Neoadjuvant Chemoradiotherapy and Consolidation Chemotherapy for Rectal Cancer: A Randomized Controlled Trial
Phase: NA
Conditions: Rectal Neoplasms
Sponsor: Larissa University Hospital

COVER PAGE
Study Protocol
OFFICIAL  TITLE:  Neoadjuvant  Chemoradiotherapy  and 
Consolidation  Chemotherapy  for  Rectal  Cancer:  A  Randomized 
Controlled Trial
BRIEF TITLE: Neoadjuvant Chemoradiotherapy and Consolidation Chemotherapy for Rectal Cancer
UNIQUE PROTOCOL ID: NCCCRC
DOCUMENT DATE: August 2022
Principal Investigator:
Konstantinos Perivoliotis, MD
Telephone: 00302413501000
Email: kperi19@gmail.com
Sub-Investigators:
Ioannis Baloyiannis
Ioannis Samaras
Athanasios Kotsakis
Georgios Kyrgias
Study Director
George Tzovaras, Professor of General Surgery
Telephone: 00302413502804
Email: gtzovaras@hotmail.com
Department of Surgery
University Hospital of Larissa
Mezourlo 41110 Larissa
Greece
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1. INTRODUCTION
1.1 Literature Review
Colorectal  cancer  is  the  second  leading  cause  of cancer-related  deaths  worldwide.  It  is 
estimated that 10% of cancer mortality is attributed to malignant neoplasms of the colon and 
rectum [1]. More specifically, in the United States alone, 53,200 colorectal cancer deaths were 
reported [2].
The current treatment of choice for locally advanced rectal cancer (Stage II/ III) is the 
combination of neoadjuvant chemoradiation followed by radical surgical resection based on the 
principles of total mesorectal excision (TME) after a 8-12 weeks period [3]. Therapy is usually 
completed  with  the  administration  of  adjuvant  chemotherapy  based  on  oxaliplatin  and 
fluoropyrimidines. This combined approach allowed the reduction of local recurrence at levels 
around 5%. Despite the impressive results in local control, the same was not confirmed for the 
long-term, overall survival. Possible explanations to that are: a) the compliance and completion of 
the treatment schemes during the postoperative period were low and b) there was a delay in the 
administration  of  adjuvant  chemotherapy;  both  could  lead  to  subclinical  metastatic  disease 
progression [4].
On the basis of achieving both goals, (i.e., local control through neoadjuvant radiotherapy and 
metastatic disease control through systemic chemotherapy) the administration of the two therapies 
in the preoperative period was proposed, in the form of combined or total neoadjuvant therapy [1, 
5–8].
Additional theoretical benefits of total neoadjuvant therapy are faster defunctioning stoma 
reversal, as well as the possibility of a more accurate evaluation of the tumor biological behavior, 
thus enabling a safer staging for patients who would be candidates for a watch and wait protocol 
[1–3, 5–12]. Furthermore, for patients who will eventually undergo surgery, total neoadjuvant 
therapy could probably increase R0 resection and sphincter-preservation rates [3, 5, 8– 10, 12].
However, many researchers question the safety and efficacy of total neoadjuvant therapy [7, 
13]. First, the administration of neoadjuvant chemotherapy significantly increases the risk of 
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severe toxicity from cytotoxic agents [14]. At the same time, according to the results of one of the 
largest prospective randomized trials, the addition of neoadjuvant chemotherapy into the treatment 
algorithm did not offer any advantage in the pathological response, 5-year overall and disease-free 
survival rates [15]. Finally, there is considerable heterogeneity in the current literature, most likely 
reflecting the different schemes used in different trials regarding the radiotherapy regimen, the 
chemotherapy regimen as well as the sequence of each one in each protocol [16].
We believe it is difficult to interpret any differences in results when multiple parameters have 
been changed in a comparative trial [17]. For this reason, when testing our current standard 
neoadjuvant protocol to the new trend of total neoadjuvant therapy we decided to keep the same 
scheme and timing for the experimental group also, and the only parameter which is different is 
the use of the classic chemotherapy scheme during the waiting period following chemoradiation 
and before surgery [18].
