Individual participant data pooled-analysis of risk factors for recurrence after neoadjuvant radiotherapy and transanal local excision of rectal cancer: the PARTTLE study.

BACKGROUND: An organ-preserving strategy may be a valid alternative in the treatment of selected patients with rectal cancer after neoadjuvant radiotherapy. Preoperative assessment of the risk for tumor recurrence is a key component of surgical planning. The aim of the present study was to increase the current knowledge on the risk factors for tumor recurrence. METHODS: The present study included individual participant data of published studies on rectal cancer surgery. The literature was reviewed according to according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses of Individual Participant Data checklist (PRISMA-IPD) guidelines. Series of patients, whose data were collected prospectively, having neoadjuvant radiotherapy followed by transanal local excision for rectal cancer were reviewed. Three independent series of univariate/multivariate binary logistic regression models were estimated for the risk of local, systemic and overall recurrence, respectively. RESULTS: We identified 15 studies, and 7 centers provided individual data on 517 patients. The multivariate analysis showed higher local and overall recurrences for ypT3 stage (OR 4.79; 95% CI 2.25-10.16 and OR 6.43 95% CI 3.33-12.42), tumor size after radiotherapy > 10 mm (OR 5.86 95% CI 2.33-14.74 and OR 3.14 95% CI 1.68-5.87), and lack of combined chemotherapy (OR 3.68 95% CI 1.78-7.62 and OR 2.09 95% CI 1.10-3.97), while ypT3 was the only factor correlated with systemic recurrence (OR 5.93). The analysis of survival curves shows that the overall survival is associated with ypT and not with cT. CONCLUSIONS: Local excision should be offered with caution after neoadjuvant chemoradiotherapy to selected patients with rectal cancers, who achieved a good response to neoadjuvant chemoradiotherapy.

Long-course preoperative chemoradiation versus 5 × 5 Gy and consolidation chemotherapy for clinical T4 and fixed clinical T3 rectal cancer: long-term results of the randomized Polish II study.

BACKGROUND: This trial evaluated whether preoperative short-course radiotherapy and consolidation chemotherapy (CCT) were superior to chemoradiation in rectal cancers with clinical (c)T4 or fixed cT3. Previously, we reported early results showing no differences in the radical surgery rate (primary end point). In the short-course/CCT group, we observed lower acute toxicity of preoperative treatment and better overall survival (OS). We updated results to determine whether the benefit in OS was sustained and to evaluate late complications. PATIENTS AND METHODS: Patients with cT4 or fixed cT3 rectal cancer were randomized either to preoperative 5 × 5 Gy and three cycles of FOLFOX4 or to chemoradiation (50.4 Gy with bolus 5-Fu, leucovorin and oxaliplatin). RESULTS: Patients (N = 515) were eligible for analysis, 261 in the short-course/CCT group and 254 in the chemoradiation group. The median follow-up was 7.0 years. The difference in OS was insignificant [hazard ratio (HR) 0.90; 95% confidence interval (CI) 0.70-1.15; P = 0.38). However, the difference in early OS favouring short-course/CCT previously reported was observed again, being 9% at 3 years (95% CI 0.5% to 17%). This difference disappeared later; at 8 years OS was 49% in both groups. There was no difference in disease-free survival (HR 0.95; 95% CI 0.75-1.19; P = 0.65) at 8 years 43% versus 41% in the short-course/CCT group versus the chemoradiation group, respectively. The corresponding values for cumulative incidences of local failure and distant metastases did not differ and were HR = 1.08, 95% CI 0.70-1.23, P = 0.60, 35% versus 32% and HR = 1.10, 95% CI 0.68-1.23, P = 0.54, 36% versus 34%, respectively. The rate of late complications was similar (P = 0.66), grade 3+ being 11% versus 9% in the short-course/CCT group versus the chemoradiation group, respectively. CONCLUSION: The superiority of preoperative short-course/CCT over chemoradiation was not demonstrated. CLINICAL TRIAL NUMBER: The trial is registered as ClinicalTrials.gov number NCT00833131.

Activation of the complement cascade enhances motility of leukemic cells by downregulating expression of HO-1.

