Neoplasms

Digestive System Diseases

All Conditions

Rare Diseases

Esophageal Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Head and Neck Neoplasms

Gastrointestinal Diseases

Esophageal Diseases

Esophageal Cancer

Antineoplastic Agents

All Drugs and Chemicals

Fluorouracil

Cetuximab

Cisplatin

Antimetabolites

Immunosuppressive Agents

Immunologic Factors

Antineoplastic Agents, Immunological

Cetuximab: Initial doses 400mg/m2 (day 1), followed by weekly doses of 250mg/m2 for 14 weeks in total, IV

5-fluorouracil (5-FU): 1000mg/m2 per day as continuous infusion on day 8-11 and 36-39, 750mg/m2/day as continuous infusion on day 71-74 and 99-102

Cisplatin 20mg/m2/day as intravenous bolus over 60 min on day 1-4 of every cycle (day 8-11, 36-39, 71-74 and 99-102)

radiotherapy: 59.4 Gy (33 fractions of 1.8 Gy) over 6.5-7 weeks (5 x 1.8 Gy per week)on primary tumor. 50.4 Gy on locoregional lymphnodes. If resectability is reached after 4-4.5 weeks (36-41.4 Gy) the radiotherapy stops after 45 Gy and the patient undergoes surgery.

5-FU: 1000mg/m2 per day as continuous infusion on day 1-4 and 29-32, 750mg/m2/day as continuous infusion on day 64-67 and 92-95

Cisplatin 20mg/m2/day as intravenous bolus over 60 min on day 1-4 of every cycle (day 1-4, 29-32, 64-67 and 92-95)

radiotherapy: 59.4 Gy (33 fractions of 1.8 Gy) over 6.5-7 weeks (5 x 1.8 Gy per week)on primary tumor. 50.4 Gy on locoregional lymphnodes. If resectability is reached after 4-4.5 weeks (36-41.4 Gy) the radiotherapy stops after 45 Gy and the patient undergoes surgery.

Initial doses 400mg/m2 (day 1), followed by weekly doses of 250mg/m2 for 14 weeks in total

5-FU: 1000mg/m2 per day as continuous infusion on day 1-4 of cycle 1 and 2, 750mg/m2/day as continuous infusion on day 1-4 of cycle 3 and 4

Cisplatin 20mg/m2/day as intravenous bolus over 60 min on day 1-4 of every cycle

Cisplatin, 5-FU

59.4 Gy (33 fractions of 1.8 Gy) over 6.5-7 weeks (5 x 1.8 Gy per week)on primary tumor. 50.4 Gy on locoregional lymphnodes. If resectability is reached after 4-4.5 weeks (36-41.4 Gy) the radiotherapy stops after 45 Gy and the patient undergoes surgery.

Radiotherapy

Dirk Rades, Prof. Dr.

Esophageal cancer is a highly aggressive tumor. Treatment options are various and range from chemotherapy to radiotherapy and several surgical techniques. Nevertheless, the overall survival rates for this disease remain poor.

During the last years the combination of cetuximab with standard chemotherapy or radiotherapy has mainly be investigated in clinical trials focusing on colorectal and/or head and neck cancer.

The results obtained from theses studies were very encouraging and led to the initiation of active clinical research in esophageal cancer patients with antibody inhibition of the epidermal growth factor receptor (EGFR).

The first data in this indication are encouraging showing that cetuximab can safely be added to chemoradiation for esophageal cancer patients with first hints of efficacy.

Based on the experiences with cetuximab in colorectal cancer and in combination with radiotherapy in head and neck cancer, the aim of the present study is to evaluate the feasibility of a combined treatment of cetuximab with continuous infusional 5-FU, cisplatin and radiotherapy in patients with esophageal cancer and to assess if the overall survival rates can be increased by addition of an EGFR-targeted therapy.

Esophageal cancer is a highly aggressive neoplasm which is fatal in the great majority of patients. On a global basis, cancer of the esophagus is the sixth leading cause of cancer death worldwide. In fact, gastric and esophageal cancers together accounted for nearly 1.3 million new cases and 980,000 deaths worldwide in 2000 - more than lung, breast, or colorectal cancer. With advances in surgical techniques and treatment, the prognosis of esophageal cancer has slowly improved over the past decades. However, with a 5-year overall survival rate of approximately 14%, at the time of development of the LEOPARD-II protocol, survival was poor, even in comparison with the dismal survival rates (4%) from the 1970s. Underlying reasons for this disappointingly low survival rate are above all the difficulties in cancer detection at an advanced stage, with over 50% of patients with unresectable disease or distant metastasis at presentation and the limited survival achieved with palliative chemotherapy alone for patients with metastatic or unresectable disease.

