Contact X-ray Brachytherapy as a Boost Therapy After Neoadjuvant (Chemo)Radiation in High-Risk Locally Advanced Rectal Cancer

Journal Pre-proof Contact X-ray Brachytherapy (CXB) as a boost therapy after neoadjuvant (chemo)radiation in high-risk locally advanced rectal cancer Ngu Wah Than MRCP , D. Mark Pritchard FRCP , David M. Hughes PhD , Carrie. A. Duckworth PhD , Helen Wong PhD , Muneeb Ul Haq MBBS , Rajaram Sripadam FRCR , Arthur Sun Myint FRCR PII: S0360-3016(24)03720-9 DOI: https://doi.org/10.1016/j.ijrobp.2024.11.113 Reference: ROB 29144 To appear in: International Journal of Radiation Oncology, Biology, Physics Received date: 16 August 2024 Revised date: 4 November 2024 Accepted date: 29 November 2024 Please cite this article as: Ngu Wah Than MRCP , D. Mark Pritchard FRCP , David M. Hughes PhD , Carrie. A. Duckworth PhD , Helen Wong PhD , Muneeb Ul Haq MBBS , Rajaram Sripadam FRCR , Arthur Sun Myint FRCR , Contact X-ray Brachytherapy (CXB) as a boost therapy after neoadjuvant (chemo)radiation in high-risk locally advanced rectal cancer, International Journal of Radiation Oncology, Biology, Physics (2024), doi: https://doi.org/10.1016/j.ijrobp.2024.11.113 This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. ©2024 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/) 1 Contact X-ray Brachytherapy (CXB) as a boost therapy after neoadjuvant (chemo)radiation in high-risk locally advanced rectal cancer Short running title: Contact radiation in high-risk rectal cancer Ngu Wah Than MRCP1,2, D. Mark Pritchard FRCP1, David M. Hughes PhD3, Carrie. A. Duckworth PhD1, Helen Wong PhD2, Muneeb Ul Haq MBBS1,2, Rajaram Sripadam FRCR2, Arthur Sun Myint FRCR1,2 1Department of Molecular and Clinical Cancer Medicine, Institute of Systems, Molecular and Integrative Biology, The University of Liverpool, L69 3GE, United Kingdom 2The Clatterbridge Cancer Centre NHS Foundation Trust, 65 Pembroke Place, Liverpool, L7 8YA, United Kingdom 3Department of Health Data Science, Institute of Population Health, The University of Liverpool, L7 3EA, United Kingdom Corresponding Author: Professor Arthur Sun Myint, [email protected] Author Responsible for Statistical Analysis: Dr David M. Hughes, [email protected] Conflicts of interest: None Funding statement: The first author's work was funded by the European Union’s Horizon 2020 research and innovation programme, Marie Skłodowska-Curie grant agreement number 857894—CAST. Data availability statement Research data are stored in the institutional repository and anonymised data will be shared upon request to the corresponding author. Acknowledgement This project was funded by the European Union’s Horizon 2020 research and innovation programme, Marie Skłodowska-Curie grant agreement number 857894—CAST. 2 Abstract Background and purpose Radical surgery following neoadjuvant therapy is the standard of care for locally advanced rectal cancer. A Contact X-ray Brachytherapy (CXB) boost can alternatively be used to treat residual disease post neoadjuvant (chemo)radiation, especially in patients who are not suitable for or do not wish to have surgery. Its role has mostly been studied to date in low to intermediate-risk patients. We have now evaluated the utility of CXB-boost in high-risk rectal cancers after their tumours have been significantly downstaged by neoadjuvant (chemo)radiation. Materials and methods Oncological outcomes and treatment tolerability were evaluated in 328 patients based on rectal cancer treatment risk stratification: low/intermediate risk (cT1-3ab, N0-1, M0, no extramural invasion (EMVI), mesorectal fascia (MRF) involvement >1mm) and high-risk (cT3cd-4/N2, M0, MRF≤1mm and/or EMVI positive). Results With median follow-up of 33(IQR:15-54) months and median age of 