Gene-expression profiles of pretreatment biopsies predict complete response of rectal cancer patients to preoperative chemoradiotherapy.

PURPOSE: Preoperative (neoadjuvant) chemoradiotherapy (CRT) and total mesorectal excision is the standard treatment for rectal cancer patients (UICC stage II/III). Up to one-third of patients treated with CRT achieve a pathological complete response (pCR). These patients could be spared from surgery and its associated morbidity and mortality, and assigned to a "watch and wait" strategy. However, reliably identifying pCR based on clinical or imaging parameters remains challenging. EXPERIMENTAL DESIGN: We generated gene-expression profiles of 175 patients with locally advanced rectal cancer enrolled in the CAO/ARO/AIO-94 and -04 trials. One hundred and sixty-one samples were used for building, training and validating a predictor of pCR using a machine learning algorithm. The performance of the classifier was validated in three independent cohorts, comprising 76 patients from (i) the CAO/ARO/AIO-94 and -04 trials (n = 14), (ii) a publicly available dataset (n = 38) and (iii) in 24 prospectively collected samples from the TransValid A trial. RESULTS: A 21-transcript signature yielded the best classification of pCR in 161 patients (Sensitivity: 0.31; AUC: 0.81), when not allowing misclassification of non-complete-responders (False-positive rate = 0). The classifier remained robust when applied to three independent datasets (n = 76). CONCLUSION: The classifier can identify >1/3 of rectal cancer patients with a pCR while never classifying patients with an incomplete response as having pCR. Importantly, we could validate this finding in three independent datasets, including a prospectively collected cohort. Therefore, this classifier could help select rectal cancer patients for a "watch and wait" strategy. TRANSLATIONAL RELEVANCE: Forgoing surgery with its associated side effects could be an option for rectal cancer patients if the prediction of a pathological complete response (pCR) after preoperative chemoradiotherapy would be possible. Based on gene-expression profiles of 161 patients a classifier was developed and validated in three independent datasets (n = 76), identifying over 1/3 of patients with pCR, while never misclassifying a non-complete-responder. Therefore, the classifier can identify patients suited for "watch and wait".

The RENAISSANCE (AIO-FLOT5) trial: effect of chemotherapy alone vs. chemotherapy followed by surgical resection on survival and quality of life in patients with limited-metastatic adenocarcinoma of the stomach or esophagogastric junction - a phase III trial of the German AIO/CAO-V/CAOGI.

BACKGROUND: Historical data indicate that surgical resection may benefit select patients with metastatic gastric and gastroesophageal junction cancer. However, randomized clinical trials are lacking. The current RENAISSANCE trial addresses the potential benefits of surgical intervention in gastric and gastroesophageal junction cancer with limited metastases. METHODS: This is a prospective, multicenter, randomized, investigator-initiated phase III trial. Previously untreated patients with limited metastatic stage (retroperitoneal lymph node metastases only or a maximum of one incurable organ site that is potentially resectable or locally controllable with or without retroperitoneal lymph nodes) receive 4 cycles of FLOT chemotherapy alone or with trastuzumab if Her2+. Patients without disease progression after 4 cycles are randomized 1:1 to receive additional chemotherapy cycles or surgical resection of primary and metastases followed by subsequent chemotherapy. 271 patients are to be allocated to the trial, of which at least 176 patients will proceed to randomization. The primary endpoint is overall survival; main secondary endpoints are quality of life assessed by EORTC-QLQ-C30 questionnaire, progression free survival and surgical morbidity and mortality. Recruitment has already started; currently (Feb 2017) 22 patients have been enrolled. DISCUSSION: If the RENAISSANCE concept proves to be effective, this could potentially lead to a new standard of therapy. On the contrary, if the outcome is negative, patients with gastric or GEJ cancer and metastases will no longer be considered candidates for surgical intervention. TRIAL REGISTRATION: The article reports of a health care intervention on human participants and is registered on October 12, 2015 under ClinicalTrials.gov Identifier: NCT02578368 ; EudraCT: 2014-002665-30.

MRI-based treatment of rectal cancer: is prognostication of the recurrence risk solid enough to render radiation redundant?