Clearly, additional strategies are needed to improve the systemic treatment options for esophageal cancer.

The optimal treatment of locally advanced esophageal cancer, a potentially curable disease, is controversial. Through several non-randomized cooperative group trials, concurrent cisplatin-based chemoradiation or surgery alone represent acceptable standards of care for patients with resectable tumors.

Metastatic or unresectable esophageal cancer is found at presentation in more than 50% of patients and is considered incurable. At the time of protocol development, chemotherapy was palliative, improving quality of life and dysphagia in 60%-80% of patients. Typical clinical and radiographic responses lasted for fewer than 4 months, with a median overall survival time of 8-10 months.

Combination chemotherapies have been demonstrated to be superior to best supportive care and chemotherapy given as a single agent, with occasional patients achieving complete responses (0%-11%). However, even with the combination regimens, the median survival time remained less than 10 months.

An improved understanding of the molecular pathogenesis of cancer has facilitated the development of novel agents designed to target critical pathways involved in cancer development and progression. Epidermal growth factor receptor (EGFR) plays a crucial role in tumour growth. EGFR-dependent signaling is involved in cell proliferation, apoptosis, angiogenesis, and metastatic spread.

The overexpression of EGFR has repeatedly been shown to predict poor prognosis in both esophageal squamous cell carcinoma and gastro esophageal junction adenocarcinoma. EGFR blockade through monoclonal antibodies (Cetuximab, Matuzumab and Panitumumab) and tyrosine kinase inhibitors (gefitinib, erlotinib) has translated into promising evidence of clinical benefit in clinical trials.

Cetuximab is a targeted therapeutic agent, a chimeric monoclonal antibody that specifically binds to the EGFR with high affinity, internalising the receptor and preventing ligands from interacting with the receptors and thus effectively blocking ligand-induced EGFR phosphorylation. In addition, cetuximab had been found to potentiate the effects of chemotherapy and radiotherapy in experimental systems. The dose of cetuximab (initial dose 400 mg/m2 and subsequent weekly doses of 250 mg/m2) has been found to be generally safe and effective in several studies in major tumor types expressing the EGFR. These included colorectal cancer and squamous cell carcinoma of the head and neck, with cetuximab given either in combination studies with chemotherapy and radiotherapy or as monotherapy.

In two phase I studies prior to LEOPARD-II, EGFR-directed antibodies had shown activity in patients with esophageal cancer. In the phase I study of the humanized EGFR monoclonal antibody (mAb) EMD72000, one patient with metastatic, pretreated squamous cell carcinoma had had a durable, 6-month partial response.

In addition, a phase I trial with a fully human EGFR mAb, had reported stable disease for 7 months in one esophageal cancer patient. Preclinical and these early clinical studies suggested potential activity and minimal toxicities with EGFR antibodies for esophageal cancer.

Furthermore, a randomised phase II compared cisplatin + 5-FU (CF) to cisplatin + 5-FU + cetuximab (CET-CF) (n=62). Cetuximab did not increase grade 3/4 toxicity, except for rash (6% versus 0%) and diarrhea (16% versus 0%). The overall response rates were 19% and 13% for the CET-CF and CF arms respectively, and the disease control rates were 75% and 57%, respectively. The median progression free survival was 5.9 and 3.6 months and median overall survival 9.5 and 5.5 months for CET-CF and CF, respectively.

With respect to the combination of Cetuximab with radiotherapy, preclinical studies have shown, that Cetuximab enhanced the radiosensitivity of EGFR expressing tumour cells in vitro and in tumour xenografts and the repopulation of epithelial tumour cells after exposure to radiation was related to the activation and expression of EGFR. Cetuximab also enhanced the efficacy of docetaxel chemoradiotherapy in human adenocarcinoma xenografts.

Rationale for the LEOPARD-II study Esophageal cancer is a highly aggressive tumor and one of the most frequent malignant diseases worldwide.