73(IQR:62-80) years, no significant differences were found between low/intermediate and high-risk groups in clinical complete response (78% vs 73%, p=0.32), local regrowth (16.6% vs 22.4%, p=0.41), nodal (1.8% vs 5.8%, p=0.051) or regional (1.3% vs 2.9%, p=0.33) relapse, or post-radiation toxicities (p=0.16). However, the high-risk group had a higher distant relapse rate (21.2% vs 10.7%, p=0.01), with no significant differences in 3-year organ preservation (80% vs 87%, p=0.25), 5-year disease-free (DFS) (62% vs 64%, p=0.46), or overall (OS) survivals (67% vs 64%, p=0.88). Longer treatment time, treatment gap >24 weeks between therapies, and administration of a higher than standard CXB dose were newly identified factors that negatively impacted outcomes. Conclusions 3 High-risk rectal cancer patients treated with CXB-boost had more distant relapses, but comparable locoregional tumour control, organ preservation, DFS and OS to lower-risk patients, with acceptable toxicities. CXB-boost is therefore a viable option for selected high-risk rectal cancer patients. Timely reassessment, prompt referral, and CXB dose optimisation are crucial for improving outcomes. Short running title: Contact radiotherapy in high-risk rectal cancer 4 Introduction Current guidelines for managing locally advanced rectal cancer recommend starting with neoadjuvant treatment, including total neoadjuvant therapy, (chemo)radiation, or immunotherapy based on tumour stage and molecular mismatch repair (MMR) status, followed by radical total mesorectal excision (TME) [1-3]. This multi-modality approach reduces pelvic recurrence (2.4-15%) and improves 5-year overall survival (64-87%) [4-6]. However, these benefits come at the cost of post-operative complications [7], stoma formation, and functional impairment of pelvic organs [8, 9]. Over the past two decades, organ-preserving strategies, including local excisions and radiation doseescalation treatments after neoadjuvant therapy, have been adopted to avoid complications related to general anaesthesia and surgery [10], and to respect patients' preferences to avoid extirpative surgery [11]. Published evidence reports that non-surgical treatment achieves long-term organ preservation (59-97%), disease-free survival (61-94%), and overall survival (71-91%) [12-16]. The UK National Institute for Health and Care Excellence (NICE) currently recommends the use of contact X-ray brachytherapy (CXB) only for high surgical risk patients who have early-stage rectal cancer, emphasising its safety and efficacy for these cases. However it is not currently recommended for locally advanced tumours, unless in a research context [17, 18]. However, in routine clinical practice, CXB is used for various indications with informed patient consent, due to the higher bowel cancer incidence in the elderly [19], increased comorbidities with advancing age [20], and patients’ preferences to avoid colostomy [11]. CXB can be used alone or as adjuvant therapy after local excision in stage-I rectal cancer, as a boost combined with (chemo)radiation in operable/more advanced tumours, and also as an alternative salvage option for luminal regrowth after watch-andwait surveillance [21-24]. Magnetic Resonance Imaging (MRI) is the standard for initial and post-therapy (re)staging and determining treatment risk categories to guide neoadjuvant therapy in rectal cancer management [25]. Over recent years, the definition of high-risk features in locally advanced rectal cancer has 5 evolved [26], with low-risk tumours currently being defined as cT1-3abN0M0, tumour to mesorectal rectal fascia (MRF) distance >1mm and no extramural venous invasion(EMVI); intermediate-risk as cT1-3abN1-2M0, MRF >1mm, no EMVI; and high-risk as cT3cd-4anyNM0, anycTN2M0, MRF ≤1mm, and/or presence of EMVI [2, 3]. Numerous studies, including two randomised controlled trials, have investigated the efficacy of CXB as a boost therapy for residual disease following neoadjuvant (chemo)radiation, but these have primarily focused on low and intermediate-risk rectal cancers [23, 27-31]. The ongoing OPAXX phase II study is currently recruiting patients to assess the one-year organ preservation rate after a CXB boost for good responders (small residual/near Complete Response (nCR)) after neoadjuvant treatment in intermediate/high-risk patients [32]. However, comprehensive reports about the efficacy of CXB boost in combination with (chemo)radiation in this context are currently lacking. We therefore conducted this study to investigate the oncological outcomes of CXB-boost therapy after significant downstaging with neoadjuvant (chemo)radiation in high-risk versus low/intermediate-risk rectal cancer patients using MRI-based treatment risk stratification along with the impact of patient-related factors, tumour characteristics, and treatment on oncological outcomes and tolerability. Materials and methods Patient selection Institutional audit approval was obtained on 3rd May 2022 for a retrospective review of all sequential patients who had undergone both (chemo)radiation and CXB with curative intent at our centre from 2008 to 2019. Patient demographics, tumour characteristics, detailed MRI staging reports, treatment details, and outcome data were entered into an institutional CXB database system and subsequently analysed. Neoadjuvant treatment 6 Neoadjuvant external beam radiation (EBRT) was administered in one of three regimens: chemoradiation (45-54Gy/25-30 fractions/5-6 weeks), or long-course (40-50Gy/20-25 fractions/4-5 weeks), or short-course (25Gy/5 fractions/1 week) radiotherapy alone, chosen based on patient performance status and comorbidities. Initially, conformal 3-dimensional radiation (3D-CRT) was the primary technique used, with a transition to Intensity Modulated Radiation Therapy (IMRT) after 2013. (Neo)adjuvant chemotherapy was not routinely administered before or following radiotherapy. Patients were reassessed using digital rectal examination (DRE), sigmoidoscopy, and/or restaging MRI scans. Those who had significant downstaging (small residual disease/near clinical Complete Response (nCR)) after neoadjuvant therapy were referred for consideration of CXB. (Supplementary figure 1) Contact X-ray Brachytherapy (CXB) as a boost therapy Patients referred from local colorectal cancer multidisciplinary teams (MDTs) across the United Kingdom were reviewed before starting CXB at the CXB MDT meeting. Suitability for administration of CXB with curative intent was assessed by digital rectal examination (DRE), identifying small, mobile or slightly tethered residual disease (≤3 cm) located within 10 cm of the anal verge. Additionally, post-neoadjuvant sigmoidoscopy and/or MRI findings had to show significant tumour downstaging and downsizing compared to pre-treatment imaging, with no evidence of nodal involvement. Treatment intent were discussed and patients were informed that CXB is not the standard care in our country and that surgery may have to be reconsidered if residual tumour or regrowth occurred following treatment. All patients were requested to sign a consent form before treatment initiation. CXB was delivered on an outpatient basis using the Papillon-50© machine (50kVp X-rays, HVL 0.64 mm Al, 2.7 mA; Ariane, Alfreton, UK). The radiation dose of 20-30Gy was administered at each fraction two weeks apart via a rectal treatment applicator (sizes 30, 25, or 22 mm) at focal source-surface distances of 29, 32, or 38 mm, respectively. A standard dose of 90Gy (rectal mucosa