: A randomized trial on the use of anti-flatulent medication as part of bowel preparation for patients having image-guided external-beam radiotherapy to the prostate

Publication date: Available online 4 November 2017
Source:Practical Radiation Oncology
Author(s): Merrylee McGuffin, Naila Devji, Lyann Kehoe, Anne Carty, Steve Russell, Lisa Di Prospero, Carlo DeAngelis, Alex Kiss, Danny Vesprini, Andrew Loblaw, Laura D'Alimonte
IntroductionRadiation therapy is a standard treatment option for prostate cancer. With growing use of escalated doses and tighter margins, procedures to limit rectal size variation are needed to reduce prostate motion, increase treatment accuracy and minimize rectal toxicity. This prospective study was done to determine whether the introduction of an anti-flatulent medication would decrease rectal distention at CT simulation and throughout a course of radiation therapy.Methods and MaterialsPatients undergoing a radical course of radiotherapy to the prostate/prostate bed were eligible to participate. Participants were randomly assigned to the intervention arm (anti-flatulent medication) or the control arm (no medication). For each participant, the number of CT simulation rescans was recorded. Rectal diameters were measured on CT simulation and treatment CBCT scans. Acute rectal toxicities were assessed at baseline and weekly using NCI CTCAE v4.0. Chi-square analysis was used to compare the number of participants requiring a rescan in each study arm. Change in rectal diameter over time was assessed using repeated measures ANOVA.ResultsA total of 78 patients participated, with equal numbers assigned to each study arm. There was no significant difference between arms in the number of participants requiring a CT simulation rescan (p=0.5551). There was no significant variation in rectal diameter between arms (p=0.8999). However, there was a significant effect of time (p=0.0017) and a significant interaction effect between study arm and time on rectal diameter (p=0.0141). No acute rectal toxicities above grade 2 were reported.ConclusionsThe addition of anti-flatulent medication did not affect the frequency of CT simulation rescans. Both time and the interaction between study arm and time had a statistically significant effect on rectal diameter, though neither finding was clinically significant. Instead, standardized bowel preparation education developed for this study may have been sufficient to limit rectal size variation.



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Multiple myeloma and a mischievous pacemaker: A teaching case involving irradiation of a cardiovascular implantable electronic device

Publication date: Available online 4 November 2017
Source:Practical Radiation Oncology
Author(s): Shane Lloyd, Olivier Morin, Isaac Whitman, David Raleigh, Shannon Fogh, Paul Menzel




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Clinical log data analysis for assessing the accuracy of the CyberKnife fiducial-free lung tumor tracking system

Publication date: Available online 4 November 2017
Source:Practical Radiation Oncology
Author(s): Masao Nakayama, Hideki Nishimura, Hiroshi Mayahara, Masaki Nakamura, Kazuyuki Uehara, Shinji Tsudou, Aya Harada, Hiroaki Akasaka, Ryohei Sasaki
PurposeThe CyberKnife Xsight Lung Tracking (XLT) and 1-View tracking systems can synchronize beam targeting to a visible lung tumor with respiratory motion during irradiation without requiring internal fiducial markers. The systems utilize a correlation model that relates external marker positions to tumor positions as well as a prediction model that predicts the target's future position. In this study, the correlation and prediction model uncertainties related to the CyberKnife fiducial-free tumor tracking system were evaluated using clinical log data.Methods and materialsData from 211 fractions in 42 patients with lung tumors were analyzed. Log files produced by the CyberKnife Synchrony system were acquired after each treatment; the mean correlation and prediction errors for each patient were calculated. Additionally, we examined the tracking tumor-related parameters and analyzed the relationships between the model errors and tracking tumor-related parameters.ResultsThe overall means ± standard deviations (SDs) of the correlation errors were 0.70±0.43mm, 0.36±0.16mm, 0.44±0.22mm, and 0.95±0.43mm for the superior–inferior (SI), left–right (LR), anterior–posterior (AP), and radial directions, respectively. The overall means ± SDs of the prediction errors were 0.13±0.11mm, 0.03±0.02mm, 0.03±0.02mm, and 0.14±0.11mm for the SI, LR, AP, and radial directions, respectively. There were no significant differences in these errors between the XLT and 1-View tracking methods. The tumor motion amplitude was moderately associated with the correlation error and strongly related to the prediction error in the SI and radial directions.ConclusionsClinical log data analysis can be used to determine the necessary margin sizes in treatment plans to compensate for correlation and prediction errors in the CyberKnife fiducial-free lung tumor tracking system. The tumor motion amplitude may facilitate margin determination.



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Towards consensus reporting of radiation-induced liver toxicity in the treatment of primary liver malignancies: defining clinically relevant endpoints

Publication date: Available online 4 November 2017
Source:Practical Radiation Oncology
Author(s): Tobias R. Chapman, Stephen R. Bowen, Stephanie K. Schaub, Rosanna H. Yeung, Sharon W. Kwan, James O. Park, Lei Yu, William P. Harris, Guy E. Johnson, Iris W. Liou, Matthew J. Nyflot, Smith Apisarnthanarax
Background and PurposeTo define the most clinically relevant "non-classic" radiation-induced liver disease (ncRILD) endpoints in cirrhotic patients receiving stereotactic body radiotherapy (SBRT) or proton beam therapy (PBT) for primary liver cancer.Material and MethodsWe retrospectively collected pre-treatment, detailed toxicity (≤6 months post-treatment), and outcomes data from 48 patients. Deaths were examined for association with RILD. Univariate (UA) and multivariate (MA) Cox models defined significant predictors of overall survival (OS)/RILD-specific survival (RILD-SS).ResultsWith median follow-up of 13 months, 23 patients (48%) had an increase in CP score (≥2, 25%) and three (6%) had ≥G3 transaminase elevation. Of 18 deaths, 6 were potentially ascribed to RILD. On UA, CP score increases of ≥1, ≥2 and CP class change predicted OS, as did ≥G3 AST elevation and ≥1 CTCAE AST toxicity grade change. On MA, CP score increase of ≥2 and ≥1 CTCAE AST toxicity grade change were the strongest independent ncRILD predictors of OS. For RILD-SS, CP score increases of ≥2, ≥G3 CTCAE ALT and ≥G2 bilirubin elevations were predictive.ConclusionsIncreased CP score of ≥2 strongly predicts of both OS and RILD-SS, and should be reported in future studies along with transaminase elevations, which are also predictive of outcomes.



