Clinical Complete Response In Patients Research Articles

Alliance A022104/NRG-GI010: A randomized phase II trial testing the efficacy of triplet versus doublet chemotherapy to achieve clinical complete response in patients with locally advanced rectal cancer—The Janus Rectal Cancer trial.

TPS3640 Background: Recent data have demonstrated that in locally advanced rectal cancer (LARC), a total neoadjuvant therapy (TNT) approach improves compliance with chemotherapy and increases rates of tumor response compared to neoadjuvant chemoradiation (CRT) alone. They further indicate that the optimal sequencing of TNT involves consolidation (rather than induction) chemotherapy to optimize complete response rates. Data, largely from retrospective studies, have also shown that patients (pts) with clinical complete response (cCR) after neoadjuvant therapy may be managed safely with the watch and wait approach (WW) instead of preemptive total mesorectal resection (TME). However, the optimal consolidation chemotherapy regimen to achieve cCR has not been established, and a randomized clinical trial has not robustly evaluated it as a primary endpoint. Collaborating with a multidisciplinary oncology team and pt groups, we designed this NCI-sponsored study of chemotherapy intensification to address these issues and to drive up cCR rates, to provide opportunity for organ preservation and improve quality of life for pts. Methods: In this Alliance for Clinical Trials in Oncology randomized phase II trial (1:1), up to 312 pts with microsatellite stable LARC, clinical stage T4N0, any T, N+ or T3N0 requiring abdominoperineal resection or coloanal anastomosis and distal margin within 12 cm of anal verge will be enrolled. Stratification factors include tumor stage (T4 vs T1-3), nodal stage (N+ vs N0) and distance from anal verge (0-4; 4-8; 8-12 cm). Pts will be randomized to receive neoadjuvant long course CRT (LCRT) followed by consolidation doublet (mFOLFOX6 or CAPOX) or triplet chemotherapy (mFOLFIRINOX) for 4 months. LCRT in both arms involves 4500 cGy in 25 fractions over 5 weeks (w) + 900 cGy boost in 5 fractions with a fluoropyrimidine (capecitabine preferred). Pts will undergo assessment 8-12 w post-TNT completion for the primary endpoint of cCR per previously validated criteria and recommended WW and surveillance if cCR is achieved or TME if an incomplete response is noted. Secondary objectives include time-to event outcomes (disease-free and overall survival, organ preservation time and time to distant metastasis) and adverse effects. Statistical power, based on cCR, incorporates a one-sided alpha = 0.048 and power = 90% yielding 312 patients (156 per arm). Biospecimens including archival tumor tissue, matched / normal blood samples and serial rectal MRI will be collected for exploratory correlative research. This study, activated in late 2022, is open across the NCTN and is actively recruiting. Support: U10CA180821, U10CA180882, U24 CA196171; https://acknowledgments.alliancefound.org . U10CA180868 (NRG); U10CA180888 (SWOG); Clinicaltrials.gov ID: NCT05610163 Clinical trial information: NCT05610163 .

Clinical Complete Response in Patients With Rectal Adenocarcinoma Treated With Short-Course Radiation Therapy and Nonoperative Management

