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.

Surgical site infections following short-term radiotherapy and total mesorectal excision: results of a randomized study examining the role of gentamicin collagen implant in rectal cancer surgery.

BACKGROUND: Despite the findings of several randomized clinical studies, the role of gentamicin collagen implant (GCI) in rectal cancer surgery is unclear. Local pelvic application of GCI following preoperative radiotherapy and total mesorectal excision (TME) was evaluated to determine the risk of surgical site infections (SSI). METHODS: In this single-center trial, 176 patients with rectal cancer after preoperative, short-term radiotherapy (5 × 5 Gy) were randomized either to the study group in which GCI was used or in the control group without GCI. Prior to surgery and intraoperatively five patients were excluded from the study. The remaining 171 patients were analyzed; 86 were in the study group and 85 in the control group. RESULTS: There were no statistically significant differences in the overall rate of early postoperative complications between the study and control group: 25.6 and 34.1 % respectively; p = 0.245, relative risk (RR) 0.750 [95 % confidence interval (CI) 0.471-1.195]. The reoperation rate was similar in both groups: 12.8 versus 9.4 %; p = 0.628; RR 1.359; (95 % CI 0.575-3.212). The total rate of SSI and organ space SSI were 22.2 and 15.8 % without differences between the study and control group. In patients without anastomotic leakage, the risk of organ space SSI was significantly reduced in patients who received GCI: 2.6 versus 13.0 %; p = 0.018. CONCLUSIONS: Application of GCI in the pelvic cavity after short-term preoperative radiotherapy and TME may reduce the risk of organ space SSI but only in the absence of anastomotic leakage.

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.

Abdominoperineal resection or anterior resection for rectal cancer: patient preferences before and after treatment.

OBJECTIVE: Literature data do not provide any evidence as to whether oncological outcome and quality of life after anterior resection (AR) are superior to those observed after abdominoperineal resection (APR) for low-lying rectal cancer. In view of this, patient preferences should play an important role in the process of decision making. The aim of this study was to investigate these preferences. PATIENTS AND METHODS: A series of consecutive patients with rectal cancer (60 prior to surgery, 65 after APR and 124 after AR) who attended our outpatient clinic were asked to express their preference as to the type of surgery. The second part of the study was performed 4 years later; 30 patients evaluated before surgery, free of disease, were again asked to express their preference as to the type of treatment. RESULTS: Patient preferences as to performing APR, AR or as to leaving the decision to the surgeon were as follows: (i) the group prior to surgery - 5%, 30% and 65%, respectively, (ii) group after APR - 46%, 22% and 32%, respectively, and (iii) group after AR - 4%, 69% and 28%, respectively. Patients after AR pointed to the type of surgery that they had undergone more frequently than patients after APR (69%vs 46%, respectively, P < 0.001). Sixty per cent of patients evaluated twice had altered their initial preferences, usually choosing the type of surgery that they had undergone. CONCLUSIONS: Our results suggest that the sequelae of AR are generally perceived as more acceptable than those of APR. Nevertheless, approximately half of the patients after APR prefer the type of surgery that they have undergone, which suggests the positive reappraisal of APR, once experienced.

Postoperative complications in patients irradiated pre-operatively for rectal cancer: report of a randomised trial comparing short-term radiotherapy vs chemoradiation.

OBJECTIVE: The primary outcome was sphincter preservation. No benefit was found with chemoradiation. The aim of this report is to analyse postoperative complications, which were the secondary outcome. MATERIAL AND METHODS: Patients with resectable T3-4 low rectal carcinoma were randomised to receive either pre-operative 5 x 5 Gy irradiation with subsequent total mesorectal excision (TME) performed within 7 days or chemoradiation (50.4 Gy, 1.8 Gy per fraction plus bolus 5-fluorouracil and leucovorin) followed by TME after 4-6 weeks. RESULTS: Three hundred and five patients (153 in 5 x 5 Gy group and 152 in chemoradiation group) were analysed. The rates of patients with postoperative complications for the 5 x 5 Gy group and for the chemoradiation group were 27 vs 21%, respectively (P = 0.27). If the values were expressed in terms of number of complications, the rates were 31 vs 22%, respectively (P = 0.06). The corresponding values for severe complications were 10 vs 11% (P = 0.85) of patients with complications and 12 vs 11% (P = 0.85) of events. CONCLUSION: The study did not demonstrate a statistically significant difference in the rate of postoperative complications after short-course pre-operative radiotherapy compared with full course chemoradiation.

Sphincter preservation following preoperative radiotherapy for rectal cancer: report of a randomised trial comparing short-term radiotherapy vs. conventionally fractionated radiochemotherapy.

BACKGROUND AND PURPOSE: The aim was to verify whether preoperative conventionally fractionated chemoradiation offers an advantage in sphincter preservation in comparison with preoperative short-term irradiation. PATIENTS AND METHODS: Patients with resectable T3-4 rectal carcinoma without sphincters' infiltration and with a lesion accessible to digital rectal examination were randomised into: preoperative 5x5Gy short-term irradiation with subsequent total mesorectal excision (TME) performed within 7 days or chemoradiation to a total dose of 50.4Gy (1.8Gy per fraction) concomitantly with two courses of bolus 5-fluorouracil and leucovorin followed by TME after 4-6 weeks. Surgeons were obliged to base the type of operation on the tumour status at the time of surgery. RESULTS: Between 1999 and 2002, 316 patients from 19 institutions were enrolled. The sphincter preservation rate was 61% in the 5x5Gy arm and 58% in the radiochemotherapy arm, P = 0.57. The tumour was on average 1.9 cm smaller (P < 0.001) among patients treated with chemoradiation compared with short-term schedule. For patients who underwent sphincter-preserving procedure, the surgeons generally followed the rule of tailoring the resection according to tumour downsizing; the median distal bowel margin was identical (2 cm) for both randomised groups. However, in the chemoradiation group, five patients underwent abdominoperineal resection despite clinical complete response. CONCLUSIONS: Despite significant downsizing, chemoradiation did not result in increased sphincter preservation rate in comparison with short-term preoperative radiotherapy. The surgeons' decisions were subjective and based on pre-treatment tumour volume at least in clinical complete responders.

Sphincter preservation after short-term preoperative radiotherapy for low rectal cancer--presentation of own data and a literature review.

This report is based on a series of 108 patients with clinically staged T2 (9), T3 (94) and T4 (5) rectal cancer treated with preoperative irradiation with 25 Gy, 5 Gy per fraction given for one week. In 77% of patients. the tumour was located within 7 cm of the anal verge and in 15% the anal canal was involved. Surgery was usually undertaken during the week after irradiation. For low tumours, total mesorectal excision was performed, and for middle and upper cancers, the whole circumference of the mesorectum was excised at least 2 cm below the lower pole of a tumour. Tumour was resected in 103 patients, and sphincter-preserving surgery was performed in 73% of them. In the subgroup where the tumour was located higher than 4 cm from the anal verge, sphincter-preserving surgery was performed in 95%. The follow-up period ranged from 10 to 49 months, with a median of 25 months. Local recurrences were observed in 4% of patients. Anorectal dysfunction caused impairment of social life in 40% of patients and 18% admitted that their quality of life was seriously affected however, none of them stated that they would have preferred a colostomy. These preliminary data suggest that following high dose per fraction short-term preoperative radiotherapy a high rate of sphincter-preserving surgery can be reached, with acceptable anorectal function and an acceptable rate of local failure and late complications. The results of our own data and literature review indicate the need for a randomized clinical trial comparing high dose per fraction preoperative radiotherapy with immediate surgery with conventional preoperative radiochemotherapy with delayed surgery.