Recurrent disease detection after resection of pancreatic ductal adenocarcinoma using a recurrence-focused surveillance strategy (RADAR-PANC): protocol of an international randomized controlled trial according to the Trials within Cohorts design.

BACKGROUND: Disease recurrence remains one of the biggest concerns in patients after resection of pancreatic ductal adenocarcinoma (PDAC). Despite (neo)adjuvant systemic therapy, most patients experience local and/or distant PDAC recurrence within 2 years. High-level evidence regarding the benefits of recurrence-focused surveillance after PDAC resection is missing, and the impact of early detection and treatment of recurrence on survival and quality of life is unknown. In most European countries, recurrence-focused follow-up after surgery for PDAC is currently lacking. Consequently, guidelines regarding postoperative surveillance are based on expert opinion and other low-level evidence. The recent emergence of more potent local and systemic treatment options for PDAC recurrence has increased interest in early diagnosis. To determine whether early detection and treatment of recurrence can lead to improved survival and quality of life, we designed an international randomized trial. METHODS: This randomized controlled trial is nested within an existing prospective cohort in pancreatic cancer centers in the Netherlands (Dutch Pancreatic Cancer Project; PACAP) and the United Kingdom (UK) (Pancreas Cancer: Observations of Practice and survival; PACOPS) according to the "Trials within Cohorts" (TwiCs) design. All PACAP/PACOPS participants with a macroscopically radical resection (R0-R1) of histologically confirmed PDAC, who provided informed consent for TwiCs and participation in quality of life questionnaires, are included. Participants randomized to the intervention arm are offered recurrence-focused surveillance, existing of clinical evaluation, serum cancer antigen (CA) 19-9 testing, and contrast-enhanced computed tomography (CT) of chest and abdomen every three months during the first 2 years after surgery. Participants in the control arm of the study will undergo non-standardized clinical follow-up, generally consisting of clinical follow-up with imaging and serum tumor marker testing only in case of onset of symptoms, according to local practice in the participating hospital. The primary endpoint is overall survival. Secondary endpoints include quality of life, patterns of recurrence, compliance to and costs of recurrence-focused follow-up, and the impact on recurrence-focused treatment. DISCUSSION: The RADAR-PANC trial will be the first randomized controlled trial to generate high level evidence for the current clinical equipoise regarding the value of recurrence-focused postoperative surveillance with serial tumor marker testing and routine imaging in patients after PDAC resection. The Trials within Cohort design allows us to study the acceptability of recurrence-focused surveillance among cohort participants and increases the generalizability of findings to the general population. While it is strongly encouraged to offer all trial participants treatment at time of recurrence diagnosis, type and timing of treatment will be determined through shared decision-making. This might reduce the potential survival benefits of recurrence-focused surveillance, although insights into the impact on patients' quality of life will be obtained. TRIAL REGISTRATION: Clinicaltrials.gov, NCT04875325 . Registered on May 6, 2021.

Perioperative or adjuvant mFOLFIRINOX for resectable pancreatic cancer (PREOPANC-3): study protocol for a multicenter randomized controlled trial.

BACKGROUND: Surgical resection followed by adjuvant mFOLFIRINOX (5-fluorouracil with leucovorin, irinotecan, and oxaliplatin) is currently the standard of care for patients with resectable pancreatic cancer. The main concern regarding adjuvant chemotherapy is that only half of patients actually receive adjuvant treatment. Neoadjuvant chemotherapy, on the other hand, guarantees early systemic treatment and may increase chemotherapy use and thereby improve overall survival. Furthermore, it may prevent futile surgery in patients with rapidly progressive disease. However, some argue that neoadjuvant therapy delays surgery, which could lead to progression towards unresectable disease and thus offset the potential benefits. Comparison of perioperative (i.e., neoadjuvant and adjuvant) with (only) adjuvant administration of mFOLFIRINOX in a randomized controlled trial (RCT) is needed to determine the optimal approach. METHODS: This multicenter, phase 3, RCT will include 378 patients with resectable pancreatic ductal adenocarcinoma with a WHO performance status of 0 or 1. Patients are recruited from 20 Dutch centers and three centers in Norway and Sweden. Resectable pancreatic cancer is defined as no arterial contact and ≤ 90 degrees venous contact. Patients in the intervention arm are scheduled for 8 cycles of neoadjuvant mFOLFIRINOX followed by surgery and 4 cycles of adjuvant mFOLFIRINOX (2-week cycle of oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, irinotecan 150 mg/m2 at day 1, followed by 46 h continuous infusion of 5-fluorouracil 2400 g/m2). Patients in the comparator arm start with surgery followed by 12 cycles of adjuvant mFOLFIRINOX. The primary outcome is overall survival by intention-to-treat. Secondary outcomes include progression-free survival, resection rate, quality of life, adverse events, and surgical complications. To detect a hazard ratio of 0.70 with 80% power, 252 events are needed. The number of events is expected to be reached after the inclusion of 378 patients in 36 months, with analysis planned 18 months after the last patient has been randomized. DISCUSSION: The multicenter PREOPANC-3 trial compares perioperative mFOLFIRINOX with adjuvant mFOLFIRINOX in patients with resectable pancreatic cancer. TRIAL REGISTRATION: Clinical Trials: NCT04927780. Registered June 16, 2021.