This study aimed to determine the clinical efficacy and safety of nonoperative management (NOM) for patients with rectal cancer with a clinical complete response (cCR) after short-course radiation therapy and consolidation chemotherapy. Patients with stage I-III rectal adenocarcinoma underwent short-course radiation therapy followed by consolidation chemotherapy between January 2018 and May 2019 (n = 90). Clinical response was assessed by digital rectal examination, pelvic magnetic resonance imaging, and endoscopy. Of the patients with an evaluable initial response, those with a cCR (n = 43) underwent NOM, and those with a non-cCR (n = 43) underwent surgery. The clinical endpoints included local regrowth-free survival, regional control, distant metastasis-free survival, disease-free survival, and overall survival. Compared with patients with an initial cCR, patients with initial non-cCR had more advanced T and N stage (P = .05), larger primary tumors (P = .002), and more circumferential resection margin involvement on diagnostic magnetic resonance imaging (P < .001). With a median follow-up of 30.1 months, the persistent cCR rate was 79% (30 of 38 patients) in the NOM cohort. The 2-year local regrowth-free survival was 81% (95% confidence interval [CI], 70%-94%) in the initial cCR group, and all patients with local regrowth were successfully salvaged. Compared with those with a non-cCR, patients with a cCR had improved 2-year regional control (98% [95% CI, 93%-100%] vs 85% [95% CI, 74%-97%], P = .02), distant metastasis-free survival (100% [95% CI, 100%-100%] vs 80% [95% CI, 69%-94%], P < .01), disease-free survival (98% [95% CI, 93%-100%] vs 71% [95% CI, 59%-87%], P < .01), and overall survival (100% [95% CI, 100%-100%] vs 88% [95% CI, 79%-98%], P = .02). No late grade 3+ gastrointestinal or genitourinary toxicities were observed in the patients who underwent continued NOM. Short-course radiation therapy followed by consolidation chemotherapy may be a feasible organ preservation strategy in rectal cancer. Additional prospective studies are necessary to evaluate the safety and efficacy of this approach.

MR Imaging of Rectal Cancer: Radiomics Analysis to Assess Treatment Response after Neoadjuvant Therapy.

Purpose To investigate the value of T2-weighted-based radiomics compared with qualitative assessment at T2-weighted imaging and diffusion-weighted (DW) imaging for diagnosis of clinical complete response in patients with rectal cancer after neoadjuvant chemotherapy-radiation therapy (CRT). Materials and Methods This retrospective study included 114 patients with rectal cancer who underwent magnetic resonance (MR) imaging after CRT between March 2012 and February 2016. Median age among women (47 of 114, 41%) was 55.9 years (interquartile range, 45.4-66.7 years) and median age among men (67 of 114, 59%) was 55 years (interquartile range, 48-67 years). Surgical histopathologic analysis was the reference standard for pathologic complete response (pCR). For qualitative assessment, two radiologists reached a consensus. For radiomics, one radiologist segmented the volume of interest on high-spatial-resolution T2-weighted images. A random forest classifier was trained to separate the patients by their outcomes after balancing the number of patients in each response category by using the synthetic minority oversampling technique. Statistical analysis was performed by using the Wilcoxon rank-sum test, McNemar test, and Benjamini-Hochberg method. Results Twenty-one of 114 patients (18%) achieved pCR. The radiomic classifier demonstrated an area under the curve of 0.93 (95% confidence interval [CI]: 0.87, 0.96), sensitivity of 100% (95% CI: 0.84, 1), specificity of 91% (95% CI: 0.84, 0.96), positive predictive value of 72% (95% CI: 0.53, 0.87), and negative predictive value of 100% (95% CI: 0.96, 1). The diagnostic performance of radiomics was significantly higher than was qualitative assessment at T2-weighted imaging or DW imaging alone (P < .02). The specificity and positive predictive values were significantly higher in radiomics than were at combined T2-weighted and DW imaging (P < .0001). Conclusion T2-weighted-based radiomics showed better classification performance compared with qualitative assessment at T2-weighted and DW imaging for diagnosing pCR in patients with locally advanced rectal cancer after CRT. © RSNA, 2018 Online supplemental material is available for this article.

Can We Reliably Predict a Clinical Complete Response in Rectal Cancer? Current Trends and Future Strategies

Prediction of clinical complete response is pivotal in the management of patients with rectal cancer. The ability to determine tumor response to neoadjuvant therapy in rectal cancer might guide subsequent treatment modalities. We review the current literature on predictors of complete response after neoadjuvant for rectal cancer with an emphasis of clinical complete response rather than pathological complete response. Clinical and radiological findings have been used to predict response, as well as a myriad of biomarkers. There is limited evidence validating most of these strategies. The role of imaging in defining tumor response has been assessed retrospectively. The TRIGGER trial is a randomized trial that will evaluate stratified management of rectal cancer based on their tumor regression grade. The management of locally advanced rectal cancer is evolving. The ability to predict clinical complete response in patients that have undergone neoadjuvant chemoradiation will allow us to select potential patients that can benefit from a “watch and wait” strategy. Identifying patients that will have a complete response will result in decreased surgical overtreatment, favoring organ-sparing strategies. Treatment individualization will require further research. Emphasis should be made in validating prediction markers; these should be cost-effective and of minimally invasive retrieval. Surveillance protocols to assess for tumor regrowth are yet to be determined.

