Long-course Radiotherapy Research Articles

Circulating tumor DNA in patients with locally advanced rectal cancer treated with multimodal treatment.

The management of locally advanced rectal cancer (LARC) relies on a multimodal approach. Neither instrumental work-up nor molecular biomarkers are currently available to identify a risk-adapted strategy. We aim to investigate the role of circulating tumor DNA (ctDNA) and its clearance at different timepoints during chemo-radiotherapy (CRT) and correlate them with clinical outcomes. Between November 2014 and November 2019, we conducted a monocentric prospective observational study enrolling consecutive patients with LARC managed with neoadjuvant standard CRT (capecitabine and concomitant pelvic long-course radiotherapy), followed by consolidation capecitabine in selected cases and surgery. Blood samples for ctDNA were obtained at pre-planned timepoints. We evaluated the correlation of baseline variant allele frequency (VAF) with pathologic complete response (pCR) down-staging, node regression (pN0), event-free survival (EFS), and overall survival (OS). Among 112 screened patients, 61 were enrolled. In all, 38 (62%) had a positive ctDNA at baseline with VAF > 0 and 23 had negative ctDNA (VAF = 0). Among patients with negative ctDNA, 30% had a complete response, while only 13% of positive ctDNA patients had pCR [odds ratio (OR) 0.35 (95% confidence interval (CI): 0.10-1.26), p = 0.11]. Similarly, 96% and 74% of pN0 were observed among negative and positive ctDNA patients, respectively [OR 0.13 (95% CI: 0.02-1.07), p = 0.058]. The presence of a baseline VAF > 0 was associated with a trend toward a lower EFS compared with VAF = 0 patients [hazard ratio (HR) = 2.30, 95% CI: 0.63-8.36, p = 0.21]. Within the limitations of small sample size, no difference in OS was observed according to the baseline ctDNA status (HR = 1.18, 95% CI: 0.35-4.06, p = 0.79). Within the limitations of a reduced number of patients, patients with baseline negative ctDNA seem to show a higher probability of pN0 status and a trend toward improved EFS. Prospective translational studies are required to define the role of ctDNA analysis in the multimodal treatment of LARC.

Radiotherapy dose escalation using pre-treatment diffusion-weighted imaging in locally advanced rectal cancer: a planning study.

Diffusion-weighted MRI (DWI) may provide biologically relevant target volumes for dose-escalated radiotherapy in locally advanced rectal cancer (LARC). This planning study assessed the dosimetric feasibility of delivering hypofractionated boost treatment to intra-tumoural regions of restricted diffusion prior to conventional long-course radiotherapy. Ten patients previously treated with curative-intent standard long-course radiotherapy (50 Gy/25#) were re-planned. Boost target volumes (BTVs) were delineated semi-automatically using 40th centile intra-tumoural apparent diffusion coefficient value with expansions (anteroposterior 11 mm, transverse 7 mm, craniocaudal 13 mm). Biased-dosed combined plans consisted of a single-fraction volumetric modulated arc therapy flattening-filter-free (VMAT-FFF) boost (phase 1) of 5, 7, or 10 Gy before long-course VMAT (phase 2). Phase 1 plans were assessed with reference to stereotactic conformality and deliverability measures. Combined plans were evaluated with reference to standard long-course therapy dose constraints. Phase 1 BTV dose targets at 5/7/10 Gy were met in all instances. Conformality constraints were met with only 1 minor violation at 5 and 7 Gy. All phase 1 and combined phase 1 + 2 plans passed patient-specific quality assurance. Combined phase 1 + 2 plans generally met organ-at-risk dose constraints. Exceptions included high-dose spillage to bladder and large bowel, predominantly in cases where previously administered, clinically acceptable non-boosted plans also could not meet constraints. Targeted upfront LARC radiotherapy dose escalation to DWI-defined is feasible with appropriate patient selection and preparation. This is the first study to evaluate the feasibility of DWI-targeted upfront radiotherapy boost in LARC. This work will inform an upcoming clinical feasibility study.

