Short-course Preoperative Radiotherapy Research Articles

Regional audit of timing of surgery in patients receiving short course pre-operative radiotherapy (SCPRT) for rectal cancer

Regional audit of timing of surgery in patients receiving short course pre-operative radiotherapy (SCPRT) for rectal cancer

Delayed versus immediate surgery following short-course neoadjuvant radiotherapy in resectable (T3N0/N+) rectal cancer.

Preoperative short-course radiotherapy (SCRT) followed by surgery has shown advantage over surgery alone in patients with resectable rectal carcinoma (RC); however, the importance of the timing of surgery after SCRT has not been well defined. This study aimed to investigate the effect of this duration on treatment outcomes. Patients who underwent surgery after SCRT (25Gy/500cGy/daily/5fr, monday-friday) for resectable and infraperitoneal rectal adenocarcinoma (T3N0/(+)) were included into the study. Patients were divided into two groups in terms of the timing of surgery: delayed surgery (>4weeks) or immediate surgery (<4weeks). A hundred and thirty-six patients were included in the study. Median time between RT and surgery was 4 ± 5.7 (1-58)weeks, where 68% (n = 93) patients underwent delayed surgery (≥4weeks). The two groups did not differ in terms of surgical margin positivity, pathological tumor regression, N downstaging, or T downstaging (p > 0.05 for all). However, the number of positive lymph nodes was higher in the immediate surgery group [median 3 (0-18) vs. 1 (0-17), p = 0.009]. Median follow-up time was 36 ± 9 (6-93)months. Delayed surgery group had significantly longer mean overall survival (p = 0.038); however, the two groups did not differ in terms of local recurrence, mean time to local recurrence, or mean disease-free survival. Our findings seem to support the benefit of a longer time interval between radiotherapy and surgery after short-course neoadjuvant radiotherapy in resectable rectal cancer in terms of overall survival. However, there is a need to better define patient characteristics that might benefit from delayed surgery.

Short-Course Radiation Therapy Versus Long-Course Chemoradiation in the Neoadjuvant Treatment of Locally Advanced Rectal Cancer: New Insights from Randomized Trials

Examine prospective evidence supporting preoperative short-course radiotherapy (SCRT) and long-course chemoradiotherapy (LCRT) for locally advanced rectal cancer and discuss recently published data that are helping to clarify the utility of SCRT. SCRT with early surgery results in lower pCR rates, lower severe acute toxicities, no difference in late toxicities, and no apparent difference in local control, DFS, and OS when compared with LCRT. When surgery is delayed after SCRT, cancer outcomes appear equivalent, including pCR rates. The addition of full-dose systemic therapy with SCRT prior to surgery is attractive to further downstage patients, particularly in patients at high risk of distant relapse. Increasing randomized evidence is accumulating to support the use of SCRT as an acceptable preoperative treatment approach for locally advanced rectal cancer. Increasing the interval from SCRT to surgery and/or adding systemic doses of chemotherapy may mitigate potential concerns related to SCRT. More mature data and future results of ongoing randomized trials will help clarify the oncologic equivalence and safety of SCRT followed by preoperative chemotherapy.

Short-course preoperative radiotherapy combined with chemotherapy, delayed surgery and local hyperthermia for rectal cancer: a phase II study

