Low energy contact X-ray brachytherapy for treatment of rectal cancer: a health technology appraisal by Health Technology Wales.

AIM: Health Technology Wales sought to evaluate the clinical and cost-effectiveness of contact X-ray brachytherapy (CXB) for early-stage rectal cancer. METHODS: Relevant studies were identified through systematic searches of MEDLINE, Embase, Cochrane Library and Scopus. A cost-utility model was developed to estimate the cost-effectiveness of CXB in National Health Service Wales, using results of the Organ Preservation in Early Rectal Adenocarcinoma (OPERA) trial. Patient perspectives were obtained through the Papillon Patient Support group and All-Wales Cancer Network. RESULTS: The OPERA randomized controlled trial showed that CXB improved complete response and organ preservation rates compared with external-beam boost for people with T2-3b, N0-1, M0 rectal cancer who are fit for surgery. Managing more of this population non-operatively after CXB was estimated to provide 0.2 quality-adjusted life years at an additional cost of £887 per person. CXB was cost effective compared with external-beam boost at a cost of £4463 per quality-adjusted life year gained. This conclusion did not change in scenario analysis and CXB was cost effective in 91% of probabilistic sensitivity analyses. Patients valued receiving clear information on all available options to support their individual treatment choices. The detrimental impact of a stoma on quality of life led some patients to reject the idea that surgery was their only option. CONCLUSION: This evidence review and cost-utility analysis indicates that CXB is likely to be clinically and cost effective, as part of a watch and wait strategy for adults fit for surgery. Wider access to CXB is supported by patient testimonies.

The safety and efficacy of total mesorectal excision (TME) surgery following dose-escalation: Surgical outcomes from the organ preservation in early rectal adenocarcinoma (OPERA) trial, a European multicentre phase 3 randomised trial (NCT02505750).

AIM: Nonsurgical treatment with chemoradiotherapy for rectal cancer is gaining interest as it avoids total mesorectal excision (TME) surgery and stoma. The OPERA trial aims to evaluate whether dose escalation with contact X-ray brachytherapy (CXB) boost improves organ preservation compared to external beam radiotherapy (EBRT) boost. It has been suggested that dose escalation adversely affects surgical outcomes and therefore we report outcomes following TME in OPERA at 36 months. METHODS: OPERA is a European multicentre phase 3 trial (NCT02505750) which randomises patients with cT2-3a-b, cN0-1, M0 to EBCRT (45 Gy in 25 fractions over 5 weeks with oral capecitabine 825 mg/m2 ) followed by EBRT boost (9 Gy in 5 fractions over 5 days) versus EBCRT followed by CXB boost (90 Gy in 3 fractions over 4 weeks). Patients were assessed at 14, 20 and 24 weeks from the start of treatment. Watch and wait management was adopted for patients who achieved a clinical complete response (cCR) at 24 weeks following treatment. Either local excision (LE) or TME surgery was offered for residual disease or local regrowth, according to patient and surgeon preference. Surgical morbidity and mortality were recorded prospectively. RESULTS: Between July 2015 and June 2020, 148 patients were randomised of which 141 were evaluable in March 2022. At median follow-up of 38.2 months (range: 34.2-42.5), surgery was performed for 66 (47%) patients. A total of 27 (20%) patients had local excision and 39 (29%) had TME surgery, 22/39 (56%) underwent anterior resection and 17/39 (44%) underwent abdominoperineal excision of the rectum. The R0 resection rate was 87%. There were no deaths, and six patients (15%) had Clavien-Dindo IIIb complications. Whilst there was a statistically significant decrease in the TME rate following CXB boost (HR 0.38, 95% CI: 0.19-0.74, p = 0.00419) there was no difference in surgical outcomes between patients who received EBRT and CXB boost. CONCLUSION: Dose escalation can facilitate nonsurgical treatment for cT2-3 rectal cancer patients who are fit but wish to avoid TME surgery and stoma. If TME surgery is required, then it can be performed safely and effectively.

