Ploidy and Stroma in Early Rectal Cancer

• Sponsor: Oxford University Hospitals NHS Trust (Other)
• Overall Status: Completed
• CT.gov ID: NCT03039595
• Collaborator: Oslo University Hospital (Other)
• Enrollment: 150
• Location: 1
• Actual Duration (Months): 28.1
• Patients Per Site Per Month: 5.3

Study Details

Study Description

Brief Summary

Early rectal cancer can be removed by minimally-invasive surgery, and the standard pathological assessment of the removed tumour gives valuable information about how advanced the tumour is. This gives an indication of how likely the cancer is to recur, so doctors and patient can decide on the most appropriate further treatment and follow-up. However there is still much uncertainty in these predictions about recurrence. This study will assess two further pathology tests, ploidy and stroma ratio in the tumour, by correlating the results with outcome. This will determine whether these two tests provide additional value in predicting outcome. If so, clinicians would be better able to advise patients with early rectal cancer about their prognosis and further management.

Condition or Disease	Intervention/Treatment	Phase
Rectal Cancer	Other: Ploidy and tumour:stromal ratio measurements

Detailed Description

Early rectal cancer can be removed by minimally-invasive surgery, and the standard pathological assessment of the removed tumour gives valuable information about how advanced the tumour is. This information is very important in indicating whether the cancer is likely to recur, and therefore in advising the patient after surgery whether further treatment is advisable, and if not, what is the most appropriate follow-up regime. However there is still a lot of uncertainty in these predictions about recurrence of the cancer, and better tests are being sought. This study aims to look at two further pathology tests, ploidy and stroma ratio in the tumour, and correlate these test results with outcome in patients who have had an early rectal cancer removed. This will allow the investigators to assess whether these two tests provide additional value in predicting outcome. If so, clinicians would be better able to advise patients with early rectal cancer about their prognosis and further management.

Routine histopathology analysis of a rectal cancer specimen removed at surgery includes assessment of tumour size, depth of invasion, vascular, lymphatic and perineural invasion, tumour involvement of resection margins and nodal involvement. This information is valuable in predicting outcome. For example, predicted rates of local recurrence at 36 months following local excision of rectal cancer by transanal endoscopic microsurgery (TEM) based on tumour size, depth of invasion and lymphatic invasion have been tabulated. However such models are not perfect, and leave room for improvement. Ploidy and stroma ratio are two further tests which have shown some promise in predicting outcome.

Ploidy refers to the number of sets of chromosomes in a cell nucleus. Most human cells are normally diploid, with two sets of 23 chromosomes. Abnormal tumour cells may have a different number of sets of chromosomes, or be aneuploid, having some replicated or deleted chromosomes. In general, aneuploidy in cancer cells is associated with a worse prognosis. An early study of DNA ploidy in rectal cancer using flow cytometry showed an independent but small predictive effective of aneuploidy on survival. Technological advances now allow more accurate and detailed assessment of ploidy. The DNA ploidy status of tumour cells in early ovarian cancer has been found to predict which patients will benefit from adjuvant chemotherapy after surgery to remove the ovarian tumour and is used routinely in some centres to aid in decision-making.

Stroma ratio refers to the tumour: stroma ratio. A lower proportion of tumour cells or, conversely, a higher percentage of stroma, in a cancer tends to be associated with a poorer prognosis. This ratio has been found to be strongly associated with tumour growth and invasion in colorectal cancers, and to independently predict survival in patients undergoing surgery to removal colorectal tumours. However previous studies have looked mainly at more advanced colon cancers, rather than early rectal cancers, and have used only cancer-related death as the endpoint, rather than looking at local recurrence and response to adjuvant treatments.

Study Design

• Study Type: Observational
• Actual Enrollment: 150 participants
• Observational Model: Cohort
• Time Perspective: Other
• Official Title: An Observational Study to Correlate the Results of Ploidy and Stroma Analysis With Prognosis in Early Rectal Cancer
• Actual Study Start Date: Mar 29, 2017
• Actual Primary Completion Date: May 31, 2019
• Actual Study Completion Date: Jul 31, 2019

Outcome Measures

Primary Outcome Measures

1. Correlation Between Ploidy Status With Local Recurrence of Cancer [a minimum of 6 months after surgery]

   Results of ploidy status will be correlated with patient follow-up information for between 6 months and 9 years following surgery, to look for any correlation with local recurrence of the rectal cancer

2. Correlation Between Tumour: Stroma Ratio With Local Recurrence of Cancer [a minimum of 6 months after surgery]

   Results of tumour:stromal ratio (TSR) will be correlated with patient follow-up information for between 6 months and 9 years following surgery, to look for any correlation with local recurrence of the rectal cancer. A 50% cut-off is used to define high TSR.