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Circle of Gratitude

Publication date: Available online 4 November 2017
Source:Practical Radiation Oncology
Author(s): Christian Molerin




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Bowel and urinary quality of life after whole-pelvic versus prostate-only volumetric-modulated arc therapy for localized prostate cancer

Publication date: Available online 5 November 2017
Source:Practical Radiation Oncology
Author(s): Kentaro Ishii, Toshiko Yamanaga, Ryo Ogino, Yukinari Hosokawa, Shun Kishimoto, Ryuta Nakahara, Chiaki Shimada, Ryu Kawamorita, Takuhito Tada, Yoshiki Hayashi, Toshifumi Nakajima
PurposeThis study aimed to compare bowel and urinary health-related quality of life (HRQOL) between prostate-only (PO) volumetric-modulated arc therapy (VMAT) and whole-pelvic (WP) VMAT in patients with localized prostate cancer.Methods and MaterialsA total of 234 patients treated with definitive VMAT to 78Gy in 39 fractions were enrolled. Of these, 108 patients received PO-VMAT, and 126 patients received initial WP-VMAT to 46.8Gy in 26 fractions using a simultaneous integrated boost technique. HRQOL was prospectively assessed before radiotherapy (baseline), and 3, 6, 12, and 24months after treatment using the Expanded Prostate Cancer Index Composite (EPIC).ResultsBaseline HRQOL scores did not differ significantly between the two groups. No significant between-group differences in HRQOL change from baseline were observed for all bowel and urinary EPIC domains. The proportion of patients showing a clinically relevant decrease in bowel and urinary HRQOL scores from baseline was similar between the groups throughout the follow-up period. An analysis of individual HRQOL items showed that patients undergoing WP-VMAT were more likely to report moderate/big problems with bloody stools (P=.039) and overall bowel problems (P=.008) than those undergoing PO-VMAT at 12months. However, there was no significant between-group difference in any individual items at 24months.ConclusionsBowel and urinary HRQOL is largely similar for patients receiving PO-VMAT and WP-VMAT during 24months of follow-up, with the only differences seen in responses to specific bowel HRQOL items at 12months.



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Radiation-Induced Undifferentiated Pleomorphic Sarcoma of the Heart: A Case Report

Publication date: Available online 4 November 2017
Source:Practical Radiation Oncology
Author(s): Alexander K. Tsai, Melissa AL. Vyfhuis, Martha Francis, Fikru Merechi, Allen P. Burke, William F. Regine




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[Clinical trials and perspectives of radiotherapy for uterine endometrial cancers].

Related Articles

[Clinical trials and perspectives of radiotherapy for uterine endometrial cancers].

Bull Cancer. 2017 Oct 31;:

Authors: Chargari C, Maroun P, Lazarescu I, Haie-Meder C

Abstract
The adjuvant management of uterine endometrial cancer has been studied in many randomized trials, leading to define postoperative therapeutic indications, depending on the risk factors for relapse, and on the expected benefit in terms of locoregional control and survival. The potential toxicity of treatments should be also considered. We review the available literature that yielded to guidelines that were recently published, on behalf of European societies, and we highlight the perspectives on ongoing studies, aimed at better defining the place and type of adjuvant treatment.

PMID: 29100604 [PubMed - as supplied by publisher]

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Cytomegalovirus reactivation in patients with refractory checkpoint inhibitor-induced colitis

Publication date: November 2017
Source:European Journal of Cancer, Volume 86
Author(s): Cindy Franklin, Isabelle Rooms, Melanie Fiedler, Henning Reis, Laura Milsch, Saskia Herz, Elisabeth Livingstone, Lisa Zimmer, Kurt Werner Schmid, Ulf Dittmer, Dirk Schadendorf, Bastian Schilling
ObjectivesImmune checkpoint inhibitors can cause severe immune-related adverse events, with immune-related diarrhea and colitis (irColitis) being among the most frequent ones. While the majority of patients with irColitis respond well to corticosteroid treatment ± other immunomodulatory drugs such as infliximab, some patients do not show resolution of their symptoms. In the present study, we analysed the frequency of therapy-refractory irColitis, the underlying cause, and useful diagnostic approaches.MethodsBetween 2006 and 2016, 370 patients with metastatic malignant melanoma were treated with checkpoint inhibitors at the Department of Dermatology at the University Hospital Essen. All patients were identified for whom diarrhea and/or colitis was documented in the digital patient records. Patients who did not respond to standard immunosuppressive therapy within 2 weeks were classified as refractory. Demographic and clinical data of all patients were collected.ResultsWe identified 41 patients with irColitis, the majority occurring during treatment with ipilimumab. Amongst these, 5 (12.2%) were refractory to standard immunomodulatory treatment with corticosteroids and infliximab. Therapy-refractory cases tended to show more severe inflammation in colonic biopsies (p = 0.04). In all therapy-refractory cases cytomegalovirus (CMV) was detectable. CMV-DNA in colonic biopsies and in plasma was significantly more often detectable in therapy-refractory cases (in colonic biopsies p = 0.005, in plasma: p = 0.002). Presence of serum CMV IgM and positive immunohistochemical stainings of colon biopsies for CMV were also associated with refractory colitis (p=0.021; p = 0.053).ConclusionsThis report on CMV reactivation during management of checkpoint inhibitor-induced colitis emphasises the need for repetitive diagnostic measures in treatment-refractory irColitis.