Immunotherapy and Radiotherapy for Older Cancer Patients during the COVID-19 Era: Proposed Paradigm by the International Geriatric Radiotherapy Group.

BACKGROUND: Older cancer patients with locally advanced or metastatic disease may benefit from chemotherapy alone or combined with radiotherapy. However, chemotherapy is often omitted either because of physician bias or because of its underlying comorbidity, thus compromising their survival. The coronavirus disease 19 (COVID-19) pandemic is compounding this issue because of the fear of immunosuppression induced by chemotherapy on the elderly which makes them more vulnerable to the virus. SUMMARY: Immunotherapy has less effect on the patient bone marrow compared to chemotherapy. The potential synergy between radiotherapy and immunotherapy may improve local control and survival for older patients with selected cancer. Preliminary data are encouraging because of better survival and local control in diseases which are traditionally resistant to radiotherapy and chemotherapy such as melanoma and renal cell carcinoma. Key Message: We propose a new paradigm combining immunotherapy at a reduced dose and/or extended dosing intervals and hypofractionated radiotherapy for older patients with selected cancer which needs to be tested in future clinical trials.

Avoiding Radical Surgery in Elderly Patients With Rectal Cancer Is Cost-Effective.

BACKGROUND: Radical surgery is associated with significant perioperative mortality in elderly and comorbid populations. Emerging data suggest for patients with a clinical complete response after neoadjuvant chemoradiotherapy that a watch-and-wait approach may provide equivalent survival and oncological outcomes. OBJECTIVE: The purpose of this study was to compare the cost-effectiveness of watch and wait and radical surgery for patients with rectal cancer after a clinical complete response following chemoradiotherapy. DESIGN: Decision analytical modeling and a Markov simulation were used to model long-term costs, quality-adjusted life-years, and cost-effectiveness after watch and wait and radical surgery. Sensitivity analysis was used to investigate the effect of uncertainty in model parameters. SETTINGS: A third-party payer perspective was adopted. PATIENTS: Patients included in the study were a 60-year-old male cohort with no comorbidities, 80-year-old male cohorts with no comorbidities, and 80-year-old male cohorts with significant comorbidities. INTERVENTIONS: Radical surgery and watch-and-wait approaches were studied. MAIN OUTCOME MEASURES: Incremental cost, effectiveness, and cost-effectiveness ratio over the entire lifetime of the hypothetical patient cohorts were measured. RESULTS: Watch and wait was more effective (60-year-old male cohort with no comorbidities = 0.63 quality-adjusted life-years (95% CI, 2.48-3.65 quality-adjusted life-years); 80-year-old male cohort with no comorbidities = 0.56 quality-adjusted life-years (95% CI, 0.52-1.59 quality-adjusted life-years); 80-year-old male cohort with significant comorbidities = 0.72 quality-adjusted life-years (95% CI, 0.34-1.76 quality-adjusted life-years)) and less costly (60-year-old male cohort with no comorbidities = $11,332.35 (95% CI, $668.50-$23,970.20); 80-year-old male cohort with no comorbidities = $8783.93 (95% CI, $2504.26-$21,900.66); 80-year-old male cohort with significant comorbidities = $10,206.01 (95% CI, $2762.014-$24,135.31)) independent of patient cohort age and comorbidity. Consequently, watch and wait was more cost-effective with a high degree of certainty (range, 69.6%-89.2%) at a threshold of $50,000/quality-adjusted life-year. LIMITATIONS: Long-term outcomes were derived from modeled cohorts. Analysis was performed for a United Kingdom third-party payer perspective, limiting generalizability to other healthcare contexts. CONCLUSIONS: Watch and wait is likely to be cost-effective compared with radical surgery. These findings strongly support the discussion of organ-preserving strategies with suitable patients.

Contact X-ray Brachytherapy as a sole treatment in selected patients with early rectal cancer - Multi-centre study.

