International Validation of the Immunoscore Biopsy in Patients With Rectal Cancer Managed by a Watch-and-Wait Strategy.

PURPOSE: No biomarker capable of improving selection and monitoring of patients with rectal cancer managed by watch-and-wait (W&W) strategy is currently available. Prognostic performance of the Immunoscore biopsy (ISB) was recently suggested in a preliminary study. METHODS: This international validation study included 249 patients with clinical complete response (cCR) managed by W&W strategy. Intratumoral CD3+ and CD8+ T cells were quantified on pretreatment rectal biopsies by digital pathology and converted to ISB. The primary end point was time to recurrence (TTR; the time from the end of neoadjuvant treatment to the date of local regrowth or distant metastasis). Associations between ISB and outcomes were analyzed by stratified Cox regression adjusted for confounders. Immune status of tumor-draining lymph nodes (n = 161) of 17 additional patients treated by neoadjuvant chemoradiotherapy and surgery was investigated by 3'RNA-Seq and immunofluorescence. RESULTS: Recurrence-free rates at 5 years were 91.3% (82.4%-100.0%), 62.5% (53.2%-73.3%), and 53.1% (42.4%-66.5%) with ISB High, ISB Intermediate, and ISB Low, respectively (hazard ratio [HR; Low v High], 6.51; 95% CI, 1.99 to 21.28; log-rank P = .0004). ISB was also significantly associated with disease-free survival (log-rank P = .0002), and predicted both local regrowth and distant metastasis. In multivariate analysis, ISB was independent of patient age, sex, tumor location, cT stage (T, primary tumor; c, clinical), cN stage (N, regional lymph node; c, clinical), and was the strongest predictor for TTR (HR [ISB High v Low], 6.93; 95% CI, 2.08 to 23.15; P = .0017). The addition of ISB to a clinical-based model significantly improved the prediction of recurrence. Finally, B-cell proliferation and memory in draining lymph nodes was evidenced in the draining lymph nodes of patients with cCR. CONCLUSION: The ISB is validated as a biomarker to predict both local regrowth and distant metastasis, with a gradual scaling of the risk of pejorative outcome.

The Prognostic Importance of ctDNA in Rectal Cancer: A Critical Reappraisal.

The treatment of locally advanced rectal cancer (LARC) has evolved during the last decades, but recurrence remains a problem. Circulating tumor DNA (ctDNA) may result in an individualized treatment approach with improved survival and quality of life, but diverging results impede further development. In this systematic review, we addressed the quality of reporting and its impact on the interpretation of ctDNA results. We performed a systematic literature search using subject headings and search terms related to ctDNA and rectal cancer. The Quality of Prognostic Studies (QUIPS) tool was used to assess bias. Nine studies, with substantial heterogeneity, were included in the analysis. Three out of nine articles had moderate or high risk of bias. No association was found between treatment response and ctDNA status at baseline. There was a negative association between ctDNA positivity at baseline, before and after surgery and survival. The ctDNA status may be of importance to the long-term prognosis, but the area of research is new and is short of dedicated studies. There is an obvious need for standardization in ctDNA research, and the issue should be addressed in future research.

The "Immunoscore" in rectal cancer: could we search quality beyond quantity of life?

Because of the function and anatomical environment of the rectum, therapeutic strategies for local advanced rectal cancer (LARC) must deal with two challenging stressors that are a high-risk of local and distal recurrences and a high-risk of poor quality of life (QoL). Over the last three decades, advances in screening tests, therapies, and combined-modality treatment options and strategies have improved the prognosis of patients with LARC. However, owing to the heterogeneous nature of LARC and genetic status, the patient may not respond to a specific therapy and may be at increased risk of side-effects without the life-prolonging benefit. Indeed, each therapy can cause its own side-effects, which may worsen by a combination of treatments resulting in long-term poor QoL. In LARC, QoL has become even more essential with the increasing incidence of rectal cancer in young individuals. Herein, we analyzed the value of the Immunoscore-Biopsy (performed on tumor biopsy at diagnosis) in predicting outcomes, alone or in association with clinical and imaging data, for each therapy used in LARC.

Long-Term Patient-Reported Outcomes After High-Dose Chemoradiation Therapy for Nonsurgical Management of Distal Rectal Cancer.

PURPOSE: Surgery is standard treatment for rectal cancer, but neoadjuvant chemoradiation therapy (CRT) may result in clinical complete response (cCR) in select patients, allowing for nonsurgical management (NSM). Prospective studies of NSM strategies are sparse, however, and long-term data on quality of life (QoL) are limited. We conducted a single-arm phase 2 trial of high-dose CRT for NSM of distal rectal cancer; we report secondary long-term patient-reported outcomes (PROs), local regrowth, and overall survival in patients managed nonsurgically. METHODS AND MATERIALS: Fifty-one patients with resectable, T2 or T3, N0-N1, low adenocarcinoma received 65 Gy (intensity modulated radiation therapy, brachytherapy boost) and oral tegafur-uracil. Patients with cCR 6 weeks after treatment (clinical examination, magnetic resonance imaging, biopsy) were referred for observation and followed closely with clinical examination, endoscopy, positron emission tomography/computed tomography, and PROs for 5 years. Overall colorectal cancer-specific QoL and specific symptom scores were evaluated at baseline and in follow-up and compared between time points. Local regrowth was estimated using cumulative incidence and overall survival using Kaplan-Meier estimates. RESULTS: Forty patients achieved cCR after treatment; 29 were in follow-up at 24 months, 21 at 36 months, and 20 at 60 months. PRO questionnaire completion rates were 90% at 24 months, 100% at 36 months, and 85% at 60 months for patients still in follow-up. Average QoL score did not differ between baseline (median 11.1) and 24 months (13.7), 48 months (11.1), or 60 months (6.9). Only rectal bleeding deteriorated from baseline, with bowel- and bladder-related symptom scores otherwise unchanged in follow-up. At median follow-up of 5.0 years, local regrowth rate and overall survival were 31% (95% confidence interval, 15%-47%) and 85% (95% confidence interval, 75%-97%), respectively. CONCLUSIONS: Long-term follow-up after NSM of distal rectal cancer showed excellent general colorectal cancer QoL and local symptom scores. Our study results indicate that high-dose CRT followed by organ preservation might be an alternative to standard treatment.