Cost-Effectiveness of Short-Course Radiotherapy Based Total Neoadjuvant Therapy for Locally Advanced Rectal Cancer in China

The phase III STELLAR (NCT02533271) trial demonstrated that four cycles of chemotherapy after short-course radiotherapy (SCRT-TNT) were not inferior to the standard care of long-course concurrent radiotherapy (LCRT) in patients with locally advanced rectal cancer (LARC). This study assessed the cost-effectiveness of SCRT-TNT versus LCRT in locally advanced rectal cancer in China on the basis of the STELLAR trial. A Markov model was used to synthesize the healthcare costs and benefits of LARC patients based on results from the STELLAR trial. The model assumes that LARC who meet the inclusion criteria of the STELLAR trial experience four possible states: No Evidence of Disease (NED), locally recurrence, distant metastases, or any death from rectal cancer or other unrelated causes, where local recurrence continues to be classified as resectable and unresectable. The transition status period is 3 month, and 5 years is used to calculate direct medical costs and health benefits. The probabilities of states transition after SCRT-TNT or LCRT were derived from the results of the STELLAR trial and previous published article (Table.1). Costs were evaluated from the Chinese payer's perspective reported in early 2022 US dollars (US$1 = 6.78 Chinese Yuan). Sensitivity analyses were performed for key variables. Cost-effectiveness was evaluated using the incremental cost-effectiveness ratio and net monetary benefits. Effectiveness was defined as quality-adjusted life-years (QALYs). Willingness-to-pay (WTP) threshold was set at $43500/QALY. Data were collected from October 3, 2020, to September 20, 2021, and analyzed from November 15, 2020, to October 25, 2021. During the 5-year horizon, for the base case scenario, SCRT-TNT incurred a lower total cost and higher QALYs compared with LCCRT. The total cost was $65767 and QALYs were 1.77 for SCRT-TNT; for LCCRT, the total cost was $72802 and QALYs were 1.64. This resulted in an ICER of -$ 55470.69 per QALY. Therefore, SCRT-TNT was a cost-saving and dominating treatment strategy compared with LCRT. Sensitivity analysis showed that ICERs were most sensitive to the parameters of distant metastases risk after treatment. SCRT-TNT in locally advanced rectal cancer can be a cost-effective alternative to LCRT in China, and should be considered in appropriately selected patients.

Timing of Surgery and Pathologic Complete Response (pCR) after Completing Total Neoadjuvant Therapy for Rectal Adenocarcinoma: A Retrospective Study of the National Cancer Database

Total neoadjuvant therapy (TNT) is a treatment strategy for rectal cancer that includes a course of multiagent chemotherapy and a separate course of radiation +/- concurrent chemotherapy before definitive surgery. The use of TNT has increased in recent years and carries the potential for improved sphincter preservation and a significant risk reduction of locoregional recurrence. However, the influence of rest period from end of radiation to surgery after TNT is unclear. The objective of this study was to evaluate the relationship between rest period and pCR using data from the National Cancer Database. We hypothesized that longer duration of rest period before surgery will be positively associated with pCR. Patients aged 18 years and older diagnosed with primary rectal cancer between 2016 and 2020, who underwent an NCCN-recommended TNT regimen followed by definitive surgery at a Commission on Cancer-accredited facility were retrospectively analyzed in the current study. We included 5,997 patients who met the following inclusion criteria: clinical stage T2 and above, any N stage, M0, adenocarcinoma histology, and not receiving any adjuvant therapy. Logistic regression methods were used to estimate odds ratios (OR) and 95% confidence intervals (CI) for the association between duration of rest period and pCR. Restricted cubic splines were used to evaluate potential non-linear relationship between duration of rest period and pCR. The median age of the study sample was 57 years old (interquartile range: 49 - 65), with majority of them being males (62.3%) and reporting Non-Hispanic White race and ethnicity (75.5%). The overall pCR rate was 18.6%. The majority received long-course radiation (76.7%) and induction chemotherapy (86.3%). In multivariable adjusted models, there was a non-linear relationship between duration of rest period and pCR (p = 0.036). Rest periods of 8-24 weeks were significantly associated with elevated odds of pCR with the odds highest at 14 weeks (OR = 2.86, 95% CI: 1.20 - 6.84) when compared to rest periods of less than a week. There was no difference in pCR between long-course vs. short course radiation and no difference between those who received induction chemotherapy vs. consolidative chemotherapy. Although the rest period is inherently longer when radiation therapy precedes consolidative chemotherapy, the order of chemotherapy to radiation itself did not impact pCR but rather the duration of rest period. These data demonstrate an ideal window for surgery to achieve pCR in rectal cancer in the TNT era and the need for further prospective investigations of optimal rest period before surgery to achieve maximal pCR with homogenous TNT treatment regimens.

