Introduction

Treatment of patients with locally advanced rectal cancer consists of neoadjuvant chemoradiotherapy (nCRT) followed by surgery¹. Remarkably, standard treatment does not consider the fact that 15-27% of rectal cancer patients achieve a pathological complete response (pCR) after nCRT^2-5 and may not need the surgery. Unfortunately, current imaging modalities lack sensitivity and specificity to adequately predict a pCR. Previously, we have proven the potential of bevacizumab-800CW for assessing the pCR⁶. Cetuximab-800CW targets endothelial growth factor receptor (EGFR) which is tumor-specific and may therefore be even more promising as biomarker.

Aims & Methods

This study aimed to determine the safety and feasibility of quantitative fluorescence molecular endoscopy (qFME) using cetuximab-800CW for evaluation of response to nCRT in rectal cancer. Patients received an intravenous dose of 15 mg cetuximab-800CW preceded by 75 mg unlabeled cetuximab 2-4 days prior to the endoscopy. In vivo FME was performed to analyze fluorescence in both potential residual tumor and healthy tissue and biopsies were taken from both sites. Additionally, both in vivo and ex vivo the fluorescent signal intensity was quantified using spectroscopy. Subsequently, extensive ex vivo analyses were performed on both biopsies and the resected specimen including immunohistochemistry and fluorescence microscopy for specific localization of the fluorescent drug and observation of the immune cell composition.

Results

Five out of ten included patients had a pCR after nCRT. Quantification showed a significantly higher fluorescent signal in the (former) tumor area when compared to healthy tissue in both patients with a partial (p<0.0001) and complete response (p<0.0001). Although immunohistochemical EGFR analysis in the biopsies showed a significantly higher expression in tumor epithelium when compared to healthy mucosa (p=0.0070) and fibrosis (p=0.0083), a clear difference between tissue with residual tumor and a pCR could not be distinguished (p=0.5334). Fluorescence microscopy revealed that specific binding of cetuximab-800CW to tumor epithelium was only visible in the submucosa. Remarkably, aspecific binding to macrophages was observed in the mucosa of both patients with a pCR and partial responders resulting in enhanced off target fluorescence signals.

Conclusion

Even though cetuximab-800CW was visualized in the “former” tumor area using qFME and during subsequent ex vivo analysis of the biopsies, cetuximab-800CW could not be used to identify pCR patients. However, due to our extensive further analysis we discovered that specific binding to tumor epithelium was not enough located at the luminal side to be detected during qFME and that the detected signal may be caused by aspecific binding to off target uptake of mucosal macrophages. Novel techniques like ultrasound guided needle biopsy single fiber fluorescence spectroscopy that can measure fluorescence below the superficial layer may enable the use of cetuximab-800CW during qFME for monitoring after nCRT in rectal cancer.

References

1. Sauer R, Becker H, Hohenberger W, Rödel C, Wittekind C, Fietkau R, et al. Preoperative versus Postoperative Chemoradiotherapy for Rectal Cancer. N Engl J Med. 2004 Oct 8;351:1731–40.
2. Bosset JF, Calais G, Mineur L, Maingon P, Radosevic-Jelic L, Daban A, et al.
Enhanced Tumorocidal Effect of Chemotherapy With Preoperative Radiotherapy for
Rectal Cancer: Preliminary Results--EORTC 22921. J Clin Oncol. 2005 Aug
18;23(24):5620–7.
3. O'Neill BD, Brown G, Heald RJ, Cunningham D, Tait DM. Non-operative treatment
after neoadjuvant chemoradiotherapy for rectal cancer. Lancet Oncol. 2007
Jul;8(7):625–33.
4. Park IJ, You YN, Agarwal A, Skibber JM, Rodriguez-Bigas MA, Eng C, et al.
Neoadjuvant Treatment Response As an Early Response Indicator for Patients With
Rectal Cancer. J Clin Oncol. 2012 May 18;30(15):1770–6.
5. Loos M, Quentmeier P, Schuster T, Nitsche U, Gertler R, Keerl A, et al. Effect of
preoperative radio(chemo)therapy on long-term functional outcome in rectal cancer
patients: a systematic review and meta-analysis. Ann Surg Oncol. 2013
Jun;20(6):1816–28.
6. Tjalma JJJ, Koller M, Linssen MD, Hartmans E, de Jongh S, Jorritsma-Smit A, et al. Quantitative fluorescence endoscopy: an innovative endoscopy approach to evaluate neoadjuvant treatment response in locally advanced rectal cancer. Gut. 2020;69(3):406-10.

Introduction

Patients with locally advanced rectal cancer (LARC) who have a complete clinical response (cCR) to nCRT may opt for organ preservation, watch & wait – (W&W). This consists of an intense surveillance program including serial endoscopies, pelvic MRI, CEA, and CT scans to detect recurrent disease at an early stage. However, identifying residual or recurrent lesions endoscopically - particularly in patients with prior radiotherapy - can be challenging due to mucosal changes such as friability and neovascularization. In this context, we developed a novel deep learning model to assist in the detection of residual or recurrent rectal cancer lesions during proctosigmoidoscopy.

