Neoplasms

Digestive System Diseases

All Conditions

Symptoms and General Pathology

Rare Diseases

Esophageal Neoplasms

Carcinoma

Adenocarcinoma

Carcinoma, Squamous Cell

Esophageal Squamous Cell Carcinoma

Pathologic Complete Response

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Neoplasms, Squamous Cell

Gastrointestinal Neoplasms

Digestive System Neoplasms

Head and Neck Neoplasms

Gastrointestinal Diseases

Esophageal Diseases

Esophageal Cancer

Antineoplastic Agents

All Drugs and Chemicals

Paclitaxel

Albumin-Bound Paclitaxel

Carboplatin

Fluorodeoxyglucose F18

Radiopharmaceuticals

Patients (\>18 years) with potentially resectable locally advanced squamous cell- or adenocarcinoma of the esophagus or gastroesophageal junction, receiving nCRT according to the CROSS regimen prior to surgery.

CROSS regimen: weekly carboplatin (doses titrated to achieve an area under the curve of 2 mg per milliliter per minute) and paclitaxel (50 mg per square meter of body-surface area) for 5 weeks and concurrent radiotherapy (41.4 Gy in 23 fractions, delivered 5 days per week on workdays with intensity modulated radiotherapy, including photon and proton therapy)

* Anatomical (T2W) and functional MRI (DWI and DCE) at a 1.5T Siemens or Philips scanner
* DWI series: sagittal (sIVIM) and high-resolution transversal (HR tDWI)
* DCE serie: dynamic20
* In total, three MRI scan series (before, during, after nCRT)
* Measurements: i.a. change in apparent diffusion coefficient (ADC) or area-under-the-gadolinium-concentration time curve (AUC) within tumor delineation over time, radiological (qualitative) assessment of residual disease

* According to European Association of Nuclear Medicine (EANM) Research Ltd guidelines (EARL)
* In total one additional PET-CT (during nCRT) for study purposes. A PET-CT scan at diagnosis and after nCRT are included in the standard diagnostic work-up for esophageal cancer.
* Measurements: i.a. change in TLG (Total Lesion Glycolysis), SUVmax (Standardized Uptake Value) or Ktrans within tumor delineation over time

PET-CT

Additional endoscopy and/or endoscopic ultrasonography (EUS) with biopsies of the primary tumor site and other suspected lesions in the esophagus after completion of nCRT and prior to surgery

Endoscopy

* Blood samples at three different time points (before, during and after nCRT) will be collected
* Blood will be collected in cell-free DNA collection tubes
* Purpose: isolation of ctDNA and subsequent mutation analysis by means of Next Generation Sequencing
* Measurements: the presence of, and changes in, ctDNA during nCRT

Blood samples

Gert J Meijer, PhD

Ingmar L Defize, MD

Hanneke WM van Laarhoven, MD, PhD

Marcel Verheij, MD, PhD

J. (Hans) A. Langendijk, MD, PhD

Gert Meijer, PhD

Rationale: For locally advanced esophageal cancer the standard treatment consists of 5 weeks of neoadjuvant chemoradiotherapy (nCRT) followed by surgery. Surgery is currently performed independent of the response to nCRT and is associated with substantial morbidity. Prior knowledge of the eventual response to nCRT would greatly impact on the optimal care for many esophageal cancer patients for two imperative reasons:

Firstly, it is argued that patients who achieved a pathologic complete response (pCR, 29%) may not have benefitted from surgery. Consequently, proper identification of pathological complete responders prior to surgery could yield an organ-preserving regimen avoiding unnecessary toxicity.

Secondly, non-responders are exposed to the side effects of nCRT without showing any tumor regression. Early identification of the non-responders during nCRT would be beneficial for this group as ineffective therapy could be stopped, and for who altered treatment strategies could be explored.

Objective: To develop a multimodal model that predicts the probability of pathologic complete response to nCRT in esophageal cancer, by integrating diffusion weighted magnetic resonance imaging (DW-MRI) and dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) in conjunction with combined 18F-fluorodeoxyglucose positron emission tomography and computed tomography (18F-FDG PET-CT) scans acquired prior to, during and after administration of nCRT.

Study design: Multi-center observational study

Study population: Patients (\>18 years) with potentially resectable locally advanced squamous cell- or adenocarcinoma of the esophagus or gastroesophageal junction, receiving nCRT prior to surgery.