Phase II study of capecitabine-based concomitant chemoradiation followed by durvalumab as a neoadjuvant strategy in locally advanced rectal cancer: the PANDORA trial

This study investigated the efficacy of chemoradiotherapy (CRT) followed by durvalumab as neoadjuvant therapy of locally advanced rectal cancer. The PANDORA trial is a prospective, phase II, open-label, single-arm, multicenter study aimed at evaluating the efficacy and safety of preoperative treatment with durvalumab (1500 mg every 4 weeks for three administrations) following long-course radiotherapy (RT) plus concomitant capecitabine (5040 cGy RT in 25-28 fractions over 5 weeks and capecitabine administered at 825 mg/m2 twice daily). The primary endpoint was the pathological complete response (pCR) rate; secondary endpoints were the proportion of clinical complete remissions and safety. The sample size was estimated assuming a null pCR proportion of 0.15 and an alternative pCR proportion of 0.30 (α= 0.05, power= 0.80). The proposed treatment could be considered promising if ≥13 pCRs were observed in 55 patients (EudraCT: 2018-004758-39; NCT04083365). Between November 2019 and August 2021, 60 patients were accrued, of which 55 were assessable for the study's objectives. Two patients experienced disease progression during treatment. Nineteen out of 55 eligible patients achieved a pCR (34.5%, 95% confidence interval 22.2% to 48.6%). Regarding toxicity related to durvalumab, grade 3 adverse events (AEs) occurred in four patients (7.3%) (diarrhea, skin toxicity, transaminase increase, lipase increase, and pancolitis). Grade 4 toxicity was not observed. In 20 patients (36.4%), grade 1-2 AEs related to durvalumab were observed. The most common were endocrine toxicity (hyper/hypothyroidism), dermatologic toxicity (skin rash), and gastrointestinal toxicity (transaminase increase, nausea, diarrhea, constipation). This study met its primary endpoint showing that CRT followed by durvalumab could increase pCR with a safe toxicity profile. This combination is a promising, feasible strategy worthy of further investigation.

P11.32.A GLIOBLASTOMA NOMOGRAM: PREDICTING THE LOCATION OF FIRST PROGRESSION AFTER LONG-COURSE CHEMORADIOTHERAPY BASED ON A NATIONAL COHORT

Abstract BACKGROUND Glioblastoma (GBM) is known for its high local failure rate, as well as its migration, leading to these possible locations of disease progression: 1. Local-only; lesion of progression is connected to the initial tumour location 2. Non-local; lesion of progression is not connected to the initial tumour location 3. Combined; both local-only and non-local progression lesions are present An upfront prediction of progression location could potentially be used to select patients for differential treatment strategies. The aim of this retrospective national study was therefore to predict location of first progression using clinical variables. MATERIAL AND METHODS All adults with newly diagnosed GBM between 2014-2019 who started long-course (chemo)radiotherapy were included, if they had a radiotherapy-planning MRI made. The MRI of first progression was identified by retrospective review following RANO-criteria, and used to assess the location of contrast-enhancing progression. Median time to progression (TTP) and survival beyond progression were estimated using the Kaplan-Meier method (log rank test for comparison). To predict location of progression in subgroups of patients, we used a multivariable multinomial model (age, biological sex, performance status, tumour location & focality & laterality, MGMT-methylation status, and extent of surgery). RESULTS We included 940 patients (MGMT methylated n=376, unmethylated n=483, not reported n=81), of whom 760 had radiographic progression. Of those, progression location was local-only in 69%, non-local in 16%, and combined in 15%. Median (95% CI) TTP in months was shortest in the combined group (8.4, 7.3-9.4), followed by the local-only (9.2, 8.5-9.8) and non-local (13.9, 12.3-15.6) (p-value <.001). Survival beyond progression in months was shortest in the combined group (5.0, 3.8-6.2), followed by the non-local (6.0, 4.4-7.6) and local-only (9.0, 8.3-9.7) (p-value <.001). When comparing patients with MGMT-methylated and unmethylated tumours, the probability (95%CI) of local-only progression was .67 (.62-.73) vs. .73 (.69-.78), non-local was .21 (.17-.26) vs. .11 (.08-.14), and combined was .12 (.08-.15) vs. .16 (.12-.19). In the multivariable model, the probability (95%CI) of local-only progression varied from .49 (.29-.69) to .86 (.74-.97), of non-local from .04 (.00-.09) to .34 (.15-.53), and of combined from .05 (.01-.10) to .34 (.07-.60) between respective subgroups. CONCLUSION Location of progression was associated with time to progression and survival beyond progression. In our study population it was feasible to identify subgroups of patients with a high chance of local-only progression, who may potentially benefit most from radiation dose-escalation. Both patients with MGMT-methylated and unmethylated tumours had the highest chance for first progression located at the initial tumour site only.