As a crucial arm of innate immunity, the complement cascade (ComC) is involved both in mobilization of normal hematopoietic stem/progenitor cells (HSPCs) from bone marrow (BM) into peripheral blood and in their homing to BM. Despite the fact that ComC cleavage fragments alone do not chemoattract normal HSPCs, we found that leukemia cell lines as well as clonogenic blasts from chronic myeloid leukemia and acute myeloid leukemia patients respond robustly to C3 and C5 cleavage fragments by chemotaxis and increased adhesion. This finding was supported by the detection of C3a and C5a receptors in cells from human malignant hematopoietic cell lines and patient blasts at the mRNA (reverse transcriptase-polymerase chain reaction) and protein level (fluorescence-activated cell sorting), and by the demonstration that these receptors respond to stimulation by C3a and C5a by phosphorylation of p42/44 and p38 mitogen-activated protein kinases (MAPK), and protein kinase B (PKB/AKT). We also found that inducible heme oxygenase 1 (HO-1) is a negative regulator of ComC-mediated trafficking of leukemic cells, and that stimulation of leukemic cells by C3 or C5 cleavage fragments activates p38 MAPK, which downregulates HO-1 expression, rendering cells more mobile. We conclude that activation of the ComC in leukemia/lymphoma patients (for example, as a result of accompanying infections) enhances the motility of malignant cells and contributes to their spread in a p38 MAPK-HO-1-dependent manner. Therefore, inhibition of p38 MAPK or upregulation of HO-1 by small-molecule modulators would have a beneficial effect on ameliorating cell migration-mediated expansion of leukemia/lymphoma cells when the ComC becomes activated.

Study of bovine gene: the temporal-spatial expression patterns, polymorphism and association analysis with meat production traits.

The gene () encodes a transcription factor belonging to the MEF2 family that plays an important role in myogenesis by transcriptional regulation of genes involved in skeletal muscle growth and development. Despite the established importance of the factors in the muscular growth and development, the temporal-spatial expression and biological function of have not been reported in cattle. The aim of this study was to analyze the level of expression in the developing longissimus dorsi muscle (LM) of 4 cattle breeds (Polish Holstein-Friesian [HF], Limousine [LIM], Hereford [HER], Polish Red [PR]), differing in terms of meat production and utility type, at 6, 9, and 12 mo of age. The genetic polymorphism and expression patterns in 6 tissues (heart, spleen, liver, semitendinosus muscle [ST], gluteus medius muscle [GM], and LM) were also investigated. The results showed that mRNA was expressed at a high level in adult skeletal and cardiac muscles. Moreover, expression was markedly greater in the GM than in the LM ( 0.05) and ST ( 0.01). An age-dependent and breed-specific comparison of mRNA level in skeletal muscle of HF, LIM, HER, and PR bulls showed that age was significant differentiating factor of transcript/protein abundance in the LM of HER and LIM ( 0.001) compared to HF and PR, for which the differences in mRNA level were not significant ( > 0.05). Regarding the breed effect on the expression, significantly greater mRNA/protein level was noticed in the LM of 9 and 12 mo-old HER than of LIM ( 0.01), HF ( 0.001), and PR ( 0.001). Four novel SNP, namely, (promoter), (exon 7), (exon 8), and (3'UTR), were identified. We found that 3'UTR variant, situated within the seed region of the miR-5187-3p and miR-6931-5p binding sites, was associated with the level of mRNA/protein in LM of 12-mo-old HF bulls. In addition, we observed a significant association between some carcass quality traits, including meat and carcass fatness quality traits, and various 3'UTR genotypes in the investigated population of HF cattle. Our finding provides new evidence of the significant role in the postnatal muscle growth and development in cattle, and indicates that can be a promising molecular marker for carcass quality-related traits in adult cattle.

Does the addition of oxaliplatin to preoperative chemoradiation benefit cT4 or fixed cT3 rectal cancer treatment? A subgroup analysis from a prospective study.

