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Rectal Neoplasms

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Rectal Diseases

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Micronutrients

Vitamins

Oxaliplatin

Leucovorin

Fluorouracil

Capecitabine

Levoleucovorin

Antimetabolites

Folinic Acid

Preoperative chemoradiotherapy (CRT) followed by Surgery plus Adjuvant chemotherapy

Preoperative CRT: capecitabine (1650 mg/m2/day) and radiotherapy (50.4 Gy/28 Fr)

Adjuvant chemotherapy: CAPOX (capecitabine+oxaliplatin) or mFOLFOX6 (5-fluorouracil+l-leucovorin+oxaliplatin) or capecitabine or 5-fluorouracil (FU) +l-leucovorin (LV)

CAPOX: oxaliplatin (130 mg/m2/day, day 1) and oral capecitabine (2000 mg/m2/day, twice daily, days 1-14)

mFOLFOX6: oxaliplatin 85 mg/m2 with l-LV 200 mg/m2 for over 2 hours followed by a fluorouracil 400 mg/m2 bolus and 2400 mg/m2 continuous infusion over 46 hours.

Capecitabine: 2000 mg/m2/day, twice daily, days 1-14

5-FU+l-LV: leucovorin 200 mg/m2 for over 2 hours followed by a fluorouracil 400 mg/m2 bolus and 2400 mg/m2 continuous infusion for over 46 hours

Surgery plus Adjuvant chemotherapy

Adjuvant chemotherapy: CAPOX or mFOLFOX6 or capecitabine or 5-FU+l-LV

CAPOX: oxaliplatin (130 mg/m2/day, day 1) and oral capecitabine (2000 mg/m2/day, twice daily, days 1-14)

mFOLFOX6: oxaliplatin 85 mg/m2 with l-LV 200 mg/m2 for over 2 hours followed by a fluorouracil 400 mg/m2 bolus and 2400 mg/m2 continuous infusion over 46 hours.

Capecitabine: 2000 mg/m2/day, twice daily, days 1-14

5-FU+l-LV: leucovorin 200 mg/m2 for over 2 hours followed by a fluorouracil 400 mg/m2 bolus and 2400 mg/m2 continuous infusion for over 46 hours

Adjuvant chemotherapy: CAPOX or mFOLFOX6 or capecitabine or 5-FU+l-LV

CAPOX: oxaliplatin (130 mg/m2/day, day 1) and oral capecitabine (2000 mg/m2/day, twice daily, days 1-14)

mFOLOX6: oxaliplatin 85 mg/m2 with l-LV 200 mg/m2 for over 2 hours followed by a fluorouracil 400 mg/m2 bolus and 2400 mg/m2 continuous infusion over 46 hours.

Capecitabine: 2000 mg/m2/day, twice daily, days 1-14

5-FU+l-LV: leucovorin 200 mg/m2 for over 2 hours followed by a fluorouracil 400 mg/m2 bolus and 2400 mg/m2 continuous infusion for over 46 hours

Chemotherapy

Preoperative chemoradiotherapy (CRT) followed by Surgery plus Adjuvant chemotherapy

Preoperative CRT: capecitabine (1650 mg/m2/day) and radiotherapy (50.4 Gy/28 Fr)

Preoperative radiotherapy

Surgery for Locally Recurrent Rectal Cancer (LRRC) will be performed within 42 days from registration for the patients in arm A, and between days 56 and 98 from the completion of the preCRT for the patients in arm B.

Appropriate surgical procedure will be performed to achieve R0 resection, such as low anterior resection, super low anterior resection, intersphincteric resection, Hartmann procedure, rectal amputation, pelvic exenteration, tumor resection, or lateral lymph node dissection

