Te Vuong

Combined analysis of VEGF and EGFR predicts complete tumour response in rectal cancer treated with preoperative radiotherapy

The ability to predict complete pathologic response or sensitivity to radiation before treatment would have a significant impact on the selection of patients for preoperative radiotherapy or chemo-radiation therapy schedules. The aim of this study was to determine the value of epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), p53, Bcl-2 and apoptosis protease-activating factor-1 (APAF-1) as predictors of complete pathologic tumour regression in patients undergoing preoperative radiotherapy for advanced rectal cancer. Pretreatment tumour biopsies from predominantly cT3 patients undergoing a preoperative high-dose-rate brachytherapy protocol were immunostained for EGFR, VEGF, p53, Bcl-2 and APAF-1. Immunoreactivity was evaluated by three pathologists. Cut-off scores for tumour marker positivity were obtained by receiver-operating characteristic (ROC) curve analysis. The association of marker expression with complete pathologic response was analysed in univariate and multivariable analysis. Multi-marker phenotypes of the independent protein markers were evaluated. In multivariable analysis, loss of VEGF (P-value=0.009; odds ratio (OR) (95% CI)=0.24 (0.08–0.69)) and positive EGFR (P-value=0.01; OR (95% CI)=3.82 (1.37–10.6)) both demonstrated independent predictive value for complete pathologic response. The odds of complete response were 12.8 for the multi-marker combination of VEGF-negative and EGFR-positive tumours. Of the 34 EGFR-negative- and VEGF-positive cases, 32 (94.1%) had no complete pathologic response. The combined analysis of VEGF and EGFR is predictive of complete pathologic response in patients undergoing preoperative radiotherapy. In addition, the findings of this study have identified a subgroup of simultaneous EGFR-negative and VEGF-positive patients who are highly resistant to radiotherapy and should perhaps be considered candidates for innovative neoadjuvant combined modalities.

A simple and reproducible scoring system for EGFR in colorectal cancer: application to prognosis and prediction of response to preoperative brachytherapy

The aim of this study was to determine the predictive and prognostic value of epidermal growth factor receptor (EGFR) expression in rectal cancers treated with preoperative high-dose rate brachytherapy and in mismatch-repair (MMR)-proficient colorectal cancers (CRCs), respectively. We validate the use of receiver operating characteristic (ROC) curve analysis to select cutoff scores for EGFR overexpression for the end points studied. Immunohistochemistry (IHC) for EGFR was performed on 82 rectal tumour biopsies and 1197 MMR-proficient CRCs using a tissue microarray. Immunoreactivity was scored as the percentage of positive tumour cells by three pathologists and the inter-observer reliability was assessed. ROC curve-derived cutoffs were used to analyse the association of EGFR overexpression, tumour response and several clinicopathological features including survival. The scoring method was found to be reproducible in rectal cancer biopsies and CRCs. The selected cutoff scores from ROC curve analysis for each clinicopathological feature were highly consistent among pathologists. EGFR overexpression was associated with response to radiotherapy (P-value <0.001) and with worse survival time (P-value <0.001). In multivariate analysis, EGFR overexpression was independently associated with adverse prognosis (P-value <0.001). Epidermal growth factor receptor is a predictive marker of response to preoperative radiotherapy and an independent adverse prognostic factor CRC.

Outcome of Local Excision of Rectal Carcinoma

PURPOSEThis study was designed to determine the results of patients with rectal adenocarcinoma treated with local excision.METHODSA retrospective, chart review was conducted for all patients treated with local excision for rectal adenocarcinoma from 1984 to 1998.RESULTSSixty-four patients were retained for analysis. The median follow-up was 37 (range, 9–125) months. There were 15 local failures with a median time to local failure of 12 months. Seven patients were salvaged with further operation (4 by repeat local excision, 4 by abdominoperineal resection, and 1 by low anterior resection). The incidence of local recurrence increased with advancing stage of the carcinoma (T1, 13 percent; T2, 24 percent; T3, 71 percent), histologic grade of differentiation, (well, 12 percent; moderately, 24 percent; poorly, 44 percent), and margin status (negative, 16 percent; close (within 2 mm), 33 percent; positive, 50 percent). Sixteen percent of carcinomas ≤ 3 cm failed compared with 47 percent for carcinomas > 3 cm. Nine percent (1/11) of T2 patients treated with adjuvant radiation therapy recurred locally compared with 36 percent (5/14) without radiation therapy. Three of four T3 patients who received radiation therapy failed locally compared with two of three who did not. Using the Kaplan-Meier method, the overall survival at five years was 71 percent, and disease-free survival was 83 percent. Actuarial local failure was 27 percent and freedom from distant metastasis was 86 percent. The sphincter preservation rate was 90 percent at five years.CONCLUSIONSLocal excision alone is an acceptable option for well-differentiated, T1 carcinomas, ≤ 3 cm. Adjuvant radiation is recommended for T2 lesions. The high local recurrence rate in patients after local excision of T3 lesions with or without adjuvant radiotherapy would mandate a radical resection.