Optimizing patient selection for stereotactic ablative radiotherapy in patients with locally advanced pancreatic cancer after initial chemotherapy - a single center prospective cohort.

Background: The role of stereotactic ablative radiation therapy (SABR) as local treatment option after chemotherapy for locally advanced pancreatic cancer (LAPC) is evolving. However adequate patient selection criteria for SABR in patients with LAPC are lacking. Methods: A prospective institutional database collected data of patients with LAPC treated with chemotherapy, mainly FOLFIRINOX, followed by SABR, which was delivered using magnetic resonance guided radiotherapy, 40 Gy in 5 fractions within two weeks. Primary endpoint was overall survival (OS). Cox regression analyses were performed to identify predictors for OS. Results: Overall, 74 patients were included, median age 66 years, 45.9% had a KPS score of ≥90. Median OS was 19.6 months from diagnosis and 12.1 months from start of SABR. Local control was 90% at one year. Multivariable Cox regression analyses identified KPS ≥90, age <70, and absence of pain prior to SABR as independent favorable predictors for OS. The rate of grade ≥3 fatigue and late gastro-intestinal toxicity was 2.7%. Conclusions: SABR is a well-tolerated treatment in patients with unresectable LAPC following chemotherapy, with better outcomes when applied in patients with higher performance score, age <70 years and absence of pain. Future randomized trials will have to confirm these findings.

Stereotactic ablative radiotherapy or best supportive care in patients with localized pancreatic cancer not receiving chemotherapy and surgery (PANCOSAR): a nationwide multicenter randomized controlled trial according to a TwiCs design.

BACKGROUND: Significant comorbidities, advanced age, and a poor performance status prevent surgery and systemic treatment for many patients with localized (non-metastatic) pancreatic ductal adenocarcinoma (PDAC). These patients are currently treated with 'best supportive care'. Therefore, it is desirable to find a treatment option which could improve both disease control and quality of life in these patients. A brief course of high-dose high-precision radiotherapy i.e. stereotactic ablative body radiotherapy (SABR) may be feasible. METHODS: A nationwide multicenter trial performed within a previously established large prospective cohort (the Dutch Pancreatic cancer project; PACAP) according to the 'Trial within cohorts' (TwiCs) design. Patients enrolled in the PACAP cohort routinely provide informed consent to answer quality of life questionnaires and to be randomized according to the TwiCs design when eligible for a study. Patients with localized PDAC who are unfit for chemotherapy and surgery or those who refrain from these treatments are eligible. Patients will be randomized between SABR (5 fractions of 8 Gy) with 'best supportive care' and 'best supportive care' only. The primary endpoint is overall survival from randomization. Secondary endpoints include preservation of quality of life (EORTC-QLQ-C30 and -PAN26), NRS pain score response and WHO performance scores at baseline, and, 3, 6 and 12 months. Acute and late toxicity will be scored using CTCAE criteria version 5.0: assessed at baseline, day of last fraction, at 3 and 6 weeks, and 3, 6 and 12 months following SABR. DISCUSSION: The PANCOSAR trial studies the added value of SBRT as compared to 'best supportive care' in patients with localized PDAC who are medically unfit to receive chemotherapy and surgery, or refrain from these treatments. This study will assess whether SABR, in comparison to best supportive care, can relieve or delay tumor-related symptoms, enhance quality of life, and extend survival in these patients. TRIAL REGISTRATION: Clinical trials, NCT05265663 , Registered March 3 2022, Retrospectively registered.

