Clinical Case Summary

An 80-year-old woman with a history of right ovarian cancer, treated with total hysterectomy and bilateral salpingo-oophorectomy followed by adjuvant radiotherapy in 1984, presented with tenesmus and rectal bleeding. She had long-standing radiation-induced enteritis. Colonoscopy revealed a 50mm ulcerated neoplasm in the distal rectum. Histopathological analysis confirmed a low-grade rectal adenocarcinoma with loss of nuclear expression of the mismatch repair proteins MSH2 and MSH6. Staging with thoracoabdominal CT and pelvic MRI showed a distal rectal adenocarcinoma invading the vagina and levator ani muscle (cT4), cN0, with a suspicious left inguinal lymph node (possible cM1). Given her prior exposure to pelvic radiotherapy and the presence of chronic radiation-induced injury, a multidisciplinary team, after discussion with the patient and her family, decided to initiate off-label neoadjuvant treatment with dostarlimab for six months, completing a total of eight cycles. Six weeks after completion of immunotherapy, flexible sigmoidoscopy demonstrated a clinical near-complete response (near-cCR) and pelvic MRI showed radiologic complete response (rCR), with no evidence of residual tumor or lymphadenopathy. A new flexible sigmoidoscopy is scheduled in four weeks. If cCR is confirmed, the patient will enter a Watch and Wait surveillance program. Traditionally, rectal cancer treatment has relied on a combination of chemoradiotherapy and surgery, resulting in pathologic complete response in up to 25% of patients, but frequently associated with complications and treatment-related toxicity. Recent studies have demonstrated promising results with immune checkpoint inhibitors, particularly dostarlimab as single agent, an antiprogrammed cell death protein 1 monoclonal antibody. In recent studies so far, this agent was remarkably effective in mismatch repair–deficient, locally advanced rectal cancer, showing high rates of cCR and prolonged overall survival.

References

Andrea Cercek et al, A Phase Two, Single-Arm, Open-Label Study With Dostarlimab Monotherapy in Participants With Untreated Stage II/III dMMR/MSI-H Locally Advanced Rectal Cancer (AZUR-1), Clinical Colorectal Cancer

A. Cercek, M. Lumish, J. Sinopoli, J. Weiss, J. Shia, M. Lamendola-Essel, I.H. El Dika, N. Segal, M. Shcherba, R. Sugarman, Z. Stadler, R. Yaeger, J.J. Smith, B. Rousseau, G. Argiles, M. Patel, A. Desai, L.B. Saltz, M. Widmar, K. Iyer, J. Zhang, N. Gianino, C. Crane, P.B. Romesser, E.P. Pappou, P. Paty, J. Garcia-Aguilar, M. Gonen, M. Gollub, M.R. Weiser, K.A. Schalper, L.A. Diaz Jr. PD-1 BLockade in Mismatch Repair-deficient, Locally Advanced Rectal Cancer

Introduction

Until now, there have only been conflicting reports regarding whether adenomas located proximal to the splenic flexure have increased association with metachronous colorectal cancer (CRC) compared to distal adenomas, and whether adenoma location should affect surveillance practice.

Aims & Methods

To address this knowledge gap, we aimed to compare metachronous colorectal cancer (CRC) and advanced adenoma (AA) risk in patients with baseline proximal vs. distal adenomas, including consideration of metachronous CRC location, baseline proximal adenomas only vs. both proximal and distal adenomas, and baseline proximal non-advanced adenoma vs. AA.
We systematically searched Pubmed, EMBASE, and Cochrane for cohort studies and clinical trials describing CRC or AA incidence at surveillance stratified according to baseline adenoma’s location. Proximal adenomas were defined as those located from the cecum to the splenic flexure. We performed a meta-analysis by calculating pooled incidence rate ratios (IRR) and corresponding 95% confidence intervals (CI) for CRC and AA using a random-effects model. Heterogeneity was assessed with the I2 statistic.

Results

The literature search yielded 5,907 studies of which 13 were included, with a total of 205,207 patients (mean age 62.3 years, 63.8% males) and a mean duration of follow-up of 8.5 years. Compared with patients with only distal adenomas, patients with any proximal adenoma and only proximal adenomas had a significantly higher risk of metachronous CRC [1.70 (95%CI: 1.17-2.46; I2=73%), and 1.97 (95%CI: 1.41-2.75; I2=0%)], respectively. Patients with any proximal AA had also a higher risk of CRC compared to those with only distal AA [2.77 (95%CI 1.77-4.34; I²=38%)]. Also, patients with any proximal adenoma had an even higher risk of proximal CRC compared to patients with baseline only distal lesions [3.65 (95%CI 1.57-8.47; I2=86%)]. Finally, patients with any baseline proximal adenoma had also a higher risk of metachronous AA [1.82 (95%CI: 1.41-2.34; I2=59%)].

Conclusion

Our findings suggest that baseline adenoma proximal location is associated with future detection of CRC and AA. Better understanding of the reasons behind this increased CRC risk, and particularly whether these can be overcome with improved colonoscopic technique or technical innovations, will inform whether baseline adenoma location should be considered in future guidelines as an independent factor to tailor surveillance recommendations.

Introduction

A decade ago, endoscopic surveillance (ES) for Barrett’s oesophagus (BO) was recommended to improve the outcome of oesophageal adenocarcinoma through early recognition and prevention¹. The yield of ES to detect dysplasia may depend on guideline adherence and quality of endoscopy^2,3,4.