Intervention: In addition to the standard diagnostic work-up for esophageal cancer that includes a 18F-FDG PET-CT scan at diagnosis and after nCRT, one 18F-FDG PET-CT scans will be performed during nCRT, as well as three MRI scans (before, during and after nCRT) within fixed time intervals. Furthermore, after response imaging after nCRT has been performed, but prior to surgery, patients will undergo (on an opt-out basis) an endoscopy and/or endoscopic ultrasonography (EUS) with biopsies of the primary tumor site, other suspected lesions and suspected lymph nodes. Furthermore, blood samples will be collected at three time points.

Main study parameters/endpoints: An accurate multimodal prediction model for the patients' individual probability of pathologic complete response after nCRT, based on the quantitative parameters derived from a longitudinal series of DW-MRI, DCE-MRI and 18F-FDG PET-CT datasets.

Preoperative Image-guided Identification of Response to Neoadjuvant Chemoradiotherapy in Esophageal Cancer

Histopathologic response of the primary tumor to nCRT according to the tumor regression grade (TRG) scale as determined by expert pathologist.

TRG 1: no residual viable tumor cells, pathologic complete response TRG 2: rare residual cancer cells TRG 3: predominant fibrosis with increased number of residual cancer cells TRG 4: residual cancer outgrowing fibrosis or no regressive change

Pathological T- and N-stage as determined by expert pathologist (based on the American Joint Committee on Cancer \[AJCC\] Tumor Node Metastasis \[TNM\] staging system)

Disease-free survival based on local follow-up policies (time to locoregional or distal recurrence of esophageal cancer).

Overall survival based on local follow-up policies.

University Medical Center Groningen

The Netherlands Cancer Institute

Koningin Wilhelmina Fonds

Amsterdam UMC, location VUmc

UMC Utrecht

PhD, Clinical Physicist at the Department of Radiation Oncology

Skin and Connective Tissue Diseases

Breast Neoplasms

Breast Diseases

Skin Diseases

Antirheumatic Agents

Anti-Infective Agents

Cyclophosphamide

Doxorubicin

Liposomal doxorubicin

Docetaxel

Immunosuppressive Agents

Immunologic Factors

Antineoplastic Agents, Alkylating

Alkylating Agents

Tubulin Modulators

Antimitotic Agents

Anti-Bacterial Agents

Antibiotics, Antitubercular

Enzyme Inhibitors

Genomically-guided treatment allocation.

This arm has the following cohorts:

* AC sensitive patients \[\>60% probability of response to AC\]
* TC sensitive patients \[\>60% probability of response to TC\]
* Patients sensitive to neither AC nor TC; randomized to AC or TC

Non-genomically-guided treatment allocation.

This arm has the following cohorts:

* In patients randomly assigned to AC:

  * Patients sensitive to AC
  * Patients sensitive to TC
  * Patients sensitive to neither AC nor TC
* In patients randomly assigned to TC:

  * Patients sensitive to AC
  * Patients sensitive to TC
  * Patients sensitive to neither AC nor TC

Doxorubicin 60 mg/m² and Cyclophosphamide 600 mg/m² (AC) or Docetaxel 75 mg/m² and Cyclophosphamide 600 mg/m² (TC) every 3 weeks for 4 cycles as neoadjuvant therapy

Doxorubicin/Cyclophosphamide (AC) or Docetaxel/Cyclophosphamide (TC)

Paul K Marcom, MD

This multi-center randomized Phase II study assigned HER2-negative early-stage breast cancer patients to receive preoperative systemic chemotherapy in either a "genomic-guided" arm or a "non-guided arm." The "genomic-guided" method (Arm 1) used genomic expression profiling to assign the preoperative therapy (Doxorubicin/Cyclophosphamide (AC) versus Docetaxel/Cyclophosphamide (TC), while Arm 2 used random assignment to these two therapies.

Primary Objective 1 was to test for an arm difference in pathological complete response rates. Secondary Objective 2 was to estimate and test the difference in pathologic complete response rates between drug-sensitive patients who received their preferred drug and drug-resistant patients randomized to AC or TC.

Secondary objectives included: to determine the 60% cutoff for the genomic profiles resulted in a larger pathologic CR rate for the guided arm than for the unguided arm; to compare the pathologic CR rates of patients whose genomic predictive probabilities indicated that they were resistant to both chemotherapy regimens with the pathologic CR rates of patients whose genomic predictive probabilities indicated that they were sensitive to only one treatment and who were then randomly assigned to a treatment for which they were resistant (combining AC and TC subgroups); Secondary Objective 3 in patients with T2 and T3 tumors classified as requiring mastectomy at baseline, compare the guided and non-guided treatment arms on rates of breast conserving surgery with negative final margins; Secondary Objective in patients with T2 tumors classified as potential candidates for breast conservation, compare the guided and non-guided arms on rates of breast conserving surgery at first attempt; Secondary Objectives 5, 6, 7 and 8 to correlate genomic profiles (i.e., genomic predictive probabilities) with clinical response, disease-free survival, sites of recurrence, and overall survival; Secondary Objective 9:to compare the mean cost of guided versus non-guided treatment; and Secondary Objective 10 to assess patient perceptions of participating in a clinical trial that evaluated cancer genomics for preoperative systemic therapy of early-stage breast cancer.