Purpose: The aim of this study was to investigate the feasibility of short-course radiotherapy with oral capecitabine, hyperthermia and delayed surgery for neoadjuvant treatment of rectal cancer.Methods: Patients with clinically staged T2-3N0-2M0 primary rectal cancer were included. All patients received short-course 25 Gy in 5 Gy fractions radiotherapy with capecitabine, local hyperthermia and metronidazole. Capecitabine 1000 mg/m2 twice a day was given on days 1–14. Local hyperthermia, 41–45 °C for 60 min, was performed on days 3–5. Metronidazole 10 g/m2 was administered per rectum on days 3 and 5. The time interval to surgery was not less than four weeks after neoadjuvant treatment. The primary end-point was pathological complete response (pCR). Secondary end-points included neoadjuvant treatment toxicity, tumour regression, surgical and oncological outcomes.Results: A total of 81 patients were included in the analysis. Ten (12.3%) patients had grade 3 toxicity and one (1.2%) patient had grade 4 toxicity. Sphincter-sparing surgery was performed for 78 (96.3%) patients. There was no postoperative mortality. Postoperative complications occurred in 11 (13.8%) patients. Sixteen (20%) patients had a pCR. The median follow-up was 40.9 months. There were no local recurrences. Nine (11.1%) patients developed distant metastases. Three-year overall survival was 97% and the three-year disease-free survival was 85%.Conclusions: Short-course radiotherapy with chemotherapy, radiosensitizers and delayed surgery is a feasible treatment for rectal cancer and may lead to tumour regression rate comparable with long-course chemoradiation.

Preoperative long-course chemoradiotherapy plus adjuvant chemotherapy versus short-course radiotherapy without adjuvant chemotherapy both with delayed surgery for stage II–III resectable rectal cancer: 5-Year survival data of a randomized controlled trial

Background and objectiveAt present, there are common recommendations for treatment for stage II–III resectable rectal cancer patients: preoperative conventional chemoradiotherapy (CRT) with delayed surgery in 6–8 weeks or preoperative short-course radiotherapy (SCRT) followed by immediate surgery. The aim of this study was to compare overall survival (OS) and disease-free survival (DFS) in two treatment groups: preoperative SCRT and CRT both with delayed surgery plus adjuvant chemotherapy in CRT arm. Materials and methodsA total of 150 patients were randomly assigned to two groups: 75 to CRT (preoperative conventional CRT, 50Gy/25 fr with fluorouracil and leucovorin on the 1st and the 5th week of RT followed by TME surgery in 6–8 weeks and 4 cycles of adjuvant fluorouracil/leucovorin every 4 weeks; then follow-up) and 75 to SCRT (preoperative short-course RT, 25Gy/5 fr followed by TME surgery in 6–8 weeks; then follow-up). The data of 140 patients (72 in CRT and 68 in SCRT group) were included in statistical analysis. Primary end points were OS and DFS. ResultsMedian follow-up was 60.5 (range, 5–108) months. The 5-year DFS was 67% in the CRT group (n=72) and 45% in the SCRT group (n=68) (P=0.013; HR=1.88; 95% CI, 1.13–3.12; P=0.015). The 5-year OS was 79% and 62% in the CRT and SCRT groups, respectively (P=0.015; HR=2.05; 95% CI, 1.13–3.70; P=0.017). The 5-year OS for intent-to-treat (ITT) population (n=150) was 78% in the CRT and 58% in the SCRT group (P=0.003; HR=2.28; 95% CI, 1.30–4.00; P=0.004). ConclusionsThe 5-year DFS and OS were significantly better in the CRT than the SCRT group. For ITT population, OS was also significantly better after CRT versus SCRT.

A Retrospective Analysis on Two-week Short-course Pre-operative Radiotherapy in Elderly Patients with Resectable Locally Advanced Rectal Cancer.