Background and purpose: Radical surgery is the standard of care for early rectal cancer. However, alternative organ-preserving approaches are attractive, especially in frail or elderly patients as these avoid surgical complications. We have assessed the efficacy of sole Contact X-ray Brachytherapy (CXB) treatment in stage-1 rectal cancer patients who were unsuitable for or declined surgery. Materials and methods: This retrospective multi-centre study (2009-2021) evaluated 76 patients with T1/2-N0-M0 rectal adenocarcinomas who were treated with CXB alone. Outcomes were assessed for the entire cohort and sub-groups based on the T-stage and the criteria for receiving CXB alone; Group A: patients who were fit enough for surgery but declined, Group B: patients who were high-risk for surgery and Group C: patients who had received prior pelvic radiation for a different cancer. Results: With a median follow-up of 26(IQR:12-49) months, initial clinical Complete Response (cCR) was 82(70-93)% with rates of local regrowth 18(8-29)%, 3-year actuarial local control (LC) 84(75-95)%, distant relapse 3 %, and no nodal relapse. 5-year disease-free survival (DFS) and overall survival (OS) were 66(48-78)% and 58(44-75)%. Lower OS was observed in Groups B [HR:2.54(95 %CI:1.17, 5.59), p = 0.02] and C [HR:2.75(95 %CI:1.15, 6.58), p = 0.03]. Previous pelvic radiation predicted lower cCR and OS. The main toxicity was G1-2 rectal bleeding (26 %) and symptoms of impaired anal sphincter function were not reported in any patients. Conclusion: CXB treatment alone achieved a high cCR rate with satisfactory LC and DFS. Inferior oncological outcomes were observed in patients who had received prior pelvic radiotherapy. CXB alone, with its favourable toxicity profile and avoidance of general anaesthesia and surgery risks, therefore, can be considered for patients who are unsuitable for or refuse surgery.

GEC ESTRO ACROP consensus recommendations for contact brachytherapy for rectal cancer.

PURPOSE: To issue consensus recommendations for contact X-Ray brachytherapy (CXB) for rectal cancer covering pre-treatment evaluation, treatment, dosimetric issues and follow-up. These recommendations cover CXB in the definitive and palliative setting. METHODS: Members of GEC ESTRO with expertise in rectal CXB issued consensus-based recommendations for CXB based on literature review and clinical experience. Levels of evidence according to the Oxford Centre for Evidence based medicine guidance are presented where possible. RESULTS: The GEC ESTRO ACROP consensus recommendations support the use of CXB to increase the chances of clinical complete remission and cure for patients who are elderly with high surgical risk, surgically unfit or refusing surgery. For palliative treatment, the use of CXB is recommended for symptomatic relief and disease control. The use of CXB in an organ-preservation setting in surgically fit patients is recommended within the setting of a clinical trial or registry. CONCLUSIONS: The GEC ESTRO ACROP recommendations for CXB are provided. Recommendations towards standardisation of reporting and prescription are given. Practitioners are encouraged to follow these recommendations and to develop further clinical trials to examine this treatment modality and increase the evidence base for its use. The routine collection of outcomes both clinical and patient-reported is also encouraged.

A multi-centre analysis of adjuvant contact X-ray brachytherapy (CXB) in rectal cancer patients treated with local excision - Preliminary results of the CONTEM1 study.

INTRODUCTION: Early rectal cancers are increasingly diagnosed through screening programmes and are often treated using local excision (LE). In the case of adverse pathological features completion total mesorectal excision surgery (TME) is the standard recommendation. The morbidity and mortality risks of TME have stimulated the use of adjunctive treatments following LE to achieve organ preservation. MATERIAL AND METHODS: Patients treated with adjuvant CXB following local excision between 2004 and 2017 in three centres were identified (Clatterbridge, Hull, Nice). All patients had adverse pathological features including: lymphovacular invasion, Sm2-3 Kikuchi level, tumour budding, pT2, positive resection margins (R1). CXB was performed with the Papillon50 tm machine to a dose of 40-60 Gy in 2 or 3 fractions over 2-4 weeks preceding/following external beam chemo/radiotherapy. Kaplan Meier survival estimates were used for outcomes measures. RESULTS: 194 patients were identified. Median age was 70 years. pT staging was: pT1:143, pT2:45, pT3:6. CXB alone was given in 24 pts and combined with EBRT in 170. Median follow-up time was 77 months (range 7-122 months). Local relapse rate was 8% and distant metastases 9%. Organ preservation was achieved in 95%. 6 year local recurrence free and overall survival was 91% and 81% respectively. Cancer specific survival was 97%. No treatment related mortality was seen. CONCLUSION: This large multi-centre cohort study using adjuvant CXB following local excision suggests excellent oncological outcomes for these patients without completion TME. This treatment approach can be considered as an alternative for selective patients compliant with long term follow up.

