Adjuvant Hyperthermic Intraperitoneal Chemotherapy in Patients With Locally Advanced Colon Cancer (COLOPEC): 5-Year Results of a Randomized Multicenter Trial.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.Whether adjuvant hyperthermic intraperitoneal chemotherapy (HIPEC) might prevent peritoneal metastases after curative surgery for high-risk colon cancer is an ongoing debate. This study aimed to determine 5-year oncologic outcomes of the randomized multicenter COLOPEC trial, which included patients with clinical or pathologic T4N0-2M0 or perforated colon cancer and randomly assigned (1:1) to either adjuvant systemic chemotherapy and HIPEC (n = 100) or adjuvant systemic chemotherapy alone (n = 102). HIPEC was performed using a one-time administration of oxaliplatin (460 mg/m2, 30 minutes, 42°C, concurrent fluorouracil/leucovorin intravenously), either simultaneously (9%) or within 5-8 weeks (91%) after primary tumor resection. Outcomes were analyzed according to the intention-to-treat principle. Long-term data were available of all 202 patients included in the COLOPEC trial, with a median follow-up of 59 months (IQR, 54.5-64.5). No significant difference was found in 5-year overall survival rate between patients assigned to adjuvant HIPEC followed by systemic chemotherapy or only adjuvant systemic chemotherapy (69.6% v 70.9%, log-rank; P = .692). Five-year peritoneal metastases rates were 63.9% and 63.2% (P = .907) and 5-year disease-free survival was 55.7% and 52.3% (log-rank; P = .875), respectively. No differences in quality-of-life outcomes were found. Our findings implicate that adjuvant HIPEC should still be performed in trial setting only.

Perioperative Systemic Therapy vs Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy Alone for Resectable Colorectal Peritoneal Metastases: A Phase 2 Randomized Clinical Trial.

Importance: To date, no randomized clinical trials have investigated perioperative systemic therapy relative to cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) alone for resectable colorectal peritoneal metastases (CPM). Objective: To assess the feasibility and safety of perioperative systemic therapy in patients with resectable CPM and the response of CPM to neoadjuvant treatment. Design, Setting, and Participants: An open-label, parallel-group phase 2 randomized clinical trial in all 9 Dutch tertiary centers for the surgical treatment of CPM enrolled participants between June 15, 2017, and January 9, 2019. Participants were patients with pathologically proven isolated resectable CPM who did not receive systemic therapy within 6 months before enrollment. Interventions: Randomization to perioperative systemic therapy or CRS-HIPEC alone. Perioperative systemic therapy comprised either four 3-week neoadjuvant and adjuvant cycles of CAPOX (capecitabine and oxaliplatin), six 2-week neoadjuvant and adjuvant cycles of FOLFOX (fluorouracil, leucovorin, and oxaliplatin), or six 2-week neoadjuvant cycles of FOLFIRI (fluorouracil, leucovorin, and irinotecan) and either four 3-week adjuvant cycles of capecitabine or six 2-week adjuvant cycles of fluorouracil with leucovorin. Bevacizumab was added to the first 3 (CAPOX) or 4 (FOLFOX/FOLFIRI) neoadjuvant cycles. Main Outcomes and Measures: Proportions of macroscopic complete CRS-HIPEC and Clavien-Dindo grade 3 or higher postoperative morbidity. Key secondary outcomes were centrally assessed rates of objective radiologic and major pathologic response of CPM to neoadjuvant treatment. Analyses were done modified intention-to-treat in patients starting neoadjuvant treatment (experimental arm) or undergoing upfront surgery (control arm). Results: In 79 patients included in the analysis (43 [54%] men; mean [SD] age, 62 [10] years), experimental (n = 37) and control (n = 42) arms did not differ significantly regarding the proportions of macroscopic complete CRS-HIPEC (33 of 37 [89%] vs 36 of 42 [86%] patients; risk ratio, 1.04; 95% CI, 0.88-1.23; P = .74) and Clavien-Dindo grade 3 or higher postoperative morbidity (8 of 37 [22%] vs 14 of 42 [33%] patients; risk ratio, 0.65; 95% CI, 0.31-1.37; P = .25). No treatment-related deaths occurred. Objective radiologic and major pathologic response rates of CPM to neoadjuvant treatment were 28% (9 of 32 evaluable patients) and 38% (13 of 34 evaluable patients), respectively. Conclusions and Relevance: In this randomized phase 2 trial in patients diagnosed with resectable CPM, perioperative systemic therapy seemed feasible, safe, and able to induce response of CPM, justifying a phase 3 trial. Trial Registration: ClinicalTrials.gov Identifier: NCT02758951.