Long-course chemoradiation plus concurrent/sequential PD-1 blockade as neoadjuvant treatment for MMR-status-unscreened locally advanced rectal cancer: protocol of a multicentre, phase 2, randomised controlled trial (the POLAR-STAR trial)

IntroductionRecent preclinical studies have discovered unique synergism between radiotherapy and immune checkpoint inhibitors, which has already brought significant survival benefit in lung cancer. In locally advanced rectal cancer (LARC), neoadjuvant...

Mismatch Repair system protein deficiency as a factor of resistance to chemo-radiotherapy treatment in patients with locally advanced rectal adenocarcinoma and its influence on disease-free survival.

3615 Background: Available data on Mismatch Repair system deficit and microsatellite instability are conflicting and are generally derived from a small number of patients due to the rarity of this condition in rectal cancer. Our study aimed to evaluate the frequency and therapeutic implications of Mismatch Repair proteins (MMR) status in patients with locally advanced rectal cancer (LARC). Methods: We retrospectively collected data from 318 patients affected by LARC adenocarcinoma (cT3-4 +/- N1-2) treated at the Medical Oncology Unit of the University Hospital of Cagliari, Italy, the Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy and at the Medical Oncology Unit, AOU Ospedali Riuniti, Ancona. Italy. All patients included in the study underwent neoadjuvant concurrent capecitabine and long-course radiotherapy (RT) (total dose of Gy 50.4), afterwards a total mesorectal excision (TME) was performed. MMR expression was evaluated through immunohistochemistry. The primary objective was major TRG (0-1 Ryan’s score) while secondary objectives were pathological complete response, disease-free survival (DFS) and overall survival (OS). Results: 160 patients (148 pMMR and 12 dMMR) were included in exploratory cohort and 158 (146 pMMR and 12 dMMR) were included in validation cohort. A major TRG has been shown in 64/148 (42,6%) and 63/146 (43,1%) patients with pMMR in exploratory cohort and validation cohort, respectively; while no major TRG have been shown in dMMR patients in exploratory cohort nor in validation cohort. Both exploratory and validation cohorts showed a statistically significant higher median DFS in pMMR patients compared to dMMR ones: NR vs 14 months in exploratory cohort ( p = 0,003) and NR vs 17 months in validation cohort ( p = 0,02). Conclusions: Our retrospective study indicated an association between dMMR and poor or no response to preoperative chemoradiotherapy. These results are consistent with the role of MMR as a predictor of poor-response to chemoradiotherapy and represent a hypothesis-generating study for the selection of these patients for immunotherapy in the neoadjuvant setting, in which the available data are immature.

Development and Validation of a Radiomics Model Based on Lymph-Node Regression Grading After Neoadjuvant Chemoradiotherapy in Locally Advanced Rectal Cancer

The response to neoadjuvant chemoradiotherapy (nCRT) varies among patients with locally advanced rectal cancer (LARC), and the treatment response of lymph nodes (LNs) to nCRT is critical in implementing a watch-and-wait strategy. A robust predictive model may help personalize treatment plans to increase the chance that patients achieve a complete response. This study investigated whether radiomics features based on prenCRT magnetic resonance imaging nodes could predict treatment response in preoperative LARC LNs. The study included 78 patients with clinical stage T3-T4, N1-2, and M0 rectal adenocarcinoma who received long-course neoadjuvant radiotherapy before surgery. Pathologists evaluated 243 LNs, of which 173 and 70 were assigned to training and validation cohorts, respectively. For each LN, 3641 radiomics features were extracted from the region of interest in high-resolution T2WI magnetic resonance imaging before nCRT. The least absolute shrinkage and selection operator regression model was used for feature selection and radiomics signature building. A prediction model based on multivariate logistic analysis, combining radiomics signature and selected LN morphologic characteristics, was developed and visualized by drawing a nomogram. The model's performance was assessed by receiver operating characteristic curve analysis and calibration curves. The radiomics signature consists of 5 selected features that were effectively discriminated within the training cohort (area under the curve [AUC], 0.908; 95% CI, 0.857%-0.958%) and the validation cohort (AUC, 0.865; 95% CI, 0.757%-0.973%). The nomogram, which consisted of radiomics signature and LN morphologic characteristics (short-axis diameter and border contours), showed better calibration and discrimination in the training and validation cohorts (AUC, 0.925; 95% CI, 0.880%-0.969% and AUC, 0.918; 95% CI, 0.854%-0.983%, respectively). The decision curve analysis confirmed that the nomogram had the highest clinical utility. The nodal-based radiomics model effectively predicts LNs treatment response in patients with LARC after nCRT, which could help personalize treatment plans and guide the implementation of the watch-and-wait approach in these patients.

