Abstract:Aims
Preoperative (chemo)radiotherapy followed by total mesorectal excision is the current standard of care for patients with locally advanced rectal cancer. The use of intensity-modulated radiotherapy (IMRT) for rectal cancer is increasing in the UK. However, the extent of IMRT implementation and current practice was not previously known. A national survey was commissioned to investigate the landscape of IMRT use for rectal cancer and to inform the development of national rectal cancer IMRT guida… Show more
“…This information will help to address the urgent need for biomarkers of response and resistance that are required by clinicians in order to tailor treatment to the patient in front of them in clinic. The radiotherapy protocol for PRIME-RT has been largely based on the novel, national IMRT rectal cancer guidance for the UK [ 32 , 33 ]. Sites recruiting to PRIME-RT will have the opportunity to implement this new guidance in the context of the PRIME-RT trial and to have prospective peer review and quality assurance for their radiotherapy volumes and plans.…”
Section: Discussionmentioning
confidence: 99%
“…It is now more feasible to deliver boost doses safely and efficiently with the use of intensity modulated radiotherapy (IMRT). The dose levels used in PRIME-RT align with recently published United Kingdom (UK) consensus guidance, which has suggested using 45 Gy to elective pelvic nodes and a 50 Gy boost to primary tumour [ 32 , 33 ]. Fig.…”
Background
Advances in multi-modality treatment of locally advanced rectal cancer (LARC) have resulted in low local recurrence rates, but around 30% of patients will still die from distant metastatic disease. In parallel, there is increasing recognition that with radiotherapy and systemic treatment, some patients achieve a complete response and may avoid surgical resection, including in many cases, the need for a permanent stoma. Extended neoadjuvant regimes have emerged to address these concerns. The inclusion of immunotherapy in the neoadjuvant setting has the potential to further enhance this strategy by priming the local immune microenvironment and engaging the systemic immune response.
Methods
PRIME-RT is a multi-centre, open label, phase II, randomised trial for patients with newly diagnosed LARC. Eligible patients will be randomised to receive either: short course radiotherapy (25 Gray in 5 fractions over one week) with concomitant durvalumab (1500 mg administered intravenously every 4 weeks), followed by FOLFOX (85 mg/m2 oxaliplatin, 350 mg folinic acid and 400 mg/m2 bolus 5-fluorouracil (5-FU) given on day 1 followed by 2400 mg/m2 5-FU infusion over 46–48 h, all administered intravenously every 2 weeks), and durvalumab, or long course chemoradiotherapy (50 Gray to primary tumour in 25 fractions over 5 weeks with concomitant oral capecitabine 825 mg/m2 twice per day on days of radiotherapy) with durvalumab followed by FOLFOX and durvalumab. The primary endpoint is complete response rate in each arm. Secondary endpoints include treatment compliance, toxicity, safety, overall recurrence, proportion of patients with a permanent stoma, and survival. The study is translationally rich with collection of bio-specimens prior to, during, and following treatment in order to understand the molecular and immunological factors underpinning treatment response. The trial opened and the first patient was recruited in January 2021. The main trial will recruit up to 42 patients with LARC and commence after completion of a safety run-in that will recruit at least six patients with LARC or metastatic disease.
Discussion
PRIME-RT will explore if adding immunotherapy to neoadjuvant radiotherapy and chemotherapy for patients with LARC can prime the tumour microenvironment to improve complete response rates and stoma free survival. Sequential biopsies are a key component within the trial design that will provide new knowledge on how the tumour microenvironment changes at different time-points in response to multi-modality treatment. This expectation is that the trial will provide information to test this treatment within a large phase clinical trial.