To validate that a two-week short-course pre-operative radiotherapy regimen is feasible, safe, and effective for the management of elderly patients with locally advanced rectal cancer (LARC), we retrospectively analyzed 99 radiotherapy-naive patients ≥70 years of age with LARC. Patients received pelvic radiation therapy (3D-CRT 30Gy/10f/2w) followed by TME surgery; some patients received adjuvant chemotherapy. The primary endpoint was OS, while the secondary endpoints were DFS, safety and response rate. The median follow-up time was 5.1 years. The 5-year OS and DFS rates were 58.3% and 51.2%, respectively. The completion rate of radiotherapy (RT) was 99.0% (98 of 99). Grade 3 acute adverse events, which resulted from RT, occurred in only 1 patient (1.0%). In addition, no grade 4 acute adverse events induced by RT were observed. All 99 patients (100%) were able to undergo R0 surgical resection, and 68.6% of the patients received sphincter-sparing surgery. The rate of occurrence of clinically relevant post-operative complications was 12.1%. Three patients (3.0%) achieved pathologic complete responses, and forty-three patients (43.4%) achieved pathologic partial responses. The rates of T-downsizing and N-downstaging were 30.3% and 55.7%, respectively. Therefore, we believe that a two-week short-course pre-operative radiotherapy is feasible in elderly patients with resectable LARC.

Preoperative Short-Course Radiation for Localized Rectal Cancer in the United States

Preoperative Short-Course Radiation for Localized Rectal Cancer in the United States

Response to Treatment and Interval to Surgery After Preoperative Short-Course Radiotherapy in Rectal Cancer

IntroductionPreoperative short-course radiotherapy with immediate surgery improves local control in patients with rectal cancer. Tumor responses are smaller than those described with radiochemotherapy. Preliminary data associate this lower response to the short period until surgery. The aim of this study is to analyze the response to preoperative short-course radiotherapy and its correlation with the interval to surgery especially analyzing patients with mesorectal fascia involvement. MethodsA total of 155 patients with locally advanced rectal cancer treated with preoperative radiotherapy (5×5Gy) were retrospectively analyzed. Tumor response in terms of rates of complete pathological response, downstaging, tumor regression grading and status of the circumferential resection margin were quantified. ResultsThe mean interval from radiotherapy to surgery was 23 days. The rate of complete pathological response was 2.2% and 28% experienced downstaging (stage decreased). No differences between these rates and interval to surgery were detected. Eighty-eight patients had magnetic resonance imaging for staging (in 31 patients the mesorectal fascia was involved). The mean time to surgery in patients with involvement of the fascia and R0 surgery was 27 days and 16 days if R1 (P=.016). The cutoff of 20 days reached the highest probability of achieving a free circumferential resection margin between patients with mesorectal fascia involvement, with no statistically significant differences: RR 3.036 95% CI=(0.691–13.328), P=.06. ConclusionsAfter preoperative short-course radiotherapy, an interval >20 days enhances the likelihood of achieving a free circumferential resection margin in patients with mesorectal fascia involvement.

Preoperative short-course radiation therapy for rectal cancer provides excellent disease control and toxicity: Results from a single US institution

PurposePreoperative short-course radiation therapy (SCRT) has rarely been used for rectal cancer in the United States, although 2 randomized phase 3 trials demonstrate equivalence to conventional chemoradiation (CRT), and recent updates to national guidelines include this regimen as a treatment option. We sought to evaluate the efficacy and safety of preoperative SCRT followed by immediate surgery within 1 week to treat rectal cancer in the US setting. Methods and materialsAll patients treated with preoperative SCRT (4 Gy × 5 fractions for total 20 Gy) followed by planned surgery within 1 week at our institution were retrospectively evaluated. Censored cases with ≥2 years of follow-up were included along with any disease failure or death. Patients with cM1 disease were excluded. Patients with yp stage II/III disease typically received adjuvant chemotherapy from the 1990s onwards. The primary outcomes were actuarial (Kaplan-Meier) 5-year locoregional control (LC), disease-free survival (DFS), and overall survival (OS) as well as late severe (greater than or equal to grade 3) toxicity. ResultsOur analysis included 202 consecutive patients with clinical stage I-III disease treated from 1977 through 2011. Median follow-up was 6.5 years (range, 2-29.2). Five-year disease outcomes were 95.9% ± 1.5% for LC, 76.4% ± 3.1% for DFS, and 84.6% ± 2.6% for OS. For patients with locally advanced rectal cancer (cT3-4 and/or cN+), 5-year LC, DFS, and OS were 95.1% ± 2.1%, 73.3% ± 4.3%, and 80.6% ± 3.7%, respectively. The late severe toxicity rate was 11.4%. ConclusionsSCRT followed by immediate surgery is a safe and effective treatment for patients with rectal cancer in the United States. Though SCRT has not been widely adopted, recent updates to the national guidelines for rectal cancer as well as financial pressures to reduce healthcare costs may lead to increased utilization of this treatment regimen in the future.