Comparing Conventional Chemotherapy to Chronomodulated Chemotherapy for Cancer Treatment: Protocol for a Systematic Review.

BACKGROUND: Chronomodulated chemotherapy aims to achieve maximum drug safety and efficacy by adjusting the time of treatment to an optimal biological time as determined by the circadian clock. Although it is a promising alternative to conventional (non-time-stipulated) chemotherapy in several instances, the lack of scientific consensus and the increased logistical burden of timed administration limit the use of a chronomodulated administration protocol. OBJECTIVE: With the goal to increase scientific consensus on this subject, we plan to conduct a systematic review of the current literature to compare the drug safety and efficacy of chronomodulated chemotherapy with those of conventional chemotherapy. METHODS: This systematic review will comply with the PRISMA (Preferred Reporting Items for the Systematic Reviews and Meta-Analysis) guidelines. In order to identify relevant studies, we conducted a comprehensive search in PubMed and Embase on May 18, 2020. We included clinical studies that compare either the safety or efficacy of chronomodulated chemotherapy with that of conventional chemotherapy. Potential studies will be reviewed and screened by 2 independent reviewers. Quality assessment will be performed using the National Institutes of Health's Study Quality Assessment Tool (Quality Assessment of Controlled Intervention Studies). Disagreements will be resolved by consulting a third independent reviewer. RESULTS: This protocol has received funding, and the search for studies from databases commenced on May 18, 2020. The systematic review is planned to be completed by October 31, 2020. CONCLUSIONS: In this systematic review, we will compare drug safety and drug efficacy for cancer patients who were administered either chronomodulated chemotherapy or conventional chemotherapy. Moreover, we will highlight the outcomes and quality of the selected trials for this review. TRIAL REGISTRATION: PROSPERO International Prospective Register of Systematic Reviews CRD42020177878; https://tinyurl.com/y53w9nq6. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/18023.

Adjuvant Systemic Chemotherapy vs Active Surveillance Following Up-front Resection of Isolated Synchronous Colorectal Peritoneal Metastases.

Importance: To date, there are no data on the value of adjuvant systemic chemotherapy following up-front resection of isolated synchronous colorectal peritoneal metastases. Objective: To assess the association between adjuvant systemic chemotherapy and overall survival following up-front resection of isolated synchronous colorectal peritoneal metastases. Design, Setting, and Participants: In this population-based, observational cohort study using nationwide data from the Netherlands Cancer Registry (diagnoses between January 1, 2005, and December 31, 2017; follow-up until January 31, 2019), 393 patients with isolated synchronous colorectal peritoneal metastases who were alive 3 months after up-front complete cytoreductive surgery with hyperthermic intraperitoneal chemotherapy were included. Patients allocated to the adjuvant systemic chemotherapy group were matched (1:1) with those allocated to the active surveillance group by propensity scores based on patient-, tumor-, and treatment-level covariates. Exposures: Adjuvant systemic chemotherapy, defined as systemic chemotherapy without targeted therapy, starting within 3 months postoperatively. Main Outcomes and Measures: Overall survival was compared between matched groups using Cox proportional hazards regression analysis adjusted for residual imbalance. A landmark analysis was performed by excluding patients who died within 6 months postoperatively. A sensitivity analysis was performed to adjust for unmeasured confounding by major postoperative morbidity. Results: Of 393 patients (mean [SD] age, 61 [10] years; 181 [46%] men), 172 patients (44%) were allocated to the adjuvant systemic chemotherapy group. After propensity score matching of 142 patients in the adjuvant systemic chemotherapy group with 142 patients in the active surveillance group, adjuvant systemic chemotherapy was associated with improved overall survival compared with active surveillance (median, 39.2 [interquartile range, 21.1-111.1] months vs 24.8 [interquartile range, 15.0-58.4] months; adjusted hazard ratio [aHR], 0.66; 95% CI, 0.49-0.88; P = .006), which remained consistent after excluding patients who died within 6 months postoperatively (aHR, 0.68; 95% CI, 0.50-0.93; P = .02) and after adjustment for major postoperative morbidity (aHR, 0.71; 95% CI, 0.53-0.95). Conclusions and Relevance: Findings of this study suggest that in patients undergoing up-front resection of isolated synchronous colorectal peritoneal metastases, adjuvant systemic chemotherapy appeared to be associated with improved overall survival. Although randomized trials are needed to address the influence of potential residual confounding and allocation bias on this association, results of this study may be used for clinical decision-making in this patient group for whom no data are available.

