Tissue-free liquid biopsies combining genomic and methylation signals for minimal residual disease detection in patients with early colorectal cancer from the UK TRACC Part B study.

PURPOSE: Absence of post-operative circulating tumour DNA (ctDNA) identifies resected colorectal cancer (CRC) patients with low recurrence risk for adjuvant chemotherapy (ACT) de-escalation. We present the largest resected CRC cohort to date with tissue-free minimal residual disease (MRD) detection. DESIGN: TRACC included stage I-III resectable CRC patients. Prospective longitudinal plasma collection for ctDNA occurred pre- and post-surgery, post-ACT, every 3m for year 1 and every 6m in years 2 and 3 with imaging annually. The Guardant Reveal assay evaluated genomic and methylation signals. The primary endpoint was 2yr recurrence free survival (RFS) by post-operative ctDNA detection. (NCT04050345) Results: Between December 2016 and August 2022, 1203 were patients enrolled. Plasma samples (n=997) from 214 patients were analysed. 143 patients were evaluable for the primary endpoint; 92 (64.3%) colon, 51 (35.7%) rectal; 2 (1.4%) stage I, 64 (44.8%) stage II, 77 (53.8%) stage III. Median follow-up was 30.3m (95% CI: 29.5-31.3). 2yr RFS was 91.1% in patients with ctDNA not detected post-operatively and 50.4% in those with ctDNA detected (HR 6.5 [2.96-14.5] p<0.0001). Landmark negative predictive value (NPV) was 91.2% (95% CI 83.9-95.9). Longitudinal sensitivity and specificity were 62.1% (95% CI 42.2-79.3) and 85.9% (95% CI 78.9-91.3) respectively. Median lead-time from ctDNA detection to radiological recurrence was 7.3m (IQR 3.3-12.5; n=9). CONCLUSIONS: Tissue-free MRD detection with longitudinal sampling predicts recurrence in stage I-III CRC without need for tissue sequencing. NPV is high supporting ACT de-escalation in patients with ctDNA not detected post-operatively, now being investigated in the UK TRACC Part C study.

Diagnostic accuracy of nodal enhancement pattern of rectal cancer at MRI enhanced with ultrasmall superparamagnetic iron oxide: findings in pathologically matched mesorectal lymph nodes.

OBJECTIVE: The purpose of this study was to evaluate the diagnostic accuracy of the pattern of nodal enhancement at MRI enhanced with ultrasmall superparamagnetic iron oxide (USPIO) in the nodal classification of rectal cancer in pathologically matched mesorectal lymph nodes. SUBJECTS AND METHODS: Twenty-five patients with adenocarcinoma of the rectum underwent prospective evaluation with 3-mm axial T2-weighted and USPIO-enhanced T2*-weighted MRI before surgery. Mesorectal nodes visible at in vivo MRI were independently scored by two radiologists as malignant or nonmalignant according to morphologic criteria (irregular nodal contour, heterogeneous signal intensity) on T2-weighted MR images and according to USPIO enhancement pattern on T2*-weighted MR images. The sensitivity, specificity, and positive and negative predictive values of morphologic and USPIO criteria in identification of malignancy in the pathologically matched mesorectal nodes were compared by use of the McNemar test. Interobserver agreement was compared by use of kappa statistics. RESULTS: After surgery, radiologic-pathologic comparison of 126 mesorectal nodes (116 benign, 10 malignant) was possible. Use of morphologic criteria resulted in an average sensitivity of 65% (95% CI, 35-88%); specificity, 75% (67-83%); positive predictive value, 19% (8-34%); and negative predictive value, 96% (91-99%). Use of USPIO criteria resulted in an average sensitivity of 65% (95% CI, 35-88%); specificity, 93% (87-96%); positive predictive value, 43% (21-67%); and negative predictive value, 97% (92-99%). Use of USPIO MRI improved diagnostic specificity for both observers (p < 0.01). Interobserver agreement was fair for morphologic criteria (kappa = 0.39) but good for USPIO criteria (kappa = 0.68). CONCLUSION: Use of the pattern of USPIO enhancement had higher diagnostic specificity than but the same sensitivity as morphologic findings in pathologically matched mesorectal lymph nodes.