Procedure

Yuichiro Tsukada, MD,PhD

Masaaki Ito, MD, PhD

Nobuhiro Takiguchi

Kazuhiro Yoshida

Shigeki Yamaguchi

Mitsugu Sekimoto

Mamoru Shimomura

Masazumi Okajima

Yoshitsugu Tajima

Hiroyuki Bando

Masaaki Ito

Hideyuki Ishida

Ryo Inada

Hideo Baba

Kazuyuki Kawamoto

Yoshito Akagi

Takaya Kobatake

Tadahiko Masaki

Koki Otsuka

Keisuke Uehara

Yasumasa Takii

Naohiro Tomita

Yoshihiro Akazai

Takeshi Kato

Kiyoshi Maeda

Yusuke Nishizawa

Hideki Yamagami

Kou Miura

Akio Shiomi

Tsunekazu Mizushima

Shu Okamura

Junji Okuda

Hideki Ueno

Yukihide Kanemitsu

Yoshihisa Saida

Kimihiko Funahashi

Yusuke Kinugasa

Akihiko Tsuchida

Keiichi Takahashi

Shin Fujita

Toshihiko Sato

Manabu Shiozawa

Tadao Fukushima

Jun Watanabe

Masafumi Inomata

Yuichi Takayama

Hitoshi Ojima

JCOG1801 is a randomized phase III trial which was initiated in Japan in August 2019 to confirm the superiority of preoperative chemoradiotherapy followed by surgery plus adjuvant chemotherapy for local relapse-free survival over standard treatment, i.e. surgery plus adjuvant chemotherapy, for previously non-irradiated locally recurrent rectal cancer.

In all, 110 patients from 43 Japanese institutions will be recruited over a period of 6 years. Eligible patients would be registered and randomly assigned to each group with an allocation ratio of 1:1. The primary endpoint is local relapse-free survival. The secondary endpoints are overall survival, relapse-free survival, proportion of local relapse, proportion of distant relapse, proportion of patients with pathological R0 resection, response rate of preoperative chemoradiotherapy (preoperative chemoradiotherapy arm), pathological complete response rate (preoperative chemoradiotherapy arm), proportion of patients who completed the protocol treatment, incidence of adverse events (adverse reactions), and quality of life after surgery.

Surgery Plus Chemo Versus Chemoradiotherapy Followed by Surgery Plus Chemo for Locally Recurrent Rectal Cancer

JCOG1801: A Phase III Randomized Controlled Trial Comparing Surgery Plus Adjuvant Chemotherapy With Preoperative Chemoradiotherapy Followed by Surgery Plus Adjuvant Chemotherapy for Locally Recurrent Rectal Cancer (RC-SURVIVE Study)

the period from registration in the trial to either the first event of local relapse or death from any cause and censored at the last date of contact for a living patient

s the time from registration to death from any cause and censored at the last date of contact for a living patient

the time from registration to either the first incidence of relapse or death from any cause and censored at the last date of contact for a living patient

Proportion of patients with pathological R0 resection

Pathological complete response rate (arm B)

Proportion of patients who completed the protocol treatment

Incidence of adverse events (adverse reactions)

QOL after surgery based on the Trial Outcome Index-Physical/Functional/Colorectal (TOI-PFC) \[0(better)-84(worse)\]

Japan Clinical Oncology Group

Japan Agency for Medical Research and Development

National Cancer Center Hospital East

Hematinics

Irinotecan

Folic Acid

Folfirinox

Folate

Vitamin B9

Protocol of chemotherapy FOLFIRINOX\*, 6 cycles :

* oxaliplatin: 85 mg/m2
* irinotecan: 180 mg/m²
* folinic acid: 400 mg/m2
* 5FU : 400 mg/m2 (bolus)
* 5FU : 2400 mg/m2 (continuous infusion)

Protocol of reirradiation consists in conformational intensity modulated external irradiation, delivering a 30.6 Gy dose (1.8 Gy/day), with concomitant chemotherapy including Capecitabine 1600 mg/m²/day, five days a week.

Protocol of chemotherapy FOLFIRINOX\*, 6 cycles :

* oxaliplatin: 85 mg/m2
* irinotecan: 180 mg/m²
* folinic acid: 400 mg/m2
* 5FU : 400 mg/m2 (bolus)
* 5FU : 2400 mg/m2 (continuous infusion)

* oxaliplatin: 85 mg/m2
* irinotecan: 180 mg/m²
* folinic acid: 400 mg/m2
* 5FU : 400 mg/m2 (bolus)
* 5FU : 2400 mg/m2 (continuous infusion)

Chemotherapy FOLFIRINOX, 6 cycles

Reirradiation consists in conformational intensity modulated external irradiation (Intensity-modulated radiotherapy Volumetric Modulated Arc Therapy or tomotherapy) delivering a 30.6 Gy dose with high-energy photons in fractions of 1.8 Gy per day (17 fractions) 5 days a week With Concomitant chemotherapy including Capecitabine 1600 mg/m²/day, five days a week.