BACKGROUND: Whether there is any benefit derived from adding oxaliplatin to fluoropyrimidine-based preoperative chemoradiation is currently unknown in cases of advanced cT3 or cT4 tumours. Our aim was to evaluate this issue by analysing a randomized trial, which compared two schedules of preoperative treatment (chemoradiation vs. 5 × 5 Gy with 3 cycles of consolidation chemotherapy) for cT4 or fixed cT3 rectal cancer. PATIENTS AND METHODS: Delivery of oxaliplatin was mandatory to the first part of the study. For the second part, its delivery in both treatment-assigned groups was left to the discretion of the local investigator. We analysed a subgroup of 272 patients (136 in the oxaliplatin group and 136 in the fluorouracil-only group) from institutions that had omitted oxaliplatin in the second part of the study. RESULTS: Circumferential resection margin negative (CRM-) status rate was 68% in the oxaliplatin group and 70% in the fluorouracil-only group, p = 0.72. The pathological complete response rate (pCR) was correspondingly 14% vs. 7%, p = 0.10. Following multivariable analysis, when comparing the CRM- status in the oxaliplatin group to the fluorouracil-only group, the odds ratio was 0.79 (95 CI 0.35-1.74), p = 0.54; there being no interaction between concomitant chemoradiation and 5 × 5 Gy with consolidation chemotherapy; pinteraction = 0.073. For pCR, the corresponding results were 0.47 (95 CI 0.19-1.16), p = 0.10, pinteraction = 0.84. CONCLUSION: No benefit was found of adding oxaliplatin in terms of CRM nor pCR rates for either concomitant or sequential settings in preoperative radiochemotherapy for very advanced rectal cancer.

Long-course oxaliplatin-based preoperative chemoradiation versus 5 × 5 Gy and consolidation chemotherapy for cT4 or fixed cT3 rectal cancer: results of a randomized phase III study.

BACKGROUND: Improvements in local control are required when using preoperative chemoradiation for cT4 or advanced cT3 rectal cancer. There is therefore a need to explore more effective schedules. PATIENTS AND METHODS: Patients with fixed cT3 or cT4 cancer were randomized either to 5 × 5 Gy and three cycles of FOLFOX4 (group A) or to 50.4 Gy in 28 fractions combined with two 5-day cycles of bolus 5-Fu 325 mg/m(2)/day and leucovorin 20 mg/m(2)/day during the first and fifth week of irradiation along with five infusions of oxaliplatin 50 mg/m(2) once weekly (group B). The protocol was amended in 2012 to allow oxaliplatin to be then foregone in both groups. RESULTS: Of 541 entered patients, 515 were eligible for analysis; 261 in group A and 254 in group B. Preoperative treatment acute toxicity was lower in group A than group B, P = 0.006; any toxicity being, respectively, 75% versus 83%, grade III-IV 23% versus 21% and toxic deaths 1% versus 3%. R0 resection rates (primary end point) and pathological complete response rates in groups A and B were, respectively, 77% versus 71%, P = 0.07, and 16% versus 12%, P = 0.17. The median follow-up was 35 months. At 3 years, the rates of overall survival and disease-free survival in groups A and B were, respectively, 73% versus 65%, P = 0.046, and 53% versus 52%, P = 0.85, together with the cumulative incidence of local failure and distant metastases being, respectively, 22% versus 21%, P = 0.82, and 30% versus 27%, P = 0.26. Postoperative and late complications rates in group A and group B were, respectively, 29% versus 25%, P = 0.18, and 20% versus 22%, P = 0.54. CONCLUSIONS: No differences were observed in local efficacy between 5 × 5 Gy with consolidation chemotherapy and long-course chemoradiation. Nevertheless, an improved overall survival and lower acute toxicity favours the 5 × 5 Gy schedule with consolidation chemotherapy. CLINICAL TRIAL NUMBER: The trial is registered as ClinicalTrials.gov number NCT00833131.

Watch and wait policy after preoperative radiotherapy for rectal cancer; management of residual lesions that appear clinically benign.

