Efficacy and Safety of Conventional Neoadjuvant Therapy Versus Total Neoadjuvant Therapy in Older Patients With Locally Advanced Rectal Cancer: a Multicentre, Open-label, Randomised Pragmatic Clinical Trial
试验速览
- 阶段
- 不适用
- 状态
- 招募中
- 入组人数
- 230
- 试验地点
- 35
- 主要终点
- Overall survival
研究概览
简要总结
The SHAPERS study is a multicentre, open-label, randomised, pragmatic clinical trial, comparing standard-of-care neoadjuvant treatment options for older (i.e., ≥70 years) subjects with high-risk stage II and stage III rectal cancer.
详细描述
The SHAPERS study is a multicentre, open-label, randomised, pragmatic clinical trial, comparing standard-of-care neoadjuvant treatment options for older (i.e., ≥70 years) subjects with high-risk stage II and stage III rectal cancer.
Subjects meeting all eligibility criteria will be randomised in a 1:1 ratio to either the conventional arm or the TNT arm (The study design is shown in figure 3.1 and 3.2).
Conventional arm consists of:
- SCRT (5 fractions of 5 Gy), followed by
- Surgery (according to the principles of TME) or watch & wait, followed by
- Optional adjuvant chemotherapy OR
- LCCRT (25-28 fractions of 1.8-2.0 Gy each +/- a boost to the primary tumour and involved lymph nodes, for a total of 50-56 Gy of radiation combined with either continuous infusion fluorouracil or capecitabine) followed by
- Surgery (according to the principles of TME) or watch & wait, followed by
- Optional adjuvant chemotherapy
TNT arm Different treatment regimens can be used in the TNT arm including Rapido, Rapido light, OPRA INCT-CRT or OPRA CRT-CNCT. The regimen to use will be decided by the investigator and will need to be declared before randomisation. No switch between regimens is allowed during the study treatment period.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Health Services Research
- 盲法
- None
入排标准
- 年龄范围
- 70 Years 至 —（Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age ≥ 70 years old
- •ECOG performance status (PS):
- •≤1 if age > 75 years old
- •≤2 if age ≤ 75 years old
- •Histologically or cytologically confirmed adenocarcinoma of the rectum
- •Distal border of the tumour below the peritoneal reflection and within 15 cm of the anal verge
- •Operable stage III or high-risk stage II rectal cancer (high-risk tumours defined as those having ≥1 of the following features: T4, mesorectal fascia (MRF) involvement/threatening [i.e.,tumour within 1 mm of the MRF], extramural venous invasion). Patient with involvement of lateral pelvic lymph nodes are also eligible.
- •Adequate bone marrow function as defined below:
- •Absolute neutrophil count ≥1,500/µL
- •Haemoglobin ≥9 g/dL
- •Platelets ≥100,000/µL
- •Adequate liver function as defined below:
- •Serum total bilirubin ≤1.5 x ULN. In case of known Gilbert's syndrome <3xUNL is allowed
- •AST (SGOT) and ALT (SGPT) ≤2.5 x ULN
- •Alkaline phosphatase ≤2.5 x ULN
- •Adequate renal function as defined by estimated glomerular filtration rate (GFR) ≥30 mL/min/1.73m² (according to the CKD-EPI 2021 equation).
- •Absence of clinical conditions that in the opinion of the investigator, would contraindicate neoadjuvant therapy and/or surgery.
- •Signed Informed Consent form (ICF) obtained prior to any study related procedure.
- •Male subjects with partners of childbearing potential must agree to use condom during the course of this study and for at least 6 months after the last administration of study drugs.
排除标准
- •Extensive growth into cranial part of the sacrum (above S2/3 junction) or the lumbosacral nerve roots indicating that surgery will never be possible even if substantial tumour down-sizing is achieved.
- •Presence of metastatic disease or recurrent rectal tumour.
- •Presence of grade ≥2 peripheral neuropathy according to the Common Toxicity Criteria for Adverse Events (CTCAE) v.5.
- •Significant medical, neuro-psychiatric, or surgical condition, currently uncontrolled by treatment, which, in the principal investigator's opinion, may interfere with completion of the study.
- •Any contraindication to pelvic irradiation as evaluated by the investigator.
- •Known hypersensitivity reactions to the study drugs or to any excipients, premedications or non-investigational medicinal products or concomitant medications.
- •Any investigational anti-cancer therapy other than the protocol specified therapies (participation in other prospective studies which do not imply any specific intervention may be allowed after discussion with the Study Chair).
- •Patients with a prior or concurrent malignancy whose natural history or treatment has the potential to interfere with the safety or efficacy assessment.
- •Clinically significant (i.e., active) cardiovascular disease: cerebral vascular accident/stroke, myocardial infarction, unstable angina, congestive heart failure (grade III or IV as classified by the New York Heart Association), or serious cardiac arrhythmia requiring medication within the past 6 months.
- •Complete dihydropyrimidine dehydrogenase (DPD) deficiency.
- •Any previous treatment for rectal cancer.
- •Use of brivudine, sorivudine or their chemically related analogues.