Secondary Outcome Measures

1. Correlation Between Ploidy Status and Overall Survival After TEM Surgery to Remove Rectal Cancer [a minimum of 6 months after surgery]

   Results of ploidy status will be correlated with patient follow-up information for between 6 months and 9 years following surgery, to look for any correlation between the test results and overall survival

2. Correlation Between Tumour:Stroma Ratio and Overall Survival After TEM Surgery to Remove Rectal Cancer [a minimum of 6 months after surgery]

   Results of tumour:stromal ratio (TSR) will be correlated with patient follow-up information for between 6 months and 9 years following surgery, to look for any correlation between the test results and overall survival. High TSR is defined using a 50% cut-off.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Participant is willing and able to give informed consent (in English) for participation in the study, or gave informed consent for donation of tissue for research at the time of surgery

• Male or Female, aged 18 years or above

• Diagnosed with operable rectal cancer

• Due to undergo, or has already undergone, TEM surgery to remove rectal cancer

• A useable tissue sample has already been, or will be, taken as part of routine surgery

Exclusion Criteria:

• Age less than 18

• Adults who are not able to give consent or who are deemed vulnerable

• Participants who do not have a useable tissue sample will be excluded

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Churchill Hospital	Oxford		United Kingdom	OX3 7LE

Sponsors and Collaborators

• Oxford University Hospitals NHS Trust
• Oslo University Hospital

Investigators

• Principal Investigator: Chris Cunningham, MD, Employee

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Oct 21, 2016

More Information

Publications

• Bach SP, Hill J, Monson JR, Simson JN, Lane L, Merrie A, Warren B, Mortensen NJ; Association of Coloproctology of Great Britain and Ireland Transanal Endoscopic Microsurgery (TEM) Collaboration. A predictive model for local recurrence after transanal endoscopic microsurgery for rectal cancer. Br J Surg. 2009 Mar;96(3):280-90. doi: 10.1002/bjs.6456.
• Downey CL, Simpkins SA, White J, Holliday DL, Jones JL, Jordan LB, Kulka J, Pollock S, Rajan SS, Thygesen HH, Hanby AM, Speirs V. The prognostic significance of tumour-stroma ratio in oestrogen receptor-positive breast cancer. Br J Cancer. 2014 Apr 2;110(7):1744-7. doi: 10.1038/bjc.2014.69. Epub 2014 Feb 18.
• Goh HS, Jass JR, Atkin WS, Cuzick J, Northover JM. Value of flow cytometric determination of ploidy as a guide to prognosis in operable rectal cancer: a multivariate analysis. Int J Colorectal Dis. 1987 Feb;2(1):17-21.
• Kristensen GB, Kildal W, Abeler VM, Kaern J, Vergote I, Tropé CG, Danielsen HE. Large-scale genomic instability predicts long-term outcome for women with invasive stage I ovarian cancer. Ann Oncol. 2003 Oct;14(10):1494-500.
• Park JH, Richards CH, McMillan DC, Horgan PG, Roxburgh CSD. The relationship between tumour stroma percentage, the tumour microenvironment and survival in patients with primary operable colorectal cancer. Ann Oncol. 2014 Mar;25(3):644-651. doi: 10.1093/annonc/mdt593. Epub 2014 Jan 23.
• West NP, Dattani M, McShane P, Hutchins G, Grabsch J, Mueller W, Treanor D, Quirke P, Grabsch H. The proportion of tumour cells is an independent predictor for survival in colorectal cancer patients. Br J Cancer. 2010 May 11;102(10):1519-23. doi: 10.1038/sj.bjc.6605674. Epub 2010 Apr 20.