Complete response after chemoradiotherapy for rectal cancer: what is the reasonable approach?

With the increasing use of preoperative treatment rather than upfront surgery, it has become evident that the response of rectal carcinoma to standard chemoradiotherapy (CRT) shows a great variety that includes histopathologiocally confirmed complete tumor regression in 10–30% of cases. Adaptive strategies to avoid radical surgery, either by local excision or non-operative management, have been proposed in these highly responsive tumors. A growing number of prospective clinical trials and experiences from large databases, such as the European Registration of Cancer Care (EURECCA) watch-and-wait database, or the recent Oncological Outcome after Clinical Complete Response in Patients with Rectal Cancer (OnCoRe) project, will provide more information on its safety and efficacy, and help to select appropriate patients. Future studies will have to establish appropriate inclusion criteria and optimize CRT regimens in order to maximize the number of patients achieving complete response. Standardized re-staging procedures have to be investigated to improve the prediction of a sustained complete response, and long-term close follow-up with thorough documentation of failure patterns and salvage therapies will have to prove the oncological safety of this approach.

Watch-and-wait approach versus surgical resection after chemoradiotherapy for patients with rectal cancer (the OnCoRe project): a propensity-score matched cohort analysis

Induction of a clinical complete response with chemoradiotherapy, followed by observation via a watch-and-wait approach, has emerged as a management option for patients with rectal cancer. We aimed to address the shortage of evidence regarding the safety of the watch-and-wait approach by comparing oncological outcomes between patients managed by watch and wait who achieved a clinical complete response and those who had surgical resection (standard care). Oncological Outcomes after Clinical Complete Response in Patients with Rectal Cancer (OnCoRe) was a propensity-score matched cohort analysis study, that included patients of all ages diagnosed with rectal adenocarcinoma without distant metastases who had received preoperative chemoradiotherapy (45 Gy in 25 daily fractions with concurrent fluoropyrimidine-based chemotherapy) at a tertiary cancer centre in Manchester, UK, between Jan 14, 2011, and April 15, 2013. Patients who had a clinical complete response were offered management with the watch-and-wait approach, and patients who did not have a complete clinical response were offered surgical resection if eligible. We also included patients with a clinical complete response managed by watch and wait between March 10, 2005, and Jan 21, 2015, across three neighbouring UK regional cancer centres, whose details were obtained through a registry. For comparative analyses, we derived one-to-one paired cohorts of watch and wait versus surgical resection using propensity-score matching (including T stage, age, and performance status). The primary endpoint was non-regrowth disease-free survival from the date that chemoradiotherapy was started, and secondary endpoints were overall survival, and colostomy-free survival. We used a conservative p value of less than 0·01 to indicate statistical significance in the comparative analyses. 259 patients were included in our Manchester tertiary cancer centre cohort, 228 of whom underwent surgical resection at referring hospitals and 31 of whom had a clinical complete response, managed by watch and wait. A further 98 patients were added to the watch-and-wait group via the registry. Of the 129 patients managed by watch and wait (median follow-up 33 months [IQR 19-43]), 44 (34%) had local regrowths (3-year actuarial rate 38% [95% CI 30-48]); 36 (88%) of 41 patients with non-metastatic local regrowths were salvaged. In the matched analyses (109 patients in each treatment group), no differences in 3-year non-regrowth disease-free survival were noted between watch and wait and surgical resection (88% [95% CI 75-94] with watch and wait vs 78% [63-87] with surgical resection; time-varying p=0·043). Similarly, no difference in 3-year overall survival was noted (96% [88-98] vs 87% [77-93]; time-varying p=0·024). By contrast, patients managed by watch and wait had significantly better 3-year colostomy-free survival than did those who had surgical resection (74% [95% CI 64-82] vs 47% [37-57]; hazard ratio 0·445 [95% CI 0·31-0·63; p<0·0001), with a 26% (95% CI 13-39) absolute difference in patients who avoided permanent colostomy at 3 years between treatment groups. A substantial proportion of patients with rectal cancer managed by watch and wait avoided major surgery and averted permanent colostomy without loss of oncological safety at 3 years. These findings should inform decision making at the outset of chemoradiotherapy. Bowel Disease Research Foundation.