A nationwide randomized controlled trial on additional treatment for isolated local pancreatic cancer recurrence using stereotactic body radiation therapy (ARCADE).

BACKGROUND: Disease recurrence is the main cause of mortality after resection of pancreatic ductal adenocarcinoma (PDAC). In 20-30% of resected patients, isolated local PDAC recurrence occurs. Retrospective studies have suggested that stereotactic body radiation therapy (SBRT) might lead to improved local control in these patients, potentially having a beneficial effect on both survival and quality of life. The "nationwide randomized controlled trial on additional treatment for isolated local pancreatic cancer recurrence using stereotactic body radiation therapy" (ARCADE) will investigate the value of SBRT in addition to standard of care in patients with isolated local PDAC recurrence compared to standard of care alone, regarding both survival and quality of life outcomes. METHODS: The ARCADE trial is nested within a prospective cohort (Dutch Pancreatic Cancer Project; PACAP) according to the 'Trials within Cohorts' design. All PACAP participants with isolated local PDAC recurrence after primary resection who provided informed consent for being randomized in future studies are eligible. Patients will be randomized for local therapy (5 fractions of 8 Gy SBRT) in addition to standard of care or standard of care alone. In total, 174 patients will be included. The main study endpoint is survival after recurrence. The most important secondary endpoint is quality of life. DISCUSSION: It is hypothesized that additional SBRT, compared to standard of care alone, improves survival and quality of life in patients with isolated local recurrence after PDAC resection. TRIAL REGISTRATION: ClinicalTrials.gov registration NCT04881487 . Registered on May 11, 2021.

Quantifying the reduction of respiratory motion by mechanical ventilation with MRI for radiotherapy.

BACKGROUND: Due to respiratory motion, accurate radiotherapy delivery to thoracic and abdominal tumors is challenging. We aimed to quantify the ability of mechanical ventilation to reduce respiratory motion, by measuring diaphragm motion magnitudes in the same volunteers during free breathing (FB), mechanically regularized breathing (RB) at 22 breaths per minute (brpm), variation in mean diaphragm position across multiple deep inspiration breath-holds (DIBH) and diaphragm drift during single prolonged breath-holds (PBH) in two MRI sessions. METHODS: In two sessions, MRIs were acquired from fifteen healthy volunteers who were trained to be mechanically ventilated non-invasively We measured diaphragm motion amplitudes during FB and RB, the inter-quartile range (IQR) of the variation in average diaphragm position from one measurement over five consecutive DIBHs, and diaphragm cranial drift velocities during single PBHs from inhalation (PIBH) and exhalation (PEBH) breath-holds. RESULTS: RB significantly reduced the respiratory motion amplitude by 39%, from median (range) 20.9 (10.6-41.9) mm during FB to 12.8 (6.2-23.8) mm. The median IQR for variation in average diaphragm position over multiple DIBHs was 4.2 (1.0-23.6) mm. During single PIBHs with a median duration of 7.1 (2.0-11.1) minutes, the median diaphragm cranial drift velocity was 3.0 (0.4-6.5) mm/minute. For PEBH, the median duration was 5.8 (1.8-10.2) minutes with 4.4 (1.8-15.1) mm/minute diaphragm drift velocity. CONCLUSIONS: Regularized breathing at a frequency of 22 brpm resulted in significantly smaller diaphragm motion amplitudes compared to free breathing. This would enable smaller treatment volumes in radiotherapy. Furthermore, prolonged breath-holding from inhalation and exhalation with median durations of six to seven minutes are feasible. TRIAL REGISTRATION: Medical Ethics Committee protocol NL.64693.018.18.

Total neoadjuvant FOLFIRINOX versus neoadjuvant gemcitabine-based chemoradiotherapy and adjuvant gemcitabine for resectable and borderline resectable pancreatic cancer (PREOPANC-2 trial): study protocol for a nationwide multicenter randomized controlled trial.