329. Prospective phase II study of preoperative short-course radiotherapy for rectal cancer with twice daily fractions of 2.5 Gy to a total dose of 25 Gy

329. Prospective phase II study of preoperative short-course radiotherapy for rectal cancer with twice daily fractions of 2.5 Gy to a total dose of 25 Gy

Evaluation of Tumor Response after Short-Course Radiotherapy and Delayed Surgery for Rectal Cancer.

PurposeNeoadjuvant therapy is able to reduce local recurrence in rectal cancer. Immediate surgery after short course radiotherapy allows only for minimal downstaging. We investigated the effect of delayed surgery after short-course radiotherapy at different time intervals before surgery, in patients affected by rectal cancer.MethodsFrom January 2003 to December 2013 sixty-seven patients with the following characteristics have been selected: clinical (c) stage T3N0 ≤ 12 cm from the anal verge and with circumferential resection margin > 5 mm (by magnetic resonance imaging); cT2, any N, < 5 cm from anal verge; and patients facing tumors with enlarged nodes and/or CRM+ve who resulted unfit for chemo-radiation, were also included. Patients underwent preoperative short-course radiotherapy with different interval to surgery were divided in three groups: A (within 6 weeks), B (between 6 and 8 weeks) and C (after more than 8 weeks). Hystopatolgical response to radiotherapy was measured by Mandard’s modified tumor regression grade (TRG).ResultsAll patients completed the scheduled treatment. Sixty-six patients underwent surgery. Fifty-three of which (80.3%) received a sphincter saving procedure. Downstaging occurred in 41 cases (62.1%). The analysis of subgroups showed an increasing prevalence of TRG 1–2 prolonging the interval to surgery (group A—16.7%, group B—36.8% and 54.3% in group C; p value 0.023).ConclusionsPreoperative short-course radiotherapy is able to downstage rectal cancer if surgery is delayed. A higher rate of TRG 1–2 can be obtained if interval to surgery is prolonged to more than 8 weeks.

Respuesta al tratamiento e intervalo de tiempo hasta la cirugía con radioterapia preoperatoria de curso corto en el cáncer de recto

IntroductionPreoperative short-course radiotherapy with immediate surgery improves local control in patients with rectal cancer. Tumor responses are smaller than those described with radiochemotherapy. Preliminary data associate this lower response to the short period until surgery. The aim of this study is to analyze the response to preoperative short-course radiotherapy and its correlation with the interval to surgery especially analyzing patients with mesorectal fascia involvement. MethodsA total of 155 patients with locally advanced rectal cancer treated with preoperative radiotherapy (5×5Gy) were retrospectively analyzed. Tumor response in terms of rates of complete pathological response, downstaging, tumor regression grading and status of the circumferential resection margin were quantified. ResultsThe mean interval from radiotherapy to surgery was 23 days. The rate of complete pathological response was 2.2% and 28% experienced downstaging (stage decreased). No differences between these rates and interval to surgery were detected. Eighty-eight patients had magnetic resonance imaging for staging (in 31 patients the mesorectal fascia was involved).The mean time to surgery in patients with involvement of the fascia and R0 surgery was 27 days and 16 days if R1 (P=.016). The cutoff of 20 days reached the highest probability of achieving a free circumferential resection margin between patients with mesorectal fascia involvement, with no statistically significant differences: RR 3.036 95% CI=(0.691-13.328), P=.06. ConclusionsAfter preoperative short-course radiotherapy, an interval>20 days enhances the likelihood of achieving a free circumferential resection margin in patients with mesorectal fascia involvement.