Estimating adjuvant treatment effects in Stage II colon cancer: Comparing the synthesis of randomized clinical trial data to real-world data.

There is an ongoing discussion regarding the impact of adjuvant chemotherapy in Stage II colon cancer. We therefore estimated adjuvant treatment effect in Stage II colon cancer using pooled disease-free survival (DFS) data from randomized clinical trials (RCT approach) and compared this to real-world data (RWD approach) estimates. First, we estimated the treatment effect in RCTs by (i) searching relevant trials reporting DFS data, (ii) generating patient-level data from reported DFS data and (iii) estimating treatment effect in the patient-level data. Second, the treatment effect was estimated in an observational cohort of 1,947 patients provided by the Netherlands Cancer Registry using three propensity score methods; matching, weighting and stratification. In the RCT approach, patient-level data of 4,489 patients (events: 853) were generated from seven trials which compared two of the following treatment arms: control, 5FU/LV or FOLFOX. A Cox model was used to estimate a hazard ratio (HR) of 0.77 (0.43;1.10) for 5FU/LV vs. control and 0.93 (0.72;1.15) for FOLFOX vs. 5FU/LV. In the RWD approach, HRs for any adjuvant treatment vs. control were 0.95 (0.50;1.80), 0.88 (0.24;3.21) and 1.05 (0.04;2.06) using matching, weighting and stratification, respectively. There was no significant difference with the estimates from the RCT approach (interaction test, p > 0.10). The RCT data suggest a clinically relevant benefit of adjuvant chemotherapy in terms of DFS, but the estimate did not reach statistical significance. Stratified analyses are required to evaluate whether treatment effect differs in specific subgroups.

"I am busy surviving" - Views about physical exercise in older adults scheduled for colorectal cancer surgery.

OBJECTIVE: Seventy percent of patients with colorectal cancer (CRC) are aged 65 years or older. Netherlands Comprehensive Cancer Organization (n.d.) [1] Surgery is an important treatment modality, depending on cancer stage and the resectability of the tumor. Frail older patients are at an increased risk for complications and reduced self-care capacity after surgery. Increasing physical fitness preoperatively (prehabilitation) might improve treatment outcomes, but challenges remain with regard to uptake, attrition, and non-compliance. The objectives of this study were to investigate the barriers, facilitators, and preferences for preoperative exercise programs in older patients scheduled for CRC surgery. METHODS: This was a qualitative study, using in-depth interviews of fifteen patients aged 65 years and older and surgically treated for CRC, thirteen informal care givers (ICs) and nine health care providers (HCPs) with experience in prehabilitation. Data analysis was done through thematic coding analysis. RESULTS: Limited time, not receiving or misunderstanding information, physical ailments, and emotional impact of the diagnosis are barriers to preoperative exercise. Not having physical complaints (Patients, ICs, HCPs), understandable information provided by a physician (Patients, ICs), and low cost programs (ICs, HCPs) facilitate exercise. Exercise should not be too intensive (Patients, ICs) and should be adjusted to personal preferences and be provided close to home (Patients, ICs, HCPs). CONCLUSIONS: To engage frail older adults with CRC in preoperative exercise programs information on exercise should improve. Exercise programs should be easily accessible and take personal preferences, needs and abilities into account.

Adjuvant hyperthermic intraperitoneal chemotherapy in patients with locally advanced colon cancer (COLOPEC): a multicentre, open-label, randomised trial.