BACKGROUND: Neoadjuvant therapy has several potential advantages over upfront surgery in patients with localized pancreatic cancer; more patients receive systemic treatment, fewer patients undergo futile surgery, and R0 resection rates are higher, thereby possibly improving overall survival (OS). Two recent randomized trials have suggested benefit of neoadjuvant chemoradiotherapy over upfront surgery, both including single-agent chemotherapy regimens. Potentially, the multi-agent FOLFIRINOX regimen (5-fluorouracil with leucovorin, irinotecan, and oxaliplatin) may further improve outcomes in the neoadjuvant setting for localized pancreatic cancer, but randomized studies are needed. The PREOPANC-2 trial investigates whether neoadjuvant FOLFIRINOX improves OS compared with neoadjuvant gemcitabine-based chemoradiotherapy and adjuvant gemcitabine in resectable and borderline resectable pancreatic cancer patients. METHODS: This nationwide multicenter phase III randomized controlled trial includes patients with pathologically confirmed resectable and borderline resectable pancreatic cancer with a WHO performance score of 0 or 1. Resectable pancreatic cancer is defined as no arterial and ≤ 90 degrees venous involvement; borderline resectable pancreatic cancer is defined as ≤90 degrees arterial and ≤ 270 degrees venous involvement without occlusion. Patients receive 8 cycles of neoadjuvant FOLFIRINOX chemotherapy followed by surgery without adjuvant treatment (arm A), or 3 cycles of neoadjuvant gemcitabine with hypofractionated radiotherapy (36 Gy in 15 fractions) during the second cycle, followed by surgery and 4 cycles of adjuvant gemcitabine (arm B). The primary endpoint is OS by intention-to-treat. Secondary endpoints include progression-free survival, quality of life, resection rate, and R0 resection rate. To detect a hazard ratio of 0.70 with 80% power, 252 events are needed. The number of events is expected to be reached after inclusion of 368 eligible patients assuming an accrual period of 3 years and 1.5 years follow-up. DISCUSSION: The PREOPANC-2 trial directly compares two neoadjuvant regimens for patients with resectable and borderline resectable pancreatic cancer. Our study will provide evidence on the neoadjuvant treatment of choice for patients with resectable and borderline resectable pancreatic cancer. TRIAL REGISTRATION: Primary registry and trial identifying number: EudraCT: 2017-002036-17 . Date of registration: March 6, 2018. Secondary identifying numbers: The Netherlands National Trial Register - NL7094 , NL61961.078.17, MEC-2018-004.

A novel amplitude binning strategy to handle irregular breathing during 4DMRI acquisition: improved imaging for radiotherapy purposes.

BACKGROUND: For radiotherapy of abdominal cancer, four-dimensional magnetic resonance imaging (4DMRI) is desirable for tumor definition and the assessment of tumor and organ motion. However, irregular breathing gives rise to image artifacts. We developed a outlier rejection strategy resulting in a 4DMRI with reduced image artifacts in the presence of irregular breathing. METHODS: We obtained 2D T2-weighted single-shot turbo spin echo images, with an interleaved 1D navigator acquisition to obtain the respiratory signal during free breathing imaging in 2 patients and 12 healthy volunteers. Prior to binning, upper and lower inclusion thresholds were chosen such that 95% of the acquired images were included, while minimizing the distance between the thresholds (inclusion range (IR)). We compared our strategy (Min95) with three commonly applied strategies: phase binning with all images included (Phase), amplitude binning with all images included (MaxIE), and amplitude binning with the thresholds set as the mean end-inhale and mean end-exhale diaphragm positions (MeanIE). We compared 4DMRI quality based on: Data included (DI); percentage of images remaining after outlier rejection. Reconstruction completeness (RC); percentage of bin-slice combinations containing at least one image after binning. Intra-bin variation (IBV); interquartile range of the diaphragm position within the bin-slice combination, averaged over three central slices and ten respiratory bins. IR. Image smoothness (S); quantified by fitting a parabola to the diaphragm profile in a sagittal plane of the reconstructed 4DMRI. A two-sided Wilcoxon's signed-rank test was used to test for significance in differences between the Min95 strategy and the Phase, MaxIE, and MeanIE strategies. RESULTS: Based on the fourteen subjects, the Min95 binning strategy outperformed the other strategies with a mean RC of 95.5%, mean IBV of 1.6 mm, mean IR of 15.1 mm and a mean S of 0.90. The Phase strategy showed a poor mean IBV of 6.2 mm and the MaxIE strategy showed a poor mean RC of 85.6%, resulting in image artifacts (mean S of 0.76). The MeanIE strategy demonstrated a mean DI of 85.6%. CONCLUSIONS: Our Min95 reconstruction strategy resulted in a 4DMRI with less artifacts and more precise diaphragm position reconstruction compared to the other strategies. TRIAL REGISTRATION: Volunteers: protocol W15_373#16.007; patients: protocol NL47713.018.14.