Aims & Methods

We trained a convolutional neural network (Wide ResNet-101-2) on a dataset of 1,795 annotated frames from proctosigmoidoscopy exams of 97 patients treated at University Hospitals Liverpool, a tertiary referral center. Residual or recurrent disease was defined by histopathological confirmation via biopsy or surgical specimen. The dataset was split into training and testing cohorts using a 90/10% patient-level split. The model’s diagnostic performance was evaluated using sensitivity, specificity, accuracy, positive predictive value (PPV), negative predictive value (NPV), and the area under the receiver operating characteristic curve (AUROC).

Results

Out of 97 patients, 24 (363 frames) had confirmed residual or recurrent disease, while 73 (1,432 frames) presented normal rectal mucosa. The model achieved an overall accuracy of 92.8%, with a sensitivity of 80.0%, specificity of 97.3%, PPV of 90.9%, NPV of 94.0%, and an AUROC of 0.886.

Conclusion

To the best of our knowledge, this is the first deep learning model specifically developed for the detection of residual or recurrent disease following in W&W patients during endoscopic examination. This tool has the potential to enhance early lesion detection, guide clinical decision-making, and increase opportunities for organ-preserving, less invasive therapeutic strategies.

Introduction

Locally advanced rectal cancer (LARC) poses a significantly challenge in clinical management, involving multimodal treatment approach. Among innovative strategies, Total Neoadjuvant Therapy (TNT) has emerged, delivering all planned chemotherapy before surgery.

Aims & Methods

Our aim was to evaluate the real-world application and efficacy of TNT and to compare it with non-TNT strategy.
This retrospective study compared 107 locally advanced rectal adenocarcinoma patients treated with Total Neoadjuvant Therapy (TNT) from 2022 and traditional chemoradiotherapy (CRT) from 2020-2021. Evaluation included primary endpoints of efficacy, tolerability, and completion rates.

Results

Among 107 patients (54.2% male, mean age 62.48 years), non-TNT and TNT follow-ups were 26.66 and 8.19 months, respectively. No differences in gender(p=0.163), staging (p=0.707), or location (p=0.727) were noted. TNT patients received more short-course radiotherapy (42.5% vs1.5%, p<0.001). Clinical responses favored TNT (p= 0.030) with no significant differences in pathological responses, recurrence rates, or survival. TNT exhibited higher chemotherapy completion (p = 0.007) and lower adverse events (p<0.001). Post-surgery events showed no significant differences (p=0.470).

Conclusion

In conclusion, our data add to the body of literature favoring the TNT treatment strategy for locally advanced rectal cancer, aiming to achieve higher complete response rates with less adverse events.

References

1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021 May;71(3):209-249. doi: 10.3322/caac.21660. Epub 2021 Feb 4. PMID: 33538338.
2. Oronsky B, Reid T, Larson C, Knox SJ. Locally advanced rectal cancer: The past, present, and future. Semin Oncol. 2020 Feb;47(1):85-92. doi: 10.1053/j.seminoncol.2020.02.001. Epub 2020 Feb 21. PMID: 32147127.
3. Maas M, Beets-Tan RG, Lambregts DM, Lammering G, Nelemans PJ, Engelen SM, van Dam RM, Jansen RL, Sosef M, Leijtens JW, Hulsewé KW, Buijsen J, Beets GL. Wait-and-see policy for clinical complete responders after chemoradiation for rectal cancer. J Clin Oncol. 2011 Dec 10;29(35):4633-40. doi: 10.1200/JCO.2011.37.7176. Epub 2011 Nov 7. PMID: 22067400.

Introduction

Radiation therapy as part of neoadjuvant treatment for rectal cancer aims to improve local disease control with increased response rates and the possibility of sphincter preservation. The addition of the "watch and wait" (W&W) strategy has increased the efficacy and safety associated with neoadjuvant radiotherapy. Despite the use of low doses (between 40-50.4 Gy), most studies report complete pathological response rates of 10-27%. However, there is still a lack of studies with higher doses to evaluate effectiveness in terms of clinical and pathological response, versus the toxicity associated with increased radiation dose.

Aims & Methods

The aim was to evaluate the efficacy and tolerance of neoadjuvant therapy for potentially resectable rectal cancer with higher radiation doses.
A retrospective observational preliminary study included 41 individuals with potentially resectable rectal cancer (T2-T4, N0-1, M0), treated with capecitabine (825mg/m2 every 12 hours, 5 days a week) and 25 sessions of 54 Gy + 50 Gy to pelvic lymph nodes, considering patients on W&W. Partial response was defined as downstaging of at least 1 level in T and/or N. Complete clinical response was defined as reevaluation by MRI, endoscopy with biopsies, and digital rectal examination without evidence of residual disease. Short- and long-term complications of increased radiation dose were also evaluated.