Radiochemotherapy

Surgery will be performed at:

* Arm A: 8 weeks (±1) after the end of treatment
* Arm B: 6 weeks (±1) after the end of treatment

Surgical procedures are defined into three categories:

* Total mesorectal excision (TME)
* Extended-TEM (e-TME)
* Pelvic exenteration (PE)

Surgery

Christophe LAURENT

GRECCAR 15 is focused on Locally Recurrent Rectal Cancer (LRRC) for patients with previous pelvic radiotherapy for the primary rectal cancer. This situation leads to a 20% higher risk of non-curative resection for the LRRC management (R1 status) impacting significantly the overall survival. The widespread use of neoadjuvant radiotherapy for primary rectal cancer introduces this new problem: the treatment of LRRC in previously irradiated area.

The objective of GRECCAR 15 is to assess the efficacy of neoadjuvant chemotherapy followed by pelvic reirradiation versus neoadjuvant chemotherapy alone on the rate of curative surgery (R0) in previously irradiated patients with LRRC.

The incidence of rectal cancer in the European Union is 15-25/100 000 per year. There is a 5-10% rate of locally recurrent rectal cancer (LRRC), with an overall survival rate of 40% at 5 years after complete resection. Curative surgery of LRRC requires multi-visceral resections which are associated with significant post-operative morbidity of 60%. Despite the combination of a potential curability and the high post-operative morbidity, there are currently neither good data from prospective randomized studies regarding optimum preoperative treatments for LRRC nor is there data assessing the efﬁcacy of response to any such treatments. Moreover, the widespread use of neoadjuvant radiotherapy for primary cancer introduced a new problem: the treatment of LRRC in previously irradiated area. Some studies investigated various modalities of reirradiation and showed acceptable late toxicity and encouraging outcome. GRECCAR 15 would be the first prospective randomized trial so far to evaluate the interest of pelvic reirradiation for LRRC, in previously irradiated patients.

The objective is to assess the efficacy of neoadjuvant chemotherapy followed by pelvic reirradiation versus neoadjuvant chemotherapy alone on the rate of curative surgery (R0) in previously irradiated patients with LRRC.

Patients will be followed every 4 months during 2 years, and every 6 months the last year with chest, abdominal and pelvic scan and tumour markers.

Chemotherapy Followed by Pelvic Reirradiation Versus Chemotherapy Alone as Pre-operative Treatment for Locally Recurrent Rectal Cancer

A Phase III Randomized Trial Evaluating Chemotherapy Followed by Pelvic Reirradiation Versus Chemotherapy Alone as Pre-operative Treatment for Locally Recurrent Rectal Cancer (GRECCAR - PRODIGE - FRENCH)

To analyse surgical morbidity (Dindo classification) during first 30 days after the surgery

To analyse surgical mortality (Dindo classification) during first 30 days after the surgery

Proportion of patients receiving full allocated neoadjuvant treatment

Rate of tumor with a decreasing size of 50% at least after preoperative treatment at MRI

The scores of questionnaire QLQ C-30 will be examined The EORTC QLQ-C30 is a patients self-rating questionnaire that measures physical, role, social, emotional, and cognitive functions as well as overall QoL. Scores can be linearly transformed to provide a score from 0 to 100. Higher scores represent better functioning on the functional scales and a higher level of symptoms of the symptom scales.

The scores of questionnaire QLQ CR-29 will be examined. The EORTC QLQ-CR29 has five functional and 18 symptom scales. Scores can be linearly transformed to provide a score from 0 to 100. Higher scores represent better functioning on the functional scales and a higher level of symptoms of the symptom scales.

University Hospital, Bordeaux

Extended margin surgery and IOERT at standard dose (10 Gy)

Extended margin surgery and IOERT at higher dose (15 Gy)

IOERT can be defined as the direct application of high-energy electron beam irradiation to a tumour bed during an operative procedure. This approach permits precise delivery of a single large fraction of radiation directly and specifically to high recurrence risk anatomical target areas, which the treating clinicians (surgeon and attending clinical oncologist) predict will be a close or involved margin, while simultaneously displacing and shielding dose-limiting radiosensitive structures such as the small bowel or ureter or any anastomoses, if not involved by tumour.

Intraoperative Electron Radiotherapy (IOERT)

Surgery intended to remove both a tumour and any metastases

Extended Margin Surgery

Alex Mirnezami, Prof

Single centre double-blinded three-arm randomised controlled trial of extended margin surgery + IOERT at standard dose (10 Gy) versus extended margin surgery + IOERT at higher dose (15 Gy) versus extended margin surgery alone in a 1:1:1 ratio in patients with Locally Advanced Rectal Cancer (LARC) or Locally Recurrent Rectal Cancer (LRRC).