EGFR and K-ras gene mutation status in squamous cell anal carcinoma: a role for concurrent radiation and EGFR inhibitors?

Background:There is a growing appreciation for radio-sensitiser use in multi-modal cancer treatment models. Squamous cell anal carcinoma (SCAC) is a rare gastrointestinal tumour traditionally treated with concurrent chemotherapy and radiation. Cetuximab, an epidermal growth factor receptor (EGFR) inhibitor, has demonstrated significant efficacy when combined with radiation in squamous cell carcinoma of the head and neck (SccH&N). We wanted to assess EGFR and Kirsten-ras (K-ras) status in SCAC to see whether it compares with SccH&N.Methods:Over 90 SCAC paraffin-embedded biopsies were mounted onto a tissue microarray and were assessed for EGFR expression by immunohistochemistry. These samples were also assessed for the most frequently mutated K-ras and EGFR exons by high-resolution melting analysis.Results:The EGFR was present in over 90% of samples tested. The K-ras and EGFR mutations were absent in all samples tested, although a synonymous single-nucleotide polymorphism was found in 3 out of 89 samples tested for EGFR exon 19.Conclusion:The low rate of K-ras and EGFR mutations, coupled with the high surface expression of EGFR, suggests similarity in the EGFR signalling pathway between SCAC and SccH&N, and thus a potential role for EGFR inhibitors in SCAC. To our knowledge this is the largest cohort of invasive SCAC samples investigated for EGFR and K-ras mutations reported to date.

Risk of Hypogonadism From Scatter Radiation During Pelvic Radiation in Male Patients With Rectal Cancer

PURPOSEnRecent studies have reported fluctuations in sex hormones during pelvic irradiation. The objective of this study was to observe the effects of radiation on hormonal profiles for two treatment modalities: conventional external beam radiotherapy (EBRT) and high-dose-rate brachytherapy (HDRBT) given neoadjuvantly for patients with rectal cancer.nnnMETHODS AND MATERIALSnRoutine serum follicle stimulating hormone (FSH), luteinizing hormone (LH), and testosterone levels were collected from 119 consecutive male patients receiving either EBRT, using 45.0-50.4 Gy in 25-28 fractions with concurrent 5-fluorouracil chemotherapy or HDRBT using 26 Gy in 4 fractions.nnnRESULTSnThirty patients with initially abnormal profiles were excluded. Profiles included in this study were collected from 51 patients treated with EBRT and 38 patients treated with HDRBT, all of whom had normal hormonal profiles before treatment. Mean follow-up times were 17 months for the entire patient cohort-14 and 20 months, respectively-for the EBRT and HDRBT arms. Dosimetry results revealed a mean cumulative testicular dose of 1.24 Gy received in EBRT patients compared with 0.27 Gy in the HDRBT group. After treatment, FSH and LH were elevated in all patients but were more pronounced in the EBRT group. The testosterone-to-LH ratio was significantly lower (p = 0.0036) in EBRT patients for tumors in the lower third of the rectum. The 2-year hypogonadism rate observed was 2.6% for HDRBT compared with 17.6% for EBRT (p = 0.09) for tumors in the lower two thirds of the rectum.nnnCONCLUSIONnHDRBT allows better hormonal sparing than EBRT during neoadjuvant treatment of patients with rectal cancer.

Patient-specific Monte Carlo dose calculations for high-dose-rate endorectal brachytherapy with shielded intracavitary applicator.

PURPOSEnAn integrated software platform was developed to perform a patient-specific dosimetric study on high-dose-rate (192)Ir endorectal brachytherapy. Monte Carlo techniques were used to examine the perturbation effects of an eight-channel intracavitary applicator with shielding and a liquid-inflatable balloon. Such effects are ignored in conventional treatment planning systems that assume water-equivalent geometries.nnnMETHODS AND MATERIALSnA total of 40 Task Group 43-based rectal patient plans were calculated using the PTRAN_CT Monte Carlo photon transport code. The silicone applicator, tungsten or lead shielding, contrast solution-filled balloon, and patient anatomy were included in the simulations. The dose to water and dose to medium were scored separately. The effects of heterogeneities and uncertainties in source positioning were examined. A superposition calculation method using pregenerated Monte Carlo dose distributions about the shielded applicator in water was developed and validated for efficient treatment planning purposes.nnnRESULTSnOn average, metal shielding decreases the mean dose to the contralateral normal tissues by 24% and reduces the target volume covered by the prescribed dose from 97% to 94%. Tissue heterogeneities contribute to dose differences of <1% relative to the prescribed dose. The differences in the dose volume indices between dose to water and dose to medium-based calculations were <1% for soft tissues, <2% for bone marrow, and >20% for cortical bone. A longitudinal shift of +/-2.5 mm and a rotational shift of +/-15 degrees in applicator insertion reduced the target volume receiving the prescribed dose by </=4%.nnnCONCLUSIONnThe shielded applicator improved dose conformity and normal tissue sparing; however, Task Group 43-based treatment planning might compromise target coverage by not accounting for shielding.