BACKGROUND: During an ongoing phase II observational study on watch and wait policy in rectal cancer, a substantial number of patients presented residual lesion after radiotherapy with a clinical benign appearance. This article aims to discuss the clinical significance of such findings. MATERIALS AND METHODS: Main entry criteria were age ≥70 years and small tumour (≤5 cm and ≤60% of circumferential involvement) located in the low rectum. Patients received chemoradiation (50 Gy, 2 Gy per fraction concomitantly with a 5-Fu bolus and leucovorin) or 5 × 5 Gy if considered unfit for chemotherapy. Patients with clinical complete response (cCR) were observed. Those with persistent tumours underwent transanal endoscopic microsurgery [TEM] if the baseline tumour was ≤3 cm and cN0 or total mesorectal excision. RESULTS: The watch and wait procedure was used in 11 out of the total 35 patients (31%) with a cCR; 17 patients (49%) with residual tumours that appeared clinically malignant were referred for TEM or abdominal surgery. In the remaining seven (20%), the residual tumour clinically appeared benign. Of these, there were two invasive cancers, four high-grade dysplasias and one low-grade dysplasia. The five patients with dysplasia, underwent local lesion resection without recurrence within a median of 11 months follow-up. CONCLUSIONS: The majority of lesions that appeared clinically benign after radio(chemo)therapy were also benign on pathological examination. Thus, local excision of such lesions should be considered.

Postoperative chemotherapy in patients with rectal cancer receiving preoperative radio(chemo)therapy: A meta-analysis of randomized trials comparing surgery ± a fluoropyrimidine and surgery + a fluoropyrimidine ± oxaliplatin.

BACKGROUND: There is no consensus on the role of postoperative chemotherapy in patients with rectal cancer who have received preoperative radio(chemo)therapy. MATERIALS AND METHODS: A systematic review and meta-analysis were performed of trials that used preoperative radio(chemo)therapy and randomized patients either between postoperative chemotherapy and observation or between a fluoropyrimidine only (FU-only) and a fluoropyrimidine with oxaliplatin (FU-OXA) as postoperative chemotherapy. RESULTS: Five randomized studies compared postoperative chemotherapy with observation in a total of 2398 patients. None of these trials demonstrated a statistically significant benefit of chemotherapy for OS and DFS. The pooled differences in OS and DFS did not differ statistically significantly between the chemotherapy group and the observation group. The hazard ratios (HRs) and 95% confidence intervals (CIs) were 0.95 (CI: 0.82-1.10), P = 0.49 and 0.92 (CI: 0.80-1.04), P = 0.19, respectively. In the subgroup of trials in which randomization was performed after surgery (n = 753), a statistically significant positive pooled chemotherapy effect was observed for DFS (HR = 0.79, 95% CI: 0.62-1.00, P = 0.047), but not for OS (P = 0.39). Four randomized trials compared adjuvant FU-OXA with adjuvant FU-only in 2710 patients. In two trials, the difference in DFS between groups was statistically significant in favour of FU-OXA, and in the other two trials, the difference was not significant. The pooled difference in DFS between the FU-OXA group and the FU-only group was not statistically significant: HR = 0.84 (CI: 0.66-1.06), P = 0.15. CONCLUSION: The use of postoperative chemotherapy in patients with rectal cancer receiving preoperative radio(chemo)therapy is not based on strong scientific evidence.

Nomograms to predict survival and the risk for developing local or distant recurrence in patients with rectal cancer treated with optional short-term radiotherapy.

BACKGROUND: In many European countries, short-term 5 × 5 Gy radiotherapy has become the standard preoperative treatment of patients with resectable rectal cancer. Individualized risk assessment might allow a better selection of patients who will benefit from postoperative treatment and intensified follow-up. PATIENTS AND METHODS: From patient's data from three European rectal cancer trials (N = 2881), we developed multivariate cox nomograms reflecting the risk for local recurrence (LR), distant metastases (DM) and overall survival (OS). Evaluated variables were age, gender, tumour distance from the anal verge, the use of radiotherapy, surgical technique (total mesorectal excision/conventional surgery), surgery type (low anterior resection/abdominoperineal resection), time from randomization to surgery, residual disease (R0 versus R1 + 2), pT-stage, pN-stage and surgical complications. RESULTS: Pathological T- and N-status are of vital importance for an accurate prediction of LR, DM and OS. Short-course radiotherapy reduces the rate of LR. The developed nomograms are capable of predicting events with a validation c-index of 0.79 (LR), 0.76 (DM) and 0.75 (OS). The proposed stratification in risk groups allowed significant distinction between Kaplan-Meier curves for outcome. CONCLUSION: The developed nomograms can contribute to better individual risk prediction for LR, DM and OS for patients operated on rectal cancer. The practicality of the defined risk groups makes decision support in the consulting room feasible, assisting physicians to select patients for adjuvant therapy or intensified follow-up.

