局所進行直腸癌患者における術前FOLFOX対術後のリスク適応化学療法
局所進行直腸癌および局所失敗のリスクが低い患者における術前FOLFOX対術後リスク適応化学療法：ドイツ直腸癌研究グループの無作為化第III相試験
This is a multicenter, prospective, randomized, stratified, controlled, open-label study comparing preoperative FOLFOX versus postoperative risk-adapted chemotherapy in patients with locally advanced rectal cancer and low risk for local failure
調査の概要
状態
状態
条件
条件
介入・治療
介入・治療
詳細な説明
Patients with locally advanced rectal cancer are generally treated with preoperative 5-FU- or capecitabine-based chemo-radiotherapy (CRT) and total mesorectal excision (TME) surgery in order to decrease the rate of local failure. In patients with low risk for local failure in the middle third of the rectum (cT3a/b, N-) as determined with quality controlled MRI, the German S3 guidelines and the ESMO clinical practice guidelines state that neoadjuvant radiotherapy may be omitted. However, distant failure rate is still substantial in the range of 20-25% in these patients highlighting the need for more effective systemic treatment.
The hereby proposed ACO/ARO/AIO-18.2 randomized trial incorporates three novel aspects: (1) patient selection relies on strict and quality controlled MRI features and therefore identifies a cohort without imminent need for radiotherapy, (2) the sequence of chemotherapy and surgery is changed in a way that chemotherapy is administered preoperatively to increase the rate of patients treated with chemotherapy, and (3) three months of neoadjuvant FOLFOX or XELOX (instead of up to 6 months adjuvant chemotherapy) are used as a sole perioperative treatment in order to administer effective doses of the presumably most effective perioperative treatment at an early time point during the course of disease.
Thus, patients with locally advanced rectal cancer but low risk for local failure (cT1/2N+ in all thirds of the rectum, cT3a/b N- in the middle third, and cT3-4 Nany in the upper third) will be included and randomized between three months of neoadjuvant FOLFOX/XELOX in Arm A and primary resection of the tumor followed by risk (i.e. stage) adapted chemotherapy in Arm B.
研究の種類
研究の種類
入学 (実際)
入学
段階
段階
- フェーズ 3
連絡先と場所
研究場所
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-
-
Mannheim、ドイツ、68167
- Unversity Hospital Mannheim
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参加基準
適格基準
適格基準
就学可能な年齢
健康ボランティアの受け入れ
受講資格のある性別
説明
Inclusion Criteria:
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Male and female patients with histologically confirmed diagnosis of rectal adenocarcinoma localised 0 - 16 cm from the anocutaneous line as measured by rigid rectoscopy (i.e. lower, middle and upper third of the rectum), depending on MRI-defined inclusion criteria (see below).
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Staging requirements: High-resolution magnetic resonance imaging (MRI) of the pelvis is the mandatory local staging procedure.
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Transrectal endoscopic ultrasound (EUS) is used to help discriminate between T1/2 and early T3 tumors.
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MRI-defined inclusion criteria:
i. Lower third (0-6 cm):
- cT1/2 with clear cN+ based on defined MRI criteria or T3a-b (i.e. maximum infiltration into the perirectal fat of 5mm), provided CRM > 2mm and EMVI-** ii. Middle third (≥ 6-12 cm):
- cT1/2 with clear cN+ provided CRM- and EMVI-**
- cT3 irrespective of the depth of invasion into the perirectal fat, provided no evidence that tumor is adjacent to (defined as within 2 mm of) the mesorectal fascia on MRI (i.e. CRM > 2 mm), N0 or N1, EMVI-** iii. Upper third (≥ 12-16 cm):
- cT1/2 with clear cN+, irrespective of CRM and EMVI
- any cT3-4 irrespective of nodal status, CRM and EMVI.
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Spiral-CT of the abdomen and chest to exclude distant metastases.
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Aged at least 18 years. No upper age limit.
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WHO/ECOG Performance Status ≤1.
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Adequate haematological, hepatic, renal and metabolic function parameters:
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Leukocytes ≥ 3.000/mm³, ANC ≥ 2.000/mm³, platelets ≥ 100.000/mm³, Hb > 9 g/dl
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Serum creatinine ≤ 1.5 x upper limit of normal
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Bilirubin ≤ 2.0 mg/dl, SGOT-SGPT, and AP ≤ 3 x upper limit of normal.