Results

Out of 41 individuals with potentially resectable disease observed during the study, downstaging was observed in 78% (n=32), with 29% (n=12) showing complete response (clinical and/or pathological). Of the patients with complete clinical response (n=12), 8 underwent total mesorectal excision due to unpassable stenosis affecting adequate visualization of the rectal mucosa (n=1), presence of rectal ulcer with negative biopsies (n=6), and concurrent ulcerative colitis (n=1). All these patients showed complete pathological response. Four patients entered the W&W protocol, 3 of them with residual ulcer and negative biopsies, without recurrence at present (4 years follow-up). Radiation therapy complications were observed in 7% (n=3) of patients, respectively due to rectal stenosis, radiation proctitis, and radiation cystitis.

Conclusion

Our study found higher rates of downstaging and complete response compared to most studies under similar conditions and with lower radiotherapy doses, with a relatively low frequency of adverse effects.

References

Anter, A., Eladawei, G., & Mosbah, M. (2013). Preoperative capecitabine and pelvic radiation in locally advanced rectal cancer: preliminary results (Mansoura experience). Translational Gastrointestinal Cancer, 2(3), 112-117.
Korkolis, D. P., Boskos, C. S., Plataniotis, G. D., Gontikakis, E., Karaitianos, I. J., Avgerinos, K., Katopodi, A., Xinopoulos, D., Dimitroulopoulos, D., Beroukas, K., & Vassilopoulos, P. P. (2007). Pre-operative chemoradiotherapy with oral capecitabine in locally advanced, resectable rectal cancer. Anticancer research, 27(1B), 541–545.
A. De Paoli, et al. (2006). Capecitabine in combination with preoperative radiation therapy in locally advanced, resectable, rectal cancer: a multicentric phase II study, Annals of Oncology, Volume 17, Issue 2, Pages 246-251,

Introduction

Watch-and-Wait is an increasingly recognized non-surgical management option for rectal cancer patients achieving a clinical complete response (cCR) following neoadjuvant therapy. This approach aims to preserve organ function by avoiding surgery, but necessitates vigilant endoscopic surveillance, to detect local tumor regrowth¹ (LTR). The specific endoscopic features associated with regrowth remain incompletely defined.

Aims & Methods

We performed a retrospective analysis of patients monitored under the Watch-and-Wait program at Karolinska University Hospital², focusing on the endoscopic characteristics of LTR. As of December 2023, 145 patients who met the criteria for clinical complete response (cCR) were included.
The neoadjuvant treatment consisted of chemoradiotherapy (CRT) in 16 patients (11%), short course radiotherapy (SCRT) + chemotherapy in 69 patients (47.6%) and SCRT alone (5 x 5 Gy) in 60 patients (41.4%). The median age of the patients was 66 years (range 29-94), with 61.4% being male. The initial tumor stage was T1/T2 in 42 patients (29%) and T3/T4 in 103 patients (71%). The nodal stage was N0 in 35 patients (24%) and N+ in 110 patients (75.9%). The median follow-up period was 29 months (range 3-102 months).
Patients were monitored with rectal digital exams, flexible endoscopy, CEA measurements, and MRI every 3 months for 2 years, and then every 6 months thereafter. During endoscopy, narrow-band imaging (NBI) and NICE classification³ was utilized.

Results

Out of the 145 patients, 28 (19.3%) experienced LTR as of December 2023. The median time from the completion of radiotherapy to regrowth was 9 months (range 3-20 months). Regrowth was detected intraluminally by endoscopy in 23 patients (82.1%), while in 5 patients (17.9%), regrowth was detected on MRI but was not visible intraluminally.
The most common endoscopic features of regrowth included a NICE 3 pattern (n=16) and contact bleeding (n=16). Additional findings included polypoid tissue (n=13), ulceration (n=10), irregular surface (n=9), fibrin cover (n=9), stenosis (n=6), and submucosal nodules (n=5).

Conclusion

As regrowth occurs in at least one of five patients and most commonly with intraluminal findings, this study highlights the importance of meticulous endoscopic follow-up. Contact bleeding and NICE type 3 lesions observed with narrow-band imaging (NBI) were key endoscopic findings in patients with tumor regrowth, while polypoid lesions were observed in less than 50%. Combining endoscopic assessment with other modalities, such as MRI, is essential, as regrowth may be undetectable endoscopically in a proportion of patients.

References

1. Cerdan-Santacruz C, Vailati BB, Sao Juliao GP, Habr-Gama A, Perez RO. Local tumor regrowth after clinical complete response following neoadjuvant therapy for rectal cancer: what happens when organ preservation falls short. Tech Coloproctol 2023;27(1):1-9. DOI: 10.1007/s10151-022-02654-5.
2. Nilsson PJ, Ahlberg M, Kordnejad S, Holm T, Martling A. Organ preservation following short-course radiotherapy for rectal cancer. BJS Open 2021;5(5). DOI: 10.1093/bjsopen/zrab093.
3. Hamada Y, Tanaka K, Katsurahara M, et al. Utility of the narrow-band imaging international colorectal endoscopic classification for optical diagnosis of colorectal polyp histology in clinical practice: a retrospective study. BMC Gastroenterol 2021;21(1):336. DOI: 10.1186/s12876-021-01898-z.

Disclosure

Stephan Haas (SLH) has received speaker's honoraria from Santax Medico, Tillotts Pharma, Lilly, Mediahuset, and Johnson & Johnson.

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