Capecitabine, Oxaliplatin, and Irinotecan (XELOXIRI) as Neoadjuvant Chemotherapy in Locally Advanced Rectal Cancer

Purpose: This study describes the efficacy and safety of irinotecan and oxaliplatin in combination with capecitabine (XELOXIRI) as a neoadjuvant chemotherapy (NAC) regimen for patients with locally advanced rectal cancer (LARC). Methods: From January 2019 through December 2022, 68 LARC patients treated with XELOXIRI were enrolled in the study. XELOXIRI is administered in a three-week cycle consisting of oxaliplatin 70-110 mg/m2 IV for >120 min on day 1; irinotecan 120-160 mg/m2 IV for 90 min on day 1; and capecitabine 700-1100 mg/m2 orally twice daily for 14 days followed by 7 days off. Sixteen cases were treated with combined radiotherapy, including 8 with long-course radiotherapy and 8 with short-course radiotherapy. The efficacy was evaluated based on pelvic MRI (including TNM stage, CRM, and EMVI status), tumor downstaging rate (to ypT0-2N0M0), pCR rate, R0 resection rate, DFS, and OS, and the safety was assessed according to the incidence of adverse events. Results: Sixty-six people had surgery; the R0 resection rate was 100%, and the rate of anal preservation was 97%. The tumor downstaging rate (to ypT0-2N0M0) in the entire group was 53.0%, and the pCR rate was 12.1%. In the XELOXIRI alone group (N = 47), the tumor downstaging rate was 55.3%, and the pCR rate was 12.8%. In the group receiving radiotherapy (N = 16), the tumor downstaging rate was 56.3%, and the pCR rate was 12.5%. In the whole group, the 3-year DFS was 89.0%, and the 3-year survival rate was 98.5%. The 3-year DFS of the XELOXIRI and XELOXIRI + RT groups was 89.9% and 87.2%, respectively. The most frequent grade 3–4 preoperative toxic reactions were neutropenia (8.8%), diarrhea (4.4%), and anemia (2.9%). All adverse events were tolerable. Conclusions: Neoadjuvant chemotherapy with XELOXIRI appears to be feasible and efficacious for patients with LARC. Although neoadjuvant XELOXIRI alone did not yield our expected pCR rate as NAC for LARC, tumor downstaging, R0 resection, sphincter preservation, local recurrence rate, 3-year DFS, OS, and safety were all satisfactory.

Preoperative chemoradiotherapy using tegafur/uracil, oral leucovorin, and irinotecan (TEGAFIRI) followed by oxaliplatin-based chemotherapy as total neoadjuvant therapy for locally advanced rectal cancer: the study protocol for a phase II trial

BackgroundTotal neoadjuvant therapy (TNT) is a novel treatment strategy that is an alternative to preoperative chemoradiotherapy (CRT) for locally advanced rectal cancer (LARC). However, an optimal protocol for TNT has not yet been established. The present study will be an open-label, single-arm, single-center trial to develop a new protocol.MethodsThirty LARC patients at high risk of distant metastasis will receive CRT consisting of long-course radiation, concurrent with tegafur/uracil, oral leucovorin, irinotecan (TEGAFIRI), followed by mFOLFOX-6 or CAPOX before undergoing surgery.DiscussionSince previous findings showed a high percentage of grade 3–4 adverse events with the TEGAFIRI regimen for CRT and TNT, the primary outcome of this study will be safety and feasibility. Our regimen for CRT consists of the biweekly administration of irinotecan for good patient compliance. The novel combination approach of this treatment may improve the long-term outcomes of LARC.Trial RegistrationJapan Registry of Clinical Trials jRCTs031210660.

