H.J.T. Rutten

The BRAF V600E mutation is an independent prognostic factor for survival in stage II and stage III colon cancer patients

BACKGROUND Molecular markers in colon cancer are needed for a more accurate classification and personalized treatment. We determined the effects on clinical outcome of the BRAF mutation, microsatellite instability (MSI) and KRAS mutations in stage II and stage III colon carcinoma. PATIENTS AND METHODS Stage II colon carcinoma patients (n = 106) treated with surgery only and 258 stage III patients all adjuvantly treated with 5-fluorouracil chemotherapy were included. KRAS mutations in codons 12 and 13, V600E BRAF mutation and MSI status were determined. RESULTS Older patients (P < 0.001), right-sided (P = 0.018), better differentiated (P = 0.003) and MSI tumors (P < 0.001) were significantly more frequent in stage II than stage III. In both groups, there was a positive association between mutated BRAF and MSI (P = 0.001) and BRAF mutation and right-sided tumors (P = 0.001). Mutations in BRAF and KRAS were mutually exclusive. In a multivariate survival analysis with pooled stage II and stage III data, BRAF mutation was an independent prognostic factor for overall survival (OS) and cancer-specific survival [hazards ratio (HR) = 0.45, 95% confidence interval (CI) 0.25-0.8 for OS and HR = 0.47, 95% CI 0.22-0.99]. KRAS mutation conferred a poorer disease-free survival (HR = 0.6, 95% CI 0.38-0.97). CONCLUSIONS The V600E BRAF mutation confers a worse prognosis to stage II and stage III colon cancer patients independently of disease stage and therapy.

Patterns of Recurrence After Surgery Alone Versus Preoperative Chemoradiotherapy and Surgery in the CROSS Trials

PURPOSE To analyze recurrence patterns in patients with cancer of the esophagus or gastroesophageal junction treated with either preoperative chemoradiotherapy (CRT) plus surgery or surgery alone. PATIENTS AND METHODS Recurrence pattern was analyzed in patients from the previously published CROSS I and II trials in relation to radiation target volumes. CRT consisted of five weekly courses of paclitaxel and carboplatin combined with a concurrent radiation dose of 41.4 Gy in 1.8-Gy fractions to the tumor and pathologic lymph nodes with margin. RESULTS Of the 422 patients included from 2001 to 2008, 418 were available for analysis. Histology was mostly adenocarcinoma (75%). Of the 374 patients who underwent resection, 86% were allocated to surgery and 92% to CRT plus surgery. On January 1, 2011, after a minimum follow-up of 24 months (median, 45 months), the overall recurrence rate in the surgery arm was 58% versus 35% in the CRT plus surgery arm. Preoperative CRT reduced locoregional recurrence (LRR) from 34% to 14% (P < .001) and peritoneal carcinomatosis from 14% to 4% (P < .001). There was a small but significant effect on hematogenous dissemination in favor of the CRT group (35% v 29%; P = .025). LRR occurred in 5% within the target volume, in 2% in the margins, and in 6% outside the radiation target volume. In 1%, the exact site in relation to the target volume was unclear. Only 1% had an isolated infield recurrence after CRT plus surgery. CONCLUSION Preoperative CRT in patients with esophageal cancer reduced LRR and peritoneal carcinomatosis. Recurrence within the radiation target volume occurred in only 5%, mostly combined with outfield failures.

Total mesorectal excision (TME) with or without preoperative radiotherapy in the treatment of primary rectal cancer. Prostpective randomsied trial with standard operative and histopathological techniques. Dutch Colorectal Cancer Group.