Objective 10 details: Due to space limitations in the Outcome Measure Description field, details are supplied here:

To assess patient motivation and participation for study participation in a clinical trial evaluating cancer genomics for treatment patients provided responses for the following questions at both baseline (the day of chemotherapy start) and following post-surgical medical oncology evaluation:

One of the goals of this study is to tailor your cancer treatments for you based upon a genomic analysis of your tumor. How much did the knowledge that the treatment is potentially tailored specifically for your tumor influence your decision to participate in this study? (Select One)

Response 1: I did not know that the treatment was tailored.

Response 2: I do not understand what "tailored treatment based upon genomic analysis of "my tumor" means.

Response 3: The information that this was a tailored treatment based upon genomic analysis of my tumor decreased my willingness to participate in this study.

Response 4: The information that this was a tailored treatment based upon genomic analysis of my tumor was of neutral value in the decision making process to participate in this study and did not influence my decision to participate.

Response 5: The information that this was a tailored treatment based upon genomic analysis of my tumor played a minor role in helping me decide to participate in the study.

Response 6: The information that this was a tailored treatment based upon genomic analysis of my tumor played a major role in helping me decide to participate in the study.

Response 7: The information that this was a tailored treatment based upon genomic analysis of my tumor was the primary reason that I decided to participate in the study.

Trial to Evaluate Genomic Expression Profiles to Direct Preoperative Chemotherapy in Early Stage Breast Cancer

A Randomized Phase II Trial Evaluating the Performance of Genomic Expression Profiles to Direct the Use of Preoperative Chemotherapy for Early Stage Breast Cancer

Pathological complete response (pCR) was defined as the disappearance of all invasive disease in the breast or if only residual in situ or lymph node disease is found. The pCR rate is presented with its 95% confidence interval for the Guided and Non-guided arms.

To determine in early stage breast cancer treated with PST whether genomic profiling can identify drug-sensitive and drug-resistant patients including a comparison of subgroups for the two individual regimens (i.e. AC and TC). To determine if the 60% cutoff for the genomic profiles is optimal in predicting the response to chemotherapy regimens.To describe the performance of the genomic profiles in assessing the relative responsiveness of: 1) Patients predicted to be resistant to both chemotherapy regimens; and 2) Patients randomly assigned to one treatment whose genomic profiles suggest receiving the other regimen (in both AC and TC subgroups).

The percentage of patients who had breast-conserving surgery with negative margins, measured in patients with T2 and T3 tumors classified as requiring mastectomy at baseline.

The percentage of patients who had breast-conserving surgery at first attempt, measured only in patients with T2 tumors classified as potential candidates for breast conservation.

WHO criteria are based on the sum of the products of the longest axis and the longest perpendicular axis. Bi-dimensional measurements were taken of all breast lesions and axillary nodes using the best imaging modality performed after completion of assigned therapy.

Clinical Complete Response (cCR): Disappearance of all target lesions by physical exam and best imaging modality.

Clinical Partial Response (cPR): At least a 30% decrease in the sum of the longest diameter (LD) of target lesions taking as reference the baseline sum LD.

Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD taking as references the sum LD at treatment initiation. Patients having a documented response with no reconfirmation of the response will be listed with stable disease.

Progression (PD): At least a 20% increase in the sum of the LD of target lesions or the appearance of one or more new lesion.

Disease-free survival is defined as the length of time from enrollment to local or distant disease recurrence, whichever comes first; disease-free deaths are censored. The 2-year disease-free survival rate is estimated with its 95% confidence interval.

Sites of Recurrence is a categorical outcome whose possible values are the organ-specific sites at which disease recurrence was observed. A patient may recur at more than one site.

Overall survival is defined as the time from enrollment to death due to any cause. The 2-year overall survival rate is estimated with the Kaplan-Meier method.

Economic Impact (i.e., cost of care) will be calculated by first assessing the quantity of clinical resources used by each patient in the study arm, and then assigning a cost to each resource using cost information derived from a costing study to be undertaken outside of this protocol.