Preoperative Radiotherapy Decision-Tree for Rectal Cancer Patients: A Real-World Analysis Based on the Swedish Colorectal Cancer Registry

BackgroundThere are 3 widely used preoperative radiotherapy (RT) procedures in rectal cancer treatment including long-course RT (LRT), short-course RT with delayed surgery (SRTW), and short-course RT with immediate surgery (SRT). However, further evidence is required to determine which treatment option results in more optimal patient survival. MethodsThis Swedish Colorectal Cancer Registry-based retrospective study of real-world data included 7766 stage I–III rectal cancer patients, of which 2982, 1089, 763, and 2932 patients received no RT (NRT), LRT, SRTW, and SRT, respectively. The Kaplan-Meier survival curve and Cox proportional hazard multivariate model were used to identify potential risk factors and to examine the independent association of RT with patient survival after adjusting for baseline confounding factors. ResultsRT effects on survival differed by age and clinical T stage (cT) subgroups. Subsequent survival analysis by age and cT subgroups confirmed that patients ≥70 years old with cT4 benefited from any RT (P < .001, NRT as reference) and equally from any RT (P > .05 pairwise between RTs). In contrast, for cT3 patients ≥70 years, SRT and LRT were associated with better survival than SRTW (P < .001). In patients <70 years, LRT and SRTW had superior survival benefits in cT4 patients but inferior to SRT (P < .001); SRT was the only effective treatment in the cT3N+ subgroup (P = .032); patients with cT3N0 and <70 years did not benefit from any RT. ConclusionThis study suggests that preoperative RT strategies may have varying effects on the survival of rectal cancer patients, depending on their age and clinical stage.

PO-1328 Comparison of short-course with long-course palliative radiotherapy for superior vena cava syndrome

PO-1328 Comparison of short-course with long-course palliative radiotherapy for superior vena cava syndrome

Effect of Radiation Schedule on Transportation-Related Carbon Emissions: A Case Study in Rectal Cancer

The health care sector is a major contributor of worldwide greenhouse gas (GHG) emissions. Indirect emissions, including those associated with transportation, make up 82% of the US health care sector's environmental footprint. Radiation therapy (RT) treatment regimens present an opportunity for environmental health care-based stewardship owing to the high incidence of cancer diagnosis, significant utilization of RT, and myriad treatment days required for curative regimens. Because the use of short-course RT (SCRT) in the treatment of rectal cancer has demonstrated noninferior clinical outcomes compared with conventional, long-course RT (LCRT), we investigate the environmental and health equity-related outcomes. Patients treated with curative, preoperative RT for newly diagnosed rectal cancer at our institution between 2004 and 2022 and living in-state were included. Travel distance was estimated using patients' reported home address. Associated GHG emissions were calculated and reported in carbon dioxide equivalents (CO2e). Of 334 patients included, the total distance traveled for the treatment course was significantly greater in patients treated with LCRT versus SCRT (median, 1417 vs 319 miles; P < .001). Total CO2e emissions for those undergoing LCRT (n=261) and SCRT (n=73) were 665.3 kg CO2e and 149.9 kg CO2e, respectively, per treatment course (P < .001), with a net difference of 515.4 kg CO2e. Relatively, this suggests that LCRT is associated with 4.5 times greater GHG emissions from patient transportation. Using treatment of rectal cancer as proof-of-principle, we advocate for the inclusion of environmental considerations in the creation of climate-resilient oncologic RT practices, especially in the context of equivocal clinical outcomes between RT fractionation schedules.

AN0025, a novel antagonist of PGE2-receptor E-type 4 (EP4), in combination with total neoadjuvant treatment of advanced rectal cancer