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2. OBJECTIVE 
2.1 Description of the proposed project
The purpose of this protocol is to compare neoadjuvant chemoradiation plus consolidation 
chemotherapy before surgical resection with the standard neoadjuvant chemoradiation followed 
by surgical resection and adjuvant chemotherapy in patients with rectal cancer.
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3. MATERIAL AND METHODS
3.1 Population
The sample will consist of males and females aged 18 to 80 years.
3.2 Diseases
The study will include patients with rectal cancer that will meet the current criteria for 
neoadjuvant chemoradiotherapy, and surgical resection based on the principles of total mesorectal 
excision (TME).
3.3 Inclusion / Exclusion Criteria
Inclusion criteria are the following [10]:
• Histologically confirmed rectal adenocarcinoma
• cT3, cT4, threatened CRM / MRF, EMVI (+), ≥N1
• Multidisciplinary tumor board decision for neoadjuvant treatment
• Tumor distance from the anal verge 15 cm based on endoscopy or magnetic resonance 
imaging
• Patient 18 to 80 years old
• General health condition status WHO 0-1
• Absence of co-morbidities that may affect treatment
• Neutrophils >1,500 / mm3, platelets >100,000 / mm3, hemoglobin> 10 g / dL, normal 
creatinine, and creatinine clearance> 50 mL / min
• Signed informed consent of the patient
Exclusion criteria are the following:
• Distant metastases
• Non-resectable cancer
• Contraindications for the administration of chemotherapy
• Previous pelvic radiotherapy or chemotherapy
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• History of inflammatory bowel disorders
• History of angina, acute myocardial infarction or heart failure
• Active sepsis or systemic infection
• Untreated physical and mental disability
• Synchronous malignancy
• Pregnancy or breast-feeding
• Lack of compliance with the protocol process
• Non-granting of signed informed consent
3.4 Study Arms
In this study there will be two arms [5, 10]. Patients that are randomized in the first arm will 
receive  neoadjuvant  chemoradiotherapy  and  consolidation  chemotherapy  and  then  undergo 
surgical resection of the tumor. In the second arm, patients will receive the standard long-course 
neoadjuvant chemoradiotherapy regimen and then undergo tumor resection. The treatment will be 
completed with adjuvant chemotherapy. In both groups, surgery will follow the principles of total 
mesorectal excision (TME).
The control group will receive the standard 5-week neoadjuvant chemoradiotherapy regimen. 
Six weeks after completion the patient will be re-staged with rectal MRI and depending on the 
response will be operated (TME): immediately in case of non-response (mrTRG 5) or after an 
additional 6-week delay (overall 12 weeks after the end of chemoradiotherapy) in case of partial 
response (mrTRG 2-4). Adjuvant chemotherapy will be, also, administered.
The experimental group will receive the standard 5-week neoadjuvant chemoradiotherapy 
(CRT). Thereafter, all patients will commence consolidation chemotherapy. At the 6th week after 
the end of CRT, patients will undergo MRI re-staging: In case of non-response (mrTRG 5) they 
will be submitted immediately to surgery, and, subsequently, excluded from the trial. In case of 
response (mrTRG 2-4) they will receive consolidation chemotherapy for the whole waiting period 
between the end of CRT and surgery - 12 weeks.
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The following interventions will be introduced:
Neoadjuvant Chemoradiotherapy. 5-week neoadjuvant radiotherapy regimen (28 x 1.8 Gy) 
combined with Capecitabine (bid 800 mg/m2, twice daily, on days 1-33-38)
Consolidation Chemotherapy. CAPOX (Capecitabine bid1000 mg/m2 and Oxaliplatin 130 
mg/m2, day 1, every 3 weeks) or alternatively FOLFOX
Adjuvant Chemotherapy. 8 cycles of CAPOX (Capecitabine bid 1000 mg/m2, twice daily, day 
1-14, every 3 weeks and Oxaliplatin 130 mg/m2, day 1, every 3 weeks) or alternatively, 12 cycles 
of folinate, fluorouracil and oxaliplatin (FOLFOX)
3.5 Anesthesia
Patients will receive general anesthesia.