A systematic review comparing radiation toxicity after various endorectal techniques.

PURPOSE: A clinical complete response is seen after neoadjuvant chemoradiation for rectal tumors in 15%-20% of patients. These patients can potentially be spared mutilating total mesorectal excision surgery through a watch-and-wait policy. Recent studies show that dose escalation by a radiation boost increases the clinical complete response rate. The boost dose to the tumor can be administered through external beam radiotherapy or through internal radiotherapy using techniques like contact therapy, low-dose-rate or high-dose-rate brachytherapy (BT). However, limited information is available concerning treatment-related toxicity of these techniques. With this systematic review, we aim to summarize and compare published data concerning acute and late toxicity after contact X-ray therapy (CXT) and BT for rectal cancer. METHODS AND MATERIALS/RESULTS: Thirty-eight studies reporting toxicity after endorectal radiation techniques for rectal cancer were included, resulting in 3682 patients for analysis. Direct comparison of toxicity by the different radiation modes was hampered by various combinations of endorectal techniques, a lack of clear reporting of toxicity scores, dose prescription, technique used, and treated volumes. ≥ Grade 3 rectal toxicity was reported in 2.9% of patients having received only CXT; 6.3% of patients who received only BT had Grade 3 rectal toxicity, and BT also caused Grade 3 urinary toxicity in 1 patient. CONCLUSION: All techniques reported some ≥ Grade 3 toxicity. Toxicity after CXT was confined to the rectum, whereas after BT, urogenital toxicity and skin toxicity were seen as well. Unfortunately, few specific conclusions could be drawn regarding the dose-related risk of toxicity for the various techniques due to nonuniform reporting strategies and missing information. To enable future comparisons and improvements, the endorectal radiation field urgently needs consensus guidelines on dose reporting, dose prescription, treatment volume specification, and toxicity reporting.

Dose Escalation Using Contact X-ray Brachytherapy After External Beam Radiotherapy as Nonsurgical Treatment Option for Rectal Cancer: Outcomes From a Single-Center Experience.

PURPOSE: To review the outcomes of rectal cancer patients treated with a nonsurgical approach using contact x-ray brachytherapy (CXB) when suspicious residual disease (≤3 cm) was present after external beam chemoradiation therapy/radiation therapy (EBCRT/EBRT). METHODS AND MATERIALS: Outcome data for rectal cancer patients referred to our institution from 2003 to 2012 were retrieved from an institutional database. These patients were referred after initial local multidisciplinary team discussion because they were not suitable for, or had refused, surgery. All selected patients received a CXB boost after EBCRT/EBRT. Most patients received a total of 90 Gy of CXB delivered in 3 fractions over 4 weeks. RESULTS: The median follow-up period was 2.5 years (range 1.2-8.3). Of 345 consecutive patients with rectal cancer referred to us, 83 with suspicious residual disease (≤3 cm) after EBCRT/EBRT were identified for a CXB boost. Their median age was 72 years (range 36-87), and 58 (69.9%) were men. The initial tumor stages were cT2 (n = 28) and cT3 (n = 55), and 54.2% were node positive. A clinical complete response (cCR) was achieved in 53 patients (63.8%) after the CXB boost that followed EBCRT/EBRT. Of these 53 patients, 7 (13.2%) developed a relapse after achieving a cCR, and the 6 patients (11.6%) with nonmetastatic regrowth underwent salvage surgery (100%). At the end of the study period, 69 of 83 patients (83.1%) were cancer free. CONCLUSIONS: Our data suggest that a CXB boost for selected patients with suspicious residual disease (≤3 cm) after EBCRT/EBRT can be offered as an alternative to radical surgery. In our series, patients with a sustained cCR had a low rate of local regrowth, and those with nonmetastatic regrowth could be salvaged successfully. This approach could provide an alternative treatment option for elderly or comorbid patients who are not suitable for surgery and those with rectal cancer who wish to avoid surgery.

