[Show abstract][Hide abstract] ABSTRACT: Chemoradiation (CRT) has been shown to lead to downsizing of an important portion of rectal cancers. In order to tailor treatment at an earlier stage during treatment, predictive models are being developed. Adding blood biomarkers may be attractive for prediction, as they can be collected very easily and determined with excellent reproducibility in clinical practice. The hypothesis of this study was that blood biomarkers related to tumor load, hypoxia and inflammation can help to predict response to CRT in rectal cancer.
Radiotherapy and Oncology 04/2014; 111(2). DOI:10.1016/j.radonc.2014.03.006 · 4.86 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To investigate the reproducibility of diffusion-weighted magnetic resonance imaging (DW-MRI) in assessing tumor response early in the course of neoadjuvant chemoradiotherapy in patients with operable esophageal cancer.
Eleven male patients (mean age 54.8 years) with newly diagnosed esophageal cancer underwent DW-MRI before and 10 days after start of chemoradiotherapy. Reproducibility of apparent diffusion coefficient (ADC) measurements by manual (freehand) and semi-automated volumetric methods was assessed.
Interobserver reproducibility for the assessment of mean tumor ADC by the manual measurement method was good, with an ICC of 0.69 (95% CI, 0.36 to 0.85; P = 0.001). Interobserver reproducibility for the assessment of mean tumor ADC by the semi-automated volumetric measurement method was very good, with an ICC of 0.96 (95% CI, 0.91 to 0.98; P<0.001).
Semi-automated volumetric ADC measurements have higher reproducibility than manual ADC measurements in assessing tumor response to chemoradiotherapy in patients with esophageal adenocarcinoma.
PLoS ONE 04/2014; 9(4):e92211. DOI:10.1371/journal.pone.0092211 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: New prognostic markers may be of value in determining survival and informing decisions of adjuvant treatment in the heterogeneous group of soft tissue sarcomas known as malignant fibrous sarcomas (MFS). Increased CD44 expression has been associated with a better outcome in cancers such as bladder tumors and could potentially relate to cell-cell interaction as a marker for potential invasion/metastasis. The aim of this pilot study was to determine if there is a correlation between the expression rate of CD44 in adult patients with MFS and clinical outcomes.
The clinical outcome of 34 adult MFS patients (19 males and 15 females, average age 62 years, median 63 years, range: 38-88 years) who underwent surgical treatment were evaluated. Twenty-five of these patients had additional adjuvant radiotherapy. Extracted RNA from sarcoma tissues was used to measure the transcripts of CD44s (standard form) and isoform expression.The pooled data for each variant of CD44 was divided in half at the median expression value into two equally sized groups (low and high). Survival modeling and multivariate analysis were used with these two groups to determine if there were differences in survival times and whether this was independent of known factors such as tumor stage/grade, patient age and resection margin status.
High CD44s and low of CD44v6 expression significantly correlated with an improved outcome (P <0.05 and P <0.02, respectively) whereas CD44v8 and hCD44 (isoforms) did not. Differences in survival were apparent within 6-12 months of operation with >30% difference in survival between low/high expressions at 5 years. These finding were independent of the other measured MFS survival predictors, though the group was homogenous.
High CD44s and low CD44v6 expression may be an independent predictor of improved survival in MFS patients in this pilot data. This is contrary to other MFS data, which did not account for the CD44 isoforms but is confirmed by data from other cancer types. Further investigation is needed to confirm CD44 isoform expression data as a relevant survival biomarker and whether it could be used to inform clinical decisions such as adjuvant therapy.
[Show abstract][Hide abstract] ABSTRACT: Purpose/objective
Chemoradiation (CRT) has been shown to lead to downsizing of an important portion of rectal cancers. In order to tailor treatment at an earlier stage during treatment, predictive models are being developed. Adding blood biomarkers may be attractive for prediction, as they can be collected very easily and determined with excellent reproducibility in clinical practice. The hypothesis of this study was that blood biomarkers related to tumor load, hypoxia and inflammation can help to predict response to CRT in rectal cancer.