Effect of Adjuvant Chemotherapy on Stage II Rectal Cancer Outcomes After Preoperative Short-Course Radiotherapy

BackgroundAdjuvant chemotherapy (AC) is offered to patients with stage II rectal cancer, but its use is controversial. We examined population-based outcomes of patients with pathologic stage II rectal cancer treated with AC after preoperative short-course radiotherapy. Materials and MethodsWe included patients diagnosed with pathologic stage II tumors from 1999 to 2009 in British Columbia. The disease-specific survival (DSS), relapse-free (RFS), and overall survival (OS) were assessed. Multivariate models adjusting for age, gender, Eastern Cooperative Oncology Group, and high-risk features (ie, pT4, poor differentiation, < 12 lymph nodes removed, lymphovascular invasion, perineural invasion, or obstruction or perforation) were constructed. ResultsOf 851 patients reviewed, 330 had received preoperative short-course radiotherapy, of whom 123 (37%) subsequently received AC. Patients treated with AC were younger (median age 61 vs. 73 years; P < .0001), reported better Eastern Cooperative Oncology Group status (P < .0001), and had more high-risk features (P < .0001). On univariate analysis, AC was associated with improved DSS (hazard ratio [HR], 0.58; 95% confidence interval [CI], 0.36-0.94; P = .028), RFS (HR, 0.62; 95% CI, 0.39-0.98; P = .043), and OS (HR, 0.42; 95% CI, 0.30-0.59; P < .0001). On multivariate analysis, these outcomes were not significant (DSS HR, 0.83; 95% CI, 0.43-1.61; P = .58; RFS HR, 0.82; 95% CI, 0.44-1.50; P = .51; OS HR, 0.62; 95% CI, 0.37-1.03; P = .064). Subgroup analysis suggested AC improved DSS (HR, 0.25; 95% CI, 0.07-0.89; P = .033), RFS (HR, 0.24; 95% CI, 0.07-0.85; P = .027), and OS (HR, 0.22; 95% CI, 0.069-0.70; P = .011) only in patients with ≥ 2-high risk features. ConclusionIn the present population-based cohort of patients with stage II rectal cancer, AC did not improve the outcomes in unselected patients. In a small subgroup of patients with ≥ 2 risk factors, we noted improved outcomes with AC use.

Multicentre study of short-course radiotherapy and transanal endoscopic microsurgery for early rectal cancer.

Organ-preserving treatment for early-stage rectal cancer may avoid the substantial perioperative morbidity and functional sequelae associated with total mesorectal excision (TME). The initial results of an organ-preserving approach using preoperative short-course radiotherapy (SCRT) and transanal endoscopic microsurgery (TEMS) are presented. Patients with cT1-2N0 rectal cancers staged using high-quality MRI and endorectal ultrasonography received SCRT, with TEMS 8-10 weeks later, at four regional referral centres between 2007 and 2013. Patients were generally considered high risk for TME surgery (a small number refused TME). Following SCRT and TEMS, 60 (97 per cent) of 62 patients had an R0 resection. Histopathological staging identified 20 ypT0 tumours, 23 ypT1, 18 ypT2 and one ypT3. Preoperative uT category was significantly associated with a complete pathological response, which was achieved in 13 of 27 patients with uT0/uT1 disease and in five of 29 with uT2 (P = 0·010). Acute complications affected 19 patients, the majority following TEMS. No fistulas occurred and no stomas were formed. Surveillance detected four intraluminal local recurrences at a median follow-up of 13 months, all in patients with tumours staged as ypT2. Salvage TME achieved R0 resection in three patients and a stent was placed in one patient owing to co-morbidities. SCRT with TEMS was effective in the majority of patients considered high risk for (or who refused) TME surgery.