Factors affecting local regrowth after watch and wait for patients with a clinical complete response following chemoradiotherapy in rectal cancer (InterCoRe consortium): an individual participant data meta-analysis.

BACKGROUND: In patients with rectal cancer who achieve clinical complete response after neoadjuvant chemoradiotherapy, watch and wait is a novel management strategy with potential to avoid major surgery. Study-level meta-analyses have reported wide variation in the proportion of patients with local regrowth. We did an individual participant data meta-analysis to investigate factors affecting occurrence of local regrowth. METHODS: We updated search results of a recent systematic review by searching MEDLINE and Embase from Jan 1, 2016, to May 5, 2017, and used expert knowledge to identify published studies reporting on local regrowth in patients with rectal cancer managed by watch and wait after clinical complete response to neoadjuvant chemoradiotherapy. We restricted studies to those that defined clinical complete response using criteria equivalent to São Paulo benchmarks (ie, absence of residual ulceration, stenosis, or mass within the rectum on clinical and endoscopic examination). The primary outcome was 2-year cumulative incidence of local regrowth, estimated with a two-stage random-effects individual participant data meta-analysis. We assessed the effects of clinical and treatment factors using Cox frailty models, expressed as hazard ratios (HRs). From these models, we derived percentage differences in mean θ as an approximation of the effect of measured covariates on between-centre heterogeneity. This study is registered with PROSPERO, number CRD42017070934. FINDINGS: We obtained individual participant data from 11 studies, including 602 patients enrolled between March 11, 1990, and Feb 13, 2017, with a median follow-up of 37·6 months (IQR 25·0-58·7). Ten of the 11 datasets were judged to be at low risk of bias. 2-year cumulative incidence of local regrowth was 21·4% (random-effects 95% CI 15·3-27·6), with high levels of between-study heterogeneity (I2=61%). We noted wide between-centre variation in patient, tumour, and treatment characteristics. We found some evidence that increasing cT stage was associated with increased risk of local regrowth (random-effects HR per cT stage 1·40, 95% CI 1·00-1·94; ptrend=0·048). In a subgroup of 459 patients managed after 2008 (when pretreatment staging by MRI became standard), 2-year cumulative incidence of local regrowth was 19% (95% CI 13-28) for stage cT1 and cT2 tumours, 31% (26-37) for cT3, and 37% (21-60) for cT4 (random-effects HR per cT stage 1·50, random-effects 95% CI 1·03-2·17; ptrend=0·0330). We estimated that measured factors contributed 4·8-45·3% of observed between-centre heterogeneity. INTERPRETATION: In patients with rectal cancer and clinical complete response after chemoradiotherapy managed by watch and wait, we found some evidence that increasing cT stage predicts for local regrowth. These data will inform clinician-patient decision making in this setting. Research is needed to determine other predictors of a sustained clinical complete response. FUNDING: None.

Dose escalation using contact X-ray brachytherapy (Papillon) for rectal cancer: does it improve the chance of organ preservation?

