Multimodality Imaging to Direct Management of Primary and Recurrent Rectal Adenocarcinoma Beyond the Total Mesorectal Excision Plane.

Rectal tumors extending beyond the total mesorectal excision (TME) plane (beyond-TME) require particular multidisciplinary expertise and oncologic considerations when planning treatment. Imaging is used at all stages of the pathway, such as local tumor staging/restaging, creating an imaging-based "roadmap" to plan surgery for optimal tumor clearance, identifying treatment-related complications, which may be suitable for radiology-guided intervention, and to detect recurrent or metastatic disease, which may be suitable for radiology-guided ablative therapies. Beyond-TME and exenterative surgery have gained acceptance as potentially curative procedures for advanced tumors. Understanding the role, techniques, and pitfalls of current imaging techniques is important for both radiologists involved in the treatment of these patients and general radiologists who may encounter patients undergoing surveillance or patients presenting with surgical complications or intercurrent abdominal pathology. This review aims to outline the current and emerging roles of imaging in patients with beyond-TME and recurrent rectal malignancy, focusing on practical tips for image interpretation and surgical planning in the beyond-TME setting. Keywords: Abdomen/GI, Rectum, Oncology © RSNA, 2024.

Complete Primary Pathological Response Following Neoadjuvant Treatment and Radical Resection for Pancreatic Ductal Adenocarcinoma.

INTRODUCTION: Neoadjuvant treatment (NAT) for borderline (BD) or locally advanced (LA) primary pancreatic cancer (PDAC) is now a widely adopted approach. We present a case series of patients who have achieved a complete pathological response of the primary tumour on final histology following neoadjuvant chemotherapy +/- chemoradiation and radical surgery. METHODS: Patients who underwent radical pancreatic resection following neoadjuvant treatment between March 2006 and March 2023 at a single institution were identified by retrospective case note review of a prospectively maintained database. RESULTS: Ten patients were identified to have a complete primary pathological response (ypT0) on postoperative histology. Before treatment, five patients were considered BD and five were LA according to National Comprehensive Cancer Network guidelines. All patients underwent staging Computed Tomography (CT) and nine underwent 18Fluorodeoxyglucose Positron Emission Tomography (18FDG-PET/CT) imaging, with a mean maximum standardized uptake value (SUVmax) of the primary lesion at 6.14 ± 1.98 units. All patients received neoadjuvant chemotherapy, and eight received further chemoradiotherapy prior to resection. Mean pre- and post-neoadjuvant treatment serum Ca19-9 was 148.0 ± 146.3 IU/L and 18.0 ± 18.7 IU/L, respectively (p = 0.01). The mean duration of NAT was 5.6 ± 1.7 months. The mean time from completion of NAT to surgery was 13.1 ± 8.3 weeks. The mean lymph node yield was 21.1 ± 10.4 nodes, with one patient found to have 1 lymph node involved. All resections were reported to be R0. The mean length of stay was 11.8 ± 6.2 days. At the time of analysis, one death was reported at 35 months postoperatively. Two cases of recurrence were reported at 16 months (surgical bed) and 33 months (pulmonary). All other patients remain alive and under active surveillance. The current overall survival is 26.6 ± 20.7 months and counting. CONCLUSIONS: Complete primary pathological response is uncommon but possible following neoadjuvant treatment in patients with PDAC. Further work to identify the common denominator within this unique cohort may lead to advances in the therapeutic approach and offer hope for patients diagnosed with borderline or locally advanced pancreatic ductal adenocarcinoma.

Radiological Biomarkers in MRI directed Rectal Cancer Radiotherapy Volume Delineation.

Our study evaluated whether an MRI reporting system highlighting areas of contiguous and discontinuous extramural venous invasion (EMVI) can improve the accuracy of gross tumour volume (GTV) delineation. Initially, 27 consecutive patients with locally advanced rectal cancer treated between 2012 and 2014 were evaluated. We used an MRI reporting proforma that documented the position of the primary tumour, lymph nodes and EMVI. The new GTVs delineated were compared with historical radiotherapy treatment volumes to identify the frequency of GTV geographical miss. We observed that the delineation of involved nodes and areas of EMVI was more likely to represent sources of uncertainty wherein nodal GTV geographical miss was evident in 5 out of 27 patients (19%). Complete EMVI GTV geographical miss occurred in two patients (7%). We re-evaluated our radiotherapy practice in a further 27 patients after the implementation of a modified MRI reporting system. An improvement was seen; nodal miss was observed in two patients (7%) and partial EMVI miss in one patient (4%), although these areas were encompassed in the planning target volume (PTV). Our study shows that extramural venous invasion and involved nodes need to be highlighted on MRI to improve the accuracy of rectal cancer GTV delineation.