BACKGROUND: Nearly a quarter of patients with locally advanced (T4 stage) or perforated colon cancer are at risk of developing peritoneal metastases, often without curative treatment options. We aimed to determine the efficacy of adjuvant hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with locally advanced colon cancer. METHODS: This multicentre, open-label trial was done in nine hospitals that specialised in HIPEC in the Netherlands. Patients with clinical or pathological T4N0-2M0-stage tumours or perforated colon cancer were randomly assigned (1:1), with a web-based randomisation application, before resection of the primary tumour, to adjuvant HIPEC followed by routine adjuvant systemic chemotherapy (experimental group) or to adjuvant systemic chemotherapy alone (control group). Patients were stratified by tumour characteristic (T4 or perforation), age (<65 years or ≥65 years), and surgical approach of the primary tumour resection (laparoscopic or open). Key eligibility criteria included age between 18 and 75 years, adequate clinical condition for HIPEC, and intention to start adjuvant systemic chemotherapy. Patients with metastatic disease were ineligible. Adjuvant HIPEC consisted of fluorouracil (400 mg/m2) and leucovorin (20 mg/m2) delivered intravenously followed by intraperitoneal delivery of oxaliplatin (460 mg/m2) for 30 min at 42°C, delivered simultaneously or within 5-8 weeks after primary tumour resection. In all patients without evidence of recurrent disease at 18 months, a diagnostic laparoscopy was done. The primary endpoint was peritoneal metastasis free-survival at 18 months, measured in the intention-to-treat population, with the Kaplan-Meier method. Adverse events were assessed in all patients who received assigned treatment. This study is registered with ClinicalTrials.gov, number NCT02231086. FINDINGS: Between April 1, 2015, and Feb 20, 2017, 204 patients were randomly assigned to treatment (102 in each group). In the HIPEC group, two patients withdrew consent after randomisation. In this group, 19 (19%) of 100 patients were diagnosed with peritoneal metastases: nine (47%) during surgical exploration preceding intentional adjuvant HIPEC, eight (42%) during routine follow-up, and two (11%) during diagnostic laparoscopy at 18-months. In the control group, 23 (23%) of 102 patients were diagnosed with peritoneal metastases, of whom seven (30%) were diagnosed by laparoscopy at 18-months and 16 during regular follow-up (therefore making them ineligible for diagnostic laparoscopy). In the intention-to-treat analysis (n=202), there was no difference in peritoneal-free survival at 18-months (80·9% [95% CI 73·3-88·5] for the experimental group vs 76·2% [68·0-84·4] for the control group, log-rank one-sided p=0·28). 12 (14%) of 87 patients who received adjuvant HIPEC developed postoperative complications and one (1%) encapsulating peritoneal sclerosis. INTERPRETATION: In patients with T4 or perforated colon cancer, treatment with adjuvant HIPEC with oxaliplatin did not improve peritoneal metastasis-free survival at 18 months. Routine use of adjuvant HIPEC is not advocated on the basis of this trial. FUNDING: Organization for Health Research and Development and the Dutch Cancer Society.

Evaluating the scientific basis of quality indicators in colorectal cancer care: A systematic review.

AIM: In colorectal cancer care, many indicators for assessment and improvement of quality of care are being used. These quality indicators serve as national and international benchmarks to compare health care on hospital and patient level. However, the scientific basis of these indicators is often unclear. Therefore, the aim of this systematic review is to examine reported quality indicators used in multidisciplinary colorectal cancer care and categorise these indicators based on scientific evidence. METHODS: We searched PubMed from 2005 to 2015 for original articles reporting on development, evaluation or validation of quality indicators in colorectal cancer care. Included articles were categorised in consensus-based, evidence-based and validation cohort studies. Extracted quality indicators were divided into structure, process and outcome indicators and grouped per discipline(s) involved. RESULTS: From 1163 studies, 41 articles were included: 12 (29%) consensus-based, 7 (17%) evidence-based and 22 (54%) validation cohort studies. In total, we identified 389 reported quality indicators: consensus-based (n = 349), evidence-based (n = 7) and validation (n = 33), respectively. Of all reported indicators, 45% (n = 186) concerned surgical items. The vast majority were process indicators (n = 315; 81%) and the remaining outcome (n = 57; 15%) or structure measurements (n = 17; 4%). Only 5 indicators were reported in the majority (≥7/12 articles) of consensus-based papers and 7 indicators were successfully validated. CONCLUSIONS: There is an abundance of reported colorectal cancer quality indicators, of which the majority are surgical, consensus-based process measures, which have not been validated in cohort studies. There is a need for international consensus on a limited evidence-based data set of validated quality indicators, with a focus on outcome indicators.