surface dose) was delivered in 3 fractions over 4 weeks. A fourth 20Gy dose (total 7 110Gy) was administered to selected patients who had minimal visible and/ palpable tumours still present after the third fraction. Follow-up Patients achieving complete or near-clinical responses (cCR/nCR) at 8-12 weeks post-treatment were regularly monitored. Follow-up included DRE, flexible sigmoidoscopy/rigid rectoscopy alternately at the patient’s local colorectal centre and our centre (if the patients were prepared to attend regular appointments at our centre), with MRI scans every 12 weeks for the first 2 years and every 6 months in the third year. Only endoscopic examinations were performed in the fourth and fifth years. Patients who did not achieve cCR, which was confirmed by the triple assessment (DRE, endoscopy, and MRI) with/without histological confirmation, by 24 weeks or who experienced local regrowth during surveillance were referred for salvage surgery if they agreed and were deemed suitable. Outcome measures This study assessed oncological outcomes across the entire cohort and two risk groups based on treatment risk stratification: low/intermediate risk (cT1-3ab, N0-1, M0, no EMVI, MRF > 1mm) and high-risk (cT3cd-4/N2, M0, MRF ≤ 1mm and/or EMVI positive). cN2 cases were excluded from the intermediate-risk group due to unspecified extra-nodal or intra-nodal details in MRI reports. Primary endpoints included cCR, rates of local, nodal, regional, and distant relapses, organ preservation rate, disease-free survival (DFS), and overall survival (OS). Local regrowth was defined as luminal recurrence at the site of the original tumour, while nodal relapse referred to recurrence limited to the mesorectal or pelvic lymph nodes. Regional relapse was defined as recurrence in a nearby structure outside the rectum, such as the vaginal wall or presacral space. The organ preservation rate was defined as the absence of transabdominal resection, and the absence of locoregional regrowth unless salvaged by transanal R0 (microscopically clear margin) excisions. DFS was calculated from the last treatment to locoregional recurrence post-R0/R1 (microscopically positive margin) resection, non-salvageable local regrowth/R2 (macroscopically positive margin) resection 8 post-salvage surgery, the occurrence of second primary/distant metastasis, or last follow-up. OS was measured from the first date of diagnosis to the last date of data review or death from any cause. Secondary outcomes included evaluating the radiation toxicities using Common Terminology Criteria for Adverse Events (CTCAE) criteria version 5.0 [33] and the influence of patient, tumour, and treatment factors on local tumour control, distant relapse, and survivals. Statistical analysis Quantitative data are presented as medians with interquartile range (IQR) or means with standard deviation (SD), while categorical data are presented as counts and percentages. Categorical variables were compared using the χ2 test, with Fisher’s exact test (two-tailed) applied when necessary. Continuous variables were compared using the Mann-Whitney U test due to non-normal distribution. Group survival differences were examined using Kaplan-Meier curves and Log-rank tests were used for statistical assessment. Associations between patient, tumour, and treatment characteristics and survival risks were analysed utilising Cox proportional hazard models. Logistic regression was employed to evaluate binary margin outcomes. Variables with p≤0.2 in the univariable analyses were included in the multivariable analyses. A p-value <0.05 was considered statistically significant. All statistical analyses were conducted using R version 4.4.0. Results A total of 402 consecutive patients who had been