研究组 & 干预措施
Conventional arm
- SCRT (5 fractions of 5 Gy)
- Surgery (according to the principle of TME) or watch & wait
- Optional adjuvant chemotherapy
OR
- LCCRT (25-28 fractions of 1.8-2.0 Gy each +/- a boost to the primary tumour and involved lymph nodes, for a total of 50-56 Gy of radiation combined with either continuous infusion fluorouracil or capecitabine) followed by
- Surgery (according to the principles of TME) or watch & wait, followed by
- Optional adjuvant chemotherapy
干预措施: Short course radiotherapy (Radiation)
Conventional arm
- SCRT (5 fractions of 5 Gy)
- Surgery (according to the principle of TME) or watch & wait
- Optional adjuvant chemotherapy
OR
- LCCRT (25-28 fractions of 1.8-2.0 Gy each +/- a boost to the primary tumour and involved lymph nodes, for a total of 50-56 Gy of radiation combined with either continuous infusion fluorouracil or capecitabine) followed by
- Surgery (according to the principles of TME) or watch & wait, followed by
- Optional adjuvant chemotherapy
干预措施: Adjuvant chemotherapy (optional) (Drug)
Conventional arm
- SCRT (5 fractions of 5 Gy)
- Surgery (according to the principle of TME) or watch & wait
- Optional adjuvant chemotherapy
OR
- LCCRT (25-28 fractions of 1.8-2.0 Gy each +/- a boost to the primary tumour and involved lymph nodes, for a total of 50-56 Gy of radiation combined with either continuous infusion fluorouracil or capecitabine) followed by
- Surgery (according to the principles of TME) or watch & wait, followed by
- Optional adjuvant chemotherapy
干预措施: Total mesorectal excision (Procedure)
Conventional arm
- SCRT (5 fractions of 5 Gy)
- Surgery (according to the principle of TME) or watch & wait
- Optional adjuvant chemotherapy
OR
- LCCRT (25-28 fractions of 1.8-2.0 Gy each +/- a boost to the primary tumour and involved lymph nodes, for a total of 50-56 Gy of radiation combined with either continuous infusion fluorouracil or capecitabine) followed by
- Surgery (according to the principles of TME) or watch & wait, followed by
- Optional adjuvant chemotherapy
干预措施: Long course chemoradiotherapy (Radiation)
TNT arm
Rapido regimen:
- SCRT (5 fractions of 5 Gy)
- Up to 18 weeks of oxaliplatin based chemotherapy (mFOLFOX6 or CAPOX)
- Surgery (according to the principle of TME) or "watch & wait"
Or
Rapido light regimen:
- SCRT
- Up to 12 weeks of oxaliplatin based chemotherapy
- Surgery or "watch & wait"
Or
OPRA with induction chemotherapy (INCT-CRT) regimen:
- Up to 16 weeks of oxaliplatin-based chemotherapy
- CRT (25-28 fractions of 1.8-2.0 Gy each +/- a boost to the primary tumour and involved lymph nodes, for a total of 50-56 Gy of radiation combined with either continuous infusion fluorouracil or capecitabine)
- Surgery or "watch & wait"
Or
OPRA with consolidation chemotherapy (CRT-CNCT) regimen:
- CRT
- Up to 16 weeks of oxaliplatin-based chemotherapy
- Surgery or "watch & wait"
干预措施: Total mesorectal excision (Procedure)
TNT arm
Rapido regimen:
- SCRT (5 fractions of 5 Gy)
- Up to 18 weeks of oxaliplatin based chemotherapy (mFOLFOX6 or CAPOX)
- Surgery (according to the principle of TME) or "watch & wait"
Or
Rapido light regimen:
- SCRT
- Up to 12 weeks of oxaliplatin based chemotherapy
- Surgery or "watch & wait"
Or
OPRA with induction chemotherapy (INCT-CRT) regimen:
- Up to 16 weeks of oxaliplatin-based chemotherapy
- CRT (25-28 fractions of 1.8-2.0 Gy each +/- a boost to the primary tumour and involved lymph nodes, for a total of 50-56 Gy of radiation combined with either continuous infusion fluorouracil or capecitabine)
- Surgery or "watch & wait"
Or
OPRA with consolidation chemotherapy (CRT-CNCT) regimen:
- CRT
- Up to 16 weeks of oxaliplatin-based chemotherapy
- Surgery or "watch & wait"
干预措施: Total neoadjuvant therapy (Combination Product)
结局指标
主要结局
Overall survival
时间窗: At 3 years after randomisation
Overall survival (OS) will be calculated from randomisation to death from any cause.
Any grade peripheral sensory neuropathy
时间窗: At 3 years after randomisation
Any grade peripheral sensory neuropathy as assessed by the investigator according to the NCI-CTCAE v5.0 will be analysed.
Progression-free survival
时间窗: At 3 years after randomisation
Progression-free survival (PFS) will be calculated from randomisation to any of the following events: unresectable tumour due to local tumour progression, R2 resection of the primary tumour, loco-regional recurrence after an R0/R1 resection, distant metastases, or death from any cause.
Grade ≥3 toxicities during treatment
时间窗: At 3 years after randomisation
Grade ≥3 toxicities during treatment (i.e., from the 1st day of treatment until the EOT visit) as assessed by the investigator according to the NCI-CTCAE v5.0 will be analysed.
次要结局
未报告次要终点