Long-Term Health-Related Quality of Life in Patients With Rectal Cancer After Preoperative Short-Course and Long-Course (Chemo) Radiotherapy

BackgroundBoth preoperative short-course radiotherapy (SC-PRT) and preoperative long-course chemo radiotherapy (CRT) have shown to reduce local recurrence rates after total mesorectal excision (TME), but neither resulted in improved survival. This study compared the long-term health-related quality of life (HRQL) and symptoms between CRT and SC-PRT. MethodsPatients who were preoperatively treated with a total dose of 50.0 to 50.4 Gy for locally advanced rectal cancers were identified from 2 hospital registries. Starting from 2011, all patients who were disease-free in the study population (n = 105) were sent a HRQL-questionnaire composed of the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 and questions on bowel and urinary function. Patients who underwent SC-PRT in the TME trial were used as a reference group. ResultsHRQL results from 85 patients receiving CRT (81.0%), with a median follow-up time of 58 months, were compared with the results of patients who underwent SC-PRT (n = 306). Apart from more nausea and vomiting reported by patients receiving CRT (mean score for CRT 5.9 vs. 1.3 for SC-PRT; P < .01; not clinically relevant) and less satisfaction with urinary function indicated by patients who received CRT (mean score for CRT 71.2 vs. 81.2 for SC-PRT; P < .01), no significant differences were found in HRQL and symptoms between patients who received CRT and SC-PRT. ConclusionsThis analysis of HRQL in patients who received CRT shows no clinically relevant differences in long-term HRQL and symptoms between patients who received CRT and SC-PRT, apart from less satisfaction with urinary function reported by patients who received CRT. These results indicate that both approaches have a comparable impact on long-term HRQL.

The impact on health-related quality of life in the first 12 months: A randomised comparison of preoperative short-course radiation versus long-course chemoradiation for T3 rectal cancer (Trans-Tasman Radiation Oncology Group Trial 01.04)

PurposeTo assess health-related quality of life (HRQOL) in patients participating in a randomised trial of neoadjuvant short course radiation (SC) or long course chemoradiation (LC) for operable rectal cancer. Patients and methodsEligible patients with T3N0-2M0 rectal cancer completed the European Organisation for Research and Treatment of Cancer quality of life questionnaire (QLQ-C30) and the colorectal cancer specific module (QLQ C38) at randomisation and 1, 2, 3, 6, 9 and 12 months later. ResultsOf 326 patients randomised, 297 (SC 143, LC 154) were eligible for completion of HRQOL questionnaires. Baseline scores were comparable across the SC and LC groups. Patients reported low scores on sexual functioning and sexual enjoyment. Defaecation problems were the worst of the symptoms at baseline. Surgery had the most profoundly negative effect on HRQOL, seen in both the SC and LC treatment groups to the same extent. The most severely affected domains were physical function and role function and the most severely affected symptoms were fatigue, pain, appetite, weight loss and male sexual problems. Most domains and symptoms returned to baseline levels by 12 months apart from body image, sexual enjoyment and male sexual problems. Future perspective was better than prior to treatment. ConclusionThere is no overall difference in HRQOL between SC and LC neoadjuvant treatment strategies, in the first 12 months, after surgery. In the immediate postoperative period HRQOL was adversely affected in both groups but for the most part was temporary. Some residual sexual functioning concerns persisted at 12 months.