Current views on clinical complete response in patients with rectal cancer following neoadjuvant chemoradiation

following neoadjuvant treatment was documented in patients treated with external beam radiation (without chemotherapy) who could not have a rectal cancer operation because the operative risk was prohibitive, the tumor was unresectable or because patients simply opted out of surgical treatment. In this cohort, cCR was 30%, and local relapse occurred in 78% of patients at 18 months. In total, 29% of patients underwent salvage surgery and the 5-year survival of these patients was 43%. The 5-year overall survival (OS) in this cohort was 27% [5]. In 2004, Habr-Gama’s group published their observations in rectal cancer patients who achieved a cCR following CRT [6]. In this study, only patients with rectal tumors within 0–7 cm from the anal verge were observed. They all received preoperative radiotherapy (50.4 Gy) and chemotherapy (5-fluorouracil [425 mg/m 2 /d] + folinic acid [20 mg/m 2 /d]). Pretreatment staging was not clearly characterized and not all patients underwent EUS. MRI was not utilized for “The introduction of circular stapling devices, total mesorectal excision and neoadjuvant chemoradiation have made substantial advances in the management of adenocarcinoma of the rectum.”

Results of the baseline positron emission tomography can customize therapy of localized esophageal adenocarcinoma patients who achieve a clinical complete response after chemoradiation

BackgroundPatients with localized esophageal adenocarcinoma (EAC) who achieve a clinical complete response (clinCR) after preoperative chemoradiation (trimodality therapy; TMT) or definitive chemoradiation (bimodality therapy; BMT) live longer than those who achieve a <clinCR (Suzuki A, Xiao LC, Hayashi Y et al. Prognostic significance of baseline positron emission tomography and importance of clinical complete response in patients with esophageal or gastroesophageal junction cancer treated with definitive chemoradiotherapy. Cancer 2011; 117: 4823–4833; Cheedella NK, Suzuki A, Xiao L et al. Association between clinical complete response and pathological complete response after preoperative chemoradiation in patients with gastroesophageal cancer: analysis in a large cohort. Ann Oncol 2013; 24: 1262–1266; Ajani JA, Correa AM, Hofstetter WL et al. Clinical parameters model for predicting pathologic complete response following preoperative chemoradiation in patients with esophageal cancer. Ann Oncol 2012; 23: 2638–2642). We hypothesized that the initial standardized uptake value (iSUV) of positron emission tomography will define novel subsets of clinCR patients. MethodsWe analyzed 323 EAC patients, from our prospective database, who achieved a clinCR. Various statistical methods were used to assess the influence of iSUV on patient outcome. ResultsThe median follow-up of 323 patients was 40.8 months [95% confidence interval (CI) 35.6–47.3 months]. Two hundred six (63.8%) patients had TMT and 117 (36.2%) had BMT. If iSUV was ≥6, TMT patients had a longer median OS (94.8 months; 95% CI 66.07–NA) than BMT patients (31.4 months; 95% CI 21.7–42.1; P ≤ 0.001). However, if iSUV was <6, the median OS of TMT and BMT patients was similar (P = 0.62). iSVU did not influence the pathologic complete response rate in TMT patients (P = 0.85). ConclusionclinCR patients with iSUV of <6 are identified as a new subset that fared equally well when treated with TMT or BMT. Future esophageal preservation strategy may be best suited for this newly identified subset of EAC patients.