Treatment options are various and range from chemotherapy to radiotherapy and several surgical techniques. Nevertheless, the overall survival rates for this disease remain poor. During the last years before protocol development the combination of cetuximab with standard chemotherapy or radiotherapy had mainly been investigated in clinical trials focusing on colorectal and/or head and neck cancer. The results obtained from these studies had been very encouraging and led to the initiation of active clinical research in esophageal cancer patients with antibody inhibition of the EGFR. The first data in this indication were encouraging showing that cetuximab could safely be added to chemoradiation for esophageal cancer patients with first hints of efficacy. Based on the experiences with cetuximab in colorectal cancer and in combination with radiotherapy in head and neck cancer, the aim of the LEOPARD-II study was to evaluate the feasibility of a combined treatment of cetuximab with continuous infusional 5-FU, cisplatin and radiotherapy in patients with esophageal cancer and to assess if the overall survival rates could be increased by addition of an EGFR-targeted therapy.

Definitive Radiochemotherapy Plus/Minus Cetuximab in Unresectable Locally Advanced Esophageal Cancer

Definitive Radiochemotherapy With 5-FU / Cisplatin Plus/Minus Cetuximab in Unresectable Locally Advanced Esophageal Cancer: a Phase II Study

Overall Survival (OS) was defined as freedom from death of any cause. Time to death was calculated from the day of randomization, and the patients were followed for a maximum of 24 months (2 years).

Overall Survival (OS) was defined as freedom from death of any cause. Time to death was calculated from the day of randomization.

For progression-free survival (PFS), the event was defined as first occurrence of radiologically proven progression or clinical progression or death due to progressive disease. Time to event was referenced from the day of randomization.

Toxicity was assessed according to the Common Terminology Criteria for Adverse Events (CTCAE) (version 4.03).

For metastases-free survival (MFS), the event was defined as first occurrence of distant metastasis. Time to event was referenced from the day of randomization.

Response was defined according to the RECIST criteria (Version 1.1) based on the assessments (computed tomography, magnetic resonance imaging or other) for target lesions, non-target lesions as well as considering the occurrence of new lesions.

The best overall response (RECIST) was chosen for each patient out of all valid tumour assessments before start of next-line therapy (complete response=CR being the best and progressive disease=PD the worst). Frequencies with percentages were to be given for each category (CR, partial response (PR), stable disease (SD), PD) by treatment group. The data were to be presented as the dichotomous endpoint of objective response, for which patients with best overall response of CR or PR were considered as responders, and those with best overall response of SD or PD as non-responders. The difference between objective response rates in the two treatment arms was to be compared with a Chi-square test.

Loco-regional failure was defined as progressive primary tumor and/or regional lymph nodes on endoscopy, endoscopic ultrasound or computed tomography.Time to event was referenced from the day of randomization.

Loco-regional failure was defined as progressive primary tumor and/or regional lymph nodes on endoscopy, endoscopic ultrasound or computed tomography. Time to event was referenced from the day of randomization.

Quality of Life was assessed with EORTC QLQ-C30 and QLQ-OES18 questionnaires. For QLQ-C30, global health status, functional scales (physical, role, emotional, cognitive and social functioning) and symptom scales (fatigue, nausea/vomiting, pain, dyspnea, loss of appetite, constipation, diarrhea, financial difficulties) were calculated. Scores ranged from 0 to 100; higher scores represented higher levels of quality of life, functioning, or symptoms/problems. Score were calculated using mean values.

For QLQ-OES18, symptom scales (problems with eating, reflux, pain, problems swallowing saliva, dry mouth, taste disorders, problems while coughing or speaking) and functional scale (dysphagia) were assessed the same way.

A change between two time points, i.e. baseline (prior to treatment) and end of treatment (after 5 to 13 weeks, depending on treatment arm (6.5 weeks without and 13 weeks with cetuximab) and achievement of resectability (end of treatment after 5 weeks), is reported.

University Hospital Schleswig-Holstein

Professor Dr. med.

