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Organ Preservation in Rectal Cancer: Contact X-ray Brachytherapy vs Extending the Waiting Interval and Local Excision (OPAXX)

Primary Purpose

Organ Preservation, Rectal Cancer, Quality of Life

Status
Recruiting
Phase
Not Applicable
Locations
Netherlands
Study Type
Interventional
Intervention
Contact x-ray brachytherapy
Local excision
Sponsored by
The Netherlands Cancer Institute
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Organ Preservation focused on measuring Organ preservation, Rectal cancer, (Chemo)radiation, Local excision, Contact x-ray brachytherapy, TAMIS

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria: histologically verified adenocarcinoma above the dentate line and within 10cm of the anal verge; neoadjuvant short-course radiotherapy for patients with 1) IRC and delayed response evaluation according to the Dutch national guidelines (cT1-3, cN1-2 lymph nodal status, no involved MRF or cT3c-d, N0-1 lymph nodal status without pres-ence of significant distant metastases) without full dose chemotherapy in the inter-val (e.g. Rapido-scheme) or 2) LARC due to comorbidity or frailty; OR neoadjuvant long-course radiotherapy (chemoradiation) for patients with 1) LARC according to the Dutch national guidelines (cT4 tumour, cN2 lymph nodal status, lateral lymph node involvement, and/or involved MRF, without the presence of significant distant metastases) or 2) early rectal cancer or IRC and a strong wish for organ preservation; clinically near-complete response or a small residual tumour mass <3 cm; technically feasible to perform both treatment options (contact x-ray brachytherapy or local excision); age >18 years; written informed consent. Exclusion Criteria: neoadjuvant or induction chemotherapy prior or adjacent to (chemo)radiation, e.g. patients with a Rapido or M1-scheme are not eligible; radiation dose >50.4 Gy or boost dose on the primary tumour; presence of suspicious lymph nodes (yN1/N2) at first response evaluation; residual tumour ≥ 3cm or over half of the circumference of the rectal lumen; patients who are unable to undergo contact x-ray brachytherapy or local excision; patients who cannot tolerate a completion- or salvage-TME because of comorbidity or frailty;

Sites / Locations

  • Medical Center LeeuwardenRecruiting
  • Radbouw University Medical CentreRecruiting
  • Catharina HospitalRecruiting
  • Antoni van LeeuwenhoekRecruiting
  • Deventer HospitalRecruiting
  • IsalaRecruiting
  • Ijsselland HospitalRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

Contact x-ray brachytherapy

Extending the waiting interval, with or without local excision

Arm Description

Contact x-ray brachytherapy will be given applied after randomisation with a maximum interval of 14 weeks after finishing the neoadjuvant (chemo)radiation. Contact x-ray brachytherapy consists of three fractions of 30Gy per fraction applied to the tumour, with a 2 week interval between each boost. Response evaluation takes place every 3 months thereafter. Patients in whom a clinical complete response is detected during follow-up are offered a watch-and-wait approach; patients in whom an incomplete response or disease progression is noted, completion or salvage TME-surgery is advised.

The waiting interval will be extended with 6-8 more weeks after the first response evaluation, followed by a second (or third in case of ongoing response) re-assessment. Patients with a clinical complete response at the time of the second (or third) response evaluation will be offered a watch-and-wait approach without any surgical treatment. Patients with a remaining small lesion will be offered transanal local excision. Depending on the final pathological staging after local excision, patients are categorized as low-risk or high-risk, and will be offered a watch-and-wait strategy or completion TME-surgery, respectively.

Outcomes

Primary Outcome Measures

Rate of successful organ preservation
Including an in-situ rectum (including patients subjected to local excision), no defunctioning stoma and absence of active loco-regional cancer failure (indicated as either local intraluminal tumour regrowth or regional recurrence in lymph nodes requiring TME-surgery)