PurposeTo assess the safety and efficacy of AN0025 in combination with preoperative radiotherapy and chemotherapy in either short course (SCRT) or long course radiotherapy (LCRT) settings for those with locally advanced rectal cancer. Patients and methodsTwenty-eight subjects with locally advanced rectal cancer participated in this multicenter, open-label, Phase Ib trial. Enrolled subjects received either 250 mg or 500 mg of AN0025 once daily for 10 weeks with either LCRT or SCRT with chemotherapy (7 subjects/group). Participants were assessed for safety/efficacy starting from the first dose of study drug administration and were followed for 2 years. ResultsNo treatment-emergent adverse or serious adverse events meeting dose-limiting criteria were observed, with only 3 subjects discontinuing AN0025 treatment due to adverse events. Twenty-five of 28 subjects completed 10 weeks of AN0025 and adjuvant therapy and were evaluated for efficacy. Overall, 36.0% of subjects (9/25 subjects) achieved a pathological complete response or a complete clinical response, including 26.7% of subjects (4/15 subjects who underwent surgery) who achieved a pathological complete response. A total of 65.4% of subjects had magnetic resonance imaging-confirmed down-staging ≤ stage 3 following completion of treatment. With a median follow-up of 30 months. The 12-month disease-free survival and overall survival were 77.5% (95% confidence interval [CI]: 56.6, 89.2) and 96.3% (95% CI: 76.5, 99.5), respectively. ConclusionsTreatment with AN0025 administered for 10 weeks along with preoperative SCRT or LCRT did not appear to worsen the toxicity in subjects with locally advanced rectal cancer, was well-tolerated and showed promise in inducing both a pathological and complete clinical response. These findings suggest its activity deserves further investigation in larger clinical trials.

Personalization of Radiation Therapy in the Primary Treatment of Malignant Epidural Spinal Cord Compression (MESCC)

"True" malignant epidural spinal cord compression (MESCC) is used here to describe a lesion compressing of infiltrating the spinal cord associated with neurologic deficits. Radiotherapy alone is the most common treatment, for which several dose-fractionation regimens are available including single-fraction, short-course and longer-course regimens. Since these regimens are similarly effective regarding functional outcomes, patients with poor survival are optimally treated with short-course or even single-fraction radiotherapy. Longer-course radiotherapy results in better local control of malignant epidural spinal cord compression. Since most in-field recurrences occur 6 months or later, local control is particularly important for longer-term survivors who, therefore, should receive longer-course radiotherapy. It is important to estimate survival prior to treatment, which is facilitated by scoring tools. Radiotherapy should be supplemented by corticosteroids, if safely possible. Bisphosphonates and RANK-ligand inhibitors may improve local control. Selected patients can benefit from upfront decompressive surgery. Identification of these patients is facilitated by prognostic instruments considering degree of compression, myelopathy, radio-sensitivity, spinal stability, post-treatment ambulatory status, and patients' performance status and survival prognoses. Many factors including patients' preferences must be considered when designing personalized treatment regimens.

Treatment of locally advanced rectal cancer and synchronous liver metastases: multicentre comparison of two treatment strategies.

Management of locally advanced rectal cancer (LARC) has been optimized during recent times through (beyond) total mesorectal excision surgery and, more recently, the introduction of total neoadjuvant treatment (TNT)1–4. For patients with synchronous liver metastases, the optimal treatment strategy is less clear, with high variability among institutions worldwide5. In the Netherlands, two specific treatment sequences have mainly been used for treating LARC and synchronous liver metastases: the liver-first approach (LFA) and the M1 schedule6–8. The LFA consists of induction systemic chemotherapy, subsequent local treatment of the liver metastases, followed by long-course (chemo)radiotherapy and resection of the primary tumour. The rationale behind LFA is to treat the rectal tumour locally only when control of synchronous liver metastases has been established. Radiotherapy and primary tumour resection can be avoided in patients with disease progression during the first phase of the schedule9. The M1 schedule starts with preoperative short-course pelvic radiotherapy (5 × 5 Gy), followed by systemic therapy, and subsequent surgical treatment of both the liver and rectum (either simultaneously, liver first or primary tumour first). The advantage of starting with radiotherapy is the immediate downstaging effect on the primary tumour. This strategy has been proven safe and effective, and leads to excellent local control10.