Common Terminology Criteria for Adverse Events (CTCAE), version 4.03

Cetuximab: Initial doses 400mg/m2 (day 1), followed by weekly doses of 250mg/m2 for 14 weeks in total, IV

5-FU: 1000mg/m2 per day as continuous infusion on day 8-11 and 36-39, 750mg/m2/day as continuous infusion on day 71-74 and 99-102

Cisplatin 20mg/m2/day as intravenous bolus over 60 min on day 1-4 of every cycle (day 8-11, 36-39, 71-74 and 99-102)

radiotherapy: 59.4 Gy (33 fractions of 1.8 Gy) over 6.5-7 weeks (5 x 1.8 Gy per week)on primary tumor. 50.4 Gy on locoregional lymphnodes. If resectability is reached after 4-4.5 weeks (36-41.4 Gy) the radiotherapy stops after 45 Gy and the patient undergoes surgery.

Cetuximab, Cisplatin, 5-FU, Radiotherapy

Cisplatin, 5-FU, Radiotherapy

Total

median

Age, Continuous

Sex: Female, Male

Ethnic origin

Race/Ethnicity, Customized

Germany

Region of Enrollment

Histology

The histological grading was performed using the following scale:

GX Grade cannot be assessed G1 Well differentiated (Low grade) G2 Moderately differentiated (Intermediate grade) G3 Poorly differentiated (High grade)

Histologic grading

T describes the size depth of local invasion by the primary tumor. A higher T-category represents a more advanced primary tumor, generally associated with a worse prognosis. Patients were staged for T-category using computed tomography and endoscopic ultrasound.

clinical T-category

N describes the extent of the involvement of regional lymph nodes. A higher N-category represents a higher number of refional lymph nodes, generally associated with a worse prognosis. Patients were staged for N-category using computed tomography and endoscopic ultrasound.

clinical N-category

M describes thew presence or absence of distant metastasis. In the 6th edition of the TNM-classification, M1a indicated metastases to the cervical or celiac axis lymph nodes, and M1b metastases to distant sites. The TNM-classification from 2009 (7th edition) used only M0 (absence) and M1 (presence) for distant metastasis. M1 is generally associated with a worse prognosis. Patients were staged for M-category using computed tomography (thorax and abdomen).

clinical M-category

Tumor site

100 - Normal; no evidence of disease. 90 - Normal activity; minor signs/symptoms. 80 - Normal activity with effort; some signs/symptoms. 70 - Cares for self; unable for normal activity or active work. 60 - Requires occasional assistance, cares for most personal needs. 50 - Requires considerable assistance + frequent medical care. 40 - Disabled; requires special care and assistance. 30 - Severely disabled; hospital admission indicated. 20 - Very sick; hospital admission + supportive treatment necessary. 10 - Moribund; fatal processes progressing rapidly. 0 - Dead

Karnofsky Performance Score (KPS)

Prof. Dr. med. Dirk Rades

Rate of Participants Who Were Alive at 2 Years

Rate of Participants Who Were Alive at 1 Year

Rate of Participants Who Were Alive Without Progression of Disease at 1 Year

Rate of Participants Who Were Alive Without Progression of Disease at 2 Years

Number of Participants Experiencing at Least One Grade >=3 Toxicity

Rate of Participants Who Were Alive Without Distant Metastases at 1 Year

Rate of Participants Who Were Alive Without Distant Metastases at 2 Years

Number of Participants Who Achieved at Least Partial Response (Responders)

Rate of Participants Who Were Alive Without Loco-regional Failure at 1 Year

Rate of Participants Who Were Alive Without Loco-regional Failure at 2 Years

Change in global health status [H]

Change in physical functioning [H]

Change in role functioning [H]

Change in emotional functioning [H]

Change in cognitive functioning [H]

Change in social functioning [H]

Change regarding fatigue [L]

Change regarding nausea/vomiting [L]

Change regarding pain [L]

Change regarding dyspnoea [L]

Change regarding insomnia [L]

Change regarding loss of appetite [L]

Change regarding constipation [L]

Change regarding diarrhea [L]

Change regarding financial difficulties [L]

Change regarding problems with eating [L]

Change regarding reflux [L]

Change regarding pain while eating [L]

Change regarding problems swallowing saliva [L]

Change regarding dry mouth [L]

Change regarding taste disorders [L]

Change regarding problems while coughing [L]

Dysphagia [H]

All scales used for the rows below in the outcome measure data table ranged between 0 and 100.

For scales indicated \[H\], a higher score represents a better situation (quality of life, functioning).