Anal squamous cell carcinoma in a high HIV prevalence population.

Anal Squamous Cell Carcinoma (ASCC) is a rare cancer that has a rapidly increasing incidence in areas with highly developed economies. ASCC is strongly associated with HIV and there appears to be increasing numbers of younger male persons living with HIV (PLWH) diagnosed with ASCC. This is a retrospective cohort study of HIV positive and HIV negative patients diagnosed with primary ASCC between January 2000 and January 2020 in a demographic group with high prevalence rates of HIV. One Hundred and seventy six patients were included, and clinical data was retrieved from multiple, prospective databases. A clinical subgroup was identified in this cohort of younger HIV positive males who were more likely to have had a prior diagnosis of Anal Intraepithelial Neoplasia (AIN). Gender and HIV status had no effect on staging or disease-free survival. PLWH were more likely to develop a recurrence (p < 0.000) but had a longer time to recurrence than HIV negative patients, however this was not statistically significant (46.1 months vs. 17.5 months; p = 0.077). Patients known to have a previous diagnosis of AIN were more likely to have earlier staging and local tumour excision. Five-year Disease-Free Survival was associated with tumour size and the absence of nodal or metastatic disease (p < 0.000).

EAES Recommendations for Recovery Plan in Minimally Invasive Surgery Amid COVID-19 Pandemic.

BACKGROUND: COVID-19 pandemic presented an unexpected challenge for the surgical community in general and Minimally Invasive Surgery (MIS) specialists in particular. This document aims to summarize recent evidence and experts' opinion and formulate recommendations to guide the surgical community on how to best organize the recovery plan for surgical activity across different sub-specialities after the COVID-19 pandemic. METHODS: Recommendations were developed through a Delphi process for establishment of expert consensus. Domain topics were formulated and subsequently subdivided into questions pertinent to different surgical specialities following the COVID-19 crisis. Sixty-five experts from 24 countries, representing the entire EAES board, were invited. Fifty clinicians and six engineers accepted the invitation and drafted statements based on specific key questions. Anonymous voting on the statements was performed until consensus was achieved, defined by at least 70% agreement. RESULTS: A total of 92 consensus statements were formulated with regard to safe resumption of surgery across eight domains, addressing general surgery, upper GI, lower GI, bariatrics, endocrine, HPB, abdominal wall and technology/research. The statements addressed elective and emergency services across all subspecialties with specific attention to the role of MIS during the recovery plan. Eighty-four of the statements were approved during the first round of Delphi voting (91.3%) and another 8 during the following round after substantial modification, resulting in a 100% consensus. CONCLUSION: The recommendations formulated by the EAES board establish a framework for resumption of surgery following COVID-19 pandemic with particular focus on the role of MIS across surgical specialities. The statements have the potential for wide application in the clinical setting, education activities and research work across different healthcare systems.

Intratumoral Hydrogen Peroxide With Radiation Therapy in Locally Advanced Breast Cancer: Results From a Phase 1 Clinical Trial.

PURPOSE: Hydrogen peroxide (H2O2) plays a vital role in normal cellular processes but at supraphysiological concentrations causes oxidative stress and cytotoxicity, a property that is potentially exploitable for the treatment of cancer in combination with radiation therapy (RT). We report the first phase 1 trial testing the safety and tolerability of intratumoral H2O2 + external beam RT as a novel combination in patients with breast cancer and exploratory plasma marker analyses investigating possible mechanisms of action. METHODS AND MATERIALS: Twelve patients with breast tumors ≥3 cm (surgically or medically inoperable) received intratumoral H2O2 with either 36 Gy in 6 twice-weekly fractions (n = 6) or 49.5 Gy in 18 daily fractions (n = 6) to the whole breast ± locoregional lymph nodes in a single-center, nonrandomized study. H2O2 was mixed in 1% sodium hyaluronate gel (final H2O2 concentration 0.5%) before administration to slow drug release and minimize local discomfort. The mixture was injected intratumorally under ultrasound guidance twice weekly 1 hour before RT. The primary endpoint was patient-reported maximum intratumoral pain intensity before and 24 hours postinjection. Secondary endpoints included grade ≥3 skin toxicity and tumor response by ultrasound. Blood samples were collected before, during, and at the end of treatment for cell-death and immune marker analysis. RESULTS: Compliance with H2O2 and RT was 100%. Five of 12 patients reported moderate pain after injection (grade 2 Common Terminology Criteria for Adverse Events v4.02) with median duration 60 minutes (interquartile range, 20-120 minutes). Skin toxicity was comparable to RT alone, with maintained partial/complete tumor response relative to baseline in 11 of 12 patients at last follow-up (median 12 months). Blood marker analysis highlighted significant associations of TRAIL, IL-1ß, IL-4, and MIP-1α with tumor response. CONCLUSIONS: Intratumoral H2O2 with RT is well tolerated with no additional toxicity compared with RT alone. If efficacy is confirmed in a randomized phase 2 trial, the approach has potential as a cost-effective radiation response enhancer in multiple cancer types in which locoregional control after RT alone remains poor.