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Recurrence dynamics of breast cancer according to baseline body mass index

Publication date: December 2017
Source:European Journal of Cancer, Volume 87
Author(s): Elia Biganzoli, Christine Desmedt, Marco Fornili, Evandro de Azambuja, Nathalie Cornez, Fernand Ries, Marie-Thérèse Closon-Dejardin, Joseph Kerger, Christian Focan, Angelo Di Leo, Jean-Marie Nogaret, Christos Sotiriou, Martine Piccart, Romano Demicheli
BackgroundIn cancer follow-up, in addition to the evaluation of survival probabilities, there is a fundamental need of assessing recurrence dynamics for optimal disease management. Although the time-dependent effect of the oestrogen receptor (ER) status of the tumour has already been described, so far no factor has proven to disentangle the multi-peak behaviour observed for breast cancer recurrences. Here, we aimed at investigating whether adiposity at diagnosis, reflected by increased patient's body mass index (BMI), could be associated with breast cancer recurrence patterns over time after primary cancer therapy.MethodsWe retrieved BMI from 734 of 777 patients with node-positive breast cancer from a phase III randomised clinical trial, which compared different chemotherapy regimens and had a median follow-up of 15.4 years. Cumulative incidence estimation as well as piecewise exponential models were carried out to estimate the distant recurrence dynamics, in all patients, as well as in subgroups based on the ER status, with the ER-positive group being further split according to the menopausal status.ResultsIn patients with ER-negative breast cancer, time-dependent analyses revealed that the hazard of late relapses could mainly be attributed to the overweight and obese patients. Within the subgroup of premenopausal patients with ER-positive tumours, obesity was associated with an early high narrow peak of distant recurrences followed by another main peak after 5 years of follow-up. The risk for overweight patients was intermediate between obese and normal-weight patients. In the postmenopausal subgroup of patients with ER-positive tumours, the distant recurrence rate was significantly more elevated in the overweight patients compared to the other BMI categories, and a second late peak of recurrences was also observed for the obese patients.ConclusionThese results demonstrate that the patient's BMI at diagnosis is associated with cancer recurrence dynamics. Patient adiposity should therefore be central to the exploration of late adjuvant treatment modalities.



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The association between health-related quality-of-life scores and clinical outcomes in metastatic castration-resistant prostate cancer patients: Exploratory analyses of AFFIRM and PREVAIL studies

Publication date: December 2017
Source:European Journal of Cancer, Volume 87
Author(s): Tomasz M. Beer, Kurt Miller, Bertrand Tombal, David Cella, De Phung, Stefan Holmstrom, Cristina Ivanescu, Konstantina Skaltsa, Shevani Naidoo
BackgroundOur exploratory analysis examined the association between health-related quality of life (HRQoL) (baseline and change over time) and clinical outcomes (overall survival [OS]/radiographic progression-free survival [rPFS]) in metastatic castration-resistant prostate cancer (mCRPC).MethodsHRQoL, OS and rPFS were assessed in phase III trials comparing enzalutamide with placebo in chemotherapy-naïve (PREVAIL; NCT01212991) or post-chemotherapy (AFFIRM; NCT00974311) mCRPC. HRQoL was assessed using the Functional Assessment of Cancer Therapy-Prostate (FACT-P). Multivariate analyses evaluated the prognostic significance of baseline and time-dependent scores after adjusting for treatment and clinical/demographic variables. Hazard ratios (HRs) and 95% confidence intervals (CIs) represented the hazard of rPFS or OS per minimally important difference (MID) score change in HRQoL variables.ResultsIn baseline and time-dependent multivariate analyses, OS was independently associated with multiple HRQoL measures across both studies. In time-dependent analyses, a 10-point (upper bound of MID range) increase (improvement) in FACT-P total score was associated with reductions in mortality risk of 19% in AFFIRM (HR 0.81 [95% CI 0.78–0.84]) and 21% in PREVAIL (HR 0.79 [0.76–0.83]). For baseline analyses, a 10-point increase in FACT-P total score was associated with reductions in mortality risk of 12% (HR 0.88 [0.84–0.93]) and 10% (HR 0.90 [0.86–0.95]) in AFFIRM and PREVAIL, respectively. rPFS was associated with a subset of HRQoL domains in both studies.ConclusionSeveral baseline HRQoL domains were prognostic for rPFS and OS in patients with mCRPC, and this association was maintained during treatment, indicating that changes in HRQoL are informative for patients' expected survival.



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Is post-mastectomy radiation therapy contributive in pN0-1mi breast cancer patients? Results of a French multi-centric cohort

Publication date: December 2017
Source:European Journal of Cancer, Volume 87
Author(s): Violaine Forissier, Agnès Tallet, Monique Cohen, Jean-Marc Classe, Fabien Reyal, Nicolas Chopin, Chafika Mazouni, Pierre Gimbergues, Emile Daraï, Pierre Emmanuel Colombo, Pierre Azuar, Eric Lambaudie, Gilles Houvenaeghel
AimTo assess the value of post-mastectomy radiation therapy (PMRT) to breast cancer (BC) patients with no or minimal lymph node (LN) involvement.Materials and methodsWe retrospectively analysed a French multi-centric cohort of 4283 patients treated by mastectomy and axillary dissection, with or without PMRT, between 1980 and 2013. Practices were analysed for three treatment periods (1980–1999, 2000–2005 and 2006–2013). The impact of PMRT on loco-regional recurrence (LRR), disease-free survival (DFS), BC-specific survival and overall survival was assessed in pN0-1mi patients using multivariate analyses (logistic regression and Cox model). It was subsequently assessed based on the number of clinicopathological recurrence-risk factors, generating a prognostic index (French-PMRT index), to isolate a pN0-1mi patients subgroup that might derive a benefit from PMRT. We tested the accuracy of the Cambridge-PMRT (c-PMRT) index to discriminate between patients with significantly different outcomes and the value of PMRT in each c-PMRT prognostic group.ResultsMore than half of the pN0-1mi patients of our cohort underwent PMRT, which almost significantly improved LRR-free survival and DFS. Matching pN0-1mi patients based on the number of clinicopathologic recurrence-risk factors identified a higher risk subpopulation (≥3 recurrence-risk factors), but PMRT did not improve patient outcomes. Although the c-PMRT index had the potential to predict patient outcomes, its use did not help in making the decision of whether or not to use PMRT.ConclusionWe failed to isolate a subgroup of early BC patients without LN involvement suitable for PMRT, despite studying a large cohort.