Prognostic Significance of Baseline Positron Emission Tomography and Importance of Clinical Complete Response in Patients With Esophageal or Gastroesophageal Junction Cancer Treated With Definitive Chemoradiotherapy

Prognostic Significance of Baseline Positron Emission Tomography and Importance of Clinical Complete Response in Patients With Esophageal or Gastroesophageal Junction Cancer Treated With Definitive Chemoradiotherapy

Long-term Follow-up Features on Rectal MRI During a Wait-and-See Approach After a Clinical Complete Response in Patients With Rectal Cancer Treated With Chemoradiotherapy

The "wait-and-see" policy instead of standard surgery for patients with rectal cancer who undergo a complete tumor regression after chemoradiation treatment is highly controversial. It is not clear yet how patients should be monitored once they are managed nonoperatively and whether follow-up by MRI has any potential role. This study aimed to describe the rectal wall MRI morphology during short-term and long-term follow-up in patients with a clinical complete tumor response undergoing a wait-and-see policy without surgical treatment. As part of an observational study in our center, a cohort of 19 carefully selected patients with a clinical complete response after chemoradiation was managed with a wait-and-see policy and followed regularly (every 3-6 mo) by clinical examination, endoscopy with biopsies, and a rectal MRI. The MR morphology of the tumor bed was studied on the consecutive MRI examinations. The primary outcome measured was the morphology of the tumor bed on the consecutive MRI examinations performed during short-term (≤6 mo) and long-term (>6 mo) follow-up. Patients with a complete tumor response after chemoradiation presented with either a normalized rectal wall (26%) or fibrosis (74%). In the latter group, 3 patterns of fibrosis were observed (full-thickness, minimal, or spicular fibrosis). The morphology patterns of a normalized rectal wall or fibrosis remained consistent during long-term follow-up in 18 of 19 patients. One patient developed a small, endoluminal recurrence, which was salvaged with transanal endoscopic microsurgery. In 26% of patients, an edematous wall thickening was observed in the first months after chemoradiation, which gradually decreased during long-term follow-up. Median follow-up was 22 months (range, 12-60). This was a small observational study, and had no histological validation. Four MR patterns of a persistent complete response of rectal cancer after chemoradiation were identified. These MR features can serve as a reference for the follow-up in a wait-and-see policy.

Prognostic significance of baseline positron emission tomography and importance of clinical complete response in patients with esophageal or gastroesophageal junction cancer treated with definitive chemoradiotherapy

Metabolic imaging is of interest in esophageal cancer; however, the usefulness of initial standardized uptake value (SUV) in positron emission tomography (PET) is unknown in patients with esophageal or gastroesophageal carcinoma treated with definitive chemoradiotherapy. The authors hypothesized that initial SUV would correlate with patient outcome. The authors retrospectively analyzed esophageal or gastroesophageal carcinoma patients who had baseline PET and endoscopic ultrasonography in addition to other routine staging. All patients received definitive chemoradiotherapy. Multiple statistical methods were used. The authors analyzed 209 consecutive esophageal or gastroesophageal carcinoma patients treated with definitive chemoradiation for outcome; of these, 180 had baseline PET for additional analyses. The median overall survival (OS) for all patients was 20.7 months (95% confidence interval, 18.8-26.3). Patients with clinical complete response (CR) lived longer than those with less than clinical CR (P < .0001). The median initial SUV was 12.7 (range, 0-51). Higher initial SUV was associated with longer tumors (P = .0001), higher T-stage status (P < .0001), positive N-stage status (P = .0001), higher overall stage (P < .0001), lack of clinical CR (P = .0002), and squamous cell histology (P < .0001). In the univariate analysis, initial SUV was associated with OS (Cox model, P = .016; log-rank test, P = .002). In the multivariate analysis, initial SUV dichotomized by the median value (P = .024) and tumor grade (P = .016) proved to be independent OS prognosticators. Median initial SUV for clinical CR patients was 10.2, compared with 15.3 for less than clinical CR patients (P = .0058). The data indicate that a higher initial SUV is associated with poorer OS in patients with esophageal or gastroesophageal carcinoma receiving definitive chemoradiation. Upon validation, baseline PET may become a useful stratification factor in randomized trials and for individualizing therapy.