Meta-analysis comparing upfront surgery with neoadjuvant treatment in patients with resectable or borderline resectable pancreatic cancer.

BACKGROUND: Studies comparing upfront surgery with neoadjuvant treatment in pancreatic cancer may report only patients who underwent resection and so survival will be skewed. The aim of this study was to report survival by intention to treat in a comparison of upfront surgery versus neoadjuvant treatment in resectable or borderline resectable pancreatic cancer. METHODS: MEDLINE, Embase and the Cochrane Library were searched for studies reporting median overall survival by intention to treat in patients with resectable or borderline resectable pancreatic cancer treated with or without neoadjuvant treatment. Secondary outcomes included overall and R0 resection rate, pathological lymph node rate, reasons for unresectability and toxicity of neoadjuvant treatment. RESULTS: In total, 38 studies were included with 3484 patients, of whom 1738 (49·9 per cent) had neoadjuvant treatment. The weighted median overall survival by intention to treat was 18·8 months for neoadjuvant treatment and 14·8 months for upfront surgery; the difference was larger among patients whose tumours were resected (26·1 versus 15·0 months respectively). The overall resection rate was lower with neoadjuvant treatment than with upfront surgery (66·0 versus 81·3 per cent; P < 0·001), but the R0 rate was higher (86·8 (95 per cent c.i. 84·6 to 88·7) versus 66·9 (64·2 to 69·6) per cent; P < 0·001). Reported by intention to treat, the R0 rates were 58·0 and 54·9 per cent respectively (P = 0·088). The pathological lymph node rate was 43·8 per cent after neoadjuvant therapy and 64·8 per cent in the upfront surgery group (P < 0·001). Toxicity of at least grade III was reported in up to 64 per cent of the patients. CONCLUSION: Neoadjuvant treatment appears to improve overall survival by intention to treat, despite lower overall resection rates for resectable or borderline resectable pancreatic cancer. PROSPERO registration number: CRD42016049374.

Modern work-up and extended resection in perihilar cholangiocarcinoma: the AMC experience.

AIM: Perihilar cholangiocarcinoma (PHC) is a challenging disease and requires aggressive surgical treatment in order to achieve curation. The assessment and work-up of patients with presumed PHC is multidisciplinary, complex and requires extensive experience. The aim of this paper is to review current aspects of diagnosis, preoperative work-up and extended resection in patients with PHC from the perspective of our own institutional experience with this complex tumor. METHODS: We provided a review of applied modalities in the diagnosis and work-up of PHC according to current literature. All patients with presumed PHC in our center between 2000 and 2016 were identified and described. The types of resection, surgical techniques and outcomes were analyzed. RESULTS AND CONCLUSION: Upcoming diagnostic modalities such as Spyglass and combinations of serum biomarkers and molecular markers have potential to decrease the rate of misdiagnosis of benign, inflammatory disease. Assessment of liver function with hepatobiliary scintigraphy provides better information on the future remnant liver (FRL) than volume alone. The selective use of staging laparoscopy is advisable to avoid futile laparotomies. In patients requiring extended resection, selective preoperative biliary drainage is mandatory in cholangitis and when FRL is small (< 50%). Preoperative portal vein embolization (PVE) is used when FRL volume is less than 40% and optionally includes the left portal vein branches to segment 4. Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) as alternative to PVE is not recommended in PHC. N2 positive lymph nodes preclude long-term survival. The benefit of unconditional en bloc resection of the portal vein bifurcation is uncertain. Along these lines, an aggressive surgical approach encompassing extended liver resection including segment 1, regional lymphadenectomy and conditional portal venous resection translates into favorable long-term survival.

Nationwide comprehensive gastro-intestinal cancer cohorts: the 3P initiative.