MRI Tumor Regression Grade and Circulating Tumor DNA as Complementary Tools to Assess Response and Guide Therapy Adaptation in Rectal Cancer.

PURPOSE: Response to preoperative chemo-radiotherapy (CRT) varies. We assessed whether circulating tumor DNA (ctDNA) might be an early indicator of tumor response or progression to guide therapy adaptation in rectal cancer. EXPERIMENTAL DESIGN: A total of 243 serial plasma samples were analyzed from 47 patients with localized rectal cancer undergoing CRT. Up to three somatic variants were tracked in plasma using droplet digital PCR. RECIST and MRI tumor regression grade (mrTRG) evaluated response. Survival analyses applied Kaplan-Meier method and Cox regression. RESULTS: ctDNA detection rates were: 74% (n = 35/47) pretreatment, 21% (n = 10/47) mid CRT, 21% (n = 10/47) after completing CRT, and 13% (n = 3/23) after surgery. ctDNA status after CRT was associated with primary tumor response by mrTRG (P = 0.03). With a median follow-up of 26.4 months, metastases-free survival was shorter in patients with detectable ctDNA after completing CRT [HR 7.1; 95% confidence interval (CI), 2.4-21.5; P < 0.001], persistently detectable ctDNA pre and mid CRT (HR 3.8; 95% CI, 1.2-11.7; P = 0.02), and pre, mid, and after CRT (HR 11.5; 95% CI, 3.3-40.4; P < 0.001) compared with patients with undetectable or nonpersistent ctDNA. In patients with detectable ctDNA, a fractional abundance threshold of ≥0.07% mid CRT or ≥0.13% after completing CRT predicted for metastases with 100% sensitivity and 83.3% specificity for mid CRT and 66.7% for CRT completion. All 3 patients with detectable ctDNA post-surgery relapsed compared with none of the 20 patients with undetectable ctDNA (P = 0.001). CONCLUSIONS: ctDNA identified patients at risk of developing metastases during the neoadjuvant period and post-surgery, and could be used to tailor treatment.

Cisplatin Substitution with Carboplatin During Radical Chemoradiotherapy for Oesophagogastric Carcinoma: Outcomes from a Tertiary Centre.

BACKGROUND/AIM: Cisplatin-based radical chemoradiotherapy (CRT) is utilised in oesophagogastric (OG) cancer but the toxicity profile of cisplatin limits its use. This study aimed to evaluate the clinical characteristics and outcomes of patients treated with either cisplatin or carboplatin based CRT at our institution. MATERIALS AND METHODS: This is a retrospective analysis of patients with localised OG cancer undergoing CRT with cisplatin/fluoropyrimidine (CX/F) or carboplatin/fluoropyrimidine (CarboX/F) between January 2001 and December 2014. RESULTS: A total of 91 eligible patients were included. Median age was 65 years (IQR=57-75) for CX/F and 77 years (IQR=69-80) for CarboX/F. Adenocarcinoma histology and Charlson comorbidity index were higher in the CarboX/F group. Endoscopic complete response (CR) was achieved in 64% of CX/F group and 48% of CarboX/F group (p=0.19). The median PFS for CX/F was 31.0 months (95%CI=18.2-NE) vs. 18.7 months for CarboX/F (95%CI=13.5-30.4; HR=1.49, p=0.21). CONCLUSION: Despite significant differences in baseline clinical characteristics, patients treated with carboplatin CRT demonstrated no significant difference in PFS or endoscopic CR rate, compared to those treated with cisplatin.

Watch-and-Wait as a Therapeutic Strategy in Rectal Cancer.