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QTc interval (Bazett**) ≤ 440 ms
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Informed consent of the patient.
"**" Formula for QTc interval calculation (Bazett): QTc= ((QT) ̅" (ms)" )/√(RR (sec))= ((QT) ̅" (ms)" )/√(60/(frequency (1/min)))
Exclusion Criteria:
- Distant metastases (to be excluded by CT scan of the thorax and abdomen).
- Prior antineoplastic therapy for rectal cancer.
- Prior radiotherapy of the pelvic region.
- Major surgery within the last 4 weeks prior to inclusion.
- Subject pregnant or breast feeding, or planning to become pregnant within 6 months after the end of treatment.
- Subject (male or female) is not willing to use highly effective*** methods of contraception during treatment and for 6 months (male or female) after the end of treatment Male patients treated with Oxaliplatin should take legal advice concerning sperm conservation before start of therapy and should additionally use a condom during treatment period. Their female partner of childbearing potential should also use an appropriate contraceptive measure.
- On-treatment participation in a clinical study in the period 30 days prior to inclusion.
- Previous or current drug abuse.
- Other concomitant antineoplastic therapy.
- Serious concurrent diseases, including neurologic or psychiatric disorders (incl. dementia and uncontrolled seizures), active, uncontrolled infections, active, disseminated coagulation disorder.
- Clinically significant cardiovascular disease in (incl. myocardial infarction, unstable angina, symptomatic congestive heart failure, serious uncontrolled cardiac arrhythmia) ≤ 6 months before enrolment.
- Chronic diarrhea (> grade 1 according NCI CTCAE).
- Prior or concurrent malignancy ≤ 3 years prior to enrolment in study (Exception: non-melanoma skin cancer or cervical carcinoma FIGO stage 0-1), if the patient is continuously disease-free.
- Known allergic reactions or hypersensitivity on study medication or to any of the other excipients.
- Evidence of peripheral sensory neuropathy > grade 1 according to CTCAE version 5.0 (see appendix).
- Severe kidney dysfunction (creatinine clearance < 30 ml/min).
- Recent or concurrent treatment with brivudine.
- Pernicious or other megaloblastic anaemia caused by vitamin B12 deficiency.
- Known dihydropyrimidine dehydrogenase deficiency.
- Psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule (these conditions should be discussed with the patient before registration in the trial).
"***"highly effective (i.e. failure rate of <1% per year when used consistently and correctly) methods: intravaginal and transdermal combined (estrogen and progestogen containing) hormonal contraception; injectable and implantable progestogen-only hormonal contraception; intrauterine device (IUD); intrauterine hormone-releasing system (IUS); bilateral tubal occlusion; vasectomized partner; sexual abstinence (complete abstinence is defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatments).
研究計画
研究はどのように設計されていますか？
デザインの詳細
- 主な目的：処理
- 割り当て：ランダム化
- 介入モデル：並列代入
- マスキング：なし（オープンラベル）
アーム数
武器と介入
参加者グループ / アーム参加者グループ / アーム |
介入・治療介入・治療 |
|---|---|
|
実験的：A (experimental arm)
The experimental arm A starts with 6 cycles of mFOLFOX or 4 cycles of XELOX. Surgery is scheduled four or six weeks after day 1 of the last mFOLFOX or XELOX cycle, respectively. No postoperative chemotherapy is planned |
neoadjuvant application Folinic acid: 400 mg/m2, 2h i.v., on day 1 Oxaliplatin: 85 mg/m2, 2-6h i.v., on day 1 5-FU: 2400 mg/m2, 46-48h i.v., on day 1. Cycles are repeated on day 15. A total of 6 cycles are administered.
他の名前：
neoadjuvant application Capecitabine: 1,000 mg/m2 bid, po, on days 1-14 Oxaliplatin: 130 mg/m2, 2-6h i.v. day 1 Cycles are repeated on day 22. A total of 4 cycles are administered.
他の名前：
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アクティブコンパレータ：B (control arm)
In the standard arm B, patients undergo surgical resection of the primary tumor followed by stage- (risk-)adapted adjuvant chemotherapy 4-8 weeks after surgery according to recommendations of the S3 guidelines in analogy to colon cancer. Details of the recommended protocols are provided in the protocol. |
adjuvant application Folinic acid: 400 mg/m2, 2h i.v., on day 1 Oxaliplatin: 85 mg/m2, 2-6h i.v., on day 1 5-FU: 2400 mg/m2, 46-48h i.v., on day 1. Cycles are repeated on day 15. A total of 6 cycles are administered.