Observation on the effect of preoperative radiotherapy on the local advanced middle and low rectal cancer

Objective To discuss the treatment efficacy and radiotherapy side effects of the preoperative long-course radiochemotherapy and preoperative short-course radiotherapy. Methods 64 patients with local advanced middle and low rectal cancer who got the treatment from April 2004 to April 2010 were analyzed retrospectively. 40 patients got the preoperative long-course radiochemotherapy under the dose of DT 45-50 Gy/25 F, 1.8-2.0 Gy/F, 5 F/W, combining with the synchronous capecitabine chemotherapy (1 650 mg/m2, 2 F/d, d1-14/d21-35), and accepted operation 4-6 weeks after the radiotherapy. The rest 24 patients underwent the preoperative short-course radiotherapy under the dose of DT 25 Gy/5 F, 5 Gy/F, 5 F/W, and got the operation in 2 weeks after the radiotherapy. Results The radical and anus reservation rates in preoperative long-course radiochemotherapy group [85.0 % (34/40), 65.0 % (26/40)] were higher than those in preoperative short-course radiotherapy group [58.3 % (14/24), 33.3 % (8/24)] (χ2 = 5.689, P= 0.019; χ2 = 6.040, P= 0.041). There were no significant differences between the two groups on the index of remission rates, radiation injury, surgical complications, and overall survival rate of 1, 3, 5 years (all P> 0.05). Conclusions The remission rate and overall survival time between the preoperative long-course radiochemotherapy group and preoperative short-course radiotherapy have no significant difference. But the preoperative long-course radiochemotherapy may improve the anus reservation rate and the radical resection rate, without increasing the radiation injury and surgical complications. Key words: Rectal neoplasms; Radiotherapy; Colorectal surgery

Neoadjuvant Treatment Strategies for Locally Advanced Rectal Cancer

Improved surgical technique plus selective preoperative radiotherapy have decreased rectal cancer pelvic local recurrence from, historically, 25% down to about 5–10%. However, this improvement has not reduced distant metastatic relapse, which is the main cause of death and a key issue in rectal cancer management.The current standard is local pelvic treatment (surgery ± preoperative radiotherapy) followed by adjuvant chemotherapy, depending on resection histology. For circumferential resection margin (CRM)-threatened cancer on baseline magnetic resonance imaging, downstaging long-course preoperative chemoradiation (LCPCRT) is generally used. However, for non-CRM-threatened disease, varying approaches are currently adopted in the UK, including straight to surgery, short-course preoperative radiotherapy and LCPCRT. Clinical trials are investigating intensification of concurrent chemoradiation. There is also increasing interest in investigating preoperative neoadjuvant chemotherapy (NAC) as a way of exposing micro-metastatic disease to full-dose systemic chemotherapy as early as possible and potentially reducing metastatic relapse. Phase II trials suggest that this strategy is feasible, with promising histological response and low rates of tumour progression during NAC. Phase III trials are needed to determine the benefit of NAC when added to standard therapy and also to determine if it can be used instead of neoadjuvant radiotherapy-based schedules. Although several measures of neoadjuvant treatment response assessment based on imaging or pathology are promising predictive biomarkers for long-term survival, none has been validated in prospective phase III studies. The phase III setting will enable this, also providing translational opportunities to examine molecular predictors of response and survival.

PTH-337 Personalising radiotherapy in locally advanced rectal cancer: can macrophages within the microenvironment predict response to radiotherapy?

