Oligometastases of the LIVer Treated With Chemotherapy With ou Without Extracranial Stereotactic Body Radiation Therapy in Patients With Colorectal Cancer (OLIVER)

The role of radiotherapy in metastatic cancer has historically been limited to palliation while metastasectomy or radiofrequency has emerged as playing a major role in disease control. Although resection is the standard of care for liver metastasis, 80-90% of patients are not resectable at diagnosis in particular because of the presence of oligometastases. Factors that favour a truly oligometastatic state include a long latent interval between the treatment of the primary tumor and the appearance of metastases.

Oligometastatic cancer is a very heterogeneous disease with respect to several factors including the location of the primary tumor. With the advent of extracranial stereotactic body radiation therapy (SBRT), higher biological equivalent doses can be safely delivered in 3 to 5 fractions, thus potentially ablating all the tissue in the treated area while protecting more efficiently the hosting organ and healthy tissues surrounding the tumors.

In patients with liver oligometastases, in-field local control rates at 2 years range from 70% to 90% with less than 5% severe grade 3 or higher toxicity rates. Retrospective studies indicate that roughly 20% of the patients remain disease-free 2 to 4 years after SBRT.

For patients treated with SBRT some authors found that half of the patients had either no metastatic progression or very little progression in terms of number and site of metastases. The patterns of failure after SBRT for oligometastases in one organ showed that 73% of patients eventually developed new metastases with higher than 80% occurring as new metastases in the same index organ. These findings support the idea of an oligometastatic state in which aggressive local therapy could improve progression-free survival (PFS).

With this phase III study, we sought to evaluate the impact of SBRT on PFS at 2 years in patients with synchronous or metachronous liver-only oligometastases from colorectal cancers patients after a first line chemotherapy for metastatic disease but not having progressed during first line chemotherapy and up to 1 year

Study Overview

• Status: Withdrawn
• Conditions: Colorectal Cancer; Liver Metastases
• Intervention / Treatment: Radiation: SBRT; Drug: Chemotherapy

• Study Type: Interventional
• Phase: Not Applicable

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Male or female with age ≥18 years and <85 years;
2. Patient with histologically proven colorectal cancer;
3. Patient with a curative surgical treatment (R0) of the primary tumor performed;
4. Oligometastatic disease defined as 1 to 3 liver-only metastases (measurable lesion as per RECIST 1.1);
5. Patient unfit for surgery or with unresectable metastases;
6. Maximal diameter of largest metastasis: 30 mm;
7. Patient naïve of chemotherapy in the metastatic setting or after a first-line of chemotherapy for metastatic disease but not having progressed up to 1 year (i.e. slowly progressing disease);
8. WHO status 0-1;
9. Adequate liver function: bilirubin <3 mg/dL, albumin >2.5 g/dL;
10. Adequate hematological function: absolute neutrophil count (ANC) >1.5 x 10⁹/L; platelets >100 x 10⁹/L, hemoglobin (Hb) >9 g/dL;
11. Normal PT (>70%) and PTT except if the patient uses anticoagulants;
12. Liver enzymes <3 times upper limit of normal;
13. Renal function must be adequate for infusion of iv. contrast agent for CT-scan according to the local policy;
14. Woman of childbearing potential and male patients must agree to use adequate contraception for the duration of study and up to 3 months following completion of therapy;
15. Patient who have received the information sheet, dated and signed the informed consent form;
16. Affiliated to the social security system.

Exclusion Criteria:

1. Healthy liver volume<700 mL
2. Life expectancy <3 months;
3. Patient fit for metastasectomy or hepatectomy;
4. Extrahepatic metastases;
5. Cirrhosis with Child Pugh score B or C;
6. More than one line of chemotherapy in the metastatic setting or rapidly progressing disease;
7. Previous local treatment of liver metastases;
8. Treatment with any other investigational agent against cancer;
9. Malignancies other than mCRC within 5 years prior to randomization, except for adequately treated carcinoma in situ of the cervix, basal or squamous cell skin cancer, localized prostate cancer treated surgically with curative intent, and ductal carcinoma in situ treated surgically with curative intent;
10. Pregnant woman or breast feeding mother;
11. Patient deprived of liberty or placed under the authority of a tutor. Patient with any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial. Patient unable to understand the purpose of the study (language, etc.).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Chemotherapy + SBRT; Patients will received 2 courses of chemotherapy before SBRT if no hepatic or extra-hepatic progression identified. All liver metastases will be irradiated. 4 doses prescription are allowed (according to the center, and the technique uded and the dosimetric constraints): 3x15 Gy, 4 x 15 Gy, 5 x10 Gy or 5 x 8 Gy. The remaining courses of chemotherapy 2 to 3 weeks after completion of SBRT will be administered	Radiation: SBRT; Patients will received 2 courses of chemotherapy before SBRT if no hepatic or extra-hepatic progression identified. All liver metastases will be irradiated. 4 doses prescription are allowed (according to the center, and the technique uded and the dosimetric constraints): 3x15 Gy, 4 x 15 Gy, 5 x10 Gy or 5 x 8 Gy. The remaining courses of chemotherapy 2 to 3 weeks after completion of SBRT will be administered; Drug: Chemotherapy; At investigator's discretion
Active Comparator: Chemotherapy; Patients will receive chemotherapy as initially scheduled	Drug: Chemotherapy; At investigator's discretion

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression Free Survival	To evaluate the impact of SBRT on Progression-Free Survival (PFS) at 1 year according to RECIST 1.1	1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Local Control rate	Defined as the time from the date of randomization to the date of a documented loco-regional event	1 and 3 years
Overall survival	Defined as the time from the date of randomization to the date of documented death of any cause	3 years
Cancer specific survival	Defined as the time from the date of randomization to the date of documented death from cancer or complication from treatment	3 years
CTCAE Toxicity Assessment	Acute/ late toxicity will be assessed according to the flowchart and performed based on CTCAE V4	up to 24 weeks
Quality of life EORTC QLQ C30	Will be assessed using self-administered questionnaires EORTC QLQ C30	up to 24 weeks
Quality of life EORTC QLQ CR29	Will be assessed using self-administered questionnaire QLQ CR29	up to 24 weeks

Collaborators and Investigators

• Sponsor: UNICANCER
• Investigators: Principal Investigator: Stéphanie SERVAGI, MD, INSTITUT JEAN GODINOT, REIMS; Principal Investigator: Gilles CREHANGE, MD, Centre Georges François Leclerc, DIJON

Study record dates

Study Major Dates

• Study Start (Anticipated): April 15, 2019
• Primary Completion (Anticipated): December 15, 2021
• Study Completion (Anticipated): August 15, 2023

Study Registration Dates

• First Submitted: January 25, 2018
• First Submitted That Met QC Criteria: May 9, 2018
• First Posted (Actual): May 22, 2018

Study Record Updates

• Last Update Posted (Actual): May 22, 2019
• Last Update Submitted That Met QC Criteria: May 20, 2019
• Last Verified: May 1, 2019

More Information

Terms related to this study

• Keywords: SBRT; Oligometastatis
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms
• Other Study ID Numbers: UC-0107/1602

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No