High-dose-rate pre-operative endorectal brachytherapy for patients with rectal cancer

High-dose-rate endorectal brachytherapy (HDREBT) is an image guided brachytherapy treatment for patients with rectal cancer. It is based on tumor imaging with magnetic resonance in particular, which is used to choose eligible patients and improve tumor visualization. Treatment planning is performed using 3D CT simulation and treatment planning. The treatment is given on an outpatient basis and requires minimal local anesthesia. The validation of the technique was carried out through a preoperative study and is now explored as part of a radical treatment for early rectal cancer or as a boost modality. We describe technical aspects of the HDREBT and we discuss the ongoing institutional review board approved studies exploring the clinical applications of this treatment modality for patients with rectal cancer: 1) as a neoadjuvant treatment for patients with operable rectal tumor; 2) as a option to improve local control in patients with newly diagnosed rectal cancer but with previous pelvic radiation.

Short-term outcome after neoadjuvant high-dose-rate endorectal brachytherapy or short-course external beam radiotherapy in resectable rectal cancer.

Total mesorectal excision with preoperative radiotherapy reduces local recurrence in rectal cancer, but radiotherapy increases the risk of complications. This study compared the immediate postoperative outcome after external beam radiotherapy with outome after high‐dose‐rate endorectal brachytherapy (HDREBT).

Silver Clear Nylon Dressing is Effective in Preventing Radiation-Induced Dermatitis in Patients With Lower Gastrointestinal Cancer: Results From a Phase III Study

PURPOSEnFor patients with anal canal and advanced rectal cancer, chemoradiation therapy is a curative modality or an important adjunct to surgery. Nearly all patients treated with chemoradiation experience some degree of radiation-induced dermatitis (RID). Prevention and effective treatment of RID, therefore, is of considerable clinical relevance. The present phase III randomized trial compared the efficacy of silver clear nylon dressing (SCND) with that of standard skin care for these patients.nnnMETHODS AND MATERIALSnA total of 42 rectal or anal canal cancer patients were randomized to either a SCND or standard skin care group. SCND was applied from Day 1 of radiation therapy (RT) until 2 weeks after treatment completion. In the control arm, sulfadiazine cream was applied at the time of skin dermatitis. Printed digital photographs taken 2 weeks prior to, on the last day, and two weeks after the treatment completion were scored by 10 blinded readers, who used the common toxicity scoring system for skin dermatitis.nnnRESULTSnThe radiation dose ranged from 50.4 to 59.4 Gy, and there were no differences between the 2 groups. On the last day of RT, when the most severe RID occurs, the mean dermatitis score was 2.53 (standard deviation [SD], 1.17) for the standard and 1.67 (SD, 1.2; P=.01) for the SCND arm. At 2 weeks after RT, the difference was 0.39 points in favor of SCND (P=.39). There was considerable intraclass correlation among the 10 observers.nnnCONCLUSIONSnSilver clear nylon dressing is effective in reducing RID in patients with lower gastrointestinal cancer treated with combined chemotherapy and radiation treatment.

A meta-analysis comparing the risk of metastases in patients with rectal cancer and MRI-detected extramural vascular invasion (mrEMVI) vs mrEMVI-negative cases

Background:Pathological extramural vascular invasion (EMVI) is an independent prognostic factor in rectal cancer, but can also be identified on MRI-detected extramural vascular invasion (mrEMVI). We perform a meta-analysis to determine the risk of metastatic disease at presentation and after surgery in mrEMVI-positive patients compared with negative tumours.Methods:Electronic databases were searched from January 1980 to March 2016. Conventional meta-analytical techniques were used to provide a summative outcome. Quality assessment of the studies was performed.Results:Six articles reported on mrEMVI in 1262 patients. There were 403 patients in the mrEMVI-positive group and 859 patients in the mrEMVI-negative group. The combined prevalence of mrEMVI-positive tumours was 0.346(range=0.198–0.574). Patients with mrEMVI-positive tumours presented more frequently with metastases compared to mrEMVI-negative tumours (fixed effects model: odds ratio (OR)=5.68, 95% confidence interval (CI) (3.75, 8.61), z=8.21, df=2, P<0.001). Patients who were mrEMVI-positive developed metastases more frequently during follow-up (random effects model: OR=3.91, 95% CI (2.61, 5.86), z=6.63, df=5, P<0.001).Conclusions:MRI-detected extramural vascular invasion is prevalent in one-third of patients with rectal cancer. MRI-detected extramural vascular invasion is a poor prognostic factor as evidenced by the five-fold increased rate of synchronous metastases, and almost four-fold ongoing risk of developing metastases in follow-up after surgery.