Secondary Outcome Measures

Incidence of radiation toxicity
Frequency of adverse events grade 3-4 defined by the common terminology criteria of adverse events (CTCAE) version 5.0
Incidence of postoperative morbidity after local excision
Frequency of post-operative complication grade 3-4 according to Clavien-Dindo
Frequency of patients with a high Low Anterior Rectal Syndrome (LARS) score
Defined by the LARS questionnaire with a score between 30-42
Frequency of patients with impaired of bowel function
Defined by an approved questionnaire IL108 from the European Organization for Research and Treatment of Cancer (EORTC) based on selected items of EORTC QLQ-PR25, QLQ-CX24 and QLQ-ANL27
Frequency of patients with impaired bladder function
Defined by an approved questionnaire IL108 from the European Organization for Research and Treatment of Cancer (EORTC) based on selected items of EORTC QLQ-PR25, QLQ-CX24 and QLQ-ANL27
Frequency of patients with a minimum important difference (MID) of 5 to 10 points on health-related quality of life score (HRQoL-scores)
Defined by the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C29/30
Regrowth rate
Regrowth rate
Disease free survival
Disease free survival
Overall survival
Overall survival
Organ preservation rate
Organ preservation rate
Number of patients with complications after completion or salvage TME-surgery
In terms of postoperative morbidity and mortality rates defined by Clavien-Dindo

Full Information

First Posted
March 4, 2021
Last Updated
March 14, 2023
Sponsor
The Netherlands Cancer Institute
Collaborators
Catharina Ziekenhuis Eindhoven, ZonMw: The Netherlands Organisation for Health Research and Development
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1. Study Identification

Unique Protocol Identification Number
NCT05772923
Brief Title
Organ Preservation in Rectal Cancer: Contact X-ray Brachytherapy vs Extending the Waiting Interval and Local Excision
Acronym
OPAXX
Official Title
Organ Preservation in Patients With a Good Clinical Response After (Chemo)Radiation for Rectal Cancer: Defining the Role of Additional Contact X-ray Brachytherapy Versus Extending the Waiting Interval and Local Excision
Study Type
Interventional

2. Study Status

Record Verification Date
March 2023
Overall Recruitment Status
Recruiting
Study Start Date
April 16, 2021 (Actual)
Primary Completion Date
March 2025 (Anticipated)
Study Completion Date
March 2029 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
The Netherlands Cancer Institute
Collaborators
Catharina Ziekenhuis Eindhoven, ZonMw: The Netherlands Organisation for Health Research and Development