A short questionnaire was administered at baseline (the day chemotherapy was started) and following post-surgical medical oncology evaluation to assess the patient's understanding of the study being conducted, and the patient's expectations of the treatment. Due to space limitations, the full survey is presented in the Detailed Description.

United States Department of Defense

Duke University

Genomically-guided \>60% probability of response to AC

AC: Doxorubicin 60 mg/m² and Cyclophosphamide 600 mg/m² (AC) every 3 weeks for 4 cycles as neoadjuvant therapy

Guided AC Sensitive

Genomically-guided treatment \>60% probability of response to TC

TC: Docetaxel 75 mg/m² and Cyclophosphamide 600 mg/m² (TC) every 3 weeks for 4 cycles as neoadjuvant therapy

Guided TC Sensitive

Genomics guided treatment \<60% probability of response to both AC and TC; randomized to AC

AC: Doxorubicin 60 mg/m² and Cyclophosphamide 600 mg/m² (AC) every 3 weeks for 4 cycles as neoadjuvant therapy

Guided AC Non-sensitive

Genomics guided treatment \<60% probability of response to both AC and TC; randomized to TC

TC: Docetaxel 75 mg/m² and Cyclophosphamide 600 mg/m² (TC) every 3 weeks for 4 cycles as neoadjuvant therapy

Guided TC Non-Sensitive

Non-genomics guided treatment; randomized to AC

AC: Doxorubicin 60 mg/m² and Cyclophosphamide 600 mg/m² (AC) every 3 weeks for 4 cycles as neoadjuvant therapy

Non-guided AC

Non-genomics guided treatment; randomized to TC

TC: Docetaxel 75 mg/m² and Cyclophosphamide 600 mg/m² (TC) every 3 weeks for 4 cycles as neoadjuvant therapy

Non-guided TC

Screen failures constitute patients who were registered to the study but were not assigned treatment for various reasons.

Screen Failures

Screen Failure

Total

Age, Continuous

Sex: Female, Male

United States

Region of Enrollment

All patients who signed a consent form are included in the baseline analysis.

P. Kelly Marcom, M.D.

Guided Arm

Non-genomically-guided treatment allocation.

Non-Guided Arm

All eligible treated patients. The three patients not included are two who had allergic reactions to the assigned treatment, and one with metastatic disease on biopsy of a spine lesion at the end of assigned treatment so never went to surgery.

Pathologic Complete Response (pCR) Rate in Patients With HER2-negative Early-stage Breast Cancer

This outcome is not summarized due to irreproducibility of the genomics-based prediction model and resulting probability estimates

Probabilities of Being Sensitive to AC and TC as Determined by the Patient's Genomic Signatures

Since final margin status was not collected, this analysis could not be done.

Percentage of Patients Who Had Breast-conserving Surgery With Negative Margins

Data from all eligible patients with non-missing values on this outcome were used.

To Percentage of Patients Who Had Breast-conserving Surgery at First Attempt.

Complete Response (cCR)

Partial Response (cPR)

Stable Disease

Progressive Disease

Not Evaluable/Not Assessed

All eligible treated patients were used in this analysis.

Clinical Response Using WHO Criteria

Disease-free Survival

Bone

Brain

Chest Wall

Liver

Lung

All eligible treated patients. Four of these 38 participants experienced recurrence of their breast cancer; two of the four patients had multiple sites of recurrence.

Sites of Recurrence

All eligible treated patients with known follow-up status.

Overall Survival

Since these data were not collected, this analysis could not be done.

Economic Impact of Using Genomic Assessment to Guide Management.

The overall enrollment was insufficient to provide for any substantive analysis.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Preoperative Image-guided Identification of Response to Neoadjuvant Chemoradiotherapy in Esophageal Cancer	NCT03474341	Esophageal Canc... Esophageal Aden... Esophageal Squa... Esophageal Neop...	MRI PET-CT Endoscopy Blood samples	18 Years -	UMC Utrecht
Preoperative Image-guided Identification of Response to Neoadjuvant Chemoradiotherapy in Esophageal Cancer	NCT03474341	Esophageal Canc... Esophageal Aden... Esophageal Squa... Esophageal Neop...	MRI PET-CT Endoscopy Blood samples	18 Years -	UMC Utrecht
Trial to Evaluate Genomic Expression Profiles to Direct Preoperative Chemotherapy in Early Stage Breast Cancer	NCT00636441	Early-Stage Bre...	Doxorubicin/Cyc...	18 Years -	Duke University

Spots Global Cancer Trial Database for pathologic complete response (pcr)