Aims & Methods

The aim is to assess whether dedicated (expert) ES (DS) is more effective than conventional (non-dedicated) ES (NS) by means of Key Performance Indicators (KPI), Dysplasia Detection Rate (DDR), use of advanced imaging and complication rate.
This multicentre (5 UK hospitals) retrospective study includes real-world ES data from 1303 procedures conducted within the last 8 years. The endoscopy and histology reports and clinical notes of consecutive procedures were accessed. The data were collected in spreadsheets and then analysed with SPSS-23. Two services were reported demographically and compared with appropriate statistical tests and logistic regression to test factors associated with DDR.

Results

Data from 680 DS and 623 NS procedures were included, comprising 906 (69.5%) males and 397 (30.5%) females (M:F=2.3:1.0). The age ranged from 14-90 yrs with a mean of 63.7 (SD±12.5) yrs. The maximum length of the BO was 18 cm with a mean of 4.1 cm (SD±3.0). There were significant differences in all the KPIs (Prague classification, Barrett’s island description, hiatus hernia delineation, visible lesion documentation, Paris classification, Seattle protocol adherence and inspection time) favoring the DS (P<0.001). Other comparisons: narrow band imaging (NBI, P<0.001), acetic acid chromoendoscopy (AAC, P<0.001), sedation (P=0.02) and acquisition of target biopsies (, P<0.001) were also significantly higher in DS while the complication rate was significantly lower (P=0.05). Importantly, the DDR was significantly higher in DS (58/680 (8.5%)) than in NS (16/623 (2.6%)) with a P<0.001. Regression analysis showed: increasing age, male sex, lesion description and Paris classification documentation were associated with higher DDR (Table 1), while other indicators showed no significant association.

Table 1. Factors associated with dysplasia detection

Conclusion

Surveillance for BO through a dedicated service with high quality endoscopy can produce a higher diagnostic yield with improved DDR and a lower complication rate. Given these benefits, large-scale prospective studies are warranted to assess the true impact on mortality, morbidity, cost benefit and patient-reported outcomes, ensuring that surveillance service provides a meaningful clinical benefit, particularly with risk stratification concerning the factors associated with disease progression.

References

1. Fitzgerald et al. (2013). BSG guidelines on Barrett’s oesophagus. Gut, 63(1), 7–42. doi:10.1136/gutjnl-2013-305372.
2. Britton et al. (2019). Improving accuracy in Barrett’s surveillance. Frontline Gastroenterol, 10(2), 128–134. doi:10.1136/flgastro-2018-101019.
3. Ratcliffe et al. (2023). Surveillance service improves dysplasia detection. Frontline Gastroenterol, 15(1), 21–27. doi:10.1136/flgastro-2023-102425.
4. Ratcliffe et al. (2023). Dedicated Barrett’s surveillance vs. standard care. iGIE, 3(1), 58–65. doi:10.1016/j.igie.2023.11.003.

Introduction

The fecal immunochemical test (FIT) is the preferred non-endoscopic test in programmatic screening worldwide. Compared to other methods, FIT may be better accepted with higher participation rates, which may counteract its lower one-time sensitivities. We performed a systematic review and meta-analysis to ascertain participation patterns, participation rates, and FIT performance in organized multi-round FIT-based screening programs worldwide.

Aims & Methods

We performed a systematic search using Pubmed, Embase, and Cochrane databases. Participation patterns were categorized as “consistent screeners” (participation in 100% of rounds), “intermittent screeners” (including drop-outs, delayed entrants, and intermittent re-screeners), and “consistent non-screeners” (never screened). Data regarding positivity rates and detection rates for adenomas, advanced adenomas (AA), and colorectal cancer (CRC) across subsequent rounds were extracted and summary estimates were obtained. Yields were calculated for 2 populations: 1) Overall Population; 2) Consistent Screeners. A sensitivity analysis was performed including only programs with biennial screening with FIT cut-off of 20μg Hb/g feces.

Results

The literature search yielded 4,414 studies of which 25 were included. Across all studies, the fraction of the population behaving as “consistent screeners”, “consistent non-screeners”, and “intermittent screeners” was 47.1%, 30.3%, and 22.7%, respectively. For the overall population, FIT-positivity from the 1^st through 4^th rounds was 6.7%, 5.5%, 5.4%, and 5.3%; and detection rates were 5.8%, 3.3%, 2.9%, and 2.5% for CRC; 32.8%, 28.3%, 22.7% and 23% for AA; 48.6%, 46.2%, 48.7% and 44.6% for adenoma. For Consistent Screeners, FIT-positivity across studies from the 1^st through 4^th rounds was 6.4%, 4.8%, 4.1%, and 3.6%, respectively; and detection rates were 6.9%, 4.6%, 3.6%, and 3.1% for CRC; 38.7%, 30.6%, 28.2% and 24.9% for AA; 53.4%, 46.7%, 42.6% and 42.4% for adenoma. Similar trends were observed for biennial screening with FIT cut-off of 20μg Hb/g feces.

Conclusion

Organized multi-round FIT-based CRC screening programs achieve consistent participation in a minority of participants, and a sizeable proportion of the population do not initiate screening at all after multiple offers. Among those participating, FIT-positivity, and yields for CRC, AA, and adenoma are highest in the 1^st round, but may stabilize at a clinically relevant steady state at rounds 3+.

References

1. Doria-Rose VP, Lansdorp-Vogelaar I, McCarthy S, Puricelli-Perin DM, Butera V, Segnan N, et al. Measures of longitudinal adherence to fecal-based colorectal cancer screening: Literature review and recommended approaches. Int J Cancer. 2021 Jul 15;149(2):316–26.
2. Duncan A, Turnbull D, Wilson C, Osborne JM, Cole SR, Flight I, et al. Behavioural and demographic predictors of adherence to three consecutive faecal occult blood test screening opportunities: A population study. BMC Public Health. 2014 Mar 7;14(1).