Faisal Siddiqui

Image-guidance protocol comparison: supine and prone set-up accuracy for pelvic radiation therapy.

Purpose. To investigate the impact of prone versus supine patient set-up and use of various image-guidance protocols on residual set-up error for radiation therapy of pelvic malignancies. We aim to identify an optimal frequency and protocol for image-guidance. Materials. Using daily online image-guidance mega-voltage CT data from 30 patients (829 MVCT; 299 prone set-up on belly board, 530 supine set-up), we retrospectively assessed the impact of various image-guidance protocols on residual set-up error. We compared daily image-guidance with three different No Action Level protocols (NAL), alternate day image-guidance with running mean and weekly image-guidance. Results. Of 5 IGRT protocols analyzed, the protocol with the highest imaging frequency, alternate day imaging with a running mean (50% imaging frequency), provided the best set-up error reduction. This protocol would have reduced the average length of 3D corrective vector shifts derived from daily image-guidance from 15.2 and 13.5 mm for prone and supine set-up, to 5 and 5.4 mm, respectively. A NAL protocol, averaging shifts of the first 3 fractions (NAL3), would have reduced the respective set-up variability to 6.3 (prone), and 7.5 mm (supine). An extended NAL (eNAL) protocol, averaging shifts of the first 3 fractions plus weekly imaging, would have reduced the daily positioning variability to 6 mm for both prone and supine set-ups. Daily image-guidance yielded set-up corrections >10 mm in 64.3% for prone and 70.3% for supine position. Use of the NAL3 protocol would have reduced the respective frequency to 14.4%, and 21.2% for prone, and supine positioning. In comparison, the alternate day running mean protocol would have reduced the frequency of shifts >10 mm to 5.5% (prone), and 8.3% (supine), respectively. Discussion. In this comparison, high frequency image-guidance provided the highest benefit with respect to residual set-up errors. However, both NAL and eNAL protocols provided significant set-up error reduction with lowered imaging frequency. While the mean 3D vector of corrective shifts was longer for prone set-up compared to the supine set-up, using any image-guidance protocol would have reduced shifts for prone set-up to a greater extent than for the supine set-up. This indicates a greater risk for systematic set-up errors in prone set-up, and larger random errors using a supine patient set-up.

Feasibility of shutter-speed DCE-MRI for improved prostate cancer detection

The feasibility of shutter‐speed model dynamic‐contrast‐enhanced MRI pharmacokinetic analyses for prostate cancer detection was investigated in a prebiopsy patient cohort. Differences of results from the fast‐exchange‐regime‐allowed (FXR‐a) shutter‐speed model version and the fast‐exchange‐limit‐constrained (FXL‐c) standard model are demonstrated. Although the spatial information is more limited, postdynamic‐contrast‐enhanced MRI biopsy specimens were also examined. The MRI results were correlated with the biopsy pathology findings. Of all the model parameters, region‐of‐interest‐averaged Ktrans difference [ΔKtrans ≡ Ktrans(FXR‐a) − Ktrans(FXL‐c)] or two‐dimensional Ktrans(FXR‐a) vs. kep(FXR‐a) values were found to provide the most useful biomarkers for malignant/benign prostate tissue discrimination (at 100% sensitivity for a population of 13, the specificity is 88%) and disease burden determination. (The best specificity for the fast‐exchange‐limit‐constrained analysis is 63%, with the two‐dimensional plot.) Ktrans and kep are each measures of passive transcapillary contrast reagent transfer rate constants. Parameter value increases with shutter‐speed model (relative to standard model) analysis are larger in malignant foci than in normal‐appearing glandular tissue. Pathology analyses verify the shutter‐speed model (FXR‐a) promise for prostate cancer detection. Parametric mapping may further improve pharmacokinetic biomarker performance. Magn Reson Med, 2013.

Cell Membrane Water Exchange Effects in Prostate DCE-MRI

Prostate Dynamic-Contrast-Enhanced (DCE) MRI often exhibits fast and extensive global contrast reagent (CR) extravasation - measured by K(trans), a pharmacokinetic parameter proportional to its rate. This implies that the CR concentration [CR] is high in the extracellular, extravascular space (EES) during a large portion of the DCE-MRI study. Since CR is detected indirectly, through water proton signal change, the effects of equilibrium transcytolemmal water exchange may be significant in the data and thus should be admitted in DCE-MRI pharmacokinetic modeling. The implications for parameter values were investigated through simulations, and analyses of actual prostate data, with different models. Model parameter correlation and precision were also explored. A near-optimal version of the exchange-sensitized model was found. Our results indicate that ΔK(trans) (the K(trans) difference returned by this version and a model assuming exchange to be effectively infinitely fast) may be a very useful biomarker for discriminating malignant from benign prostate tissue. Using an exchange-sensitized model, we find that the mean intracellular water lifetime (τ(i)) - an exchange measure - can be meaningfully mapped for the prostate. Our results show prostate glandular zone differences in τ(i) values.

Colorectal Cancer Emergencies

IntroductionColorectal cancer (CRC) is a common type of malignancy encountered in the United States. A significant proportion of patients with CRC will seek emergency medical care during the course of their illness and treatment.BackgroundEmergent presentations can be the result of either local tumor invasion, regional progression, or therapeutic techniques. Specific complications of CRC which present emergently include rectal bleeding, abdominal pain, and bowel obstruction. Less common issues encountered include malignant ascites, neutropenic enterocolitis, and radiation enteropathy.ConclusionThe care of CRC patients in the setting of an acute severe illness typically requires the joint efforts of the emergency medical team in consultation with surgical, medical, and radiation oncology. A high degree of suspicion for the typical and atypical complications of CRC is important for all clinicians who are responsible for the care of these patients.