295 patients with locally advanced rectal cancer who were planned to undergo CRT were prospectively entered into a biobank protocol (NCT01067872). Blood samples were drawn before start of CRT. Nine biomarkers were selected, based on a previously defined hypothesis, and measured in a standardized way by a certified lab: CEA, CA19-9, LDH, CRP, IL-6, IL-8, CA IX, osteopontin and 25-OH-vitamin D. Outcome was analyzed in two ways: pCR vs. non-pCR and responders (defined as ypT0-2N0) vs. non-responders (all other ypTN stages).
276 patients could be analyzed. 20.7% developed a pCR and 47.1% were classified as responders. In univariate analysis CEA (p = 0.001) and osteopontin (p = 0.012) were significant predictors for pCR. Taking response as outcome CEA (p < 0.001), IL-8 (p < 0.001) and osteopontin (p = 0.004) were significant predictors. In multivariate analysis CEA was the strongest predictor for pCR (OR 0.92, p = 0.019) and CEA and IL-8 predicted for response (OR 0.97, p = 0.029 and OR 0.94, p = 0.036). The model based on biomarkers only had an AUC of 0.65 for pCR and 0.68 for response; the strongest model included clinical data, PET-data and biomarkers and had an AUC of 0.81 for pCR and 0.78 for response.
CEA and IL-8 were identified as predictive biomarkers for tumor response and PCR after CRT in rectal cancer. Incorporation of these blood biomarkers leads to an additional accuracy of earlier developed prediction models using clinical variables and PET-information. The new model could help to an early adaptation of treatment in rectal cancer patients.
[Show abstract][Hide abstract] ABSTRACT: A previous study showed promising results for gadofosveset-trisodium as a lymph node magnetic resonance imaging (MRI) contrast agent in rectal cancer. The aim of this study was to prospectively confirm the diagnostic performance of gadofosveset MRI for nodal (re)staging in rectal cancer in a second patient cohort.
Seventy-one rectal cancer patients were prospectively included, of whom 13 (group I) underwent a primary staging gadofosveset MRI (1.5-T) followed by surgery (± preoperative 5 × 5 Gy) and 58 (group II) underwent both primary staging and restaging gadofosveset MRI after a long course of chemoradiotherapy followed by surgery. Nodal status was scored as (y)cN0 or (y)cN+ by two independent readers (R1, R2) with different experience levels. Results were correlated with histology on a node-by-node basis.
Sensitivity, specificity and area under the receiver operating characteristics curve (AUC) were 94 %, 79 % and 0.89 for the more experienced R1 and 50 %, 83 % and 0.74 for the non-experienced R2. R2's performance improved considerably after a learning curve, to an AUC of 0.83. Misinterpretations mainly occurred in nodes located in the superior mesorectum, nodes located in between vessels and nodes containing micrometastases.
This prospective study confirms the good diagnostic performance of gadofosveset MRI for nodal (re)staging in rectal cancer.
• Gadofosveset-enhanced MRI shows high performance for nodal (re)staging in rectal cancer. • Gadofosveset MRI may facilitate better selection of patients for personalised treatment. • Results can be reproduced by non-expert readers. • Experience of 50-60 cases is required to achieve required expertise level. • Main pitfalls are nodes located between vessels and nodes containing micrometastases.
European Radiology 09/2013; 24(2). DOI:10.1007/s00330-013-3016-6 · 4.34 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The implementation of neoadjuvant chemoradiotherapy (CRT) in esophageal cancer (EC) patients has led to improved survival rates. Worldwide, different CRT regimens are applied. It is unknown how these regimens relate to each other regarding efficacy. Therefore, the aim of this study was to determine the preferred regimen regarding toxicity of, response to CRT, and long-term survival after esophagectomy in EC patients. EC patients in two centers who underwent CRT with different regimens prior to surgery were included in this study. CRT consisted of 50.4Gy combined with two cycles of cisplatin and 5-FU(center A), or 41.4Gy combined with five cycles of carboplatin and paclitaxel (center B). Toxicity, response to therapy and long-term survival were compared between groups. One hundred sisty-five patients were included. Forty-one percent of patients in center A developed ≥1 toxicity ≥ grade 3 versus 25% in center B (P = 0.025). CRT with a cisplatin-based regimen was an independent predictor for development of toxicity ≥ grade 3 (P = 0.043). There were no differences in response between both regimens (P = 0.904). Three-year survival was 61% (A) versus 57% (B) (P = 0.725). The carboplatin/paclitaxel/41.4Gy regimen causes less toxicity compared to the cisplatin/5-FU/50.4Gy regimen with nonsignificant differences in response rates and long-term survival; therefore our results support this regimen to be the preferred regimen for EC patients.