Anorectal and sexual functions after preoperative radiotherapy and full-thickness local excision of rectal cancer.

AIMS: Local excision with preoperative radiotherapy may be considered as alternative management to abdominal surgery alone for small cT2-3N0 tumours. However, little is known about anorectal and sexual functions after local excision with preoperative radiotherapy. Evaluation of this issue was a secondary aim of our previously published prospective multicentre study. METHODS: Functional evaluation was based on a questionnaire completed by 44 of 64 eligible disease-free patients treated with preoperative radiotherapy and local excision. Additionally, ex post, these results were confronted with those recorded retrospectively in the control group treated with anterior resection alone (N = 38). RESULTS: In the preoperative radiotherapy and local excision group, the median number of bowel movements was two per day, incontinence of flatus occurred in 51% of patients, incontinence of loose stool in 46%, clustering of stools in 59%, and urgency in 49%; these symptoms occurred often or very often in 11%-21% of patients. Thirty-eight per cent of patients claimed that their quality of life was affected by anorectal dysfunction. Nineteen per cent of men and 20% of women claimed that the treatment negatively influenced their sexual life. The anorectal functions in the preoperative radiotherapy and local excision group were not much different from that observed in the anterior resection alone group. CONCLUSIONS: Our study suggests that anorectal functions after preoperative radiotherapy and local excision may be worse than expected and not much different from that recorded after anterior resection alone. It is possible that radiotherapy compromises the functional effects achieved by local excision.

Palliative radiotherapy and chemotherapy instead of surgery in symptomatic rectal cancer with synchronous unresectable metastases: a phase II study.

BACKGROUND: In stage IV rectal cancer, palliative surgery is often carried out upfront. This study investigated whether the surgery can be avoided. PATIENTS AND METHODS: Forty patients with symptomatic primary rectal adenocarcinoma and synchronous distant metastases deemed to be unresectable received 5 × 5 Gy irradiation and then oxaliplatin-based chemotherapy. Before treatment, 38% of patients had a near-obstructing lesion. The palliative effect was evaluated by questionnaires completed by the patients. RESULTS: The median follow-up for living patients was 26 months (range 19-34). The median overall survival was 11.5 months. Eight patients (20%) required surgery during the course of their disease: seven patients required stoma creation and one had local excision. Thirty percent of patients had a complete resolution of pelvic symptoms during the whole course of the disease, and 35% had significant improvement. In the subgroup with a near-obstructing lesion, 23% of patients required stoma creation. In all patients, the probability of requiring palliative surgery at 2 years was 17.5% [95% confidence interval (CI) 13% to 22%), and the probability of sustained good palliative effect after radiotherapy and chemotherapy was 67% (95% CI 58% to 76%). CONCLUSION: Short-course radiotherapy and chemotherapy allowed most patients to avoid surgery, even those with a near-obstructing lesion. CLINICALTRIALS: The trial is registered with ClinicalTrials.gov: number NCT01157806.

Altering the therapeutic paradigm towards a distal bowel margin of < 1 cm in patients with low-lying rectal cancer: a systematic review and commentary.

