Krzysztof Bujko

Long‐term results of a randomized trial comparing preoperative short‐course radiotherapy with preoperative conventionally fractionated chemoradiation for rectal cancer

Neoadjuvant chemoradiotherapy does not alter anal sphincter preservation or postoperative complications compared with short‐course radiotherapy alone in patients with clinical stage T3 or T4 resectable rectal cancer. The aim of this study was to compare survival, local control and late toxicity in the two treatment groups.

Randomized Phase III Study Comparing Preoperative Radiotherapy With Chemoradiotherapy in Nonresectable Rectal Cancer

PURPOSE Preoperative chemoradiotherapy is considered standard treatment for locally advanced rectal cancer, although the scientific evidence for the chemotherapy addition is limited. This trial investigated whether chemotherapy as part of a multidisciplinary treatment approach would improve downstaging, survival, and relapse rate. PATIENTS AND METHODS The randomized study included 207 patients with locally nonresectable T4 primary rectal carcinoma or local recurrence from rectal carcinoma in the period 1996 to 2003. The patients received either chemotherapy (fluorouracil/leucovorin) administered concurrently with radiotherapy (50 Gy) and adjuvant for 16 weeks after surgery (CRT group, n = 98) or radiotherapy alone (50 Gy; RT group, n = 109). RESULTS The two groups were well balanced according to pretreatment characteristics. An R0 resection was performed in 82 patients (84%) in the CRT group and in 74 patients (68%) in the RT group (P = .009). Pathologic complete response was seen in 16% and 7%, respectively. After an R0 + R1 resection, local recurrence was found in 5% and 7%, and distant metastases in 26% and 39%, respectively. Local control (82% v 67% at 5 years; log-rank P = .03), time to treatment failure (63% v 44%; P = .003), cancer-specific survival (72% v 55%; P = .02), and overall survival (66% v 53%; P = .09) all favored the CRT group. Grade 3 or 4 toxicity, mainly GI, was seen in 28 (29%) of 98 and six (6%) of 109, respectively (P = .001). There was no difference in late toxicity. CONCLUSION CRT improved local control, time to treatment failure, and cancer-specific survival compared with RT alone in patients with nonresectable rectal cancer. The treatments were well tolerated.

Nomograms for Predicting Local Recurrence, Distant Metastases, and Overall Survival for Patients With Locally Advanced Rectal Cancer on the Basis of European Randomized Clinical Trials

PURPOSE The purpose of this study was to develop accurate models and nomograms to predict local recurrence, distant metastases, and survival for patients with locally advanced rectal cancer treated with long-course chemoradiotherapy (CRT) followed by surgery and to allow for a selection of patients who may benefit most from postoperative adjuvant chemotherapy and close follow-up. PATIENTS AND METHODS All data (N = 2,795) from five major European clinical trials for rectal cancer were pooled and used to perform an extensive survival analysis and to develop multivariate nomograms based on Cox regression. Data from one trial was used as an external validation set. The variables used in the analysis were sex, age, clinical tumor stage stage, tumor location, radiotherapy dose, concurrent and adjuvant chemotherapy, surgery procedure, and pTNM stage. Model performance was evaluated by the concordance index (c-index). Risk group stratification was proposed for the nomograms. RESULTS The nomograms are able to predict events with a c-index for external validation of local recurrence (LR; 0.68), distant metastases (DM; 0.73), and overall survival (OS; 0.70). Pathologic staging is essential for accurate prediction of long-term outcome. Both preoperative CRT and adjuvant chemotherapy have an added value when predicting LR, DM, and OS rates. The stratification in risk groups allows significant distinction between Kaplan-Meier curves for outcome. CONCLUSION The easy-to-use nomograms can predict LR, DM, and OS over a 5-year period after surgery. They may be used as decision support tools in future trials by using the three defined risk groups to select patients for postoperative chemotherapy and close follow-up (http://www.predictcancer.org).

Multicentre analysis of oncological and survival outcomes following anastomotic leakage after rectal cancer surgery

The association between diverting stomas and symptomatic anastomotic leakage after rectal cancer surgery was studied, as well as the impact of leakage on local recurrence, distant metastasis, and disease‐free, overall and cancer‐specific survival.

Does adjuvant fluoropyrimidine-based chemotherapy provide a benefit for patients with resected rectal cancer who have already received neoadjuvant radiochemotherapy? A systematic review of randomised trials

BACKGROUND The results of the recently published large European randomised study in rectal cancer (European Organisation for Research and Treatment of Cancer 22921 trial) do not support current guidelines recommending postoperative chemotherapy for patients who have previously undergone preoperative radiochemotherapy or radiotherapy [radio(chemo)therapy]. To evaluate this discrepancy further, a systematic review of relevant randomised trials was undertaken. MATERIALS AND METHODS A systematic literature search was carried out in order to identify randomised studies exploring adjuvant chemotherapy against observation in patients with rectal cancer previously treated with preoperative radio(chemo)therapy. RESULTS A statistically significant benefit of adjuvant chemotherapy was not found in any of the four relevant randomised trials. Non-protocolised subgroup analysis of one study indicated a beneficial effect of adjuvant chemotherapy for high rectal tumours and for patients downstaged to ypT0-2N0 but no effect for low-lying rectal tumours. However, the body of evidence indicates that patients downstaged after radio(chemo)therapy to ypT0-2N0 disease are not candidates for testing adjuvant chemotherapy in future trials due to the considerable over-treatment anticipated by this manoeuvre. CONCLUSIONS To resolve the issue in question, a meta-analysis of relevant studies is required, and new trials should be launched to explore new drug combinations against observation. Currently, delivery of adjuvant chemotherapy in patients undergoing preoperative radio(chemo)therapy is not evidence based.