Diseases of the Esophagus 09/2013; 27(4). DOI:10.1111/dote.12110 · 2.06 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To determine retrospectively the additional value of DWI-MRI toT2-MRI for predicting complete response (ypT0N0 = CR) after chemoradiation-therapy (CRT) in locally advanced rectal cancer.
Seventy locally advanced rectal cancer patients underwent CRT followed by restaging MRI and resection. Two readers with different experience levels independently scored T2 images for CR and, in a second reading, combined T2 and DWI. A 5-point confidence-level score was used to generate ROC curves. Areas under the ROC curves (AUC) and interobserver agreement were compared for both readings. Histology served as reference standard.
The interobserver agreement increased after addition of DWI from 0.35 to 0.58 but the AUC improved only for the experienced reader (0.77 to 0.89, p = 0.005 vs. 0.74 to 0.70, p > 0.05). Sensitivity and NPV improved from 20-30 % to 40-70 %, respectively 88 % to 91-95 %. Specificity and PPV improved only for the experienced reader (87 to 93 % respectively 27 to 63 %).
Adding DWI to T2-MRI improves consistency between readers and has potential to improve readers' accuracy dependent on his/her experience. DWI could be of additional value, particularly in ruling out CR (high NPV), but considering the sub-optimal PPV one should be cautious about relying solely on MRI for the clinical decision to offer a wait-and-see strategy.
• Diffusion-weighted magnetic resonance imaging is increasingly used to assess rectal tumours • Adding DWI to T2-MRI potentially improves diagnostic accuracy for identifying complete responders • Adding DWI to T2-MRI improves consistency among readers with different experience levels. • This combination can help rule out complete tumour response. • Patients should not be selected for wait-and-see strategies by MRI alone.
European Radiology 07/2013; 23(12). DOI:10.1007/s00330-013-2956-1 · 4.34 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: PURPOSE: Neoadjuvant chemoradiotherapy is increasingly used in oesophageal cancer patients. In general, small tumours are associated with a survival benefit compared to large tumours. Little is known, however, about the relationship between initial tumour volume and response to chemoradiotherapy. Therefore, the aim of this study was to determine whether the pretherapy metabolic tumour volume (MTV) on diagnostic PET/CT in oesophageal cancer patients is correlated with response to chemoradiotherapy in the resection specimen. METHODS: A consecutive series of patients underwent diagnostic PET/CT scanning prior to chemoradiotherapy and oesophagectomy. MTVs were determined on PET/CT and an automated tumour contour was generated using specified standard uptake value thresholds. Response to chemoradiotherapy was determined in the resection specimen according to the scoring system developed by Mandard et al. Patients were divided into different groups according to response to chemoradiotherapy. RESULTS: Between January 2008 and May 2011 a total of 115 patients underwent an oesophagectomy. The MTV determined on diagnostic PET/CT scans was available in 79 patients. Of these 79 patients, 30 (38 %) showed no residual tumour cells at the location of the primary tumour. Three of these patients presented with residual tumour cells in the lymph nodes; 27 patients (34 %) had a complete pathological response. There was a trend towards a better response in patients with a smaller MTV (p = 0.084). CONCLUSION: This study demonstrated a trend towards a correlation between response to chemoradiotherapy in oesophageal cancer patients and smaller MTVs as determined on diagnostic PET/CT prior to neoadjuvant chemoradiotherapy. However, tumour volumes overlapped between groups, indicating the need for multifactorial parameters as predictors. In addition, a complete local tumour response may be accompanied by residual disease in the regional lymph nodes.