Female urogenital dysfunction following total mesorectal excision for rectal cancer.

BACKGROUND: The effect of Total Mesorectal Excision (TME) on sexual function in the male is well documented. However, there is little literature in female patients. The aim of this study was to review the pelvic autonomic nervous anatomy in the female and to perform a retrospective audit of urinary and sexual function in women following surgery for rectal cancer where TME had been performed. Urogenital dysfunction was assessed through interview and questionnaire. METHOD: Twenty-three questionnaires, eighteen returned, were sent to women with a mean age 65.5 yrs (range 34-86). All had undergone total mesorectal excision for rectal cancer between 1998-2001. Mean follow-up was 18.8 months (range 3-35). RESULTS: Preoperatively 5/18 (28%) were sexually active, 3/18 (17%) of patients described urinary frequency and nocturia and 7/18 (39%) described symptoms of stress incontinence prior to surgery. Postoperatively all sexually active patients remained active although all described some discomfort with penetration. Two of the patients sexually active described reduced libido secondary to the stoma. Postoperative urinary symptoms developed with 59% reporting the development of nocturia, 18% developed stress incontinence and one patient required a permanent catheter. Of those with symptoms, 80% persisted longer than three months from surgery. Symptoms were predominant in those patients with low rectal cancers, particularly those undergoing abdomino-perineal excision and in those who had previously undergone abdominal hysterectomy. CONCLUSION: The treatment of rectal cancer involves surgery to the pelvic floor. Despite nerve preservation this is associated with the development of worsening nocturia and stress incontinence. This is most marked in those patients who had previously undergone a hysterectomy. Further studies are warranted to assess the interaction with previous gynaecological surgery.

Eight years experience of high-powered endoscopic diode laser therapy for palliation of colorectal carcinoma.

PURPOSE: Endoscopic laser therapy using neodymium: yttrium-aluminum-garnet (Nd:YAG) laser has been shown to be effective in palliating symptoms of obstruction, bleeding, and discharge in patients with colorectal cancer. These patients usually have advanced inoperable disease at presentation or are unfit for surgery. We have used high-powered diode laser to palliate patients with inoperable colorectal cancer since 1994. This study was designed to determine the success rate of high-powered diode laser in palliating inoperable colorectal carcinoma and compare these figures with those published for Nd:YAG laser. METHODS: A retrospective analysis was performed of all patients undergoing high-powered diode laser therapy for colorectal carcinoma between June 1994 and October 2002 (inclusive) at St. George's Hospital, London, United Kingdom. Patient's notes and endoscopy records were reviewed to determine the indications for treatment, success of symptom palliation, complications, and survival for each patient. RESULTS: Fifty-seven patients (28 males), with a median age at first treatment of 82 (range, 51-93) years, were identified who had been palliated with high-powered diode laser therapy for colorectal carcinoma. The median number of treatments received by each patient was three (range, 1-16 treatments), with a median interval between treatments of 9.5 (range, 1-25) weeks. Lifelong palliation of symptoms occurred in 51 patients (89 percent). Major complications were two perforations and one hemorrhage, giving an overall complication rate of 5.3 percent. One of the patients who experienced perforation died, giving an overall mortality rate of 1.8 percent for the procedure. The median survival of the 51 patients palliated completely by laser therapy was 8.5 (range, 0.6-52) months, with a probability of survival at 24 months of 15 percent. CONCLUSIONS: High-powered diode laser therapy is an effective method of providing palliation for obstruction, bleeding, and discharge in those patients with inoperable colorectal carcinoma. It produces results comparable to therapy with Nd:YAG laser and the equipment is cheaper, more compact, and portable.