Trial registration
Clinicaltrials.gov NCT04621370 (Registered 9th Nov 2020)
EudraCT number 2019-001471-36 (Registered 6th Nov 2020)
“…This information will help to address the urgent need for biomarkers of response and resistance that are required by clinicians in order to tailor treatment to the patient in front of them in clinic. The radiotherapy protocol for PRIME-RT has been largely based on the novel, national IMRT rectal cancer guidance for the UK [ 32 , 33 ]. Sites recruiting to PRIME-RT will have the opportunity to implement this new guidance in the context of the PRIME-RT trial and to have prospective peer review and quality assurance for their radiotherapy volumes and plans.…”
Section: Discussionmentioning
confidence: 99%
“…It is now more feasible to deliver boost doses safely and efficiently with the use of intensity modulated radiotherapy (IMRT). The dose levels used in PRIME-RT align with recently published United Kingdom (UK) consensus guidance, which has suggested using 45 Gy to elective pelvic nodes and a 50 Gy boost to primary tumour [ 32 , 33 ]. Fig.…”
Background
Advances in multi-modality treatment of locally advanced rectal cancer (LARC) have resulted in low local recurrence rates, but around 30% of patients will still die from distant metastatic disease. In parallel, there is increasing recognition that with radiotherapy and systemic treatment, some patients achieve a complete response and may avoid surgical resection, including in many cases, the need for a permanent stoma. Extended neoadjuvant regimes have emerged to address these concerns. The inclusion of immunotherapy in the neoadjuvant setting has the potential to further enhance this strategy by priming the local immune microenvironment and engaging the systemic immune response.
Methods
PRIME-RT is a multi-centre, open label, phase II, randomised trial for patients with newly diagnosed LARC. Eligible patients will be randomised to receive either: short course radiotherapy (25 Gray in 5 fractions over one week) with concomitant durvalumab (1500 mg administered intravenously every 4 weeks), followed by FOLFOX (85 mg/m2 oxaliplatin, 350 mg folinic acid and 400 mg/m2 bolus 5-fluorouracil (5-FU) given on day 1 followed by 2400 mg/m2 5-FU infusion over 46–48 h, all administered intravenously every 2 weeks), and durvalumab, or long course chemoradiotherapy (50 Gray to primary tumour in 25 fractions over 5 weeks with concomitant oral capecitabine 825 mg/m2 twice per day on days of radiotherapy) with durvalumab followed by FOLFOX and durvalumab. The primary endpoint is complete response rate in each arm. Secondary endpoints include treatment compliance, toxicity, safety, overall recurrence, proportion of patients with a permanent stoma, and survival. The study is translationally rich with collection of bio-specimens prior to, during, and following treatment in order to understand the molecular and immunological factors underpinning treatment response. The trial opened and the first patient was recruited in January 2021. The main trial will recruit up to 42 patients with LARC and commence after completion of a safety run-in that will recruit at least six patients with LARC or metastatic disease.
Discussion
PRIME-RT will explore if adding immunotherapy to neoadjuvant radiotherapy and chemotherapy for patients with LARC can prime the tumour microenvironment to improve complete response rates and stoma free survival. Sequential biopsies are a key component within the trial design that will provide new knowledge on how the tumour microenvironment changes at different time-points in response to multi-modality treatment. This expectation is that the trial will provide information to test this treatment within a large phase clinical trial.
Trial registration
Clinicaltrials.gov NCT04621370 (Registered 9th Nov 2020)
EudraCT number 2019-001471-36 (Registered 6th Nov 2020)
“…In spite of the advantages of using oral contrast, there is concern about possible dosimetric deviations if the dose calculation is performed in the contrast-enhanced CT. 1,4 To avoid these theoretical deviations, it is a common practice to obtain two CT scans during the same simulation session: one unenhanced and one enhanced. 5…”
Section: Discussionmentioning
confidence: 99%
“…1,4 In order to avoid this problem, it is a common practice to obtain two CT scans during the same simulation session: one unenhanced and one enhanced. 5 However, it has been described that performing two CT scans during the simulation not only exposes the patient to additional radiation but also reduces the optimisation of resources in the radiation oncology department by extending the simulation time. 6 Consequently, waiting times for radiotherapy increase.…”
Introduction:
Contrast media are frequently used during radiation therapy simulation. However, there are concerns about dosimetric variations when dose calculation is done on contrast-enhanced computed tomography (CT). This study evaluates the dosimetric effect of oral contrast during three-dimensional conformal radiotherapy (3D-CRT) and volumetric modulated arc radiotherapy (VMAT) planning.