Local Treatment of Unresectable Colorectal Liver Metastases: Results of a Randomized Phase II Trial.

Background: Tumor ablation is often employed for unresectable colorectal liver metastases. However, no survival benefit has ever been demonstrated in prospective randomized studies. Here, we investigate the long-term benefits of such an aggressive approach. Methods: In this randomized phase II trial, 119 patients with unresectable colorectal liver metastases (n < 10 and no extrahepatic disease) received systemic treatment alone or systemic treatment plus aggressive local treatment by radiofrequency ablation ± resection. Previously, we reported that the primary end point (30-month overall survival [OS] > 38%) was met. We now report on long-term OS results. All statistical tests were two-sided. The analyses were according to intention to treat. Results: At a median follow up of 9.7 years, 92 of 119 (77.3%) patients had died: 39 of 60 (65.0%) in the combined modality arm and 53 of 59 (89.8%) in the systemic treatment arm. Almost all patients died of progressive disease (35 patients in the combined modality arm, 49 patients in the systemic treatment arm). There was a statistically significant difference in OS in favor of the combined modality arm (hazard ratio [HR] = 0.58, 95% confidence interval [CI] = 0.38 to 0.88, P = .01). Three-, five-, and eight-year OS were 56.9% (95% CI = 43.3% to 68.5%), 43.1% (95% CI = 30.3% to 55.3%), 35.9% (95% CI = 23.8% to 48.2%), respectively, in the combined modality arm and 55.2% (95% CI = 41.6% to 66.9%), 30.3% (95% CI = 19.0% to 42.4%), 8.9% (95% CI = 3.3% to 18.1%), respectively, in the systemic treatment arm. Median OS was 45.6 months (95% CI = 30.3 to 67.8 months) in the combined modality arm vs 40.5 months (95% CI = 27.5 to 47.7 months) in the systemic treatment arm. Conclusions: This phase II trial is the first randomized study demonstrating that aggressive local treatment can prolong OS in patients with unresectable colorectal liver metastases.

Challenging the dogma of colorectal peritoneal metastases as an untreatable condition: Results of a population-based study.

PURPOSE: To determine the impact of the implementation of novel systemic regimens and locoregional treatment modalities on survival at population level in colorectal cancer (CRC) patients presenting with peritoneal metastases (PMs). METHODS: All consecutive CRC patients with synchronous PM (<3 months) between 1995 and 2014 were extracted from the Eindhoven area of the Netherlands Cancer Registry. Trends in treatment and overall survival were assessed in four time periods. Multivariable regression analysis was used to analyse the impact of systemic and locoregional treatment modalities on survival. RESULTS: A total of 37,036 patients were diagnosed with primary CRC between 1995 and 2014. Synchronous PM was diagnosed in 1,661 patients, of whom 55% had also metastases at other sites (n = 917) and 77% received anticancer therapy (n = 1,273). Treatment with systemic therapy increased from 23% in 1995-1999 to 56% in 2010-2014 (p < 0.0001). Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) was applied since 2005 and increased from 10% in 2005-2009 to 23% in 2010-2014. Surgery for lymphatic or haematogenous metastases increased from 2% to 10% in these periods. Median overall survival of the complete cohort improved from 6.0 months in 1995-2000 to 12.5 months in 2010-2014 (p < 0.0001), with a doubling of survival for both PM alone and PM with other involved sites. The influence of year of diagnosis on survival (hazard ratio, 2010-2014 versus 1995-1999; 0.5, 95% confidence interval: 0.43-0.62; p < 0.0001) disappeared after including systemic therapy and locoregional treatment modalities in subsequent multivariable models. CONCLUSION: CRC patients presenting with PM are increasingly offered a multidisciplinary treatment approach, resulting in an increased overall survival for the entire cohort.

Adjuvant hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with colon cancer at high risk of peritoneal carcinomatosis; the COLOPEC randomized multicentre trial.