PURPOSE OF REVIEW: Pathological complete response is seen in approximately one fifth of rectal cancer patients following neoadjuvant chemoradiation. Since these patients have excellent oncological outcomes, there has been a rapidly growing interest in organ preservation for those who develop a clinical complete response. We review the watch-and-wait strategy and focus on all aspects of this hot topic, including who should be considered for this approach, how should we identify treatment response and what are the expected outcomes. RECENT FINDINGS: The major challenges in interpreting the data on watch-and-wait are the significant heterogeneity of patients selected for this approach and of methods employed to identify them. The evidence available comes mostly from retrospective cohort studies, but has shown good oncological outcomes, including the rate of successful salvage surgery, locoregional control and overall survival. SUMMARY: There is currently not enough and not robust enough evidence to support watch-and-wait as a standard approach, outside a clinical trial, for patients achieving clinical complete response following neoadjuvant chemoradiation. Furthermore, there is a lack of data on long-term outcomes. However, the results we have so far are promising, and there is therefore an urgent need for randomised control studies such as the TRIGGER trial to confirm the safety of this strategy.

Target volume motion during anal cancer image guided radiotherapy using cone-beam computed tomography.

OBJECTIVE: Literature regarding image-guidance and interfractional motion of the anal canal (AC) during anal cancer radiotherapy is sparse. This study investigates interfractional AC motion during anal cancer radiotherapy. METHODS: Bone matched cone beam CT (CBCT) images were acquired for 20 patients receiving anal cancer radiotherapy allowing population systematic and random error calculations. 12 were selected to investigate interfractional AC motion. Primary anal gross tumour volume and clinical target volume (CTVa) were contoured on each CBCT. CBCT CTVa volumes were compared to planning CTVa. CBCT CTVa volumes were combined into a CBCT-CTVa envelope for each patient. Maximum distortion between each orthogonal border of the planning CTVa and CBCT-CTVa envelope was measured. Frequency, volume and location of CBCT-CTVa envelope beyond the planning target volume (PTVa) was analysed. RESULTS: Population systematic and random errors were 1 and 3 mm respectively. 112 CBCTs were analysed in the interfractional motion study. CTVa varied between each imaging session particularly T location patients of anorectal origin. CTVa border expansions ≥ 1 cm were seen inferiorly, anteriorly, posteriorly and left direction. The CBCT-CTVa envelope fell beyond the PTVa ≥ 50% imaging sessions (n = 5). Of these CBCT CTVa distortions beyond PTVa, 44% and 32% were in the upper and lower thirds of PTVa respectively. CONCLUSION: The AC is susceptible to volume changes and shape deformations. Care must be taken when calculating or considering reducing the PTV margin to the anus. Advances in knowledge: Within a limited field of research, this study provides further knowledge of how the AC deforms during anal cancer radiotherapy.

KRAS and BRAF mutations in circulating tumour DNA from locally advanced rectal cancer.

There are limited data on circulating, cell-free, tumour (ct)DNA analysis in locally advanced rectal cancer (LARC). Digital droplet (dd)PCR was used to investigate KRAS/BRAF mutations in ctDNA from baseline blood samples of 97 LARC patients who were treated with CAPOX followed by chemoradiotherapy, surgery and adjuvant CAPOX ± cetuximab in a randomised phase II trial. KRAS mutation in G12D, G12V or G13D was detected in the ctDNA of 43% and 35% of patients with tumours that were mutant and wild-type for these hotspot mutations, respectively, according to standard PCR-based analyses on tissue. The detection rate in the ctDNA of 10 patients with less common mutations was 50%. In 26 cases ctDNA analysis revealed KRAS mutations that were not previously found in tissue. Twenty-two of these (84.6%) were detected following repeat tissue testing by ddPCR. Overall, the ctDNA detection rate in the KRAS mutant population was 66%. Detection of KRAS mutation in ctDNA failed to predict prognosis or refine patient selection for cetuximab. While this study confirms the feasibility of ctDNA analysis in LARC and the high sensitivity of ddPCR, larger series are needed to better address the role of ctDNA as a prognostic or predictive tool in this setting.

Diagnostic accuracy of high-resolution MRI as a method to predict potentially safe endoscopic and surgical planes in patients with early rectal cancer.

INTRODUCTION: Early rectal cancer (ERC) assessment should include prediction of the potential excision plane to safely remove lesions with clear deep margins and feasibility of organ preservation. METHOD: MRI accuracy for differentiating ≤T1sm2 (partially preserved submucosa) or ≤T2 (partially preserved muscularis) versus >T2 tumours was compared with the gold standard of pT stage T1sm1/2 versus ≤pT2 versus >pT2. N stage was also compared. The MRI protocol employed a standard surface phased array coil with a high resolution (0.6×0.6×3 mm resolution). The staging data were analysed from a prospectively recorded database of all ERC (≤mrT3b) treated by primary surgery. RESULTS: Of 65 0.7 suggesting good agreement. 44 out of 65 patients underwent radical surgery and 22 out of 44 were ≤mrT2. MRI accuracy to predict lymph node status was 84% (95% CI 70% to 92%), PPV 71% and NPV 90%. Among the 21 out of 65 (32%) patients undergoing local excision or TEM, 20 out of 21 were staged as MR≤T2 and confirmed as such by pathology. On follow-up, none had relapse. If the decision had been made to offer local excision on MRI TN staging rather than clinical assessment, a significant increase in organ preservation surgery from 32% to 60% would have been observed (difference 23%, 95% CI 9% to 35%). CONCLUSIONS: MRI is a useful tool for multidisciplinary teams (MDTs) wishing to optimise treatment options for ERC; these study findings will be validated in a prospective multicentre trial.

