The main objective of this study is to determine the maximum tolerated dose (MTD) of 5 fractions MRgRT for patients with AC following FLOT therapy. The secondary objectives are feasibility, non-dose limiting toxicity, oncological outcomes and to…
ID
Source
Brief title
Condition
- Malignant and unspecified neoplasms gastrointestinal NEC
- Gastrointestinal neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary endpoint is the incidence of a dose limiting toxicity (DLT). Early
DLT is defined as radiation induced esophageal fistula/ perforation/
hemorrhage/ necrosis or tracheal, bronchial or bronchopleural fistula/tracheal
or bronchopulmonary hemorrhage grade >= 3 or any non-hematological grade >= 4
toxicity, assessed clinically significant and related to the radiotherapy,
according to Common Toxicity Criteria for Adverse Events (CTCAE) version 5.0
occurring within 16 weeks after the start of radiotherapy and before surgery or
postponing of surgery > 16 weeks after the end of radiotherapy due to any grade
of treatment-related toxicity. Subacute DLT is defined as peri- and/or
postoperative complications occurring within 30 days after surgery, defined as
postoperative anastomotic leakage or pneumonitis >= 3b according to
Clavien-Dindo.
Secondary outcome
Secondary endpoints are non-DLT toxicity, the technical feasibility of dose
delivery, perioperative complications. and oncological outcomes including R0
resection rate, histopathological tumor response, local and regional recurrence
and death from any cause.
Background summary
Esophageal cancer (EC) is the seventh most frequently diagnosed cancer and the
sixth leading cause of cancer-related death worldwide. As a result of the late
onset of symptoms, most patients with EC present in an advanced stage with a
corresponding poor prognosis. Poor disease outcome after surgery alone (5-yr
overall survival between 25-40%) prompted many researchers to explore
neoadjuvant chemoradiotherapy (nCRT) or neoadjuvant or perioperative
chemotherapy (nCT/pCT) approaches.
In the Netherlands, neoadjuvant chemoradiation has become standard of care for
esophageal cancer since publication of the CROSS trial showing a benefit of
nCRT over surgery alone for both adenocarcinoma (AC) and squamous cell
carcinoma (SCC) (van Hagen et al., 2012). However, the benefit of nCRT was less
pronounced in AC, which was also reflected by pathologic complete response
(pCR) rates: 23% in AC vs. 49% in SCC. Furthermore, SCC and AC differ in
patterns of recurrence after nCRT or chemotherapy. AC is more likely to develop
distant metastases while SCC has a predisposition for locoregional recurrences.
This difference in response to nCRT and in recurrence pattern indicates that
histology-tailored treatment strategies should be explored. In the modern
multidisciplinary discussion on the optimal approach to locally advanced
adenocarcinoma of the esophagus and junction, both a trimodiality approach or
perioperative chemotherapy are acceptable and evidence based. Therefore both
are viable options within current guidelines.
As mentioned above, patients with an AC of the esophagus are especially prone
to develop distant recurrences. In addition, response to nCRT is only moderate
in AC. Therefore, we hypothesize that the ideal neoadjuvant treatment should
consist of adding MR-guided radiotherapy to standard pCT in order to achieve
maximum systemic control and achieve maximum local control.
Study objective
The main objective of this study is to determine the maximum tolerated dose
(MTD) of 5 fractions MRgRT for patients with AC following FLOT therapy. The
secondary objectives are feasibility, non-dose limiting toxicity, oncological
outcomes and to explore variables for early response evaluation.
Study design
6+3 dose-escalation design with 4 radiotherapy dose levels.
Intervention
5 sequential, homogenous fractions of 4-8 Gy within 2 weeks on the gross tumor
volume (GTV) following preoperative FLOT (as part of standard perioperative
chemotherapy) using MR-guided online adaptive radiotherapy on the MR-linac.
Start in dose level 0, of 5 x 5Gy per patient, and if safe this is increased
step-wise to a maximum dose level of 5 x 8Gy per patient.
Study burden and risks
The benefits for the patients may include higher probability of complete
primary tumor and lymph node metastases response that initially lead to
increased survival and could eventually result in organ-sparing treatment
programs. Possible risks are mainly esophageal fistula/perforation and
broncho-esophageal fistula or hemorrhage.
Heidelberglaan 100
Utrecht 3584 CX
NL
Heidelberglaan 100
Utrecht 3584 CX
NL
Listed location countries
Age
Inclusion criteria
Patients with adenocarcinoma of the esophagus or gastroesophageal junction
(Siewert I or II), potentially resectable tumor , eligible for perioperative
FLOT chemotherapy, age >= 18 years, WHO performance status 0-2.
Exclusion criteria
Squamous cell carcinoma, non-resectable, inoperable or metastatic
adenocarcinoma of the esophagus or gastroesophageal junction, prior
radiotherapy to the mediastinum, pregnant or breastfeeding patients.
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| CCMO | NL87824.041.24 |