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Response rate as a potential surrogate for survival and efficacy in patients treated with novel immune checkpoint inhibitors: A meta-regression of randomised prospective studies

Publication date: November 2017
Source:European Journal of Cancer, Volume 86
Author(s): Giandomenico Roviello, Fabrice Andre, Sergio Venturini, Barbara Pistilli, Giuseppe Curigliano, Massimo Cristofanilli, Pietro Rosellini, Daniele Generali
IntroductionTo assess the role of the tumour response rate (RR) after immune checkpoint inhibitors–based therapy as a potential surrogate end-point of progression-free survival (PFS) and overall survival (OS) in patients with solid tumours, we performed a trial-based meta-regression of randomised studies comparing different immune checkpoint inhibitors–based treatments.MethodsThe systematic literature search included the electronic databases and the proceedings of oncologic meetings. Treatment effects on PFS and OS were expressed as hazard ratios (HRs); treatment effects on RR were expressed as odds ratios (ORs). A weighted regression analysis was performed on log-transformed treatment effect estimates to test the association between treatment effects on the surrogate outcome and treatment effects on the clinical outcome.ResultsTwenty-four trials, for a total of 11,894 patients, were included in the analysis. Using the complete set of data, the regression of either the log(HR) for PFS or the log(HR) for OS on the log(OR) for RR demonstrated weak associations (R² = 0.47; 95% confidence interval [CI], 0.03–0.77; P = 0.001; and R² = 0.32; 95% CI, 0.02–0.76; P = 0.01, respectively). The pre-planned analyses stratifying trials according to different type of disease and different mechanism of action of immune checkpoint inhibitors showed a very weak association of the RR with the OS for non–small cell lung cancer indicated and a modest association of the RR with the PFS for cytotoxic T lymphocyte–associated antigen 4 checkpoint inhibitors.ConclusionThe results of the trial-based meta-regression analysis indicated a weak correlation between RR and OS, supporting future investigations to assess the surrogacy of RR in the patient treated with immune checkpoint inhibitors.



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Weekly cabazitaxel plus prednisone is effective and less toxic for ‘unfit’ metastatic castration-resistant prostate cancer: Phase II Spanish Oncology Genitourinary Group (SOGUG) trial

Publication date: December 2017
Source:European Journal of Cancer, Volume 87
Author(s): Miguel Ángel Climent, Begoña Pérez-Valderrama, Begoña Mellado, Eva María Fernández Parra, Ovidio Fernández Calvo, María Ochoa de Olza, Laura Muinelo Romay, Urbano Anido, Montserrat Domenech, Susana Hernando Polo, José Ángel Arranz Arija, Cristina Caballero, María José Juan Fita, Daniel Castellano
AimCabazitaxel (CBZ), a novel tubulin-binding taxane, improves overall survival in metastatic castration-resistant prostate cancer (mCRPC) that progresses during or after docetaxel treatment. We have designed a phase II study to evaluate the efficacy and safety of CBZ as a weekly schedule for 'unfit' mCRPC patients after docetaxel failure.MethodsIn this single arm phase II study. CBZ was weekly administered in 1-hour infusion on days 1, 8, 15 and 22, every 5 weeks at 10 mg/m² to eligible 'unfit' patients; oral prednisone (5 mg) was administered twice a day. Circulating tumour cells (CTCs) were also collected. New treatment scheme was considered effective if at least 65% of patients met a clinical benefit criteria based on prostate-specific antigen (PSA)-progression-free survival (PFS) values at week 12.ResultsSeventy patients (median age: 73.9 years) were enrolled; overall, 71.4% had an Eastern Cooperative Oncology Group Performance Status (ECOG-PS) of 2; and 84%, 16% and 11% had bone, liver and lung metastases, respectively. Objective partial response or stable disease was achieved in 61% of patients, while PSA responses of ≥50% and ≥80% were observed in 34.8% and 10.6%, respectively. The median PSA-PFS was 4.8 months; and 68.6% of patients had no progression at week 12. The most frequent grade 3/4 toxicities were neutropenia (2.8%), leukopenia (5.7%) and thrombocytopaenia (9%); no cases of febrile neutropenia were reported. Early CTC response was significantly correlated with PSA-PFS.ConclusionsCBZ/prednisone administered weekly to 'unfit' mCRPC patients appears to be as effective as classical standard 3-week scheme (TROPIC study) but with significantly lower toxicities and better tolerance. Early CTC response appears to be valuable as an early end-point of therapeutic efficacy.



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Site of childhood cancer care in the Netherlands

Publication date: December 2017
Source:European Journal of Cancer, Volume 87
Author(s): A.M.J. Reedijk, M. van der Heiden-van der Loo, O. Visser, H.E. Karim-Kos, J.A. Lieverst, J.G. de Ridder-Sluiter, J.W.W. Coebergh, L.C. Kremer, R. Pieters
BackgroundDue to the complexity of diagnosis and treatment, care for children and young adolescents with cancer preferably occurs in specialised paediatric oncology centres with potentially better cure rates and minimal late effects. This study assessed where children with cancer in the Netherlands were treated since 2004.MethodsAll patients aged under 18 diagnosed with cancer between 2004 and 2013 were selected from the Netherlands Cancer Registry (NCR) and linked with the Dutch Childhood Oncology Group (DCOG) database. Associations between patient and tumour characteristics site of care were tested statistically with logistic regression analyses.ResultsThis population-based study of 6021 children diagnosed with cancer showed that 82% of them were treated in a paediatric oncology centre. Ninety-four percent of the patients under 10 years of age, 85% of the patients aged 10–14 and 48% of the patients aged 15–17 were treated in a paediatric oncology centre. All International Classification of Childhood Cancers (ICCC), 3rd edition, ICCC-3 categories, except embryonal tumours, were associated with a higher risk of treatment outside a paediatric oncology centre compared to leukaemia. Multivariable analyses by ICCC-3 category revealed that specific tumour types such as chronic myelogenous leukaemia (CML), embryonal carcinomas, bone tumours other type than osteosarcoma, non-rhabdomyosarcomas, thyroid carcinomas, melanomas and skin carcinomas as well as lower-staged tumours were associated with treatment outside a paediatric oncology centre.ConclusionThe site of childhood cancer care in the Netherlands depends on the age of the cancer patient, type of tumour and stage at diagnosis. Collaboration between paediatric oncology centre(s), other academic units is needed to ensure most up-to-date paediatric cancer care for childhood cancer patients at the short and long term.