Rectal cancer is a cancer that occurs in the pelvis from the rectum. Locally advanced rectal cancer outgrows the rectum and attaches to other body parts in the pelvis and locally recurrent rectal cancer is a rectal cancer that comes back after surgery, and usually attaches to many different pelvic structures. They are both difficult to manage. The standard of care treatment involves chemotherapy and radiotherapy, followed by what is known as an extended margin operation to remove all cancer affected organs and not leave any cancer cells behind. If cancer cells reach the edge of the removed tissue, there is a high chance of leaving cancer cells behind. This is a key predictor of negative outcome in patients. Intraoperative electron beam radiotherapy (IOERT) was developed to help improve patient outcomes. Once the cancer has been removed, the surgeon and a cancer radiotherapy specialist examine the patient's scans, the cancer specimen and the area the cancer was in, and if there is concern about small numbers of cancer cells being left behind they treat the area with radiotherapy to destroy these cells. Patients that are due to receive treatment for these subsets of rectal cancer will be approached to take part. If eligible on the day of surgery the patient will be randomised to one of three arms: Arm A - standard of care (No IOERT), Arm B - extended margin surgery plus IOERT (10 Gy), or Arm C - extended margin surgery plus higher dose IOERT (15 Gy). The surgeon, cancer specialist team and patient will be blinded to study treatment. Patients will be followed up at 30 days, 3 months and for a minimum of 12 months post surgery as part of the trial and they will be followed up for 5 years as part of standard care.

A single centre double-blinded three-arm randomised controlled trial of extended margin surgery + IOERT at standard dose (10 Gy) versus extended margin surgery + IOERT at higher dose (15 Gy) versus extended margin surgery alone (no IOERT) in a 1:1:1 ratio in patients with LARC or LRRC.

This is a double-blinded trial, which means both the participant and clinicians will not know the treatment allocation. The surgeon, oncologist and patient will remain blinded throughout the study, while the radiotherapy delivery team will know the outcome of the randomisation.

Patient allocation will be provided to the unblinded radiotherapy staff via an Interactive Web Response System (IWRS). The randomisation code will be retained by the system. Deaths and serious adverse events (SAE) will be reviewed in a blinded manner.

Unblinding will be required in the event that any participants further treatment may benefit from further radiotherapy, and if potential IOERT treatment and its dose may impact this.

Intraoperative Electron Radiotherapy in Rectal Cancer - A Feasibility Trial

Number and percentage of patients meeting eligibility criteria and number of patients referred to a sMDT over the trial period

Number and percentage of patients accepting randomisation

Number and percentage of patients for which IOERT was successfully delivered as planned as part of the trial

Number and percentage of patients and clinicians for which blinding was maintained for IOERT delivery

Percentage of patients whose questionnaires can be analysed

Percentage of patients for whom we can collect information on potential primary outcomes

IOERT Field Recurrence is defined as the area directly within the IOERT field as marked by ligaclips or identified by the surgical oncologist for future radiological surveillance.

Overall local recurrence (OLR) is defined as including both IOERT-field and non-IOERT field loco-regional recurrences.

Treatment related toxicity graded by CTCAE v5

Cost will be estimated for the NHS. An NHS and social care perspective will be used, including intervention costs, outpatient visits and investigations, A\&E attendances, hospital admissions, number and dose of each radiotherapy treatment. Itemised resource usage date will be priced using appropriate national sources: Personal Social Services Research Unit (PSSRU), NHS Reference costs and BNF (British National Formulary) for the UK.

IntraOp Medical Corporation

PLANETS Cancer Charity

Cancer Research UK

University Hospital Southampton NHS Foundation Trust

Induction chemotherapy followed by neoadjuvant chemoradiotherapy and surgery

Neoadjuvant chemoradiotherapy followed by surgery

Induction chemotherapy consists of either three three-weekly cycles of CAPOX (oxaliplatin 130 mg/m2 BSA IV + capecitabine 1000 mg/m2 BSA, orally, twice daily) or four two-weekly cycles of FOLFOX (85 mg/m2 BSA of oxaliplatin IV + 400 mg/m2 BSA of leucovorin IV + 400 mg/m2 BSA of bolus 5-fluorouracil IV followed by 2400 mg/m2 BSA of continuous 5-fluorouracil IV). It is left to the discretion of the treating medical oncologist which of the two will be administered. In case of (previous) unacceptable toxicity (physician's discretion) to oxaliplatin, FOLFIRI may be prescribed. FOLFIRI (180 mg/m2 BSA of irinotecan IV + 400 mg/m2 BSA of leucovorin IV + 400 mg/m2 BSA of bolus 5-fluorouracil IV followed by 2400 mg/m2 BSA of continuous 5-fluorouracil IV) consists of four two-weekly cycles.