AIM: The 1-cm rule of distal bowel clearance in patients with low-lying rectal cancer undergoing anterior resection is based mainly on pathological data showing distal intramural spread. Because clinical data are contradictory, a review that includes only cancers located ≤ 5 or ≤ 6 cm from the anal verge was carried out. METHOD: A systematic review of the literature identified seven studies that presented results in relation to a margin of ≤ 1 cm (n = 293) vs > 1 cm (n = 315). In six studies, pre- or postoperative radiotherapy was implemented, and in one study patients were treated with surgery alone. Three studies, all implementing radiotherapy, reported results related to a margin of ≤ 5 mm (n = 51) vs > 5 mm (n = 125). RESULTS: In none of the studies were the differences in local recurrence rate between the small and large margin groups statistically significant. The pooled analysis of six studies, in which patients received perioperative radiotherapy, showed a 1.2% [95% confidence interval (Cl) -4.5-7.0%] higher local recurrence rate in the ≤ 1 cm margin group compared with the > 1 cm margin group (P = 0.6). The corresponding figures for the ≤ 5 mm cut-off point were 0.5% (95% CI -7.6-8.7%, P = 0.9). The 5-year local recurrence rate in the only study in which radiotherapy had not been used was 8.6% higher in the ≤ 1 cm margin group compared with the > 1 cm margin group (P = 0.09). CONCLUSION: Clinical evidence does not support the 1-cm rule in patients with low-lying rectal cancer undergoing pre- or postoperative radiotherapy.

Acceptance of a 5-mm distal bowel resection margin for rectal cancer: is it safe?

AIM: Acceptance of a short distal bowel margin results in a higher rate of anterior resection but may compromise oncological safety. This study aimed to evaluate the safety of a 5-mm distal margin. METHOD: A retrospective analysis was carried out of 412 consecutive patients with rectal cancer treated with anterior resection with a negative circumferential resection margin. Radiotherapy was given to 63% of patients with an advanced tumour. The median follow up was 75 months. RESULTS: Fewer patients in the group with a distal margin of ≤ 5 mm had a tumour with an advanced pT stage compared to patients in the group with a distal margin of > 5 mm (P = 0.033). Two patients were converted to abdominoperineal resection because of a positive 'doughnut', leaving 410 patients, in whom 5.4% (95% CI, 0-11.3%) of the group with a distal margin of ≤ 5 mm had local recurrence at 5 years compared with 4.2% (95% CI, 2.1-6.3%) of the group with a distal margin of > 5 mm (P = 0.726). The corresponding figures for the 5-year overall survival were 82.4% (95% CI, 72.6-92.2%) vs 76.3% (95% CI, 71.8-80.8%) (P = 0.581). All four anastomotic recurrences occurred in the group with a distal margin of > 5 mm. CONCLUSION: A distal margin of ≤ 5 mm did not compromise oncological safety in patients undergoing preoperative radiation for an advanced rectal cancer.

Laparoscopic extraperitoneal rectal cancer surgery: the clinical practice guidelines of the European Association for Endoscopic Surgery (EAES).

BACKGROUND: The laparoscopic approach is increasingly applied in colorectal surgery. Although laparoscopic surgery in colon cancer has been proved to be safe and feasible with equivalent long-term oncological outcome compared to open surgery, safety and long-term oncological outcome of laparoscopic surgery for rectal cancer remain controversial. Laparoscopic rectal cancer surgery might be efficacious, but indications and limitations are not clearly defined. Therefore, the European Association for Endoscopic Surgery (EAES) has developed this clinical practice guideline. METHODS: An international expert panel was invited to appraise the current literature and to develop evidence-based recommendations. The expert panel constituted for a consensus development conference in May 2010. Thereafter, the recommendations were presented at the annual congress of the EAES in Geneva in June 2010 in a plenary session. A second consensus process (Delphi process) of the recommendations with the explanatory text was necessary due to the changes after the consensus conference. RESULTS: Laparoscopic surgery for extraperitoneal (mid- and low-) rectal cancer is feasible and widely accepted. The laparoscopic approach must offer the same quality of surgical specimen as in open surgery. Short-term outcomes such as bowel function, surgical-site infections, pain and hospital stay are slightly improved with the laparoscopic approach. Laparoscopic resection of rectal cancer is not inferior to the open in terms of disease-free survival, overall survival or local recurrence. Laparoscopic pelvic dissection may impair genitourinary and sexual function after rectal resection, like in open surgery. CONCLUSIONS: Laparoscopic surgery for mid- and low-rectal cancer can be recommended under optimal conditions. Still, most level 1 evidence is for colon cancer surgery rather than rectal cancer. Upcoming results from large randomised trials are awaited to strengthen the evidence for improved short-term results and equal long-term results in comparison with the open approach.