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The use of sentinel lymph node biopsy in the treatment of breast ductal carcinoma in situ: A Danish population-based study

Publication date: December 2017
Source:European Journal of Cancer, Volume 87
Author(s): Emil Villiam Holm-Rasmussen, Maj-Britt Jensen, Eva Balslev, Niels Kroman, Tove Filtenborg Tvedskov
ObjectivesThe risk of axillary metastases in breast cancer patients with only ductal carcinoma in situ (DCIS) is low. Thus, axillary staging with sentinel lymph node biopsy (SLNB) should only be used according to the current guidelines to avoid over-treatment and unnecessary morbidity. In the present study, the use of SLNB in patients with DCIS was evaluated nationally and compared across Danish departments.Material and methodsA register-based study was conducted using the Danish Breast Cancer Group database. The use of SLNB in DCIS patients according to year of diagnosis, age at diagnosis, size of lesion, Van Nuys classification, palpability, location and department of surgery was evaluated. The chi-squared test was used to test differences between the groups.ResultsData from 2618 Danish female patients diagnosed with DCIS between 2004 and 2015 were included; 54.3% of patients underwent SLNB. The use of SLNB increased from 26.6% in 2004 to 65.1% in 2015. A total of 1877 (71.7%) patients underwent breast-conserving surgery (BCS), and 577 (22.0%) underwent mastectomy, of which 43.9% and 86.0% respectively had a concomitant SLNB. The SLNB was performed in 23.8% of 454 patients not included by the guidelines. The use of SLNB in combination with BCS differed significantly between departments ranging from 19.7% to 63.8%. A significant difference in the use of SLNB with BCS and mastectomy according to department capacity (high-volume departments versus low-volume departments) was observed.ConclusionThe use of SLNB in patients with DCIS and adherence to the Danish national guidelines varies among Danish breast surgery departments. To optimise the axillary treatment of patients with DCIS, an improved compliance to the national DCIS guidelines is necessary.



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Identification of single nucleotide polymorphisms of the PI3K-AKT-mTOR pathway as a risk factor of central nervous system metastasis in metastatic breast cancer

Publication date: Available online 2 November 2017
Source:European Journal of Cancer
Author(s): Emilie Le Rhun, Nicolas Bertrand, Aurélie Dumont, Emmanuelle Tresch, Marie-Cécile Le Deley, Audrey Mailliez, Matthias Preusser, Michael Weller, Françoise Revillion, Jacques Bonneterre
IntroductionThe PI3K-AKT-mTOR pathway may be involved in the development of central nervous system (CNS) metastasis from breast cancer. Accordingly, herein we explored whether single nucleotide polymorphisms (SNPs) of this pathway are associated with altered risk of CNS metastasis formation in metastatic breast cancer patients.MethodsThe GENEOM study (NCT00959556) included blood sample collection from breast cancer patients treated in the neoadjuvant, adjuvant or metastatic setting. We identified patients with CNS metastases for comparison with patients without CNS metastasis, defined as either absence of neurological symptoms or normal brain magnetic resonance imaging (MRI) before death or during 5-year follow-up. Eighty-eight SNPs of phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian (or mechanistic) target of rapamycin (mTOR) pathway genes were selected for analysis: AKT1 (17 SNPs), AKT2 (4), FGFR1 (2), mTOR (7), PDK1 (4), PI3KR1 (11), PI3KCA (20), PTEN (17), RPS6KB1 (6).ResultsOf 342 patients with metastases, 207 fulfilled the inclusion criteria: One-hundred-and-seven patients remained free of CNS metastases at last follow-up or date of death whereas 100 patients developed CNS metastases. Among clinical parameters, hormonal and human epidermal growth factor receptor-2 (HER2) status as well as vascular tumour emboli was associated with risk of CNS metastasis. Only PI3KR1-rs706716 was associated with CNS metastasis in univariate analysis after Bonferroni correction (p < 0.00085). Multivariate analysis showed associations between AKT1-rs3803304, AKT2-rs3730050, PDK1-rs11686903 and PI3KR1-rs706716 and CNS metastasis .ConclusionPI3KR1-rs706716 may be associated with CNS metastasis in metastatic breast cancer patients and could be included in a predictive composite score to detect early CNS metastasis irrespective of breast cancer subtype.



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Clinical relevance of molecular diagnostics in gastrointestinal (GI) cancer: European Society of Digestive Oncology (ESDO) expert discussion and recommendations from the 17th European Society for Medical Oncology (ESMO)/World Congress on Gastrointestinal Cancer, Barcelona

Publication date: November 2017
Source:European Journal of Cancer, Volume 86
Author(s): Alexander Baraniskin, Jean-Luc Van Laethem, Lucjan Wyrwicz, Ulrich Guller, Harpreet S. Wasan, Tamara Matysiak-Budnik, Thomas Gruenberger, Michel Ducreux, Fatima Carneiro, Eric Van Cutsem, Thomas Seufferlein, Wolff Schmiegel
Background and scopeIn the epoch of precision medicine and personalised oncology, which aims to deliver the right treatment to the right patient, molecular genetic biomarkers are a topic of growing interest. The aim of this expert discussion and position paper is to review the current status of various molecular tests for gastrointestinal (GI) cancers and especially considering their significance for the clinical routine use.MethodologyOpinion leaders and experts from diverse nationalities selected on scientific merit were asked to answer to a prepared set of questions about the current status of molecular diagnostics in different GI cancers. All answers were then discussed during a plenary session and reported here in providing a well-balanced reflection of both clinical expertise and updated evidence-based medicine.ResultsPreselected molecular genetic biomarkers that are described and disputed in the current medical literature in different GI cancers were debated, and recommendations for clinical routine practice were made whenever possible. Furthermore, the preanalytical variations were commented and proposals for quality controls of biospecimens were made.ConclusionThe current article summarises the recommendations of the expert committee regarding prognostic and predictive molecular genetic biomarkers in different entities of GI cancers. The briefly and comprehensively formulated guidelines should assist clinicians in the process of decision making in daily clinical practice.