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The goal of this prospective phase II feasibility study is to evaluate two additional local treatment options in rectal cancer patients with a good clinical response after neoadjuvant (chemo)radiation: contact x-ray brachytherapy versus extension of the waiting interval with or without local excision, and to investigate which rate of organ preservation can be achieved.
Detailed Description
Rationale: The organ preservation approach for rectal cancer has been explored increasingly, aiming at improving quality of life by prevention of total mesorectal excision (TME-surgery). In patients with intermediate rectal cancer (IRC) and locally advanced rectal cancer (LARC) who receive neoadjuvant (chemo)radiotherapy (in general a short-course radiotherapy or a long-course chemoradiation, respectively) subsequent TME-surgery is still standard of care. In patients with a good clinical response after neoadjuvant (chemo)radiation, organ preservation may be considered, depending on the extent of the response monitored by radiological and endoscopic assessment. Some patients show a clinical complete response and can be monitored closely in a watch-and-wait approach. In case of a good, but not complete response, it remains unclear which patients may benefit from extension of the observation period after (chemo)radiation in order to achieve a complete clinical response over time, or in whom additional local treatment options (such as contact x-ray brachytherapy or local excision) are beneficial in obtaining organ preservation eventually. Objective: The aim of this study is to investigate which rate of organ preservation can be achieved in patients with rectal cancer treated with neoadjuvant (chemo)radiotherapy with a good clinical response, and to optimize the different treatment strategies. In patients with a near-complete response or a small residual tumour mass, participation is offered in a phase II feasibility trial, in which two potential organ preservation treatment strategies are evaluated: contact x-ray brachytherapy or extension of the waiting interval with or without additional local excision in case of residual disease. Study design: This is a prospective study with a mixed design. It concerns a phase II feasibility study for patients in whom a good, but not complete response has been achieved after (chemo)radiation (OPAXX study): two parallel single study-arms evaluate the efficacy of experimental organ preservation approaches. To allow for a better comparison of secondary parameters (toxicity and morbidity of both additional local treatments) eligible patients will be randomized between two experimental arms. Furthermore, an observational cohort study is established to register rectal cancer patients with a good but not complete clinical response after (chemo)radiation who are not eligible for randomisation in the OPAXX study (OPAXX registration study). Study population: In general, patients with IRC receiving short-course radiotherapy with delayed surgery (patients with initially a cT1-3, cN1-2 lymph nodal status, no involved MRF or cT3c-d, N0-1 lymph nodal status) or patients with LARC receiving neoadjuvant long-course chemoradiation (patients with initially cT4 tumour, cN2 lymph node status, lateral lymph node involvement and/or an involved mesorectal fascia (MRF+)) according to the Dutch national guideline are eligible for this study when at the first response assessment 6-8 weeks after finishing the (chemo)radiation a good clinical response is seen. A good clinical response has been defined as a clinical complete response, a near-complete response or a small residual tumour mass <3 cm on endoscopy, but also no evidence of residual nodal disease on magnetic resonance imaging (MRI) (ycN0). In case of a clinical complete response the current strategy of watchful waiting is offered. Eligible patients in whom a good, but not complete response is detected will be randomized to one of the two experimental OPAXX study arms, provided that both additional local treatment options are technically feasible. Intervention arms OPAXX study: Arm 1: Contact x-ray brachytherapy will be given applied after randomisation with a maximum interval of 14 weeks after finishing the neoadjuvant (chemo)radiation. Contact x-ray brachytherapy consists of three fractions of 30Gy per fraction applied to the tumour, with a 2 week interval between each boost. Response evaluation takes place every 3 months thereafter. Patients in whom a clinical complete response is detected during follow-up are offered a watch-and-wait approach; patients in whom an incomplete response or disease progression is noted, completion or salvage TME-surgery is advised. Arm 2: The waiting interval will be extended with 6-8 more weeks after the first response evaluation, followed by a second (or third in case of ongoing response) re-assessment. Patients with a clinical complete response at the time of the second (or third) response evaluation will be offered a watch-and-wait approach without any surgical treatment. Patients with a remaining small lesion will be offered transanal local excision. Depending on the final pathological staging after local excision, patients are categorized as low-risk or high-risk, and will be offered a watch-and-wait strategy or completion TME-surgery, respectively. Main study parameters/endpoints: The primary endpoint of the OPAXX study reflects the efficacy of both additional treatment options: the rate of successful organ preservation (defined as an in-situ rectum, no defunctioning stoma and absence of active locoregional cancer failure) at one year following randomisation in rectal cancer patients with a good, but not complete clinical response after (chemo)radiation. Secondary endpoints are related to toxicity and morbidity of the two additional treatment options in the randomisation study, as well as to oncological and functional outcomes at one, two and five years of follow-up. For patients with a good but not complete clinical response after (chemo)radiation who are not eligible for randomisation in the OPAXX study an observational cohort study is conducted (OPAXX registration study). Nature and extent of the burden and risks associated with participation, benefit and group relatedness: Standard treatment of IRC and LAR consists of neoadjuvant short-course or long-course (chemo)radiotherapy followed by TME-surgery. If a clinical complete response is seen at response evaluation, a watch-and-wait approach is currently considered a valid strategy in selected patients according to the Dutch national guidelines. In the ongoing Dutch national prospective registry patients with a near-complete response are currently offered an extension of the observation period rather than TME-surgery, and, subsequently, a watch-and-wait policy when a clinical complete response is noted over time. On the other hand, all patients with a persistent residual lesion will proceed to TME-surgery. In the current study, two experimental approaches are introduced that could increase organ preservation rates in patients with a good, but not-complete response at the first response evaluation: additional endoluminal contact x-ray brachytherapy and local excision of the tumour remnant. Prior to randomisation, eligible patients are well informed about the risks of the two experimental treatment strategies (i.e. unclear long-term oncological outcome), and are offered standard-of-care TME-surgery. Moreover, patients will be informed that additional treatment with contact x-ray brachytherapy or local excision might increase the morbidity rates in case completion or salvage TME-surgery is required. Finally, in both arms of this phase II study an intensive surveillance program has been established, in order to detect treatment failure, tumour regrowth or disease recurrence at an early stage, in order to proceed to completion or salvage TME-surgery when needed and when possible.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Organ Preservation, Rectal Cancer, Quality of Life, Locally Advanced Rectal Carcinoma
Keywords
Organ preservation, Rectal cancer, (Chemo)radiation, Local excision, Contact x-ray brachytherapy, TAMIS