3.7 Primary endpoint
Disease Free Survival. Occurence of Disease Free Survival. If such an episode occurs, then it 
will be defined as=1 'YES' If such an episode does not occur, then it will be defined as=0 'NO'. 
[Time Frame: 3 years postoperatively]
3.8 Secondary endpoints
Secondary endpoints of the present study are:
Complete Pathological Response. Occurence of Complete Pathological Response. If such an 
episode occurs, then it will be defined as=1 'YES' If such an episode does not occur, then it will 
be defined as=0 'NO'. [Time Frame: 1 month postoperatively] 
Postoperative Complications. Occurence of postoperative complications based on the Clavien 
Dindo Classification [20]. If such an episode occurs, then it will be defined as=1 'YES' If such an 
episode does not occur, then it will be defined as=0 'NO'. [Time Frame: 1 month postoperatively] 
Length  of  Hospital  Stay.  Postoperative  time  that  the  patient  can  be  safely  discharged. 
Measurement unit: days. The patient will be discharged, when it is ensured that is medically safe 
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to be released. In particular, as the exit time of the patient, will be regarded the time that the 
patient will fulfil the Clinical Discharge Criteria. [Time Frame: Maximum time frame 39 days 
postoperatively] 
Readmission. Occurence of postoperative readmission. If such an episode occurs, then it will 
be defined as=1 'YES' If such an episode does not occur, then it will be defined as=0 'NO'. [Time 
Frame: 1 month postoperatively] 
Negative Resection Margin. Occurence of Negative Resection Margin. If such an episode 
occurs, then it will be defined as=1 'YES' If such an episode does not occur, then it will be defined 
as=0 'NO'. [Time Frame: 1 month postoperatively] 
Overall Survival. Occurence of Overall Survival. If such an episode occurs, then it will be 
defined as=1 'YES' If such an episode does not occur, then it will be defined as=0 'NO'. [Time 
Frame: 3 years postoperatively] 
Chemotherapy Toxicity. Occurence of Chemotherapy Toxicity. If such an episode occurs, 
then it will be defined as=1 'YES' If such an episode does not occur, then it will be defined as=0 
'NO'. [Time Frame: 3 years postoperatively] 
Local Recurrence. Occurence of Local Recurrence. If such an episode occurs, then it will be 
defined as=1 'YES' If such an episode does not occur, then it will be defined as=0 'NO'. [Time 
Frame: 3 years postoperatively] 
Treatment Compliance. Occurence of Treatment Compliance. If such an episode occurs, then 
it will be defined as=1 'YES' If such an episode does not occur, then it will be defined as=0 'NO'. 
[Time Frame: 3 years postoperatively] 
3.9 Calculation of the sample size
The sample size calculation was based on the primary endpoint. According to the literature, the 
disease-free survival Hazard Ratio between standard practice and combined neoadjuvant therapy is 
0.23 [21]. Therefore, for a prospective randomized study with alpha: 5%, power: 90% and dropout 
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rate: 15%, the estimated number of patients in each group is 42. A total of 84 patients will be 
required.
3.10 Randomization
The randomization of the patients will be performed using a dedicated software with a 1:1 
allocation ratio. The allocation group will be concealed with opaque envelopes.
3.11 Blindness
There will be no blindness at the level of the patient, the treating physicians (surgeon, 
oncologist, radiotherapist) and the researcher who will record the data.
3.12 Exit criteria
The patient will be discharged when it is ensured that is medically safe to be released. The exit 
time will be regarded as the time that the patient will fulfill the Clinical Discharge Criteria. More 
specifically, the patient should display the following: steady vital signs, fully oriented, without 
nausea or vomiting, mobilized with a steady gait and without a notable bleeding [22].