BACKGROUND: The peritoneum is the second most common site of recurrence in colorectal cancer. Early detection of peritoneal carcinomatosis (PC) by imaging is difficult. Patients eventually presenting with clinically apparent PC have a poor prognosis. Median survival is only about five months if untreated and the benefit of palliative systemic chemotherapy is limited. Only a quarter of patients are eligible for curative treatment, consisting of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CR/HIPEC). However, the effectiveness depends highly on the extent of disease and the treatment is associated with a considerable complication rate. These clinical problems underline the need for effective adjuvant therapy in high-risk patients to minimize the risk of outgrowth of peritoneal micro metastases. Adjuvant hyperthermic intraperitoneal chemotherapy (HIPEC) seems to be suitable for this purpose. Without the need for cytoreductive surgery, adjuvant HIPEC can be performed with a low complication rate and short hospital stay. METHODS/DESIGN: The aim of this study is to determine the effectiveness of adjuvant HIPEC in preventing the development of PC in patients with colon cancer at high risk of peritoneal recurrence. This study will be performed in the nine Dutch HIPEC centres, starting in April 2015. Eligible for inclusion are patients who underwent curative resection for T4 or intra-abdominally perforated cM0 stage colon cancer. After resection of the primary tumour, 176 patients will be randomized to adjuvant HIPEC followed by routine adjuvant systemic chemotherapy in the experimental arm, or to systemic chemotherapy only in the control arm. Adjuvant HIPEC will be performed simultaneously or shortly after the primary resection. Oxaliplatin will be used as chemotherapeutic agent, for 30 min at 42-43 °C. Just before HIPEC, 5-fluorouracil and leucovorin will be administered intravenously. Primary endpoint is peritoneal disease-free survival at 18 months. Diagnostic laparoscopy will be performed routinely after 18 months postoperatively in both arms of the study in patients without evidence of disease based on routine follow-up using CT imaging and CEA. DISCUSSION: Adjuvant HIPEC is assumed to reduce the expected 25 % absolute risk of PC in patients with T4 or perforated colon cancer to a risk of 10 %. This reduction is likely to translate into a prolonged overall survival. TRIAL REGISTRATION NUMBER: NCT02231086 (Clinicaltrials.gov).

Maintenance treatment with capecitabine and bevacizumab in metastatic colorectal cancer (CAIRO3): a phase 3 randomised controlled trial of the Dutch Colorectal Cancer Group.

BACKGROUND: The optimum duration of first-line treatment with chemotherapy in combination with bevacizumab in patients with metastatic colorectal cancer is unknown. The CAIRO3 study was designed to determine the efficacy of maintenance treatment with capecitabine plus bevacizumab versus observation. METHODS: In this open-label, phase 3, randomised controlled trial, we recruited patients in 64 hospitals in the Netherlands. We included patients older than 18 years with previously untreated metastatic colorectal cancer, with stable disease or better after induction treatment with six 3-weekly cycles of capecitabine, oxaliplatin, and bevacizumab (CAPOX-B), WHO performance status of 0 or 1, and adequate bone marrow, liver, and renal function. Patients were randomly assigned (1:1) to either maintenance treatment with capecitabine and bevacizumab (maintenance group) or observation (observation group). Randomisation was done centrally by minimisation, with stratification according to previous adjuvant chemotherapy, response to induction treatment, WHO performance status, serum lactate dehydrogenase concentration, and treatment centre. Both patients and investigators were aware of treatment assignment. We assessed disease status every 9 weeks. On first progression (defined as PFS1), patients in both groups were to receive the induction regimen of CAPOX-B until second progression (PFS2), which was the study's primary endpoint. All endpoints were calculated from the time of randomisation. Analyses were done by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00442637. FINDINGS: Between May 30, 2007, and Oct 15, 2012, we randomly assigned 558 patients to either the maintenance group (n=279) or the observation group (n=279). Median follow-up was 48 months (IQR 36-57). The primary endpoint of median PFS2 was significantly improved in patients on maintenance treatment, and was 8·5 months in the observation group and 11·7 months in the maintenance group (HR 0·67, 95% CI 0·56-0·81, p<0·0001). This difference remained significant when any treatment after PFS1 was considered. Maintenance treatment was well tolerated, although the incidence of hand-foot syndrome was increased (64 [23%] patients with hand-foot skin reaction during maintenance). The global quality of life did not deteriorate during maintenance treatment and was clinically not different between treatment groups. INTERPRETATION: Maintenance treatment with capecitabine plus bevacizumab after six cycles of CAPOX-B in patients with metastatic colorectal cancer is effective and does not compromise quality of life. FUNDING: Dutch Colorectal Cancer Group (DCCG). The DCCG received financial support for the study from the Commissie Klinische Studies (CKS) of the Dutch Cancer Foundation (KWF), Roche, and Sanofi-Aventis.