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Divergent oestrogen receptor-specific breast cancer trends in Ireland (2004–2013): Amassing data from independent Western populations provide etiologic clues

Publication date: November 2017
Source:European Journal of Cancer, Volume 86
Author(s): Maeve Mullooly, Jeanne Murphy, Gretchen L. Gierach, Paul M. Walsh, Sandra Deady, Thomas I. Barron, Mark E. Sherman, Philip S. Rosenberg, William F. Anderson
The aetiology and clinical behaviour of breast cancers vary by oestrogen receptor (ER) expression, HER2 expression and over time. Data from the United States and Denmark show rising incidence rates for ER+ and falling incidence rates for ER– breast cancers. Given that Ireland is a somewhat similar Western population but with distinctive risk exposures (especially for lactation), we analysed breast cancer trends by ER status; and for the first time, by the joint expression of ER±/HER2±. We assessed invasive breast cancers (n = 24,845; 2004–2013) within the population-based National Cancer Registry of Ireland. The population at risk was obtained from the Irish Central Statistics Office (n = 10,401,986). After accounting for missing ER and HER2 data, we assessed receptor-specific secular trends in age-standardised incidence rates (ASRs) with the estimated annual percentage change (EAPC) and corresponding 95% confidence intervals (95% CI). Age-period-cohort models were also fitted to further characterise trends accounting for age, calendar-period and birth-cohort interactions. ASRs increased for ER+ (EAPC: 2.2% per year [95% CI: 0.97, 3.45%/year]) and decreased for ER– cancers (EAPC: −3.43% per year [95% CI: −5.05, −1.78%/year]), as well as for specific age groups at diagnosis (<30–49, 50–64 and ≥65 years). ER+/HER2– cancers rose, ER+/HER2+ cancers were statistically flat and ER–/HER± cancers declined. Secular trends for ER± cancers in Ireland were like those previously observed. Stratification by HER2± expression did not substantively alter ER± trends. The divergence of ER± incidence rates among independent Western populations likely reflects calendar-period and/or risk factor changes with differential effects for ER+ and ER– breast cancers.



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Clinical and molecular characterisation of hereditary and sporadic metastatic colorectal cancers harbouring microsatellite instability/DNA mismatch repair deficiency

Publication date: November 2017
Source:European Journal of Cancer, Volume 86
Author(s): R. Cohen, O. Buhard, P. Cervera, E. Hain, S. Dumont, A. Bardier, J.-B. Bachet, J.-M. Gornet, D. Lopez-Trabada, S. Dumont, R. Kaci, P. Bertheau, F. Renaud, F. Bibeau, Y. Parc, D. Vernerey, A. Duval, M. Svrcek, Thierry André
BackgroundPatients treated with chemotherapy for microsatellite unstable (MSI) and/or mismatch repair deficient (dMMR) cancer metastatic colorectal cancer (mCRC) exhibit poor prognosis. We aimed to evaluate the relevance of distinguishing sporadic from Lynch syndrome (LS)-like mCRCs.Patients and methodsMSI/dMMR mCRC patients were retrospectively identified in six French hospitals. Tumour samples were screened for MSI, dMMR, RAS/RAF mutations and MLH1 methylation. Sporadic cases were molecularly defined as those displaying MLH1/PMS2 loss of expression with BRAFV600E and/or MLH1 hypermethylation and no MMR germline mutation.ResultsAmong 129 MSI/dMMR mCRC patients, 81 (63%) were LS-like and 48 (31%) had sporadic tumours; 22% of MLH1/PMS2-negative mCRCs would have been misclassified using an algorithm based on local medical records (age, Amsterdam II criteria, BRAF and MMR statuses when locally tested), compared to a systematical assessment of MMR, BRAF and MLH1 methylation statuses. In univariate analysis, parameters associated with better overall survival were age (P < 0.0001), metastatic resection (P = 0.001) and LS-like mCRC (P = 0.01), but not BRAFV600E. In multivariate analysis, age (hazard ratio (HR) = 3.19, P = 0.01) and metastatic resection (HR = 4.2, P = 0.001) were associated with overall survival, but not LS. LS-like patients were associated with more frequent liver involvement, metastatic resection and better disease-free survival after metastasectomy (HR = 0.28, P = 0.01). Median progression-free survival of first-line chemotherapy was similar between the two groups (4.2 and 4.2 months; P = 0.44).ConclusionsLS-like and sporadic MSI/dMMR mCRCs display distinct natural histories. MMR, BRAF mutation and MLH1 methylation testing should be mandatory to differentiate LS-like and sporadic MSI/dMMR mCRC, to determine in particular whether immune checkpoint inhibitors efficacy differs in these two populations.



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Genetic polymorphisms in angiogenesis-related genes are associated with worse progression-free survival of patients with advanced gastrointestinal stromal tumours treated with imatinib

Publication date: November 2017
Source:European Journal of Cancer, Volume 86
Author(s): Michiel C. Verboom, Jacqueline S.L. Kloth, Jesse J. Swen, Tahar van der Straaten, Judith V.M.G. Bovée, Stefan Sleijfer, Anna K.L. Reyners, Ron H.J. Mathijssen, Henk-Jan Guchelaar, Neeltje Steeghs, Hans Gelderblom
BackgroundImatinib 400 mg per day is first-line therapy for patients with gastrointestinal stromal tumours (GISTs). Although clinical benefit is high, progression-free survival (PFS) is variable. This study explores the relationship of single nucleotide polymorphisms (SNPs) in genes related to imatinib pharmacokinetics and pharmacodynamics and PFS in imatinib-treated patients with advanced GIST.MethodsIn 227 patients a pharmacogenetic pathway analysis was performed. Genotype data from 36 SNPs in 18 genes were tested in univariate analyses to investigate their relationship with PFS. Genetic variables which showed a trend (p < 0.1) were tested in a multivariate model, in which each singular SNP was added to clinicopathological factors.ResultsIn univariate analyses, PFS was associated with synchronous metastases (p = 0.0008) and the mutational status (p = 0.004). Associations with rs1870377 in KDR (additive model, p = 0.0009), rs1570360 in VEGFA (additive model, p = 0.053) and rs4149117 in SLCO1B3 (mutant dominant model, 0.027) were also found. In the multivariate model, significant associations and trends with shorter PFS were found for synchronous metastases (HR 1.94, p = 0.002), KIT exon 9 mutation (HR 2.45, p = 0.002) and the SNPs rs1870377 (AA genotype, HR 2.61, p = 0.015), rs1570360 (AA genotype, HR 2.02, p = 0.037) and rs4149117 (T allele, HR 0.62, p = 0.083).ConclusionIn addition to KIT exon 9 mutation and synchronous metastases, SNPs in KDR, VEGFA and SLCO1B3 appear to be associated with PFS in patients with advanced GIST receiving 400-mg imatinib. If validated, specific SNPs may serve as predictive biomarkers to identify patients with an increased risk for progressive disease during imatinib therapy.