Introduction While neoadjuvant radiotherapy is the standard of care in locally invasive rectal carcinoma (LIRC), only half of patients show a response. A predictive test enabling better patient selection could avoid unneccessary radiation exposure to poor responders. Macrophages within the tumour immune microenvironment with tumoricidal M1 and tumour-protective M2 phenotypes could be modulating this response. This study investigated the possible predictive value of M1 and M2 subpopulations in identifying patients’ likely response to short-course preoperative radiotherapy. Method Biopsy samples were taken from 29 patients with locally invasive rectal carcinoma before treatment with short course radiotherapy and surgical specimens obtained after resection following short-course preoperative radiotherapy. Dual-staining immunohistochemistry was performed with CD68 as macrophage marker, HLA-DR as M1 marker, and CD163 as M2 marker. Samples were scored for hot-and-random spots by Nuance software (version 3.0.2) and compared with patients’ outcome data. Tumour response was measured by assessment of reduction of tumour-cell density. Results Samples revealing a low score for HLA-DR positive M1 macrophages exhibited a better response to short-course radiotherapy with up to 80% (median 80·38% [IQR 46·94–84·73]) reduction in the tumour cell density. On the other hand those with a high score exhibited a poor response with only up to 20% (20·26 [0–48·19]) reduction. The difference in response between the two groups was significant (p = 0·017). No such trends were observed for CD163 + M2 macrophages. The ratio of HLA–DR+ to CD163 + macrophages for biopsy and resection samples was significantly different showing a drop in the HLA-DR positive macrophages in the resection samples (p 0.024). The mean of the difference between the biopsy (median 2·53 [IQR 1.98 – 3.08]) and resection (1·38 [IQR 0.96 – 1.8]) was 1·15 (p = 0·024). Conclusion Patients with a variable macrophage phenotype composition within biopsy samples from patients with locally invasive rectal carcinoma respond differently to short-course preoperative radiotherapy. Further investigation involving a panel of macrophage and other immune-cell markers could verify and validate these findings and develop them as predictive tests identifying good responders to radiotherapy in patients with locally invasive rectal carcinoma. Disclosure of interest None Declared.

A phase II single arm feasibility trial of neoadjuvant chemotherapy (NAC) with oxaliplatin/fluorouracil (OxMdG) then short-course preoperative radiotherapy (SCPRT) then immediate surgery in operable rectal cancer (ORC): COPERNICUS (NCT01263171).

Background: Feasibility was assessed of giving NAC prior to SCPRT then immediate surgery in ORC at high risk of metastatic relapse. Methods: Patients (pts) had non-metastatic rectal adenocarcinoma. Pre-treatment pelvic MRI showed resection margin was not at risk (disease > 1mm from mesorectal fascia) but adverse risk factors were present (disease > T3b or node positive or extramural vascular invasion). Pts received 4x2-weekly cycles of oxaliplatin 85mg/m² + levofolinic acid 175 mg, fluorouracil (FU) 400 mg/m² (bolus), then FU 2400 mg/m² (continuous IV in 46 hr). Within 14 days pts had pelvic SCPRT to 25 Gy in 5 daily fractions. Definitive surgery then occurred within a week. Post surgery pts received 16 weeks of OxMdG or oxaliplatin/capecitabine. The primary endpoint was the proportion of pts completing protocol treatment including surgery. Results: 60 UK pts were recruited May 2012-June 2014. At baseline: male 44 (73%), median age 63 (IQR: 56.5-70), WHO PS 0/1 55/5. On pre-treatment MRI tumour was T2/3x/3a/3b/3c/3d/4 in 2/2/16/24/12/1/3 and N0/1/2 in 7/40/13 pts. All pts commenced OxMdG with 57(95%) receiving all 4 cycles. 20 pts (33%) needed a dose reduction and 22 (37%) a dose delay. 58 pts commenced SCPRT (all received full dose) and 57 underwent surgery: anterior resection in 43 (75%), abdominoperineal resection in 11 (19%), Hartmanns in 3 (5%). Three pts withdrew prior to surgery: one lost to follow up after SCPRT, one pt choice and one due to cardiospasm during NAC. Median gap between OxMdG and starting SCPRT was 10 days (IQR: 5-15) and between completing SCPRT and surgery 10 days (IQR: 5-13). Postoperative histology was T0/1/2/3a/3b/3c/4a in 7/3/19/8/9/10/1 pts, N0/1/2 in 39/13/5 pts and ypT0ypN0 in 7/57 pts (12%). All 57 resected pts had a clear (R0) resection margin with no 30 day postoperative mortality. Conclusions: This is the first trial to report on giving NAC prior to SCPRT then surgery within a short time interval in ORC, which proved feasible with good compliance and promising efficacy. The UK NCRI intend to include a similar regimen in a future phase III trial. Clinical trial information: NCT01263171