Trial Title:
Radical vs Local Excision for Rectal Cancer With Clinically Complete Remission
NCT ID:
NCT05964530
Condition:
Rectal Cancer
Conditions: Official terms:
Rectal Neoplasms
Conditions: Keywords:
Rectal cancer
Concomitant chemoradiation therapy
Radical surgery
Local excision
Study type:
Interventional
Study phase:
N/A
Overall status:
Recruiting
Study design:
Allocation:
Randomized
Intervention model:
Parallel Assignment
Primary purpose:
Treatment
Masking:
Single (Outcomes Assessor)
Intervention:
Intervention type:
Procedure
Intervention name:
Surgery
Description:
Surgery procedures include LAR+ anal preservation or APR
Arm group label:
Surgical group
Arm group label:
Watch and wait group
Summary:
In the present project, the investigators plan to more accurately select the rectal
cancer patients with pathological complete response (pCR) to preoperative concomitant
chemoradiation therapy (CCRT), taking advantage of quantification of circulating tumor
DNA (ctDNA) in addition to the current available diagnostic modalities, including CT,
MRI, PET and colonoscopy. The patients with suspected pCR to CCRT will be randomized to
radical surgery and local excision groups, followed by the comparison of the oncologic
outcomes between two treatment methods. The investigators hypothesized that if the pCR
for patients with rectal cancer after CCRT can be more accurately predicted, such
patients can be safely treated with limited surgery to enhance the post-treatment life
quality, in comparison with patients undergoing radical surgery.
Detailed description:
In Taiwan, patients with stage Ⅱ or Ⅲ rectal cancer represented around 30% of all cases
of colorectal cancer(n=15,000 annually). Standard treatment of locally advanced rectal
cancer consists of neoadjuvant chemoradiotherapy (nCRT), total mesorectal excision (TME),
and postoperative adjuvant chemotherapy. This intensive treatment leads to good local
tumor control and patient survival, but is associated with short- and long-term morbidity
that impairs each patient's quality of life permanently. Although nCRT followed by
adjuvant chemotherapy are associated with specific toxicity and may compound
surgery-related morbidity, most of the side effects of multimodal treatment that impair
the patient's quality of life are attributable to TME with sphincter-preservation or
abdomino-perineal resection (APR). Even with the technological advances of robotic and
transanal TME, some patients with distal rectal cancer will still require a permanent
colostomy. In addition, patients who undergo a sphincter-saving procedure develop a
combination of defecatory symptoms known as low anterior resection syndrome. These
symptoms are associated with significant impairment of patients' quality of life. With
the age-adjusted incidence of rectal cancer increasing steadily in young patients,
alternatives to TME are needed.
Some patients with locally advanced rectal cancer have a pathological complete response
(pCR) to nCRT. Because patients with pCR have excellent prognosis,8 surgeons question the
added value of TME for patients with a clinical complete response (cCR) to CRT. Several
institutional case series have reported that a watch-and-wait strategy can result in
sustained organ preservation in patients with a cCR to nCRT. Remarkably, up to 30% of
patients entered in watch-and-wait protocols eventually experienced tumor re-growth, but
most of the cases were surgically salvageable.9 In some series, the survival rate in
patients with clinical complete response (cCR) entered in a watch-and-wait protocol was
equivalent to that in patients found to have a pCR after TME. However, most of these
series, recently published together as an international multicenter registry study, are
heterogeneous in terms of tumor stages, radiation dosage, sensitizing chemotherapy, the
criteria and timing for assessment of response, and surveillance follow-up protocols.
Because these series included only selected patients entering in the watch-and-wait
protocol without reporting the total number of patients with similar-stage rectal tumors
treated with neoadjuvant therapy during the study period, the possibility of selection
bias cannot be excluded. Without a reference denominator, the number of patients who
would have potentially benefited from organ preservation by using a watch-and-wait
strategy is unknown.
With above-mentioned reasons, most of the patients, including the international case
series and our previous case reports, still receive radical surgery for their rectal
cancer with cCR to neoadjuvant CRT; some patients with cCR even received a theoretically
unnecessary APR procedure and wore a colostoma for life. To enhance the life quality for
such patients with cCR to nCRT, the guidelines of the National Comprehensive Cancer
Network for treatment of rectal cancer included total neoadjuvant therapy (TNT; systemic
chemotherapy before rather than after TME), which was developed in part as a strategy to
increase the rate of tumor response. However, to date, the impact of TNT on the potential
for organ preservation through avoidance of surgery is unknown.
There is no denying that the organ preservation with no immediate surgery, i.e., the
watch-and-wait strategy, in selected patients with a cCR after nCRT is currently at the
forefront of rectal cancer management. This strategy is considered as an attractive
option to avoid major surgery and the associated morbidity and mortality risks, and
functional consequences. However, with the watch-and-wait approach, there is a risk for
the development of local regrowth, systemic recurrence, or both, despite the initial
achievement of a clinical complete response. Overall, the risk of local re-growth within
3 years from attaining a clinical complete response is 25-30%, and even the occurrence of
local re-growth at as long as 7 years from the completion of neoadjuvant
chemoradiotherapy has been reported. Therefore, long-term and intensive surveillance
protocols have been recommended for patients managed by a watch-and-wait strategy.
