RHYTHM-I: Investigating Hypoxia in Rectal Tumours

Inclusion criteria

(Group A):

• T2-3 N0 histologically proven adenocarcinoma of the rectum (if the MDT has an index of suspicion of malignancy high enough to proceed to surgical resection despite repeatedly non-diagnostic biopsies, the patient should be considered eligible).
• The tumour on MRI and/or CT measures at least 2 cm by 2 cm.
• MRI confirmation that the circumferential resection margin is not involved or threatened
• Agreement from the local multi-disciplinary team (MDT) that the tumour is operable and does not require pre-operative CRT.
• The patient is medically fit for operative resection of the tumour.
• Male or female, Age at least 18 years.
• ECOG performance score of 0-2 and be capable of co-operating with protocol.
• Written (signed and dated) informed consent.
• Haematological and biochemical indices within the ranges shown below:

• Haemoglobin (Hb) ≥12.0 g/dL
• Platelet count ≥ 100 x 109/L
• PT 10-14 seconds
• Renal function:

Serum Creatinine <120 mmol/L OR Calculated GFR >50 ml/min

Inclusion criteria

(Group B):

• Histologically confirmed invasive adenocarcinoma of the rectum
• Pelvic MRI defined disease:

a. Mesorectal fascia (MRF) involved or breached i. Includes involvement of adjacent organ b. Mesorectal fascia threatened (tumour ≤ 1mm from MRF). This includes i. Primary tumour ≤ 1mm from MRF ii. Extramural vascular invasion ≤ 1mm from MRF iii. Tumour deposit with irregular border and mixed signal intensity ≤ 1mm from MRF c. Low tumours at/below the level of the levators where: i. Tumour ≤ 1mm from levator on two imaging planes ii. Tumour through full thickness of muscularis propria or beyond at level of puborectalis sling or below iii. Tumour involving the intersphincteric plane iv. Tumour involving the external anal sphincter

• Patient is considered likely to be fit for surgical resection following CRT
• Patient has been considered to be medically fit to receive CRT by their treating oncologist
• Male or female, Age at least 18 years.
• ECOG performance score of 0-2.
• The patient is willing and able to give informed consent and to comply with the protocol for the duration of the study.
• Haematological and biochemical indices within the ranges shown below:

• Haemoglobin (Hb) ≥12.0 g/dL
• Absolute neutrophil count ≥1.5 x 10^9/L
• Platelet count ≥ 100 x 109/L
• PT 10-14 seconds
• Renal function:

Serum Creatinine <120 mmol/L OR Calculated GFR >50 ml/min

Exclusion criteria

(Group A):

• Unequivocal evidence of metastatic disease. Patients with equivocal lesions will be determined as eligible on consensus of the MDT.
• Previous pelvic radiotherapy.
• Pregnant or breast-feeding women, or women of childbearing potential unless effective methods of contraception are used.
• Treatment with any other investigational agent, or participation in another interventional clinical trial within 28 days prior to enrolment.
• Currently taking anti-coagulants
• Patients who for any reason are unable to undergo MRI and/or CT scans as per local guidelines e.g. if they are fitted with a pacemaker, have metal fragments in or around the eye, cannot tolerate the scan for any reason or are allergic to contrast agents.
• Patients who are known to be serologically positive for Hepatitis B, Hepatitis C or HIV.

Exclusion criteria

(Group B):

• Previous pelvic radiotherapy (including brachytherapy)
• Unequivocal evidence of metastatic disease. Patients with equivocal lesions will be determined as eligible on consensus of the MDT.
• Pregnant or breast-feeding women, or women of childbearing potential unless effective methods of contraception are used.
• Currently taking anti-coagulants
• Gastrointestinal disorder which would interfere with oral therapy and its bioavailability
• Treatment with any other investigational agent, or participation in another clinical trial within 28 days prior to enrolment.
• Other psychological, social or medical condition, physical examination finding or a laboratory abnormality that the Investigator considers would make the patient a poor trial candidate or could interfere with protocol compliance or the interpretation of trial results.
• Patients who for any reason are unable to undergo MRI and/or CT scans as per local guidelines e.g. they are fitted with a pacemaker, have metal fragments in or around the eye, cannot tolerate the scan for any reason or are allergic to contrast agents.
• Patients who are known to be serologically positive for Hepatitis B, Hepatitis C or HIV.

Exclusion criteria

(Optional supplemental oxygen breathing Groups A and B):

• Ongoing supplemental oxygen as part of clinical care
• Known lung disease with carbon dioxide retention
• Chronic obstructive airways disease with known or at risk of hypercapnia
• Most recent available arterial blood gas (ABG) from the current hospital admission demonstrates hypoxia or hypercapnia on room air.
• Any patient not felt to be suitable for supplemental oxygen as considered by an appropriately trained clinician.