Impairment of cognitive functioning during Sunitinib or Sorafenib treatment in cancer patients: a cross sectional study.

BACKGROUND: Impairment of cognitive functioning has been reported in several studies in patients treated with chemotherapy. So far, no studies have been published on the effects of the vascular endothelial growth factor receptor (VEGFR) inhibitors on cognitive functioning. We investigated the objective and subjective cognitive function of patients during treatment with VEGFR tyrosine kinase inhibitors (VEGFR TKI). METHODS: Three groups of participants, matched on age, sex and education, were enrolled; 1. metastatic renal cell cancer (mRCC) or GIST patients treated with sunitinib or sorafenib (VEGFR TKI patients n = 30); 2. patients with mRCC not receiving systemic treatment (patient controls n = 20); 3. healthy controls (n = 30). Sixteen neuropsychological tests examining the main cognitive domains (intelligence, memory, attention and concentration, executive functions and abstract reasoning) were administered by a neuropsychologist. Four questionnaires were used to assess subjective cognitive complaints, mood, fatigue and psychological wellbeing. RESULTS: No significant differences in mean age, sex distribution, education level or IQ were found between the three groups. Both patient groups performed significantly worse on the cognitive domains Learning & Memory and Executive Functions (Response Generation and Problem Solving) compared to healthy controls. However only the VEGFR TKI patients showed impairments on the Executive subdomain Response Generation. Effect sizes of cognitive dysfunction in patients using VEGFR TKI were larger on the domains Learning & Memory and Executive Functions, compared to patient controls. Both patients groups performed on the domain Attention & Concentration the same as the healthy controls. Longer duration of treatment on VEGFR TKI was associated with a worse score on Working Memory tasks. CONCLUSIONS: Our data suggest that treatment with VEGFR TKI has a negative impact on cognitive functioning, specifically on Learning & Memory, and Executive Functioning. We propose that patients who are treated with VEGFR TKI are monitored and informed for possible signs or symptoms associated with cognitive impairment. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01246843.

Adjuvant chemotherapy in stage III colon cancer: guideline implementation, patterns of use and outcomes in daily practice in The Netherlands.

BACKGROUND: Little is known about how well guidelines about adjuvant chemotherapy in colon cancer are followed in daily practice. We evaluated the current guideline, which is based on the MOSAIC trial, by examining implementation, treatment patterns and disease-free survival. MATERIAL AND METHODS: We analysed a population-based cohort of 391 patients treated with adjuvant chemotherapy for stage III colon cancer in 2005-2006. Data were gathered from the Dutch Cancer Registry and medical records of 19 hospitals. Patients were classified according to whether or not they fulfilled MOSAIC trial eligibility criteria. RESULTS: The administered regimens were: fluorouracil-leucovorin (17 patients), capecitabine (93), fluorouracil-leucovorin plus oxaliplatin (145), and capecitabine plus oxaliplatin (136). After its inclusion in national guidelines, oxaliplatin was prescribed in 16 hospitals within six months. Patients receiving oxaliplatin were younger and had less comorbidity than other patients. Dose schedules corresponded well with guidelines. Two-year disease-free survival probability of oxaliplatin patients meeting MOSAIC eligibility criteria was 78.4% (95% CI 72.5-84.3), which was comparable to MOSAIC trial results. CONCLUSION: Guidelines for adjuvant chemotherapy in stage III colon cancer are generally well followed in daily practice. However, uncertainty remains regarding the optimal treatment of elderly patients and patients with comorbidities, which underscores the need for practical clinical trials including these patients.

Influence of body mass index on outcome in advanced colorectal cancer patients receiving chemotherapy with or without targeted therapy.