OBJECTIVE: A watch and wait policy for patients with a clinical complete response (cCR) after external beam chemoradiotherapy (EBCRT) for rectal cancer is an attractive option. However, approximately one-third of tumours will regrow, which requires surgical salvage for cure. We assessed whether contact X-ray brachytherapy (CXB) can improve organ preservation by avoiding surgery for local regrowth. METHODS: From our institutional database, we identified 200 of 573 patients treated by CXB from 2003 to 2012. Median age was 74 years (range 32-94), and 134 (67%) patients were males. Histology was confirmed in all patients and was staged using CT scan, MRI or endorectal ultrasound. All patients received combined CXB and EBCRT, except 17 (8.5%) who had CXB alone. RESULTS: Initial cCR was achieved in 144/200 (72%) patients. 38/56 (68%) patients who had residual tumour received immediate salvage surgery. 16/144 (11%) patients developed local relapse after cCR, and 124/144 (86%) maintained cCR. At median follow up of 2.7 years, 161 (80.5%) patients were free of cancer. The main late toxicity was bleeding (28%). Organ preservation was achieved in 124/200 (62%) patients. CONCLUSION: Our data suggest that CXB can reduce local regrowth to 11% compared with around 30% after EBCRT alone. Organ preservation of 62% achieved was higher than reported in most published watch and wait studies. Advances in knowledge: CXB is a promising treatment option to avoid salvage surgery for local regrowth, which can improve the chance of organ preservation in patients who are not suitable for or refuse surgery.

Past, present, and future of radiotherapy for the benefit of patients.

Radiotherapy has been driven by constant technological advances since the discovery of X-rays in 1895. Radiotherapy aims to sculpt the optimal isodose on the tumour volume while sparing normal tissues. The benefits are threefold: patient cure, organ preservation and cost-efficiency. The efficacy and tolerance of radiotherapy were demonstrated by randomized trials in many different types of cancer (including breast, prostate and rectum) with a high level of scientific evidence. Such achievements, of major importance for the quality of life of patients, have been fostered during the past decade by linear accelerators with computer-assisted technology. More recently, these developments were augmented by proton and particle beam radiotherapy, usually combined with surgery and medical treatment in a multidisciplinary and personalized strategy against cancer. This article reviews the timeline of 100 years of radiotherapy with a focus on breakthroughs in the physics of radiotherapy and technology during the past two decades, and the associated clinical benefits.

Preoperative chemoradiotherapy using concurrent capecitabine and irinotecan in magnetic resonance imaging-defined locally advanced rectal cancer: impact on long-term clinical outcomes.

PURPOSE: To assess long-term clinical outcomes of preoperative chemoradiotherapy of magnetic resonance imaging (MRI)-defined locally advanced rectal adenocarcinoma using concurrent irinotecan and capecitabine. PATIENTS AND METHODS: One hundred ten patients without distant metastases entered this phase II trial North West/North Wales Clinical Oncology Group (NWCOG) -2 after MRI demonstration of tumor threatening (≤ 2 mm) or involving mesorectal fascia. Pelvic radiotherapy was given to 45 Gy in 25 fractions over 5 weeks with concurrent oral capecitabine at 650 mg/m(2) twice per day continuously days 1 through 35 and intravenous irinotecan at 60 mg/m(2) once weekly weeks 1 to 4. One hundred seven patients subsequently underwent surgical resection. RESULTS: Comparing prechemoradiotherapy MRI scans with histology of the resected specimen, 72 patients (67%) had their initial MRI T stage downstaged and 64 patients (80%) had their N stage downstaged. Twenty-four patients (22%) demonstrated a pathologic complete response (ypCR) and 98 patients (92%) demonstrated a negative circumferential resection margin (> 1 mm). Three-year local recurrence-free survival was 96.9%, metastasis-free survival (MFS) was 71.1%, disease-free survival was (DFS) 63.5%, and overall survival (OS) was 88.2%. By univariate analysis, lower histologic stage was significantly associated with superior MFS, DFS, and OS, whether expressed as ypT0-2 versus ypT3-4, ypN0 versus ypN1-2, or ypCR/microfoci (near-ypCR) versus other patients. By multivariate analysis both ypN stage (P = .048) and ypCR/microfoci/others (P = .013) remained significant predictors of DFS but only ypCR/microfoci/others for OS (P = .005) with no difference in outcome between ypCR compared to microfoci. CONCLUSION: This regimen demonstrates high response rates and promising long-term survival. Downstaging to ypCR/microfoci may be a useful short-term surrogate for long-term survival but needs validation in large phase III trials powered for survival outcomes.