BACKGROUND: Most current guidelines recommend neoadjuvant short course radiotherapy (sRT) or radio-chemotherapy (nRCT) for rectal cancer stage II and III. After the introduction of total mesorectal excision (TME) and magnetic resonance imaging (MRI), this proceeding has been questioned and omission of neoadjuvant treatment according to preoperative MRI-criteria has been propagated. Aim of the present paper is to review the state of evidence regarding MRI-based treatment decision depending on the predicted width of the circumferential resection margin (CRM). METHODS: A comprehensive survey of the literature was performed using the search terms "rectal cancer", "radiotherapy", "radio-chemotherapy", "MRI-based therapy", "circumferential resection margin". Data from lately published observational studies were compared to results from randomized trials and outcome analyses of the Norwegian national cancer registry. RESULTS: Only one observational study using MRI-based treatment according to the anticipated CRM provided 5 year local recurrence data, however only for 65 patients. The second study did not yet evaluate recurrence rates. Two randomized trials comparing sRT to primary TME showed significantly worse outcome for non-irradiated patients. Data from the Norwegian rectal cancer registry demonstrate that TME alone is associated with higher LRR than achievable with preoperative RT. CONCLUSIONS: Current evidence does not support the omission of neoadjuvant treatment for stage II-III rectal cancer on the basis of an MRI-predicted negative CRM. Randomized studies are warranted to clarify whether and for which subgroups TME alone is safe in terms of local recurrences.

Neoadjuvant capecitabine combined with standard radiotherapy in patients with locally advanced rectal cancer: mature results of a phase II trial.

PURPOSE: The objective of this expanded phase II trial was to confirm the safety results of the preceding phase I study and establish the efficacy of neoadjuvant radiochemotherapy with capecitabine in rectal cancer in a multicenter setting. PATIENTS AND METHODS: 96 patients (63% male, age 34-81 years) with advanced rectal cancer (cT3-4 or cN+) from seven university centers in Germany were recruited. All were to receive a total irradiation dose of 50.4-55.8 Gy with conventional fractions. Capecitabine was given at an oral dosage of 825 mg/m(2)bid on each day of the radiotherapy period with the first daily dose applied 2 h before irradiation, followed by surgery 6 weeks later. RESULTS: Most of the patients suffered from an advanced primary tumor (cT3: 57%, cT4: 40%) with lymph node involvement in 60%. After neoadjuvant treatment, with a mean of 99% of the scheduled radiation dose actually delivered, a clinical response rate of 68% (95% confidence interval: 57-78%) was observed. Out of 87 evaluable patients undergoing surgery, a sphincter-preserving procedure could be performed in 51% and R0 resection in 94%. A pathologically complete response was achieved in six patients (7%, 95% confidence interval: 3-14%). The comparison of initial diagnosis and pathologic findings showed a downstaging in 61%. Acute toxicity with > 5% incidence of NCI (National Cancer Institute) grade >/= 3 included lymphopenia (12%), leukopenia (6%), and diarrhea (7%). Mild to moderate hand-foot syndrome occurred in 12% only. After a median follow-up of 48 months, the 5-year overall survival and tumor control data were, with regard to patient selection, in the expected range with an overall survival of 65%, a relapse-free survival of 47%, and a local recurrence rate after 5 years of 17%. CONCLUSION: The data clearly confirm that capecitabine is an adequate substitute for 5-fluorouracil in preoperative chemoradiation of rectal cancer with a favorable safety profile.

Combined modality therapy for rectal cancer.

The standard adjuvant treatment for cT3 and/or N+ rectal cancer is preoperative chemoradiation. However, there are many controversies regarding this approach. These include the role of short course radiation, whether postoperative adjuvant chemotherapy necessary for all patients and whether the type of surgery after chemoradiation should be based on the response rate. More accurate imaging techniques and/or molecular markers may help identify patients with positive pelvic nodes to reduce the chance of overtreatment with preoperative therapy. Will more effective systemic agents both improve the results of radiation as well as modify the need for pelvic radiation? These questions and others remain active areas of clinical investigation.