European Journal of Nuclear Medicine 06/2013; 40(10). DOI:10.1007/s00259-013-2468-x · 5.38 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: Long-term survival can be obtained with local treatment of lung metastases from colorectal cancer. However, it is unclear as to what the optimal local therapy is: surgery, radiofrequency ablation (RFA) or stereotactic radiotherapy (SBRT). METHODS: A systematic review included 27 studies matching with the a priori selection criteria, the most important being ⩾50 patients and a follow-up period of ⩾24months. No SBRT studies were eligible. The review was therefore conducted on 4 RFA and 23 surgical series. RESULTS: Four of the surgical studies were prospective, all others were retrospective. No randomized trial was found. The reporting of data differed between the studies, which led to difficulties in the analyses. Treatment-related mortality rates for RFA and surgery were 0% and 1.4-2.4%, respectively, whereas morbidity rates were reported inconsistently but seemed the lowest for surgery. CONCLUSION: Due to the lack of phase III trials, no firm conclusions can be drawn, although most evidence supports surgery as the most effective treatment option. High-quality trials comparing currently used treatment modalities such as SBRT, RFA and surgery are needed to inform treatment decisions.
Cancer Treatment Reviews 06/2013; 40(1). DOI:10.1016/j.ctrv.2013.05.004 · 6.47 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND AND PURPOSE: Rectal bleeding can occur following radiotherapy for prostate cancer and negatively impacts quality of life for cancer survivors. Treatment and clinical factors do not fully predict rectal bleeding, and genetic factors may be important. MATERIALS AND METHODS: A genome-wide association study (GWAS) was performed to identify SNPs associated with the development of late rectal bleeding following radiotherapy for prostate cancer. Logistic regression was used to test the association between 614,453 SNPs and rectal bleeding in a discovery cohort (79 cases, 289 controls), and top-ranking SNPs were tested in a replication cohort (108 cases, 673 controls) from four independent sites. RESULTS: rs7120482 and rs17630638, which tag a single locus on chromosome 11q14.3, reached genome-wide significance for association with rectal bleeding (combined p-values 5.4×10(-8) and 6.9×10(-7) respectively). Several other SNPs had p-values trending toward genome-wide significance, and a polygenic risk score including these SNPs shows a strong rank-correlation with rectal bleeding (Sommers' d=5.0×10(-12) in the replication cohort). CONCLUSIONS: This GWAS identified novel genetic markers of rectal bleeding following prostate radiotherapy. These findings could lead to the development of a predictive assay to identify patients at risk for this adverse treatment outcome so that dose or treatment modality could be modified.
Radiotherapy and Oncology 05/2013; 107(3). DOI:10.1016/j.radonc.2013.05.001 · 4.86 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: PURPOSE: To investigate the toxicity of nelfinavir, administered during preoperative chemoradiotherapy (CRT) in patients with locally advanced rectal cancer. MATERIAL AND METHODS: Twelve patients were treated with chemoradiotherapy to 50.4Gy combined with capecitabine 825mg/m(2) BID. Three dose levels (DL) of nelfinavir were tested: 750mg BID (DL1), 1250mg BID (DL2) and an intermediate level of 1000mg BID (DL3). Surgery was performed between 8 and 10weeks after completion of CRT. Primary endpoint was dose-limiting toxicity (DLT), defined as any grade 3 or higher non-hematological or grade 4 or higher hematological toxicity. RESULTS: Eleven patients could be analyzed: 5 were treated in DL1, 3 in DL2 and 3 in DL3. The first 3 patients in DL1 did not develop a DLT. In DL2 one patient developed gr 3 diarrhea, 1 patient had gr 3 transaminase elevation and 1 patient had a gr 3 cholangitis with unknown cause. An intermediate dose level was tested in DL3. In this group 2 patients developed gr 3 diarrhea and 1 patient gr 3 transaminase elevation and gr 4 post-operative wound complication. Three patients achieved a pathological complete response (pCR). CONCLUSIONS: Nelfinavir 750mg BID was defined as the recommended phase II dose in combination with capecitabine and 50.4Gy pre-operative radiotherapy in rectal cancer. First tumor response evaluations are promising, but a further phase II study is needed to get more information about efficacy of this treatment regimen.