Patient-reported Bowel Function and Bowel-related Quality of Life After Pelvic Radiation for Rectal Adenocarcinoma: The Impact of Radiation Fractionation and Surgical Resection

IntroductionMultimodality treatment for locally advanced rectal cancer (LARC) can include long-course radiotherapy (LCRT) or short course radiotherapy (SCRT). Nonoperative management is increasingly pursued for those achieving a complete clinical response. Data regarding long-term function and quality-of-life (QOL) are limited. MethodsPatients with LARC treated with radiotherapy from 2016 to 2020 completed the Functional Assessment of Cancer Therapy- General (FACT-G7), the Low Anterior Resection Syndrome Score (LARS) and the Fecal Incontinence QOL Scale (FIQOL). Univariate and multivariable linear regression analyses identified associations between clinical variables including radiation fractionation and the use of surgery versus non-operative management. ResultsOf 204 patients surveyed, 124 (60.8%) responded. Median (interquartile range) time from radiation to survey completion was 30.1 (18.3-43) months. Seventy-nine (63.7%) respondents received LCRT, and 45 (36.3%) received SCRT; 101 (81.5%) respondents underwent surgery, and 23 (18.5%) pursued nonoperative management. There were no differences in LARS, FIQoL or FACT-G7 between patients receiving LCRT versus SCRT. On multivariable analysis, only nonoperative management was associated with lower LARS score signifying less bowel dysfunction. Nonoperative management and female sex were associated with a higher FIQoL score signifying less disruption and distress from fecal incontinence issues. Finally, lower BMI at the time of radiation, female sex, and higher FIQoL score were associated with higher FACT-G7 scores signifying better overall QOL. ConclusionsThese results suggest long-term patient-reported bowel function and QOL may be similar for individuals receiving SCRT and LCRT for the treatment of LARC, but nonoperative management may lead to improved bowel function and QOL.

Interim result of phase II, prospective, single-arm trial of long-course chemoradiotherapy combined with concurrent tislelizumab in locally advanced rectal cancer.

Neoadjuvant chemoradiotherapy is the standard treatment for locally advanced rectal cancer, with modest benefits on tumor regression and survival. Since chemoradiotherapy combined with immune checkpoint inhibitors has been reported to have synergic effects. This study aims to explore the safety and efficacy of long-course chemoradiotherapy combined with concurrent tislelizumab as a neoadjuvant treatment regimen for patients with locally advanced rectal cancer. This manuscript reported the interim result of a prospective, multicenter, single-arm, phase II trial. Patients with mid-to-low locally advanced rectal cancer with clinical stages of cT3-4a N0M0 or cT1-4a N1-2M0 were included. The patients received long-course radiotherapy (50 Gy/25 f, 2 Gy/f, 5 days/week) and three 21-day cycles of capecitabine (1000 mg/m2, bid, day1-14) plus concurrent three 21-day cycles of tislelizumab (200 mg, day8), followed by a radical surgery 6-8 weeks after radiotherapy. The primary endpoint was the pathological complete response rate. (Clinical trial number: NCT04911517). A total of 26 patients completed the treatment protocol between April 2021 and June 2022. All patients completed chemoradiotherapy, 24 patients received three cycles of tislelizumab, and 2 patients received two cycles. The pathological complete remission (ypT0N0) was achieved in 50% (13/26) of the patients with all proficient mismatch repair tumors. The immune-related adverse event occurred in 19.2% (5/26) of patients. Patients with no CEA elevation or age less than 50 were more likely to benefit from this treatment regimen. Long-course chemoradiotherapy combined with concurrent tislelizumab in patients with locally advanced low rectal cancer had favorable safety and efficacy, and does not increase the complication rate of surgery. Further study is needed to confirm these results.

Integrated Intensified Chemoradiation in the Setting of Total Neoadjuvant Therapy (TNT) in Patients with Locally Advanced Rectal Cancer: A Retrospective Single-Arm Study on Feasibility and Efficacy.

While surgery is considered the main treatment for early-stage rectal cancer, locally advanced rectal cancer needs to be handled with a multidisciplinary approach. Based on literature data suggesting promising advantages of total neoadjuvant therapy (TNT), we performed a retrospective, single-arm, single-center study on 45 patients affected by histologically and radiologically proven locally advanced rectal cancer, with the aim of analyzing the feasibility and short-term efficacy of an integrated intensified treatment in the setting of TNT. Each analyzed patient performed three cycles of FOLFOX4 or De Gramont induction chemotherapy (iCT), followed by concurrent chemoradiotherapy (CRT) with long course radiotherapy (LCRT) plus concomitant boost and continuous 5-FU infusion, followed by three cycles of FOLFOX4 or De Gramont consolidation chemotherapy (conCT) and then surgery with total mesorectal excision. At a median follow-up of 30 months, this strategy has shown to be feasible and effective in terms of pathological complete response (pCR) and short-term disease-free survival (DFS).