7. Study Design

Primary Purpose
Treatment
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Model Description
This is a prospective study with a mixed design. It concerns a phase II feasibility study for patients in whom a good, but not complete response has been achieved after (chemo)radiation (OPAXX study): two parallel single study-arms evaluate the efficacy of experimental organ preservation approaches. To allow for a better comparison of secondary parameters (toxicity and morbidity of both additional local treatments) eligible patients will be randomized between two experimental arms. Furthermore, an observational cohort study is established to register rectal cancer patients with a good but not complete clinical response after (chemo)radiation who are not eligible for randomisation in the OPAXX study (OPAXX registration study).
Masking
None (Open Label)
Allocation
Randomized
Enrollment
168 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Contact x-ray brachytherapy
Arm Type
Experimental
Arm Description
Contact x-ray brachytherapy will be given applied after randomisation with a maximum interval of 14 weeks after finishing the neoadjuvant (chemo)radiation. Contact x-ray brachytherapy consists of three fractions of 30Gy per fraction applied to the tumour, with a 2 week interval between each boost. Response evaluation takes place every 3 months thereafter. Patients in whom a clinical complete response is detected during follow-up are offered a watch-and-wait approach; patients in whom an incomplete response or disease progression is noted, completion or salvage TME-surgery is advised.
Arm Title
Extending the waiting interval, with or without local excision
Arm Type
Experimental
Arm Description
The waiting interval will be extended with 6-8 more weeks after the first response evaluation, followed by a second (or third in case of ongoing response) re-assessment. Patients with a clinical complete response at the time of the second (or third) response evaluation will be offered a watch-and-wait approach without any surgical treatment. Patients with a remaining small lesion will be offered transanal local excision. Depending on the final pathological staging after local excision, patients are categorized as low-risk or high-risk, and will be offered a watch-and-wait strategy or completion TME-surgery, respectively.
Intervention Type
Radiation
Intervention Name(s)
Contact x-ray brachytherapy
Intervention Description
With contact x-ray brachytherapy an intraluminal radiation boost up to 90 Gy is applied to the primary rectal tumour, with minimal collateral damage to the surrounding normal tissues due to minimal penetration of the 50 kVolt therapy.
Intervention Type
Procedure
Intervention Name(s)
Local excision
Intervention Description
Local excision will basically be performed by the TAMIS-procedure (transanal minimally invasive surgery).
Primary Outcome Measure Information:
Title
Rate of successful organ preservation
Description
Including an in-situ rectum (including patients subjected to local excision), no defunctioning stoma and absence of active loco-regional cancer failure (indicated as either local intraluminal tumour regrowth or regional recurrence in lymph nodes requiring TME-surgery)
Time Frame
At one year following randomisation
Secondary Outcome Measure Information:
Title
Incidence of radiation toxicity
Description
Frequency of adverse events grade 3-4 defined by the common terminology criteria of adverse events (CTCAE) version 5.0
Time Frame
Short-term (< 3 months after end of treatment) and long-term (< 12 months after end of treatment)
Title
Incidence of postoperative morbidity after local excision
Description
Frequency of post-operative complication grade 3-4 according to Clavien-Dindo
Time Frame
Short term (occurring within 3 months after local excision) and long-term (within one year)
Title
Frequency of patients with a high Low Anterior Rectal Syndrome (LARS) score
Description
Defined by the LARS questionnaire with a score between 30-42
Time Frame
At baseline, at 3 months, one, two and five year
Title
Frequency of patients with impaired of bowel function
Description
Defined by an approved questionnaire IL108 from the European Organization for Research and Treatment of Cancer (EORTC) based on selected items of EORTC QLQ-PR25, QLQ-CX24 and QLQ-ANL27
Time Frame
At baseline, at 3 months, one, two and five year
Title
Frequency of patients with impaired bladder function
Description
Defined by an approved questionnaire IL108 from the European Organization for Research and Treatment of Cancer (EORTC) based on selected items of EORTC QLQ-PR25, QLQ-CX24 and QLQ-ANL27
Time Frame
At baseline, at 3 months, one, two and five year
Title
Frequency of patients with a minimum important difference (MID) of 5 to 10 points on health-related quality of life score (HRQoL-scores)
Description
Defined by the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C29/30
Time Frame
At baseline, at 3 months, one, two and five year
Title
Regrowth rate
Description
Regrowth rate
Time Frame
At one- and two year
Title
Disease free survival
Description
Disease free survival
Time Frame
At one- and two year
Title
Overall survival
Description
Overall survival
Time Frame
At one- and two year
Title
Organ preservation rate
Description
Organ preservation rate
Time Frame
At two years
Title
Number of patients with complications after completion or salvage TME-surgery
Description
In terms of postoperative morbidity and mortality rates defined by Clavien-Dindo
Time Frame
Within the first 30 days after surgery