OBJECTIVE To document local recurrence in primary rectal cancer when standardised techniques of surgery, radiotherapy, and pathology are used, and to investigate whether the local recurrence rate after total mesorectal excision permits the omission of adjuvant short term preoperative radiotherapy. DESIGN Prospective randomised study. SETTING Dutch (n = 80), English (n = 1), German (n = 1), Swedish (n = 9), and Swiss (n = 1) hospitals. SUBJECTS The first 500 randomised Dutch patients with primary rectal cancer. MAIN OUTCOME MEASURES Local recurrence, survival, operation-related factors, specific pathological tumour characteristics, short and long term morbidity, and quality of life. RESULTS Between January 1996 and April 1998, 871 Dutch and 94 other patients were randomised. Our feasibility analysis shows that cooperation between and within the participating disciplines goes well. With regard to the surgical part, this can be confirmed by the large number of operations attended by consultant surgeons (58%). The number of abdominoperineal resections appeared to be low (30%), as did the percentage of lateral margins involved (13%). The rate of adverse effects of radiotherapy was acceptable. Apart from a larger operative blood loss and a higher infective complication rate in the irradiated group, no significant differences were found with regard to morbidity and mortality between the randomised groups. CONCLUSIONS The accrual of our trial is going well and it is feasible; short term preoperative radiotherapy is safe even in combination with TME.

Adjuvant chemotherapy for rectal cancer patients treated with preoperative (chemo)radiotherapy and total mesorectal excision: a Dutch Colorectal Cancer Group (DCCG) randomized phase III trial

BACKGROUND The discussion on the role of adjuvant chemotherapy for rectal cancer patients treated according to current guidelines is still ongoing. A multicentre, randomized phase III trial, PROCTOR-SCRIPT, was conducted to compare adjuvant chemotherapy with observation for rectal cancer patients treated with preoperative (chemo)radiotherapy and total mesorectal excision (TME). PATIENTS AND METHODS The PROCTOR-SCRIPT trial recruited patients from 52 hospitals. Patients with histologically proven stage II or III rectal adenocarcinoma were randomly assigned (1:1) to observation or adjuvant chemotherapy after preoperative (chemo)radiotherapy and TME. Radiotherapy consisted of 5 × 5 Gy. Chemoradiotherapy consisted of 25 × 1.8-2 Gy combined with 5-FU-based chemotherapy. Adjuvant chemotherapy consisted of 5-FU/LV (PROCTOR) or eight courses capecitabine (SCRIPT). Randomization was based on permuted blocks of six, stratified according to centre, residual tumour, time between last irradiation and surgery, and preoperative treatment. The primary end point was overall survival. RESULTS Of 470 enrolled patients, 437 were eligible. The trial closed prematurely because of slow patient accrual. Patients were randomly assigned to observation (n = 221) or adjuvant chemotherapy (n = 216). After a median follow-up of 5.0 years, 5-year overall survival was 79.2% in the observation group and 80.4% in the chemotherapy group [hazard ratio (HR) 0.93, 95% confidence interval (CI) 0.62-1.39; P = 0.73]. The HR for disease-free survival was 0.80 (95% CI 0.60-1.07; P = 0.13). Five-year cumulative incidence for locoregional recurrences was 7.8% in both groups. Five-year cumulative incidence for distant recurrences was 38.5% and 34.7%, respectively (P = 0.39). CONCLUSION The PROCTOR-SCRIPT trial could not demonstrate a significant benefit of adjuvant chemotherapy with fluoropyrimidine monotherapy after preoperative (chemo)radiotherapy and TME on overall survival, disease-free survival, and recurrence rate. However, this trial did not complete planned accrual. REGISTRATION NUMBER Dutch Colorectal Cancer group, CKTO 2003-16, ISRCTN36266738.