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Long-term survival of sorafenib-treated FLT3-ITD–positive acute myeloid leukaemia patients relapsing after allogeneic stem cell transplantation

Publication date: November 2017
Source:European Journal of Cancer, Volume 86
Author(s): S.K. Metzelder, T. Schroeder, M. Lübbert, M. Ditschkowski, K. Götze, S. Scholl, R.G. Meyer, P. Dreger, N. Basara, M.F. Fey, H.R. Salih, A. Finck, T. Pabst, A. Giagounidis, G. Kobbe, E. Wollmer, J. Finke, A. Neubauer, A. Burchert
BackgroundFms-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD)–positive acute myeloid leukaemia (AML) relapsing after allogeneic stem cell transplantation (allo-SCT) has a dismal prognosis with limited therapeutic options. FLT3-ITD kinase inhibition is a reasonable but palliative experimental treatment alternative in this situation. Information on long-term outcome is not available.MethodsWe performed a long-term follow-up analysis of a previously reported cohort of 29 FLT3-ITD–positive AML patients, which were treated in relapse after allo-SCT with sorafenib monotherapy.FindingsWith a median follow-up of 7.5 years, 6 of 29 patients (21%) are still alive. Excluding one patient who received a second allo-SCT, five patients (17%) achieved sustained complete remissions with sorafenib. Four of these patients are in treatment-free remission for a median of 4.4 years.InterpretationSorafenib may enable cure of a proportion of very poor risk FLT3-ITD–positive AML relapsing after allo-SCT.



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First-in-man phase I study assessing the safety and pharmacokinetics of a 1-hour intravenous infusion of the doxorubicin prodrug DTS-201 every 3 weeks in patients with advanced or metastatic solid tumours

Publication date: November 2017
Source:European Journal of Cancer, Volume 86
Author(s): Patrick Schöffski, Jean-Pierre Delord, Etienne Brain, Jacques Robert, Herlinde Dumez, Jamal Gasmi, André Trouet
PurposeDTS-201 is a doxorubicin (Dox) prodrug that shows encouraging data in experimental models in terms of both efficacy and safety compared with conventional Dox. The purpose of this phase I study was to assess the safety profile, to establish the recommended dose (RD) for clinical phase II studies and to assess potential anticancer activity of the compound.Experimental designDTS-201 was administered as a 1-hour infusion every 3 weeks in eligible patients with advanced solid tumours according to common clinical phase I criteria. Dose escalation was performed according to a modified Fibonacci schema.ResultsTwenty-five patients with a median age of 58 years (range, 30–72) were enrolled in the study. The median number of treatment cycles was 2 (range, 1–8). DTS-201 was administered at four dose levels (DLs) ranging from 80 to 400 mg/m², which is equivalent to 45–225 mg/m² of conventional Dox. No dose-limiting toxicity (DLT) occurred at the first two DLs. Three DLTs were observed at DL3 and DL4 (diarrhoea for DL3, vomiting and neutropenia for DL4). DL4 (400 mg/m²) was considered the maximum tolerated dose. Myelosuppression was the main toxicity, and NCI-CTC grade III–IV neutropenia was common at RD. Non-haematological adverse reactions were mild to moderate and included nausea, anorexia, asthenia and alopecia. No treatment-related severe cardiac adverse events were observed.ConclusionsDTS-201 is well tolerated and safe in heavily pretreated solid tumour patients. A high equivalent dose of Dox could be delivered without severe drug-related cardiac events. DTS-201 showed evidence of clinical activity with a confirmed partial response in a patient with soft-tissue sarcoma. The recommended phase II dose is 400 mg/m².



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Elderly patients with gastrointestinal stromal tumour (GIST) receive less treatment irrespective of performance score or comorbidity – A retrospective multicentre study in a large cohort of GIST patients

Publication date: November 2017
Source:European Journal of Cancer, Volume 86
Author(s): Sheima Farag, Frits van Coevorden, Esther Sneekes, Dirk J. Grunhagen, Anna K.L. Reyners, Pieter A. Boonstra, Winette T. van der Graaf, Hans J. Gelderblom, Neeltje Steeghs
ObjectiveAlthough gastrointestinal stromal tumours (GIST) predominantly occur in older patients, data on treatment patterns in elderly GIST patients are scarce.MethodsPatients registered in the Dutch GIST Registry (DGR) from January 2009 until December 2016 were included. Differences in treatment patterns between elderly (≥75 years) and younger patients were compared. Multivariate analyses were conducted using logistic regression.ResultsData of 145 elderly and 665 non-elderly patients were registered (median age 78 and 60 years respectively). In elderly patients, performance score (WHO-PS) and age-adjusted Charlson comorbidity index (ACCI) were significantly higher (p < 0.05; p < 0.001), and albumin level significantly lower (p = 0.04).Hundred-and-nine (75.2%) elderly and 503 (75.6%) non-elderly patients had only localised disease. Surgery was performed in 57% of elderly versus 84% of non-elderly patients (p = 0.003, OR: 0.26, 95% CI: 0.11–0.63). No differences in surgery outcome or complications were found. Thirty-eight percent of elderly with an indication for adjuvant treatment did receive imatinib versus 68% of non-elderly (p = 0.04, OR: 0.47, 95% CI: 0.23–0.95).Thirty-six elderly and 162 non-elderly patients had metastatic disease. Palliative imatinib was equally given (mean dose 400 mg) and adverse events were mostly minor (p = 0.71). In elderly, drug-related toxicity was in 32.7% reason to discontinue imatinib versus 5.1% in non-elderly (p = 0.001, OR 13.5, 95% CI: 2.8–65.0). Median progression-free survival (PFS) was 24 months in elderly and 33 months in non-elderly (p = 0.10). Median overall survival (OS) was 34 months and 59 months respectively (p = 0.01).ConclusionsElderly GIST patients with localised disease receive less surgery and adjuvant treatment, irrespective of comorbidity and performance score. Drug-related toxicity results more often in treatment discontinuation. This possibly results in poor outcome.