Remarkably, in consideration of the watch-and-wait policy requires intensive medical
resources, it has been not adopted in Taiwan and most of the centers of excellence
worldwide.
On the other hand, the GRECCAR2 multicenter randomized trial showed that no evidence of
difference in oncological outcomes between local excision and total mesorectal excision
in term of 5-year overall survival. Local excision can be proposed in selected patients
having a small T2-T3 low rectal cancer with a good clinical response after
chemoradiotherapy. However, their study subjects were not limited to rectal cancer with
cCR to preoperative CCRT.
The investigators believe that local excision can be applied to the highly selective
patients with rectal cancer, especially those with cCR to operative CCRT. However, up to
date, there is still no diagnostics to accurately predict the pCR of the rectal cancer to
CCRT. And therefore, both the colorectal surgeons and patients has been receiving radical
surgery as the major treatment modality. Remarkably, with advent of genetic technology,
it become feasible to utilize ctDNA for predicting the response to neoadjuvant
chemoradiotherapy and prognosis assessment in locally advanced rectal cancer.
The ctDNA (mutant allele) has been known to be with an extremely short plasma half-life
(shorter than 2 hours) compared with tumor markers (such as CEA and CA19-9). After
curative resection, therefore, ctDNA rapidly disappears from the blood if no residual
cancer exists. Utilizing these characteristics of ctDNA, a diagnostic system for
detecting minimal residual disease (MRD) using a next generation sequencing technology is
being developed. Remarkably, SignateraTM is a novel ctDNA detection system for MRD
detection developed by Natera Inc., U.S.A. First, whole exon analysis of tumor tissue
samples is performed, followed by extraction of 16 somatic mutations from the detected
tumor-specific single nucleotide variants using an original program, and the primer set
that detects these variants is established for each patient and tumor. SignateraTM is a
test system that extracts ctDNA from the blood obtained postoperatively, using this
primer set, and detects the presence or absence of somatic mutations derived from tumors
using a next generation sequencer. In SignateraTM, the sensitivity limit for ctDNA allele
frequency is 0.005%, the 90% sensitivity limit is 0.010%, and the specificity is at least
99.5%. In a multicenter prospective cohort study in patients with Stage I-III colorectal
carcinoma, 130 patients with Stage I-III colorectal carcinoma were enrolled. The ctDNA
positive rate at 30 days after the curative resection was 10.6%, and the relapse rate was
7 times or more higher in the ctDNA positive group than in the ctDNA negative group
(hazard ratio [HR] = 7.2; 95% CI, 2.7-19.0). In addition, of the 58 patients who were
evaluable for ctDNA after completing postoperative adjuvant chemotherapy, 7 patients
(12.0%) were positive for ctDNA, and 51 patients (88.0%) were negative for ctDNA, with
relapse observed in all ctDNA-positive patients, which was significantly higher than the
relapse rate in ctDNA-negative patients (7/51 patients, 13.7%) (HR = 17.5; 95% CI,
5.4-56.5). Moreover, of the 75 patients who were tested for ctDNA chronologically, 14 out
of 15 ctDNA-positive patients (93.3%) had a relapse, and of the 60 patients who were
negative for ctDNA, only 2 patients had a relapse. With respect to time-to-relapse, the
median time to confirmation of a relapse by ordinary CT scan was 14.2 months, while the
median time to detection of positive ctDNA was 5.5 months.
In the present project, the investigators plan to more accurately select the rectal
cancer patients with pCR to preoperative CCRT, taking advantage of quantification of
ctDNA in addition to the current available diagnostic modalities, including CT, MRI, PET
and colonoscopy. The patients with suspected pCR to CCRT will be randomized to radical
surgery and local excision groups, followed by the comparison of the oncologic outcomes
between two treatment methods. The investigators hypothesized that if the pCR for
patients with rectal cancer after CCRT can be more accurately predicted, such patients
can be safely treated with limited surgery to enhance the post-treatment life quality, in
comparison with patients undergoing radical surgery.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
1. rectal adenocarcinoma completed nCRT and the imaging studies showed no residual
malignancy;
2. physical status is within American Society of Anesthesiology（ASA）class Ⅰ to Ⅲ;
3. the lesion side can be reached by the transanal local excision, generally within 6
cm above anal verge;
4. age is 18-75 years.
Exclusion Criteria:
1. Quantification of ct DNA shows residual malignancy;
2. Body mass index（BMI）>40 kg/m2;
3. Previous abdominal or pelvic surgery;
4. abnormal hepatologic (Bil>2.0 mg/dl), renal (Cre≧2.0) and hematologic(WBC<3000,
HB<8.0, platelet<50000) profiles after CCRT.
Gender:
All
Minimum age:
18 Years
Maximum age:
75 Years
Healthy volunteers:
No
Locations:
Facility:
Name:
Jin-Tung LIANG
Address:
City:
Taipei
Zip:
100
Country:
Taiwan
Status:
Recruiting
Contact:
Last name:
Jin-Tung LIANG, MD
Phone:
+886972651432
Email:
jintung@ntu.edu.tw
Start date:
April 19, 2023
Completion date:
October 19, 2026
Lead sponsor:
Agency:
National Taiwan University Hospital
Agency class:
Other
Source:
National Taiwan University Hospital
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05964530