Overall survival analysis of neoadjuvant chemoradiotherapy and esophagectomy for esophageal cancer

BACKGROUND Patients treated with neoadjuvant chemoradiotherapy (NAC) followed by esophagectomy are more likely to have negative margins at resection, be downstaged, and have improved overall survival (OS). The specific aim of this study was to analyze OS outcomes using NAC followed by esophagectomy at a single, tertiary care academic medical center. METHODS We retrospectively analyzed 106 patients that underwent NAC with platinum-based chemotherapy plus 5-fluorouracil (5-FU) or capecitabine followed by esophagectomy from September 1996 to May 2011. OS was analyzed by the Kaplan Meier method. RESULTS Initial staging determined that of 106 patients, 62% had stage III (n=66), 31% stage II (n=33), and 7% had stage I disease (n=7). Following NAC, 92.5% (n=98) were resected with negative (R0) margins and pathologic staging revealed 59% (n=62) were downstaged, 9% (n=10) were upstaged, and 32% (n=34) remained at the same stage. A pathologic complete response (pCR) was achieved in 29% (n=31) of the cohort. Median OS was 35.2 months for all patients, 42 months for downstaged patients, 13 months when upstaged, and 17 months for those who remained at the same stage (P=0.08). OS by histological type was 30 months for adenocarcinoma and 71 months for squamous cell carcinoma (P=0.06). CONCLUSIONS NAC was effective in downstaging 59% of patients and effectively increased the chance for an R0 resection. These patients, in turn, had improved OS compared to the median OS. Patients with squamous cell carcinoma showed a trend towards more favorable OS.

Upper Gastrointestinal Cancers

What is the approximate number of new annual cases of esophageal cancer in the United States?

TNF-α deficiency as protection against sickness behavior related to external beam radiation of the pelvis in mice.

208 Background: Prostate cancer patients undergoing localized external beam radiation therapy (EBRT), experience significant fatigue during treatment, which can affect physical functioning and QOL. We hypothesize that cancer treatment related fatigue (CTRF) is the same as sickness behavior caused, in part, by increases in TNF-α. Our previous data demonstrate that pelvic EBRT induces systemic increases in TNF-α and a decline in voluntary wheel running activity (VWRA) , an objective measure of sickness in mice. A specific aim of this study was to determine the requirement of EBRT for TNF-α for the induction of sickness behavior. METHODS Daily VWRA was monitored in male WT (n=10) and TNF-α-/- (n=10) anesthetized mice undergoing pelvic EBRT at 4.6 Gy/fraction, 5 days per week for 15 fractions for a total dose of 69 Gy [4.6 X 15 = 69, not 70]. Control WT (n=10) and TNF-α-/- (n= 10) mice underwent anesthesia followed by sham EBRT. The effect of treatment on weight and food intake was also determined by calculating change in weight and daily food intake during treatment. A 2 x 2 repeated measure analysis of covariance ANCOVA was used to determine whether there was a significant interaction between treatment group (EBRT or Control) and genotype (WT or TNF-α-/-) on voluntary wheel running activity controlling for baseline differences in this variable. Similarly a 2 x 2 ANOVA was used to determine whether there was a drug x genotype interaction between change in body weight or food intake. RESULTS There was a significant effect of EBRT on VWRA (p< 0.001), food intake (p0.002), and weight (p<0.001). We did not however observe a significant interaction between EBRT and genotype in VWRA (p= 0.756), food intake (p=0.654), or weight (p= 0.450). CONCLUSIONS Targeting TNF-α using specific cytokine blocking agents has been suggested as a potential strategy for preventing or managing EBRT related fatigue. Although our prior data support that localized EBRT to the pelvis may induce TNF-α and sickness behavior in mice, our latest data do not support a direct role for this cytokine in mediating these effects.

Retrospective analysis of neoadjuvant chemoradiotherapy for esophageal cancer: The Knight Cancer Institute experience.

126 Background: Neoadjuvant chemoradiotherapy (NAT) followed by esophagectomy has been established as standard of care for early stage (II - III), resectable esophageal cancer (EC). Patients (pts) treated with NAT are more likely to be downstaged and have a complete (R0) resection. Additionally, pts with aggressive disease are more likely to progress during NAT and, consequently, avoid unnecessary surgery. The aim of the current report was to analyze the outcomes of trimodality therapy at the Knight Cancer Institute. METHODS A retrospective study of 124 pts who underwent NAT followed by esophagectomy for EC from 1999-2010 at our institution was performed. All pts were initially staged by imaging (EUS, CT and/or PET imaging) prior to commencing treatment. After esophagectomy, pathological staging was compared to initial staging to determine the effect of NAT. RESULTS There were 25 women and 99 men. Initial staging is shown in the table below. Patients received cisplatin, oxaliplatin or carboplatin with 5-FU plus concurrent radiotherapy (RT). RT total dose of 45 Gy to the tumor and regional nodes was given in 1.8 Gy daily fractions, followed by a boost to the tumor for final dose 50.4-54 Gy. 27 (21.8%) of the pts had a pathologic complete response. Additionally, 54 (43.6%) pts were downstaged by chemoradiation. Of the pts that had complete remission or were downstaged, pre-treatment clinical stage was Stage II (22 pts), Stage III (55 pts), and Stage IVa (4 pts). CONCLUSIONS NAT was effective in complete remission or downstaging of two-thirds (81) pts, including 4 pts that were initially unresectable (Stage IVa) and successfully underwent subsequent esophagectomy. As has been shown previously, NAT is effective for downstaging prior to esophagectomy making it more likely that pts will undergo R0 resection. This study also demonstrated that some pts with clinically unresectable tumors could undergo successful esophagectomy after NAT. [Table: see text].