Total mesorectal excision (TME) with or without preoperative radiotherapy in the treatment of primary rectal cancer

OBJECTIVE To document local recurrence in primary rectal cancer when standardised techniques of surgery, radiotherapy, and pathology are used, and to investigate whether the local recurrence rate after total mesorectal excision permits the omission of adjuvant short term preoperative radiotherapy. DESIGN Prospective randomised study. SETTING Dutch (n = 80), English (n = 1), German (n = 1), Swedish (n = 9), and Swiss (n = 1) hospitals. SUBJECTS The first 500 randomised Dutch patients with primary rectal cancer. MAIN OUTCOME MEASURES Local recurrence, survival, operation-related factors, specific pathological tumour characteristics, short and long term morbidity, and quality of life. RESULTS Between January 1996 and April 1998, 871 Dutch and 94 other patients were randomised. Our feasibility analysis shows that cooperation between and within the participating disciplines goes well. With regard to the surgical part, this can be confirmed by the large number of operations attended by consultant surgeons (58%). The number of abdominoperineal resections appeared to be low (30%), as did the percentage of lateral margins involved (13%). The rate of adverse effects of radiotherapy was acceptable. Apart from a larger operative blood loss and a higher infective complication rate in the irradiated group, no significant differences were found with regard to morbidity and mortality between the randomised groups. CONCLUSIONS The accrual of our trial is going well and it is feasible; short term preoperative radiotherapy is safe even in combination with TME.

HEPATIC RESECTIONS FOR COLORECTAL METASTASES IN THE NETHERLANDS - A MULTIINSTITUTIONAL 10-YEAR STUDY

Background and Methods. The records of 118 patients who had hepatic resections for colorectal liver metastases were analyzed retrospectively.

Evaluation of short-course radiotherapy followed by neoadjuvant bevacizumab, capecitabine, and oxaliplatin and subsequent radical surgical treatment in primary stage IV rectal cancer

BACKGROUND To evaluate the efficacy and tolerability of preoperative short-course radiotherapy followed by capecitabine and oxaliplatin treatment in combination with bevacizumab and subsequent radical surgical treatment of all tumor sites in patients with stage IV rectal cancer. PATIENTS AND METHODS Adults with primary metastasized rectal cancer were enrolled. They received radiotherapy (5 × 5 Gy) followed by bevacizumab (7.5 mg/kg, day 1) and oxaliplatin (130 mg/m2, day 1) intravenously and capecitabine (1000 mg/m2 twice daily orally, days 1-14) for up to six cycles. Surgery was carried out 6-8 weeks after the last bevacizumab dose. The percentage of radical surgical treatment, 2-year survival and recurrence rates, and treatment-related toxicity was evaluated. RESULTS Of 50 included patients, 42 (84%) had liver metastases, 5 (10%) lung metastases, and 3 (6%) both liver and lung metastases. Radical surgical treatment was possible in 36 (72%) patients. The 2-year overall survival rate was 80% [95% confidence interval (CI) 66.3%-90.0%]. The 2-year recurrence rate was 64% (95% CI 49.8%-84.5%). Toxic effects were tolerable. No treatment-related deaths occurred. CONCLUSIONS Radical surgical treatment of all tumor sites carried out after short-course radiotherapy, and bevacizumab-capecitabine-oxaliplatin combination therapy is a feasible and potentially curative approach in primary metastasized rectal cancer.BACKGROUND To evaluate the efficacy and tolerability of preoperative short-course radiotherapy followed by capecitabine and oxaliplatin treatment in combination with bevacizumab and subsequent radical surgical treatment of all tumor sites in patients with stage IV rectal cancer. PATIENTS AND METHODS Adults with primary metastasized rectal cancer were enrolled. They received radiotherapy (5 × 5 Gy) followed by bevacizumab (7.5 mg/kg, day 1) and oxaliplatin (130 mg/m(2), day 1) intravenously and capecitabine (1000 mg/m(2) twice daily orally, days 1-14) for up to six cycles. Surgery was carried out 6-8 weeks after the last bevacizumab dose. The percentage of radical surgical treatment, 2-year survival and recurrence rates, and treatment-related toxicity was evaluated. RESULTS Of 50 included patients, 42 (84%) had liver metastases, 5 (10%) lung metastases, and 3 (6%) both liver and lung metastases. Radical surgical treatment was possible in 36 (72%) patients. The 2-year overall survival rate was 80% [95% confidence interval (CI) 66.3%-90.0%]. The 2-year recurrence rate was 64% (95% CI 49.8%-84.5%). Toxic effects were tolerable. No treatment-related deaths occurred. CONCLUSIONS Radical surgical treatment of all tumor sites carried out after short-course radiotherapy, and bevacizumab-capecitabine-oxaliplatin combination therapy is a feasible and potentially curative approach in primary metastasized rectal cancer.