treated with (chemo)radiation followed by CXB boost therapy were initially identified from the institutional database (2008-2019). After excluding patients with unknown staging (Tx/Nx) (n=3), those staged solely by CT scan (n=16) (because of its lower sensitivity and specificity for tumour staging compared with MRI [34]), individuals treated palliatively (n=17), cases with prior local excision (n=1), under-dosed CXB recipients for various reasons (30-60Gy) (n=18), and those lost to follow-up (n=19), 328 patients were eligible for analysis. The study profile is outlined in Figure 1. 15 Ethics board approval As this study was a retrospective observational study, it was approved by the institutional audit committee on 3rd May 2022, and no ethical approval was required. References 1. Excellence, N.I.f.C., Colorectal cancer. NICE guideline [NG151]. 2020. Available from: https://www.nice.org.uk/guidance/ng151 [Assessed 31 May 2024] 2. 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Clin Med Insights Oncol, 2024. 18: p. 11795549241227423. https://doi.org/10.1177/11795549241227423 23 List of figures Low/intermediate risk n=224 High risk n=104 Figure 1: Study profile 1. Compare oncological and clinical outcomes 2. Influence of patient, tumour, and treatment factors on oncological outcomes Included cases n=328 Excluded cases Lost follow-up after last treatment=19 Palliative intent=17 Post-excision case=1 CXB under-dosed (30-60Gy) cases=18 Tx/Nx cases=3 Staging using CT scan=16 Consecutively treated patients CXB boost after (chemo)radiation (2008-2019) n=402 24 Figure 2: Flow diagram illustrating the oncological outcomes of the two risk groups CXB boost after (chemo)radiation n=328 Low-intermediate risk n=224 High risk n=104 Initial cCR n=175(78%) Residual disease n=49(22%) Initial cCR n=76(73%) 00 Residual disease n=28(27%) Local regrowth n=29/175(16.6%) APER=15 Hartmann’s= 1 EMR=1 BSC=12 Nodal relapse n=3 TEMS=3 LAR=3 APER=11 Exenteration=2 BSC=20 cCR: clinical Complete Response, APER; Abdomino Peritoneal Excision of Rectum, Hartmann’s: Hartmann’s operation, LAR: Low Anterior Resection, Exenteration: Pelvic Exenteration, EMR: Endoscopic Mucosal Resection, TEMS: Transanal Endoscopic Microsurgery, SBRT: Stereotactic Body Radiotherapy, BSC: Best Supportive Care Distant relapse n=5 Distant relapse n=11 Distant relapse n=3 Distant relapse n=4 Distant relapse=1 Regional relapse=1 APER=1 SBRT=1 BSC=1 Local regrowth n=17/76(22.4%) Distant relapse n=4 APER=9 Hartmann’s=1 TEMS=1 BSC=6 Distant relapse n=1 Distant relapse n=4 Nodal relapse n=3 Exenteration= 1 BSC=2 APER=13 Hartmann’s=1 TEMS=1 BSC=13 Distant relapse=7 Nodal relapse=1 Regional relapse=2 Distant relapse n=4 Nodal relapse n=3 Regional relapse=1 Distant relapse n=2 Regional relapse=2 Nodal relapse n=1 31 Mean tumour size at time of CXB (cm) 1.7±0.9 1.6±0.9 1.8±1.1 0.19ǂ Tumour size group at CXB ≤3cm >3-5cm Not recorded 315(96) 12(3.7) 1(0.3) 218(97) 6(3) 0(0) 97(93) 6(6) 1(1) 0.16¥ Distance from anal verge 3-≤6cm >6-12cm Not recorded 226(69) 85(26) 17(5) 152(68) 59(26) 13(6) 74(71) 26(25) 4(4) 0.72¥ EBRT regimen Short course Long course Chemoradiation 54(16.5) 59(18.0) 215(65.5) 48(21.4) 44(19.6) 132(59) 6(5.8) 15(14.4) 83(79.8) <0.001¥ Restaging with MRI Yes No Not recorded 201(61) 107(33) 20(6) 85(38) 123(55) 16(7) 78(75) 22(21) 4(4) 0.001¥ Stage after (chemo)radiation yT0,yN0,yM0 yT1/2,yN0,yM0 yT2/3,yN0,yM0 yT3/4,yN0,yM0 Unknown 41(12.5) 120(36.5) 34(10) 6(2) 127 (39) 20(9) 84(37) 17(8) 2(1) 101(45) 21(20) 36(35) 17(16) 4(4) 26(25) 0.02¥ Treatment gap time between EBRT and CXB <12 weeks 12-24 weeks >24-48 weeks 155(47.3) 132(40.2) 41(12.5) 115(51.3) 85(38) 24(10.7) 40(39) 47(45) 17(16) 0.07¥ Overall treatment time Conventional Unconventional 188(57.3) 