• Responsible Party: Chris Cunningham, Consultant colorectal surgeon, Oxford University Hospitals NHS Trust
• ClinicalTrials.gov Identifier: NCT03039595
• Other Study ID Numbers: 11846
• First Posted: Feb 1, 2017
• Last Update Posted: Jun 9, 2022
• Last Verified: Mar 1, 2022

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Chris Cunningham, Consultant colorectal surgeon, Oxford University Hospitals NHS Trust: Early rectal cancer; Ploidy; Tumour:stroma ratio
• Additional relevant MeSH terms: Rectal Neoplasms

Study Results

Participant Flow

Arm/Group Title	Patients
Arm/Group Description	All patients. This is an observational study; no interventions were used.
Period Title: Overall Study
STARTED	150
COMPLETED	143
NOT COMPLETED	7

Baseline Characteristics

Arm/Group Title	Patients
Arm/Group Description	All patients
Overall Participants	143
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	69
Sex: Female, Male (Count of Participants)
Female	56 39.2%
Male	87 60.8%
Race and Ethnicity Not Collected (Count of Participants)
Region of Enrollment (participants) [Number]
United Kingdom	143 100%
Tumour stage (Count of Participants)
pT1 (tumour confined to the inner layer of the bowel)	76 53.1%
pT2 (tumour extends into the muscle layer of the bowel wall)	58 40.6%
pT3 (tumour has reached the outer lining of the bowel wall)	9 6.3%
Post-TEM management (Count of Participants)
Surveillance	88 61.5%
Completion radical surgery	13 9.1%
Adjuvant radiotherapy	42 29.4%

Outcome Measures

1. Primary Outcome

Title	Correlation Between Ploidy Status With Local Recurrence of Cancer
Description	Results of ploidy status will be correlated with patient follow-up information for between 6 months and 9 years following surgery, to look for any correlation with local recurrence of the rectal cancer
Time Frame	a minimum of 6 months after surgery

Outcome Measure Data

Analysis Population Description

Only patients for whom ploidy status was available were included in the analysis (ploidy assessment failed in 3 patients for technical reasons)

Arm/Group Title	Patients
Arm/Group Description	All patients
Measure Participants	140
Diploid - Local recurrence	3 2.1%
Diploid - No local recurrence	31 21.7%
Non-diploid - Local recurrence	14 9.8%
Non-diploid - No local recurrence	92 64.3%

2. Primary Outcome

Title	Correlation Between Tumour: Stroma Ratio With Local Recurrence of Cancer
Description	Results of tumour:stromal ratio (TSR) will be correlated with patient follow-up information for between 6 months and 9 years following surgery, to look for any correlation with local recurrence of the rectal cancer. A 50% cut-off is used to define high TSR.
Time Frame	a minimum of 6 months after surgery

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Patients
Arm/Group Description	All patients
Measure Participants	143
High TSR - Local recurrence	2 1.4%
High TSR - No local recurrence	9 6.3%
Low TSR - Local recurrence	17 11.9%
Low TSR - No local recurrence	115 80.4%

3. Secondary Outcome

Title	Correlation Between Ploidy Status and Overall Survival After TEM Surgery to Remove Rectal Cancer
Description	Results of ploidy status will be correlated with patient follow-up information for between 6 months and 9 years following surgery, to look for any correlation between the test results and overall survival
Time Frame	a minimum of 6 months after surgery

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Patients
Arm/Group Description	All patients
Measure Participants	140
Diploid - Alive	27 18.9%
Diploid - Deceased	7 4.9%
Non-diploid - Alive	86 60.1%
Non-diploid - Deceased	20 14%

4. Secondary Outcome

Title	Correlation Between Tumour:Stroma Ratio and Overall Survival After TEM Surgery to Remove Rectal Cancer
Description	Results of tumour:stromal ratio (TSR) will be correlated with patient follow-up information for between 6 months and 9 years following surgery, to look for any correlation between the test results and overall survival. High TSR is defined using a 50% cut-off.
Time Frame	a minimum of 6 months after surgery

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Patients
Arm/Group Description	All patients
Measure Participants	143
High TSR - Alive	6 4.2%
High TSR - Deceased	5 3.5%
Low TSR - Alive	110 76.9%
Low TSR - Deceased	22 15.4%

Adverse Events

Time Frame	Up to 12 years following surgery
Arm/Group Title	Patients
Arm/Group Description	All patients
All Cause Mortality
	Patients
	Affected / at Risk (%)	# Events
Total	27/143 (18.9%)
Serious Adverse Events
	Patients
	Affected / at Risk (%)	# Events
Total	0/143 (0%)
Other (Not Including Serious) Adverse Events
	Patients
	Affected / at Risk (%)	# Events
Total	0/143 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.