Comparison between MRI and pathology in the assessment of tumour regression grade in rectal cancer.

BACKGROUND: Limited data exist regarding the correlation between MRI tumour regression grade (mrTRG) and pathological TRG (pTRG) in rectal cancer. METHODS: mrTRG and pTRG were compared in rectal cancer patients from two phase II trials (EXPERT and EXPERT-C). The agreement between radiologist and pathologist was assessed with the weighted κ test while the Kaplan-Meier method was used to estimate survival outcomes. RESULTS: One hundred ninety-one patients were included. Median time from completion of neoadjuvant treatment to pre-operative MRI and surgery was 4.1 weeks (interquartile range (IQR): 3.7-4.7) and 6.6 weeks (IQR: 5.9-7.6), respectively. Fair agreement was found between mrTRG and pTRG when regression was classified according to standard five-tier systems (κ=0.24) or modified three-tier systems (κ=0.25). Sensitivity and specificity of mrTRG 1-2 (complete/good radiological regression) for the prediction of pathological complete response was 74.4% (95% CI: 58.8-86.5) and 62.8% (95% CI: 54.5-70.6), respectively. Survival outcomes of patients with intermediate pathological regression (pTRG 2) were numerically better if complete/good regression was also observed on imaging (mrTRG 1-2) compared to poor regression (mrTRG 3-5) (5-year recurrence-free survival 76.9% vs 65.9%, P=0.18; 5-year overall survival 80.6% vs 68.8%, P=0.22). CONCLUSIONS: The agreement between mrTRG and pTRG is low and mrTRG cannot be used as a surrogate of pTRG. Further studies are warranted to assess the ability of mrTRG to identify pathological complete responders for the adoption of non-operative management strategies and to provide complementary prognostic information to pTRG for better risk-stratification after surgery.

A rectal cancer feasibility study with an embedded phase III trial design assessing magnetic resonance tumour regression grade (mrTRG) as a novel biomarker to stratify management by good and poor response to chemoradiotherapy (TRIGGER): study protocol for a randomised controlled trial.

BACKGROUND: Pre-operative chemoradiotherapy (CRT) for MRI-defined, locally advanced rectal cancer is primarily intended to reduce local recurrence rates by downstaging tumours, enabling an improved likelihood of curative resection. However, in a subset of patients complete tumour regression occurs implying that no viable tumour is present within the surgical specimen. This raises the possibility that surgery may have been avoided. It is also recognised that response to CRT is a key determinant of prognosis. Recent radiological advances enable this response to be assessed pre-operatively using the MRI tumour regression grade (mrTRG). Potentially, this allows modification of the baseline MRI-derived treatment strategy. Hence, in a 'good' mrTRG responder, with little or no evidence of tumour, surgery may be deferred. Conversely, a 'poor response' identifies an adverse prognostic group which may benefit from additional pre-operative therapy. METHODS/DESIGN: TRIGGER is a multicentre, open, interventional, randomised control feasibility study with an embedded phase III design. Patients with MRI-defined, locally advanced rectal adenocarcinoma deemed to require CRT will be eligible for recruitment. During CRT, patients will be randomised (1:2) between conventional management, according to baseline MRI, versus mrTRG-directed management. The primary endpoint of the feasibility phase is to assess the rate of patient recruitment and randomisation. Secondary endpoints include the rate of unit recruitment, acute drug toxicity, reproducibility of mrTRG reporting, surgical morbidity, pathological circumferential resection margin involvement, pathology regression grade, residual tumour cell density and surgical/specimen quality rates. The phase III trial will focus on long-term safety, regrowth rates, oncological survival analysis, quality of life and health economics analysis. DISCUSSION: The TRIGGER trial aims to determine whether patients with locally advanced rectal cancer can be recruited and subsequently randomised into a control trial that offers MRI-directed patient management according to radiological response to CRT (mrTRG). The feasibility study will inform a phase III trial design investigating stratified treatment of good and poor responders according to 3-year disease-free survival, colostomy-free survival as well as an increase in cases managed without a major resection. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT02704520 . Registered on 5 February 2016.