Population-based survival of patients with peritoneal carcinomatosis from colorectal origin in the era of increasing use of palliative chemotherapy

BACKGROUND Palliative chemotherapy improves survival in patients with metastasised colorectal cancer. However, there is a lack of data regarding the effectiveness of modern chemotherapy in patients with isolated peritoneal carcinomatosis (PC). PATIENTS AND METHODS All patients with synchronous PC of colorectal origin diagnosed in the Eindhoven Cancer Registry registration area between 1995 and 2008 were included (N = 904). We assessed the use of chemotherapy and overall survival in three time periods related to the availability of different chemotherapy regimens. RESULTS Chemotherapy use gradually increased over time. Median survival (MS) for patients with PC without other metastases diagnosed in 1995-2000 was 35 weeks [95% confidence interval (CI) 24-43] and 34 weeks (25-54) in 2005-2008. MS in patients diagnosed with PC plus other metastases was 21 weeks (15-27) in 1995-2000 and 26 weeks (18-33) in 2005-2008. In multivariable regression analysis, use of chemotherapy had a beneficial influence on survival only in 2005-2008. In the first two periods, chemotherapy treatment did not decrease the risk for death. CONCLUSION Despite increasing usage of palliative chemotherapy and availability of new agents, population-based survival of patients with PC did not improve until very recently. Response to palliative chemotherapy in PC should be evaluated separately from haematogenous metastases.

Localization of non-palpable breast cancer using a radiolabelled titanium seed.

Resection guided by a radiologically placed hookwire is the most common surgical technique for non‐palpable breast cancer. This technique has several well described disadvantages such as incidental migration, kinking or fracture of the wire, and difficult logistics between the radiology, surgical and nuclear medicine departments. Use of an iodine‐125‐radiolabelled (I‐125) seed for localization of non‐palpable breast tumours could potentially prevent these problems.

Quality of life of older rectal cancer patients is not impaired by a permanent stoma

BACKGROUND The current study was undertaken to investigate the impact of a stoma on the HRQL with a special focus on age. MATERIALS AND METHODS Using the Eindhoven Cancer Registry, rectal cancer patients diagnosed between 1998 and 2007 in 4 hospitals were identified. All patients underwent TME surgery. Survivors were approached to complete the SF-36 and EORTC QLQ-C38 questionnaires. HRQL scores of the four groups, stratified by stoma status (stoma/no stoma) and age at operation (<70 and ≥ 70), were compared. The SF-36 and the QLQ-CR38 sexuality subscale scores of the survivors were compared with an age- and sex-matched Dutch norm population. RESULTS Median follow-up of 143 patients was 3.4 years. Elderly had significantly worse physical function (p = 0.0003) compared to younger patients. Elderly (p = 0.005) and patients without a stoma (p = 0.009) had worse sexual functioning compared to younger patients and patients with a stoma. Older males showed more sexual dysfunction (p = 0.01) when compared to younger males. In comparison with the normative population, elderly with a stoma had worse physical function (p < 0.01), but slightly better mental health (p < 0.05). Elderly without a stoma had better emotional role function (p < 0.01), and younger patients had worse sexual functioning and enjoyment (both p < 0.0001). CONCLUSIONS Older patients with a stoma have comparable HRQL to older patients without a stoma or the normative population, indicating the feasibility of a permanent stoma for elderly patients with a low situated rectal carcinoma. The negative impact of treatment on sexual functioning as found in the current study calls for further attention to alleviate this problem in sexually active patients.