140(42.7) 130(58) 94(42) 58(55.8) 46(44.2) 0.70¥ CXB total dose 80-90Gy 110Gy 224(68.3) 104(31.7) 152(68) 72(32) 72(69) 32(31) 0.80¥ Total CXB treatment time Standard (4-6 weeks) Unconventional (>6-9 weeks) 216(66) 112(34) 149(66.5) 75(33.5) 67(64) 37(36) 0.71¥ IQR: Interquartile Range, WHO: World Health Organization, EBRT: External Beam Radiation, CXB: Contact X-ray Brachytherapy, MRI: Magnetic Resonance Imaging, ǂ= Mann-Whitney U test, ¥= χ2 test 32 Table 2: Oncological and clinical outcomes of the whole cohort and risk group studies Outcome Total n=328(%) Risk stratification Low/intermediate n=224(%) High n=104(%) P value (χ2 test) Near/complete Clinical Response (n/cCR) 251(76.5) 175(78) 76(73) 0.32 Residual disease 77(23.5) 49(22) 28(27) Number of patients who underwent salvage surgery and outcomes 34/77 (44) R0=27 R1=6 R2=1 19/49(39) R0=18 R1=1 15/28 (54) R0=9 R1=5 R2=1 Local regrowth 46/251(18.3) 29/175(16.6) 17/76(22.4) 0.41 Number of patients who underwent salvage surgery and outcomes 28/46 (61) R0=22 R1=5 R2=1 17/29 (59) R0=14 R1=3 11/17 (65) R0=8 R1=2 R2=1 Nodal relapse 10(3.0) 4(1.8) 6(5.8) 0.051 Regional relapse 6(1.8) 3(1.3) 3(2.9) 0.33 Number of patients (both nodal and regional) who underwent salvage surgery and outcomes 7/16 (44) R0=4 R1=2 CR=1 5/7 (71) R0=2 R1=2 (SBRT – CR) 2/9 (22) R0=2 Distant relapse 46(14) 24(10.7) 22(21.2) 0.01 Number of patients who underwent salvage surgery and outcomes 6/46 (13) All CR 2/24 (8) Lung resection=2 4/22 (18) Lung resection=3 Liver resection=1 Total incidence of radiation toxicities 96(29.3) 64(28.6) 32(30.8) 0.16 Acute proctitis (erratic bowel, pain) Grade 1-2 Grade 3 28(8.5) 0(0) 20(9) 0(0) 8(7.7) (0) Late rectal bleeding Grade 1/2 Grade 3 58(17.7) 3(0.9) 35(15.6)3(1.4) 23(22.3) 0(0) Faecal incontinence Grade 1-2 Grade 3 4(1.2) 0(0) 3(1) 0(0) 1(0.9) 0(0) Stricture Grade 1-2 Grade 3 3(0.9) 0(0) 3(3.7) 0(0) 0(0) 0(0) R0= microscopically negative margin resection, R1= microscopically positive margin resection, R2= macroscopically positive margin resection, SBRT= Stereotactic Body Radiotherapy, CR= Complete Response 33 Supplementary Table on Generalizability of Study Population(s) Condition Description Disease, problem, or condition under investigation High-risk locally advanced rectal adenocarcinoma Relevant considerations of disease, problem, or condition in relation to: Note any relevant considerations in boxes below: Sex and gender In 2019, 142,462 cases of colon and rectum cancer were reported in the UK: 75,581 among males and 66,881 among females. The incidence rate was 36 per 100,000 standard population and was 42 per 100,000 males and 32 per 100,000 females. Age Incidence rates for bowel cancer in the UK are highest in people aged 85 to 89 (2017-2019). Each year more than 4 in 10 (43%) of all new bowel cancer cases in the UK are diagnosed in people aged 75 and over (2017-2019). Race or ethnic group Incidence rates for bowel cancer are lower in the Asian and Black ethnic groups, and in people of mixed or multiple ethnicity, compared with the White ethnic group, in England (2013-2017). Geography Large geographical variations in incidence and mortality rates are observed. The incidence rates are highest in Europe and Australia and New Zealand, and the mortality rates are highest in Eastern Europe. Other considerations Study Description Overall assessment of generalizability of the study population This study was conducted in an older cohort with a median age of 73(IQR:62-80) years, who had high-risk locally advanced rectal cancer. 73% of patients were male. Data on ethnicity was not available, although the majority were white British. All patients were from the United Kingdom. The treatment protocol used in this study is applicable to all populations.