Preoperative Chemoradiotherapy With Raltitrexed for Intermediate or Locally Advanced Rectal Cancer in the Fit Elderly

Study Overview
=================
Brief Summary
-----------------
The aim of this multicenter phase II study is to evaluate the response rate, local control, disease-free survival and treatment-related toxicity of preoperative chemoradiation for intermediate or locally advanced rectal cancer in the fit elderly.

Detailed Description
-----------------
The concurrent chemoradiotherapy has become the standard treatment for patients with intermediate or locally advanced rectal cancer. However, the data from prospective trial for elderly patients is still lacking. The aim of this multicenter phase II study is to evaluate the response rate, local control, disease-free survival and treatment-related toxicity of preoperative chemoradiation with Raltitrexed for intermediate or locally advanced rectal cancer in the fit elderly aged 70 years above. And all the participants have to be evaluated by comprehensive geriatric assessment (CGA). Clinical stage was evaluated by chest and abdominal computed tomography, endorectal ultrasound, and/or pelvic magnetic resonance imaging. 5 weeks after the preCRT, the multi-disciplinary team decided the following treatment of patients based on imaging evaluation. Surgical resection would be done with a minimum interval of 6 weeks after the last radiation. Acute toxicity was evaluated during and within 2 weeks after CRT. Toxicities were assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. Sample size consideration.It has been calculated that 68 patients will need to be included, according to the following assumptions: Recruitment period of 24 months. Minimum follow-up period of 24 months. We estimated that 51 patients were required to test the hypothesis that the 2-year DFS was equal to or greater than 78% with 80% power and to reject the hypothesis that the 2-year DFS rate was less than 63% at a significance level of 5% (one sided).Taking into account that a 5% percentage of losses, 20% of patients will refuse surgery, 68 patients are expected to be included in the study. The interim analysis design. An interim safety evaluation will be carried out when 39 patients have finished their preoperative CRT. As the tolerance of elderly patients for nonhematological toxicities (such as diarrhoea) was often more poor than hematological toxicities, we estimated that 39 patients were required to test the hypothesis that the nonhematological G3 or higher acute toxicities rate was equal to or less than 21% ( safety result of patients aged 70 years or older from ACCOR12/PRODIGE 2 phase III trial) with 80% power and to reject the hypothesis that the rate was more than 36% at a significance level of 10% (one sided). If nonhematological G3 or higher acute toxicites is observed in12 or more patients, the H0 hypothesis will be rejected, and the protocal should be re-evaluated. Biospecimen Retention. Blood, plasma, feces and tissue (optional). Feces were collected before any treatment. Peripheral blood samples of 10-20mL were collected from the patients for CTCs analysis, exploration analysis for frailty and tumor marker before and after preCRT, before and after surgery, and then on each follow up visit, according to our study protocal.

Official Title
-----------------
Multicenter, Phase II Study of Preoperative Chemoradiotherapy With Raltitrexed for Intermediate or Locally Advanced Rectal Cancer in the Fit Elderly

Conditions
-----------------
Rectal Neoplasms Malignant

Intervention / Treatment
-----------------
* Radiation: Preoperative radiation
* Drug: Raltitrexed
* Procedure: Pelvic surgery


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Rectal adenocarcinoma, clinical stage II/III(T3-4 or N+, AJCC 7th), and fulfils the intermediate or locally advanced risk category standard of ESMO recal cancer clinical practice guidelines 2013. KPS status no less than 70; Charlson comorbidity no more than 2; Fit status evaluated by CGA. Life expectancy more than 6 months. Hemoglobin >= 100g/L, white blood cell >= 3.5*10E9/L, neutrophil >= 1.5*10E9/L, platelet >= 100*10E9/L. Creatin normal, Total bilirubin normal, AST and AST normal, AKP normal. Do not receive surgery ( except palliative colostomy) or chemotherapy or other anti-cancer treatment. No previously pelvic irradiation history. Through MDT discussion, the patient is considered to be candidate for preoperative CRT followed by surgery. Informed consent signed. Exclusion Criteria: Other cancer history, except curable non-melanoma skin cancer or cervix in-situ carcinoma. Allergy history to analog of quinazoline folate. Active infection existed. Severe complication, such as acute myocardial infarction in 6 months, uncontrolled diabetes ( Plasma glucose concentrations in any time of a day≥11.1mmol/L）, severe cardiac arrhythmia, etc. Anticipate other clinical trials in four weeks before enrollment.

Ages Eligible for Study
-----------------
Minimum Age: 71 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: preCRT+surgery<br>Treatment including preoperative chemoradiotherapy (preoperative radiation with concurrent chemotherapy) with Raltitrexed followed by surgery. Radiotherapy will be delivered to a planning target volume with a dose of 45-50.4Gy (1.8-2.0Gy daily) using with Intensity-Modulated Radiotherapy or Volumetric-Modulated Arc Therapy technique. During the radiation treatment, concurrent chemotherapy will be delivered (Raltitrexed, intravenous infusion, 3 mg/m2, on d1 and d22). Pelvic surgery is planned 6 weeks after completion of CRT based on the decision of MDT. | Radiation: Preoperative radiation<br>* Radiation treatment before surgery<br>* Other names: Preoperative radiotherapy;Drug: Raltitrexed<br>* concurrent chemotherapy<br>* Other names: Raltitrexed Injection;Procedure: Pelvic surgery<br> <br> |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 2-year disease-free survival probability (%) | The probability of staying free from recurrence at 2 year after surgery or clinical complete response of tumor validated on imaging or pathological examination. | 2 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 5-year overall survival probability | The probability of staying alive at 5 year after surgery or end of CRT (for those who did not receive surgery). | 5 year | 
| 5-year cancer-specific survival probability | The probability of staying free from death caused by cancer at 5 year after surgery or end of CRT (for those who did not receive surgery). | 5 year | 
| The ratio of patients occured pCR | The ratio of patients occured pathological complete response of tumor. | 2 weeks after surgery | 
| The ratio of patients occured Grade 3 or higher adverse events. |  | During chemoradiotherapy and within 180 days after surgery | 
| QOL | The quality of life assessment score by EORTC QLQ-C30 and EORTC QLQ-CR29. | Before and after chemoradiotherapy and surgery, and then follow up for 3 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
elderly patients, rectal cancer, preoperative chemoradiotherapy, comprehensive geriatric assessment