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: histologically verified adenocarcinoma above the dentate line and within 10cm of the anal verge; neoadjuvant short-course radiotherapy for patients with 1) IRC and delayed response evaluation according to the Dutch national guidelines (cT1-3, cN1-2 lymph nodal status, no involved MRF or cT3c-d, N0-1 lymph nodal status without pres-ence of significant distant metastases) without full dose chemotherapy in the inter-val (e.g. Rapido-scheme) or 2) LARC due to comorbidity or frailty; OR neoadjuvant long-course radiotherapy (chemoradiation) for patients with 1) LARC according to the Dutch national guidelines (cT4 tumour, cN2 lymph nodal status, lateral lymph node involvement, and/or involved MRF, without the presence of significant distant metastases) or 2) early rectal cancer or IRC and a strong wish for organ preservation; clinically near-complete response or a small residual tumour mass <3 cm; technically feasible to perform both treatment options (contact x-ray brachytherapy or local excision); age >18 years; written informed consent. Exclusion Criteria: neoadjuvant or induction chemotherapy prior or adjacent to (chemo)radiation, e.g. patients with a Rapido or M1-scheme are not eligible; radiation dose >50.4 Gy or boost dose on the primary tumour; presence of suspicious lymph nodes (yN1/N2) at first response evaluation; residual tumour ≥ 3cm or over half of the circumference of the rectal lumen; patients who are unable to undergo contact x-ray brachytherapy or local excision; patients who cannot tolerate a completion- or salvage-TME because of comorbidity or frailty;
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Barbara M Geubels, MD
Phone
0205129001
Email
b.geubels@nki.nl
First Name & Middle Initial & Last Name or Official Title & Degree
Brechtje A Grotenhuis, MD, PhD
Phone
020 239 9111
Email
b.grotenhuis@nki.nl
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Brechtje A Grotenhuis, MD, PhD
Organizational Affiliation
Antoni van Leeuwenhoek Hospital
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Pim Burger, MD, PhD
Organizational Affiliation
Catharina Ziekenhuis Eindhoven
Official's Role
Principal Investigator
Facility Information:
Facility Name
Medical Center Leeuwarden
City
Leeuwarden
State/Province
Friesland
ZIP/Postal Code
8934 AD
Country
Netherlands
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Hoff, MD
Phone
058 286 6666
Email
c.hoff@mcl.nl
Facility Name
Radbouw University Medical Centre
City
Nijmegen
State/Province
Gelderland
ZIP/Postal Code
6500 HB
Country
Netherlands
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
de Wilt, MD, PhD
Phone
024 361 1111
Email
hans.dewilt@radboudumc.nl
Facility Name
Catharina Hospital
City
Eindhoven
State/Province
Noord-Brabant
ZIP/Postal Code
5623EJ
Country
Netherlands
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Burger, MD, PhD
Phone
040 239 9111
Email
pim.burger@catharinaziekenhuis.nl
Facility Name
Antoni van Leeuwenhoek
City
Amsterdam
State/Province
Noord-Holland
ZIP/Postal Code
1066CX
Country
Netherlands
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Grotenhuis, MD, PhD
Phone
020-5129111
Email
b.grotenhuis@nki.nl
Facility Name
Deventer Hospital
City
Deventer
State/Province
Overijssel
ZIP/Postal Code
7416 SE
Country
Netherlands
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Talsma, MD, PhD
Phone
0570 535 353
Email
k.talsma@dz.nl
Facility Name
Isala
City
Zwolle
State/Province
Overijssel
ZIP/Postal Code
8025 AB
Country
Netherlands
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
van Westreenen, MD, PhD
Phone
088 624 5000
Email
h.l.van.westreenen@isala.nl
Facility Name
Ijsselland Hospital
City
Capelle Aan Den IJssel
State/Province
Zuid-Holland
ZIP/Postal Code
2906 ZC
Country
Netherlands
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Vermaas, MD, PhD
Phone
010 258 5000
Email
mvermaas@ysl.nl

12. IPD Sharing Statement

Plan to Share IPD
No
Links:
URL
https://www.opaxx.nl/
Description
study website

Learn more about this trial

Organ Preservation in Rectal Cancer: Contact X-ray Brachytherapy vs Extending the Waiting Interval and Local Excision

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