Methods:
Rectal cancer patients were consecutively enrolled. For each patient, one unenhanced CT and one contrast-enhanced CT were taken using oral and intravenous contrast. Then, a 3D-CRT plan and an Intensity-modulated radiation therapy (IMRT)/VMAT plan were generated in the enhanced CT, and the dose distribution was recalculated in the respective unenhanced CT. The beam intensities were kept the same as for the enhanced CT plans. Finally, the unenhanced and enhanced plans were compared by calculating the gamma index.
Results:
For 3D-CRT plans, there were statistically significant differences in second phase planning target volume (PTV) D2% (Mean difference (MD) between unenhanced and enhanced CT 0·01 Gy, 95% CI [0·003 to 0·02 Gy]) and in maximum doses to the bladder (MD 0·26 Gy, 95% CI [0·05 to 0·47 Gy]). For IMRT/VMAT plans, there were statistically significant differences in small intestine V45 Gy (MD 3·1 cc, 95% CI [0·81 to 5·4 cc]), bladder V45 Gy (MD 2·9%, 95% CI [1·4 to 4·3%]) and maximum dose to the bladder (MD 0·65 Gy, 95% CI [0·46 Gy to 0·85 Gy]). In addition, for PTV D98% the MD between unenhanced and enhanced CT was 0·22 Gy 95% CI [0·05 to 0·39].
Conclusions:
For most of the dose metrics, the differences were not clinically meaningful. The greatest differences were found in VMAT plans, especially in V45 Gy of the small intestine. This difference could lead to an underestimation of dose–volume metrics when the plan is based on an enhanced CT. The use of small bowel oral contrast does not significantly influence dose calculations and may not affect the acceptability of plans when adhering to constraints.
“…Preoperative use of IMRT for LARC is increasing rapidly with great variations in clinical practice among centres 24 indicating a lack of quality clinical studies reporting treatment outcome and toxicity for different fractionation regimes. To date, only four prospective phase II studies have been published with short-term outcome data after preoperative IMRT concomitant with capecitabine in patients with LARC 9 , 16 , 25 , 26 , but none of them reported long-term results.…”
Background
We conducted a phase II study to investigate the feasibility and safety of preoperative radiochemo-therapy experimental fractionation, using intensity-modulated radiation therapy with simultaneous integrated boost (IMRT SIB) to shorten the overall treatment time without dose escalation in intermediate/locally advanced rectal cancer with the aim to improving treatment outcome.
Patients and methods
A total of 51 patients with operable stage II–III rectal carcinoma were included between January 2014 and January 2015. Fifty patients completed preoperative IMRT treatment with an elective dose of 41.8 Gy and simultaneously delivered 46.2 Gy to T2/T3 and 48.4 Gy to T4 tumour in 22 fractions, with concomitant capecitabine (825 mg/m2/12 h, including at weekends). Median follow-up was 70 months (range 11–80 m).
Results
Forty-seven patients completed treatment per protocol. Acute toxicity occurred in 2 (4%) patients. R0 resection was achieved in all but 1 and pathologic complete response (pCR) in 12 (25.5%) patients who had 5-year overall survival (OS), disease-free survival (DFS) and local control (LC) of 91.7%, 100% and 100%, respectively. The intention-to-treat analysis showed that the type of surgery significantly moderated OS and DFS, while total downstaging and pN were predictive for DFS only. For treatment per protocol 5-year OS, DFS and LC were 80.9% (95% confidence interval [CI] 69.7–92.1), 77.1% (95% CI 65.1–89.1) and 95.2% (95% CI 88.7–100), respectively. The proportion of patients with severe late (CTCAE G ≥ 3) gastrointestinal, urinary and sexual toxicity was 15%, 2% and 8% respectively, with one reported secondary carcinoma.
Conclusions
Preoperative IMRT-SIB without dose escalation was well tolerated, with a low acute toxicity profile, we achieved a high rate of pCR and showed encouraging 5-year OS, DFS and LC.
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