If a patient has stable or responsive disease, induction chemotherapy will be continued with either one three-weekly cycle of CAPOX or two two-weekly cycles of FOLFOX/FOLFIRI.

Combination drug

Concomitant chemotherapy agent: capecitabine

Radiotherapy dose: full course radiotherapy consists of 25x2.0 or 28x1.8 Gy. In case of previous radiotherapy, the radiotherapy dose will consist of 15x2.0 Gy.

Chemoradiotherapy

Type of surgery depends on the location of the recurrence and involvement of adjacent structures and is left to the discretion of the operating surgeon.

Intraoperative radiotherapy is optional.

Surgery locally recurrent rectal cancer

Stefi Nordkamp, MD

Floor Piqeur, MD

Gabrielle van Ramshorst, MD, PhD

Miranda Kusters, MD, PhD

Arend Aalbers, MD, PhD

Pim Burger, MD, PhD

Klaas Havenga, MD, PhD

Fabian Holman, Md, PhD

Andreas Marinelli, MD, PhD

Jarno Melenhorst, MD, PhD

Cornelis Verhoef, MD, PhD

Marianne Guren, MD, PhD

João Maciel, MD, PhD

Eva Angenete, MD, PhD

Sofia Heyman, MD, PhD

Pamela Buchwald, MD, PhD

Henrik Iversen, MD, PhD

Pim Burger, MD

This is a multicentre, open-label, parallel arms, phase IIII study that randomises patients with locally recurrent rectal cancer in a 1:1 ratio to receive either induction chemotherapy followed by neoadjuvant chemoradiotherapy and surgery (experimental arm) or neoadjuvant chemoradiotherapy and surgery alone (control arm)

Induction Chemotherapy for Locally Recurrent Rectal Cancer

Multicentre, Open-label, Randomised, Controlled, Parallel Arms Clinical Trial of Induction Chemotherapy Followed by Chemoradiotherapy Versus Chemoradiotherapy Alone as Neoadjuvant Treatment for Locally Recurrent Rectal Cancer - PelvEx II

Participant-level datasets and statistical codes will become available upon reasonable request after the results of the study have been published.

A resection margin is considered clear (R0), if there are no tumour cells in any of the resection surfaces as determined by microscopy (resection margin \> 0mm)

Adverse events grade 3 or higher according to the NCI-CTCAE v5.0

including data on intra-operative radiotherapy

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Surgery Plus Chemo Versus Chemoradiotherapy Followed by Surgery Plus Chemo for Locally Recurrent Rectal Cancer	NCT04288999	Rectal Cancer R...	Chemotherapy Preoperative ra... Procedure	20 Years - 80 Years	National Cancer Center Hospital East
Chemotherapy Followed by Pelvic Reirradiation Versus Chemotherapy Alone as Pre-operative Treatment for Locally Recurrent Rectal Cancer	NCT03879109	Rectal Cancer	Chemotherapy FO... Radiochemothera... Surgery	18 Years -	University Hospital, Bordeaux
Intraoperative Electron Radiotherapy in Rectal Cancer - A Feasibility Trial	NCT05877352	Locally Advance... Locally Recurre...	Intraoperative ... Extended Margin...	16 Years -	University Hospital Southampton NHS Foundation Trust
Induction Chemotherapy for Locally Recurrent Rectal Cancer	NCT04389086	Recurrent Recta...	Combination dru... Chemoradiothera... Surgery locally...	18 Years -	Catharina Ziekenhuis Eindhoven
Induction Chemotherapy for Locally Recurrent Rectal Cancer	NCT04389086	Recurrent Recta...	Combination dru... Chemoradiothera... Surgery locally...	18 Years -	Catharina Ziekenhuis Eindhoven

Spots Global Cancer Trial Database for locally recurrent rectal cancer