For scales indicated \[L\], a lower value represents a better outcome (symptoms/problems).

Change in Quality of Life Between Baseline and End of Treatment (After 5 to 13 Weeks)

Overall Study

Symptoms and General Pathology

Neoplasm Metastasis

Colorectal Neoplasms

Intestinal Neoplasms

Colonic Diseases

Intestinal Diseases

Rectal Diseases

Neoplastic Processes

Capecitabine

Bevacizumab

Angiogenesis Inhibitors

Growth Inhibitors

Chemoradiation with different radiotherapy regimes (depending on location and size of irradiated lesions; e.g. conventional radiotherapy with a total dose of 35 Gy, delivered in 2.5Gy fractions for 14 days or intensity-modulated and image-guided radiotherapy with a total dose of 40 Gy, delivered in 4.0 Gy fractions for 10 days or 3-8 fractions with 8-15 Gy) combined with bevacizumab (7.5mg/kg day 1) and capecitabine (825mg/m2 bid on day 1-5, 8-12 and 15-19)

(conventional or intensity-modulated and image-guided radiotherapy)

Cordula Petersen, Prof.

This study tries to evaluate the role of chemoradiation with capecitabine and bevacizumab in oligometastatic patients neither being progressive nor resectable after chemotherapy.

Combining chemoradiation with an antiangiogenic agent has a strong biological rationale, and preclinical studies consistently show an increase in radiosensitization with combined treatment. It is well described that hypoxia or HIF-1 expression is associated with a lower radiation response and progression in solid tumors. Radiation itself induces transient tumor hypoxia, which in turn stimulates VEGF production and VEGFR-2 expression what may also serve as a paracrine proliferative stimulus that promotes out-of-field growth. The combination of radiotherapy with an antiangiogenic agent (e.g. bevacizumab) thus offers the potential to enhance the effect of radiation, and avoid further spread of disease. Furthermore, targeting tumor vasculature improves the delivery of cytotoxic drugs (e.g. capecitabine) leading to increased efficacy of chemoradiation. Combination with cytotoxic drugs could additionally limit treatment-induced hypoxia (Senan and Smit 2007; Mazeron, Anderson et al. 2011).

Chemoradiotherapy for Patients With Oligometastatic Colorectal Cancer

Capecitabine and Bevacizumab With Radiotherapy After 3-6 Months Chemotherapy for Patients With Oligometastatic Colorectal Cancer (OLGA Trial)

Progression free survival rate at 12 months after start of induction treatment (PFSR@12)

Time to progression (TTP) in 2 cohorts:

1. regards only progression within (TTPir) and
2. in- and outside irradiated areas ("overall" TTP)

Efficacy of the investigational therapy shown by the Overall Response Rate (CR and PR) according to RECIST v1.1

Quality of life using the EORTC QLQ-C30 and the module CR29

Prognostic and predictive value of PET scan at baseline and at 2 months after chemoradiation

Number of adverse events, according to NCI CTCAE v4.0)

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Definitive Radiochemotherapy Plus/Minus Cetuximab in Unresectable Locally Advanced Esophageal Cancer	NCT01787006	Esophageal Canc...	Cetuximab Cisplatin, 5-FU Radiotherapy	18 Years -	University Hospital Schleswig-Holstein
Chemoradiotherapy for Patients With Oligometastatic Colorectal Cancer	NCT01759238	Colorectal Canc... Metastases	Capecitabine Bevacizumab Radiotherapy	18 Years -	Universitätsklinikum Hamburg-Eppendorf
Chemoradiotherapy for Patients With Oligometastatic Colorectal Cancer	NCT01759238	Colorectal Canc... Metastases	Capecitabine Bevacizumab Radiotherapy	18 Years -	Universitätsklinikum Hamburg-Eppendorf
Chemoradiotherapy for Patients With Oligometastatic Colorectal Cancer	NCT01759238	Colorectal Canc... Metastases	Capecitabine Bevacizumab Radiotherapy	18 Years -	Universitätsklinikum Hamburg-Eppendorf
Definitive Radiochemotherapy Plus/Minus Cetuximab in Unresectable Locally Advanced Esophageal Cancer	NCT01787006	Esophageal Canc...	Cetuximab Cisplatin, 5-FU Radiotherapy	18 Years -	University Hospital Schleswig-Holstein

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