他の名前：
adjuvant application Capecitabine: 1,000 mg/m2 bid, po, on days 1-14 Oxaliplatin: 130 mg/m2, 2-6h i.v. day 1 Cycles are repeated on day 22. A total of 4 cycles are administered.
他の名前：
adjuvant application Capecitabine: 1,250 mg/m2 bid, po, on days 1-14 Cycles are repeated on day 22. A total of 8 cycles are administered.
他の名前：
adjuvant application Folinic acid 2h i.v. 500 mg/m² 5-FU 2,600mg/m² (24h infusion) Days 1, 8, 15, 22, 29, 36; cycle is repeated day 57 (representing one cycle); a total of 3 cycles should be administered.
他の名前：
adjuvant application Folinic acid 2h i.v. 200 mg/m² days 1 and 2 5-FU 400mg/m² bolus followed by 600mg/m² 22h infusion days 1 and 2 The cycle is repeated day 15; a total of 12 cycles should be administered.
他の名前：
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この研究は何を測定していますか？
主要な結果の測定
主要な結果の測定
結果測定 |
メジャーの説明 |
時間枠 |
|---|---|---|
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disease-free survival
時間枠：up to 3 years
|
time from randomisation to one of the following events: no surgery or non-radical (R2) surgery of the primary tumour, locoregional recurrence after R0/1 resection of the primary tumour, second primary colorectal or other cancer, metastatic disease or progression, or death from any cause, whichever occurred first. |
up to 3 years
|
二次結果の測定
二次結果の測定
結果測定 |
メジャーの説明 |
時間枠 |
|---|---|---|
|
Acute and late toxicity
時間枠：From date of informed consent until the End of Treatment or 30 days after the last dose of study treatment
|
assessment of acute and late toxicity according to NCI CTCAE version 5.0 |
From date of informed consent until the End of Treatment or 30 days after the last dose of study treatment
|
|
Compliance (completion rate) of chemotherapy
時間枠：From date of randomization until end of chemotherapy, approx. 12 (arm A) respectively up to 34 (arm B) weeks after randomization
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Rate of completion of administered chemotherapy |
From date of randomization until end of chemotherapy, approx. 12 (arm A) respectively up to 34 (arm B) weeks after randomization
|
|
Surgical morbidity and complications
時間枠：After surgery, approx. 2 (arm B) respectively 20 (arm A) weeks after randomization
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Surgical morbidity and complications if surgery is performed and events occur |
After surgery, approx. 2 (arm B) respectively 20 (arm A) weeks after randomization
|
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Pathological UICC-staging, including pCR (ypT0N0) rate
時間枠：After surgery, approx. 2 (arm B) respectively 20 (arm A) weeks after randomization
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Pathological staging according UICC criteria, including detailed information about pathologically assessed complete response rate (ypT0N0) |
After surgery, approx. 2 (arm B) respectively 20 (arm A) weeks after randomization
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R0 resection rate, Negative circumferential resection rate (CRM > 1mm)
時間枠：After surgery, approx. 2 (arm B) respectively 20 (arm A) weeks after randomization
|
defined as microscopically margin negative resection with no gross or microscopic tumor remains in the area of the primary tumor and/or samples regional lymph nodes based on evaluation by the local pathologist |
After surgery, approx. 2 (arm B) respectively 20 (arm A) weeks after randomization
|
|
Tumor regression grading according to Dworak in the experimental arm
時間枠：After surgery, approx. 2 (arm B) respectively 20 (arm A) weeks after randomization
|
Grading of tumor regression according to Dworak in the experimental arm |
After surgery, approx. 2 (arm B) respectively 20 (arm A) weeks after randomization
|
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Rate of sphincter-sparing surgery
時間枠：After surgery, approx. 2 (arm B) respectively 20 (arm A) weeks after randomization
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Rate of sphincter-sparing surgery if surgery is performed |