3.13 Monitoring
Following hospital discharge, the patient will be called for reassessment at one month after the 
operation. Patients will be included in the standard monitoring protocol (CT, MRI, cancer markers), 
unless otherwise required. At the same time, the pathological assessment of the specimen will be 
recorded. In addition, at 3 and 5 years postoperatively, overall, disease-free survival and recurrence 
rates will be recorded.
3.14 Medication
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Both preoperative and postoperative patient treatment will be standardized. The principles of the 
ERAS protocols will be applied to patients [23]. More specifically, antimicrobial prophylaxis will 
include the administration  of intravenous  antibiotics  within 60 minutes  prior to the onset of 
operation.  Patients  will  receive  preoperative,  mechanical  bowel  preparation  and  per-os 
antimicrobial prophylaxis. Prior to surgery, patients will abstain from solid and liquid foods for 6 
and 2 hours, respectively. The nasogastric tube will be removed postoperatively and repositioned 
only in case of ileus. Postoperative analgesia will include a multidisciplinary approach using 
analgesics (paracetamol, lornoxicam) in combination with dorsal or epidural analgesia. Opioid 
administration  will  be  avoided.  Postoperative  nausea  and  vomiting  prophylaxis  will  include 
granisetron 3mg / 3ml IV. Mechanical and pharmaceutical thromboprophylaxis will be used. A 
zero-balance approach to fluid losses will be applied. Mobilization will be initiated from the first 
postoperative day.  Feeding will be initiated on the basis of the intestinal function recovery.
3.15 Study Group
All participating members have years of experience in their field and have, therefore, completed 
the learning curve for the required techniques. Data collection and recording will be carried out by 
an independent, third party, researcher.
3.16 Conducting a Study
The study will be conducted in the Department of Surgery of University Hospital of Larissa in 
collaboration with the Oncology and Radiation Oncology Department of University Hospital. 
Patient data will be recorded both in the patient charts and in an electronic database. The required 
laboratory examinations will be defrayed by the patient insurance funds.
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4. LITERATURE
1. Liu S, Jiang T, Xiao L, et al (2021) Total Neoadjuvant Therapy (TNT) versus Standard 
Neoadjuvant Chemoradiotherapy for Locally Advanced Rectal Cancer: A Systematic Review 
and  Meta ‐ Analysis . Oncologist 26 :. https://doi.org/10.1002/onco.13824
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Locally  Advanced  Rectal  Cancer.  JAMA  Netw  Open  3:  e2030097. 
https://doi.org/10.1001/jamanetworkopen.2020.30097
3. Sutera P, Solomina J, Wegner RE, et al (2021) Post-Operative Morbidity and Mortality 
Following  Total  Neoadjuvant  Therapy  Versus  Conventional  Neoadjuvant 
Chemoradiotherapy in Locally Advanced Rectal Cancer. J Gastrointest Cancer 52: 976–982. 
https://doi.org/10.1007/s12029-020-00401-3
4. Chang  H,  Jiang  W,  Ye  WJ,  et  al  (2018)  Is  a  long  interval  from  neoadjuvant 
chemoradiotherapy to optimal surgery for rectal cancer in the era of intensity-modulated 
radiotherapy?  :  a  prospective  observational  study.  Onco  Targets  Ther  11:  6129–6138. 
https://doi.org/ 10.2147/OTT.S169985
5. Bahadoer RR, Dijkstra EA, van Etten B, et al (2021) Short-course radiotherapy followed by 
chemotherapy  before  total  mesorectal  excision  (TME)  versus  preoperative 
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7. Shi DD, Mamon HJ (2021) Playing With Dynamite? A Cautious Assessment of TNT. J Clin 
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16. Fang Y, Sheng C, Ding F, et al (2021) Adding Consolidation Capecitabine to Neoadjuvant 
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