The abdominoperineal resection itself is associated with an adverse outcome: The European experience based on a pooled analysis of five European randomised clinical trials on rectal cancer

PURPOSE The aim of this study is to identify factors associated with the decision to perform an abdominoperineal resection (APR) and to assess if these factors or the surgical procedure itself is associated with circumferential resection margin (CRM) involvement, local recurrence (LR), overall survival (OS) and cancer-specific survival (CSS). PATIENTS AND METHODS The Swedish Rectal Cancer Trial (SRCT), TME trial, CAO/ARO/AIO-94 trial, EORTC 22921 trial and Polish Rectal Cancer Trial (PRCT) were pooled. A propensity score was calculated, which indicated the predicted probability of undergoing an APR given gender, age and distance, and used in the multivariate analyses. RESULTS An APR procedure was associated with an increased risk of CRM involvement [odd ratio (OR) 2.52, p<0.001], increased LR rate [hazard ratio (HR) 1.53, p=0.001] and decreased CSS rate (HR 1.31, p=0.002), whereas the propensity score was not. CONCLUSION The results suggest that the APR procedure itself is a significant predictor for non-radical resections and increased risk of LR and death due to cancer for patients with advanced rectal cancer.

Preoperative radiotherapy and local excision of rectal cancer with immediate radical re-operation for poor responders: A prospective multicentre study

PURPOSE To assess local control after preoperative radiation and local excision and to determine an optimal radiotherapy regimen. METHODS Eighty-nine patients with G1-2 rectal adenocarcinoma <3-4 cm; unfavourable cT1N0 (23.6%), cT2N0 (62.9%) or borderline cT2/cT3N0 (13.5%) received 5 × 5 Gy plus 4 Gy boost (71.9%) or 55.8 Gy in 31 fractions with 5-FU and leucovorin (28.1%). Local excision (traditional technique 56.2%, transanal endoscopic microsurgery 41.6%, Kraske procedure 2.2%) was performed 6-8 weeks later. If patients were downstaged to ypT0-1 without unfavourable factors (good responders), this was deemed definitive treatment. Immediate conversion to radical surgery was recommended for remaining patients. RESULTS Good response to radiation was seen in 67.2% of patients in the short-course group and in 80.0% in the chemoradiation group, p = 0.30. Local recurrence at 2 years (median follow-up) in good responders was 11.8% in the short-course group and 6.2% in the chemoradiation group, p = 0.53. In the total group, a lower rate of local recurrence at 2 years was observed in elderly patients (>69 years, median value) when compared to the younger patients; 8.3% vs. 27.7%, Cox analysis hazard ratio 0.232, p = 0.016. A total of 18 patients initially managed with local excision required conversion to abdominal surgery but either refused it or were unfit. In this group, local recurrence at 2 years was 37.1%. CONCLUSIONS This study suggests an acceptable local recurrence rate after preoperative radiotherapy and local excision of small, radiosensitive tumours in elderly patients.

Is the 1-cm Rule of Distal Bowel Resection Margin in Rectal Cancer Based on Clinical Evidence? A Systematic Review

Background Distal intramural spread is present within 1 cm from visible tumor in a substantial proportion of patients. Therefore, ≥1 cm of distal bowel clearance is recommended as minimally acceptable. However, clinical results are contradictory in answering the question of whether this rule is valid. The aim of this review was to evaluate whether in patients undergoing anterior resection, a distal bowel gross margin of <1 cm jeopardizes oncologic safety.

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.

Preoperative radiotherapy and local excision of rectal cancer with immediate radical re-operation for poor responders

BACKGROUND AND PURPOSE To report an early analysis of prospective study exploring preoperative radiotherapy and local excision in rectal cancer. MATERIALS AND METHODS Mucosa at tumour edges was tattooed. Patients with cT1-3N0 tumour <3-4 cm were treated with either 5x5Gy+4Gy boost (N=31) or chemoradiation (50.4Gy+5.4Gy boost, 1.8Gy per fraction+5-fluorouracyl and leucovorin; N=13). Thirteen patients from the short-course group were unfit for chemotherapy. The interval from radiation to full-thickness local excision was 6 weeks. The protocol called for conversion to a transabdominal surgery in case of ypT2-3 disease or positive margin. RESULTS The postoperative complications requiring hospitalization were recorded in 9% of patients. The rate of pathological complete response was 41%. The rate of patients requiring conversion was 34%; however, 18% actually underwent conversion and the remaining 16% refused or were unfit. During the 14 months of median follow-up, local recurrence was detected in 7% of patients and all underwent salvage surgery. Of 19 patients in whom initially anterior resection was likely, 16% had abdominoperineal resection performed for a conversion or as a rescue procedure. CONCLUSION Our study suggests that the short-course radiation prior to local excision is a treatment option for high-risk patients.