BACKGROUND: The increasing sub-classification of cancer patients due to more detailed molecular classification of tumors, and limitations of current trial designs, require innovative research designs. We present the design, governance and current standing of three comprehensive nationwide cohorts including pancreatic, esophageal/gastric, and colorectal cancer patients (NCT02070146). Multidisciplinary collection of clinical data, tumor tissue, blood samples, and patient-reported outcome (PRO) measures with a nationwide coverage, provides the infrastructure for future and novel trial designs and facilitates research to improve outcomes of gastrointestinal cancer patients. MATERIAL AND METHODS: All patients aged ≥18 years with pancreatic, esophageal/gastric or colorectal cancer are eligible. Patients provide informed consent for: (1) reuse of clinical data; (2) biobanking of primary tumor tissue; (3) collection of blood samples; (4) to be informed about relevant newly identified genomic aberrations; (5) collection of longitudinal PROs; and (6) to receive information on new interventional studies and possible participation in cohort multiple randomized controlled trials (cmRCT) in the future. RESULTS: In 2015, clinical data of 21,758 newly diagnosed patients were collected in the Netherlands Cancer Registry. Additional clinical data on the surgical procedures were registered in surgical audits for 13,845 patients. Within the first two years, tumor tissue and blood samples were obtained from 1507 patients; during this period, 1180 patients were included in the PRO registry. Response rate for PROs was 90%. The consent rate to receive information on new interventional studies and possible participation in cmRCTs in the future was >85%. The number of hospitals participating in the cohorts is steadily increasing. CONCLUSION: A comprehensive nationwide multidisciplinary gastrointestinal cancer cohort is feasible and surpasses the limitations of classical study designs. With this initiative, novel and innovative studies can be performed in an efficient, safe, and comprehensive setting.

The BIG 2.04 MRC/EORTC SUPREMO Trial: pathology quality assurance of a large phase 3 randomised international clinical trial of postmastectomy radiotherapy in intermediate-risk breast cancer.

INTRODUCTION: SUPREMO is a phase 3 randomised trial evaluating radiotherapy post-mastectomy for intermediate-risk breast cancer. 1688 patients were enrolled from 16 countries between 2006 and 2013. We report the results of central pathology review carried out for quality assurance. PATIENTS AND METHODS: A single recut haematoxylin and eosin (H&E) tumour section was assessed by one of two reviewing pathologists, blinded to the originally reported pathology and patient data. Tumour type, grade and lymphovascular invasion were reviewed to assess if they met the inclusion criteria. Slides from potentially ineligible patients on central review were scanned and reviewed online together by the two pathologists and a consensus reached. A subset of 25 of these cases was double-reported independently by the pathologists prior to the online assessment. RESULTS: The major contributors to the trial were the UK (75%) and the Netherlands (10%). There is a striking difference in lymphovascular invasion (LVi) rates (41.6 vs. 15.1% (UK); p = <0.0001) and proportions of grade 3 carcinomas (54.0 vs. 42.0% (UK); p = <0.0001) on comparing local reporting with central review. There was no difference in the locally reported frequency of LVi rates in node-positive (N+) and node-negative (N-) subgroups (40.3 vs. 38.0%; p = 0.40) but a significant difference in the reviewed frequency (16.9 vs. 9.9%; p = 0.004). Of the N- cases, 104 (25.1%) would have been ineligible by initial central review by virtue of grade and/or lymphovascular invasion status. Following online consensus review, this fell to 70 cases (16.3% of N- cases, 4.1% of all cases). CONCLUSIONS: These data have important implications for the design, powering and interpretation of outcomes from this and future clinical trials. If critical pathology criteria are determinants for trial entry, serious consideration should be given to up-front central pathology review.

Guidelines for time-to-event end point definitions in breast cancer trials: results of the DATECAN initiative (Definition for the Assessment of Time-to-event Endpoints in CANcer trials)†.

BACKGROUND: Using surrogate end points for overall survival, such as disease-free survival, is increasingly common in randomized controlled trials. However, the definitions of several of these time-to-event (TTE) end points are imprecisely which limits interpretation and cross-trial comparisons. The estimation of treatment effects may be directly affected by the definitions of end points. The DATECAN initiative (Definition for the Assessment of Time-to-event Endpoints in CANcer trials) aims to provide recommendations for definitions of TTE end points. We report guidelines for randomized cancer clinical trials (RCTs) in breast cancer. PATIENTS AND METHODS: A literature review was carried out to identify TTE end points (primary or secondary) reported in publications of randomized trials or guidelines. An international multidisciplinary panel of experts proposed recommendations for the definitions of these end points based on a validated consensus method that formalize the degree of agreement among experts. RESULTS: Recommended guidelines for the definitions of TTE end points commonly used in RCTs for breast cancer are provided for non-metastatic and metastatic settings. CONCLUSION: The use of standardized definitions should facilitate comparisons of trial results and improve the quality of trial design and reporting. These guidelines could be of particular interest to those involved in the design, conducting, reporting, or assessment of RCT.