Radiotherapy and Oncology 05/2013; 107(2). DOI:10.1016/j.radonc.2013.03.023 · 4.86 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: PURPOSE: Accurate tumor positioning in stereotactic body radiation therapy (SBRT) of liver lesions is often hampered by motion and setup errors. We combined 3-dimensional ultrasound imaging (3DUS) and active breathing control (ABC) as an image guidance tool. METHODS AND MATERIALS: We tested 3DUS image guidance in the SBRT treatment of liver lesions for 11 patients with 88 treatment fractions. In 5 patients, 3DUS imaging was combined with ABC. The uncertainties of US scanning and US image segmentation in liver lesions were determined with and without ABC. RESULTS: In free breathing, the intraobserver variations were 1.4 mm in left-right (L-R), 1.6 mm in superior-inferior (S-I), and 1.3 mm anterior-posterior (A-P). and the interobserver variations were 1.6 mm (L-R), 2.8 mm (S-I), and 1.2 mm (A-P). The combined uncertainty of US scanning and matching (inter- and intraobserver) was 4 mm (1 SD). The combined uncertainty when ABC was used reduced by 1.7 mm in the S-I direction. For the L-R and A-P directions, no significant difference was observed. CONCLUSION: 3DUS imaging for IGRT of liver lesions is feasible, although using anatomic surrogates in the close vicinity of the lesion may be needed. ABC-based breath-hold in midventilation during 3DUS imaging can reduce the uncertainty of US-based 3D table shift correction.
International journal of radiation oncology, biology, physics 10/2012; 85(4). DOI:10.1016/j.ijrobp.2012.08.016 · 4.18 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: PURPOSE: To identify single nucleotide polymorphisms (SNPs) associated with development of erectile dysfunction (ED) among prostate cancer patients treated with radiation therapy. METHODS AND MATERIALS: A 2-stage genome-wide association study was performed. Patients were split randomly into a stage I discovery cohort (132 cases, 103 controls) and a stage II replication cohort (128 cases, 102 controls). The discovery cohort was genotyped using Affymetrix 6.0 genome-wide arrays. The 940 top ranking SNPs selected from the discovery cohort were genotyped in the replication cohort using Illumina iSelect custom SNP arrays. RESULTS: Twelve SNPs identified in the discovery cohort and validated in the replication cohort were associated with development of ED following radiation therapy (Fisher combined P values 2.1 × 10(-5) to 6.2 × 10(-4)). Notably, these 12 SNPs lie in or near genes involved in erectile function or other normal cellular functions (adhesion and signaling) rather than DNA damage repair. In a multivariable model including nongenetic risk factors, the odds ratios for these SNPs ranged from 1.6 to 5.6 in the pooled cohort. There was a striking relationship between the cumulative number of SNP risk alleles an individual possessed and ED status (Sommers' D P value = 1.7 × 10(-29)). A 1-allele increase in cumulative SNP score increased the odds for developing ED by a factor of 2.2 (P value = 2.1 × 10(-19)). The cumulative SNP score model had a sensitivity of 84% and specificity of 75% for prediction of developing ED at the radiation therapy planning stage. CONCLUSIONS: This genome-wide association study identified a set of SNPs that are associated with development of ED following radiation therapy. These candidate genetic predictors warrant more definitive validation in an independent cohort.
International journal of radiation oncology, biology, physics 09/2012; 85(1). DOI:10.1016/j.ijrobp.2012.08.003 · 4.18 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Introduction Standard chemotherapy is increasingly discontinued after successful “induction” in patients (pts) undergoing 1st line treatment for mCRC. MGN1703 is a synthetic DNA-based immunomodulator acting as an agonist of TLR-9 that has shown preclinical
activity in mCRC. This study has been conducted to assess clinical efficacy, immunogenicity, and safety of MGN1703 as maintenance