Ignite Creation Date:
2024-05-06 @ 7:18 PM
Last Modification Date:
2024-10-26 @ 3:04 PM
Study NCT ID:
NCT05964530
Status:
RECRUITING
Last Update Posted:
2023-07-28
First Post:
2023-07-17
Brief Title:
Radical vs Local Excision for Rectal Cancer With Clinically Complete Remission
Sponsor:
National Taiwan University Hospital
Organization:
National Taiwan University Hospital
Study Overview
Official Title:
Comparing the Oncologic Efficacy of Radical Versus Local Excision for Rectal Cancer With Clinically Complete Remission to Neoadjuvant Chemoradiation Therapy A Randomized Controlled Clinical Trial
Status:
RECRUITING
Status Verified Date:
2024-09
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief 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 cancern15000 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 patients 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 patients 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 prognosis8 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 salvageable9 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 ie 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 USA 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 0005 the 90 sensitivity limit is 0010 and the specificity is at least 995 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 106 and the relapse rate was 7 times or more higher in the ctDNA positive group than in the ctDNA negative group hazard ratio HR 72 95 CI 27-190 In addition of the 58 patients who were evaluable for ctDNA after completing postoperative adjuvant chemotherapy 7 patients 120 were positive for ctDNA and 51 patients 880 were negative for ctDNA with relapse observed in all ctDNA-positive patients which was significantly higher than the relapse rate in ctDNA-negative patients 751 patients 137 HR 175 95 CI 54-565 Moreover of the 75 patients who were tested for ctDNA chronologically 14 out of 15 ctDNA-positive patients 933 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 142 months while the median time to detection of positive ctDNA was 55 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
Some patients with locally advanced rectal cancer have a pathological complete response pCR to nCRT Because patients with pCR have excellent prognosis8 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 salvageable9 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 ie 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 USA 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 0005 the 90 sensitivity limit is 0010 and the specificity is at least 995 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 106 and the relapse rate was 7 times or more higher in the ctDNA positive group than in the ctDNA negative group hazard ratio HR 72 95 CI 27-190 In addition of the 58 patients who were evaluable for ctDNA after completing postoperative adjuvant chemotherapy 7 patients 120 were positive for ctDNA and 51 patients 880 were negative for ctDNA with relapse observed in all ctDNA-positive patients which was significantly higher than the relapse rate in ctDNA-negative patients 751 patients 137 HR 175 95 CI 54-565 Moreover of the 75 patients who were tested for ctDNA chronologically 14 out of 15 ctDNA-positive patients 933 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 142 months while the median time to detection of positive ctDNA was 55 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
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None