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Revisiting the definition of dose-limiting toxicities in paediatric oncology phase I clinical trials: An analysis from the Innovative Therapies for Children with Cancer Consortium

Publication date: November 2017
Source:European Journal of Cancer, Volume 86
Author(s): Francisco Bautista, Lucas Moreno, Lynley Marshall, Andrew D.J. Pearson, Birgit Geoerger, Xavier Paoletti
BackgroundDose-escalation trials aim to identify the maximum tolerated dose and, importantly, the recommended phase II dose (RP2D) and rely on the occurrence of dose-limiting toxicities (DLTs) during the first treatment cycle. Molecularly targeted agents (MTAs) often follow continuous and prolonged administrations, displaying a distinct toxicity profile compared to conventional chemotherapeutics, and classical DLT criteria might not be appropriate to evaluate MTAs' toxicity. We investigated this issue in children.MethodsThe Innovative Therapies for Children with Cancer Consortium (ITCC) phase I trials of novel anticancer agents between 2004 and 2015 were analysed. Data from investigational product, trial design, items defining DLT/RP2D were extracted. A survey on dose-escalation process, DLTs and RP2D definition was conducted among the ITCC clinical trials committee members.ResultsThirteen phase I trials with 15 dose-escalation cohorts were analysed. They explored 11 MTAs and 2 novel cytotoxics; 12 evaluated DLT during cycle 1. Definition of DLT was heterogeneous: Grade III–IV haematologic toxicities that were transient or asymptomatic and grade III–IV non-haematological toxicities manageable with adequate supportive care were often excluded, whereas some included dose intensity or grade II toxicities into DLT. None of the studies considered delayed toxicity into the RP2D definition.ConclusionDLTs should be homogeneously defined across trials, limiting the number of exceptions due to specific toxicities. Dose escalation should still be based on safety data from cycle 1, but delayed and overall toxicities, pharmacokinetic parameters and pharmacodynamic data should be considered to refine the final RP2D. The evaluation of long-term toxicity in the developing child cannot be adequately addressed in early trials.



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The prognostic benefit of tumour-infiltrating Natural Killer cells in endometrial cancer is dependent on concurrent overexpression of Human Leucocyte Antigen-E in the tumour microenvironment

Publication date: November 2017
Source:European Journal of Cancer, Volume 86
Author(s): M.A.C. Versluis, S. Marchal, A. Plat, G.H. de Bock, T. van Hall, M. de Bruyn, H. Hollema, H.W. Nijman
BackgroundHuman Leucocyte Antigen- E (HLA-E) has been reported as both a positive and negative prognostic marker in cancer. This apparent discrepancy may be due to opposing actions of HLA-E on tumour-infiltrating immune cells. Therefore, we evaluated HLA-E expression and survival in relation to the presence of intratumoural natural killer (NK) cells and cytotoxic T cells (CTLs).MethodsTissue microarrays (TMAs) of endometrial tumours were used for immunohistochemical staining of parameters of interest. The combined impact of clinical, pathological and immune parameters on survival was analysed using log rank testing and Cox regression analyses.ResultsUpregulation of HLA-E was associated with an improved disease-free and disease-specific survival in univariate analysis (HR 0.58 95% CI 0.37–0.89; HR 0.42 95% CI 0.25–0.73, respectively). In multivariate analysis, the presence of NK cells predicts survival with a hazard ratio (HR) 0.28 (95% confidence interval (CI) 0.09–0.91) when HLA-E expression is upregulated; but it is associated with a worse prognosis when HLA-E expression is normal (HR 13.43, 95% CI 1.70–106.14). By contrast, the prognostic benefit of T cells was not modulated by HLA-E expression.ConclusionsTaken together, we demonstrate that the prognostic benefit of NK cells, but not T-cells, is influenced by HLA-E expression in endometrial cancer (EC) and propose a model to explain our observations.



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Phase II randomised discontinuation trial of cabozantinib in patients with advanced solid tumours

Publication date: November 2017
Source:European Journal of Cancer, Volume 86
Author(s): Patrick Schöffski, Michael Gordon, David C. Smith, Razelle Kurzrock, Adil Daud, Nicholas J. Vogelzang, Yihua Lee, Christian Scheffold, Geoffrey I. Shapiro
BackgroundCabozantinib is an inhibitor of tyrosine kinases, including MET, vascular endothelial growth factor receptor, AXL and RET. This multi-cohort phase II randomised discontinuation trial explored anticancer activity of cabozantinib in nine tumour types.Patients and methodsCabozantinib was administered (100 mg, once daily) to patients with advanced, recurrent or metastatic cancers. Those with stable disease at week 12 were randomised 1:1 to cabozantinib or placebo. Primary end-points were objective response rate (ORR) at week 12 and progression-free survival (PFS) in the randomised phase.ResultsA total of 526 patients were enrolled. The highest ORR was observed in ovarian cancer (OC) (21.7%); the largest PFS benefit was observed in castration-resistant prostate cancer (CRPC) (median 5.5 versus 1.4 months for placebo; hazard ratio 0.14, 95% confidence interval: 0.04, 0.52). Disease control rates were >40% for CRPC, OC, melanoma, metastatic breast cancer (MBC), hepatocellular carcinoma (HCC) and non–small cell lung cancer. Median duration of response ranged from 3.3 (MBC) to 11.2 months (OC). Encouraging efficacy results and symptomatic improvements prompted early suspension of the randomised stage and conversion to open-label non-randomised expansion cohorts. Dose reductions to manage adverse events (AEs) occurred in 48.7% of patients. The most frequent grade III–IV AEs were fatigue (12.4%), diarrhoea (10.5%), hypertension (10.5%) and palmar-plantar erythrodysesthesia syndrome (8.7%).ConclusionsClinical antitumour activity of cabozantinib was observed in a subset of tumour types: CRPC and OC were evaluated further in expansion cohorts. Phase III programs were initiated in CRPC and HCC. Interpretation of efficacy outcomes was limited by early termination of the randomised portion of the trial.Trial registration numberNCT00940225.



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