After surgery, approx. 2 (arm B) respectively 20 (arm A) weeks after randomization
|
|
Rate of W&W with or without local regrowth
時間枠：Up to 5 years after end of treatment
|
Number of performed watch&wait approaches with or without local regrowth compared to planned and performed surgery |
Up to 5 years after end of treatment
|
|
Cumulative incidence of local and distant recurrences
時間枠：Up to 5 years after end of treatment
|
Total number of local and distant recurrences, if they occur |
Up to 5 years after end of treatment
|
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Overall survival
時間枠：Up to at least 3 years and until 5 years
|
Overall survival is defined as the time interval between the date of randomization and the date of death of any cause. Patients who are still alive when last traced will be censored at the date of last follow-up |
Up to at least 3 years and until 5 years
|
|
Patient reported outcome: Quality of life according to questionnaire EORTC-QLQ-C30
時間枠：From date of randomization until the date of first documented progression or date of death from any cause, whichever occured first, assessed up to approximately 68 months
|
Quality of life scores according to validated questionnaires EORTC-QLQ-C30, based on treatment arm, and surgical procedures. 30 questions; score values from 1 (not at all) to 4 (very much) respectively from 1 (very poor) to 7 (excellent). Score outcome depends on score type. |
From date of randomization until the date of first documented progression or date of death from any cause, whichever occured first, assessed up to approximately 68 months
|
|
Patient reported outcome: Quality of life according to questionnaire EORTC-QLQ-CR29
時間枠：From date of randomization until the date of first documented progression or date of death from any cause, whichever occured first, assessed up to approximately 68 months
|
Quality of life scores according to validated questionnaires EORTC-QLQ-CR29, based on treatment arm, and surgical procedures. 29 questions; score values from 1 (not at all) to 4 (very much). Score outcome depends on score type. |
From date of randomization until the date of first documented progression or date of death from any cause, whichever occured first, assessed up to approximately 68 months
|
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Patient reported outcome: Functional outcome according to Wexner score
時間枠：From date of randomization until the date of first documented progression or date of death from any cause, whichever occured first, assessed up to approximately 68 months
|
Functional score according to validated Wexner score, based on treatment arm, and surgical procedures. 5 questions; five score values from "never" to "1 per day or more often". The more often the worse the outcome. |
From date of randomization until the date of first documented progression or date of death from any cause, whichever occured first, assessed up to approximately 68 months
|
協力者と研究者
協力者
協力者
捜査官
捜査官
- 主任研究者：Ralf-Dieter Hofheinz, Prof. Dr.、Universitätsmedizin Mannheim
研究記録日
主要日程の研究
研究開始 (実際)
研究開始
一次修了 (実際)
一次修了
研究の完了 (実際)
研究の完了
試験登録日
最初に提出
最初に提出
QC基準を満たした最初の提出物
QC基準を満たした最初の提出物
最初の投稿 (実際)
最初の投稿
学習記録の更新
投稿された最後の更新 (実際)
投稿された最後の更新
QC基準を満たした最後の更新が送信されました
QC基準を満たした最後の更新が送信されました
最終確認日
最終確認日
詳しくは
本研究に関する用語
キーワード
追加の関連 MeSH 用語
- 部位別新生物
- 新生物
- 腸の病気
- 消化器腫瘍
- 消化器系腫瘍
- 消化器系疾患
- 消化器疾患
- 結腸直腸腫瘍
- 腸の腫瘍
- 直腸疾患
- 直腸腫瘍
- 有機化学物質
- 複素環化化合物、1リング
- 複素環化化合物
- 複素環化化合物、2リング
- 複素環化化合物、融合リング
- 医薬品準備
- 治療
- 核酸、ヌクレオチド、およびヌクレオシド
- 化学作用と用途
- 酵素と補酵素
- 調整錯体
- デオキシシチジン
- シチジン
- ピリミジンヌクレオシド
- ピリミジン
- 化学物質の専門用途
- 製薬エイズ
- ヌクレオシド
- ホルミルテトラヒドロフォレート
- テトラヒドロフォレート
- 葉酸
- 羽毛
- プテリジン
- ウラシル
- ピリミジノン
- コエンザイム
- デオキシリボヌクレオシド
- 組み合わせたモダリティ療法
- カペシタビン
- オキサリプラチン
- フルオロウラシル
- ロイコボリン
- アジュバント、製薬
- ネオアジュバント療法
- Xelox
その他の研究ID番号
その他の研究ID番号
- ACO/ARO/AIO-18.2
- 2018 (米国 NIH グラント/契約)
- 2018-001356-35 (EudraCT番号)
個々の参加者データ (IPD) の計画
個々の参加者データ (IPD) を共有する予定はありますか?
医薬品およびデバイス情報、研究文書
米国FDA規制医薬品の研究
米国FDA規制機器製品の研究
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