PURPOSE: Obesity is associated with an increased risk of development and recurrence of colorectal cancer. However, the role of obesity in advanced colorectal cancer (ACC) patients is unknown. We investigated the effect of body mass index (BMI) on overall survival (OS) in ACC patients receiving systemic treatment in two large phase III studies (CAIRO and CAIRO2). PATIENTS AND METHODS: Treatment data were obtained and analysed from 796 ACC patients who were treated with chemotherapy in the CAIRO study, and from 730 ACC patients who were treated with chemotherapy plus targeted therapy in the CAIRO2 study. Baseline height and weight were used to assign patients to one of the following BMI categories: A (<18.5 kg/m(2)), B (18.5-24.9 kg/m(2)), C (25.0-29.9 kg/m(2)) and D (≥30.0 kg/m(2)). RESULTS: In 796 patients of the CAIRO study a high BMI was associated with better median OS (8.0, 14.9, 18.4 and 19.5 months for BMI categories A, B, C, and D, respectively; P=0.001), and was an independent prognostic factor for OS in a multivariate analysis. BMI was not associated with OS in 730 patients who participated in the CAIRO2 study, although a trend was observed. CONCLUSIONS: These results show that BMI is an independent prognostic factor for survival in patients receiving chemotherapy, but not in patients receiving chemotherapy and targeted therapy. The possible decreased efficacy of bevacizumab in obese patients may explain this discrepant result. The role of BMI in patients receiving targeted therapy should be further tested.

Cancer patients treated with sunitinib or sorafenib have sufficient antibody and cellular immune responses to warrant influenza vaccination.

PURPOSE: The tyrosine kinase inhibitors sorafenib and sunitinib have efficacy in several types of cancer. Recent studies indicate that these agents affect the immune system. The way it affects the immune response to influenza vaccination is unknown. The aim of this study was to elucidate the specific immune response to seasonal flu vaccination in cancer patients treated with sunitinib or sorafenib. PATIENTS AND METHODS: Sunitinib- or sorafenib-treated cancer patients were vaccinated against seasonal influenza with an inactivated vaccine. Healthy controls and patients with metastatic renal cell cancer (mRCC) without systemic treatment (nontreated mRCC controls) were included for comparison. Antibody responses were measured at baseline, day 8, and day 22 by a standard hemagglutination inhibition assay and cellular T-cell responses at baseline and day 8 by proliferation assay and secretion of cytokines. RESULTS: Forty subjects were enrolled: 16 patients treated with sunitinib, 6 patients with sorafenib, 7 nontreated mRCC controls, and 11 healthy controls. All patients treated with sunitinib and sorafenib developed seroprotection rates comparable with controls. Functional T-cell reactivity was observed in all groups, except for patients treated with sorafenib who showed a decreased proliferation rate and IFN-γ/IL-2 production and increased IL-10 compared with healthy controls. CONCLUSION: We conclude that influenza vaccination should be recommended to cancer patients treated with sunitinib or sorafenib.

Randomized phase III study of panitumumab with fluorouracil, leucovorin, and irinotecan (FOLFIRI) compared with FOLFIRI alone as second-line treatment in patients with metastatic colorectal cancer.

PURPOSE: Panitumumab is a fully human anti-epidermal growth factor receptor (EGFR) monoclonal antibody that improves progression-free survival (PFS) in chemotherapy-refractory metastatic colorectal cancer (mCRC). This trial evaluated the efficacy and safety of panitumumab plus fluorouracil, leucovorin, and irinotecan (FOLFIRI) compared with FOLFIRI alone after failure of initial treatment for mCRC by tumor KRAS status. PATIENTS AND METHODS: Patients with mCRC, one prior chemotherapy regimen for mCRC, Eastern Cooperative Oncology Group performance status 0 to 2, and available tumor tissue for biomarker testing were randomly assigned 1:1 to panitumumab 6.0 mg/kg plus FOLFIRI versus FOLFIRI every 2 weeks. The coprimary end points of PFS and overall survival (OS) were independently tested and prospectively analyzed by KRAS status. RESULTS: From June 2006 to March 2008, 1,186 patients were randomly assigned 1:1 and received treatment. KRAS status was available for 91% of patients: 597 (55%) with wild-type (WT) KRAS tumors, and 486 (45%) with mutant (MT) KRAS tumors. In the WT KRAS subpopulation, when panitumumab was added to chemotherapy, a significant improvement in PFS was observed (hazard ratio [HR] = 0.73; 95% CI, 0.59 to 0.90; P = .004); median PFS was 5.9 months for panitumumab-FOLFIRI versus 3.9 months for FOLFIRI. A nonsignificant trend toward increased OS was observed; median OS was 14.5 months versus 12.5 months, respectively (HR = 0.85, 95% CI, 0.70 to 1.04; P = .12); response rate was improved to 35% versus 10% with the addition of panitumumab. In patients with MT KRAS, there was no difference in efficacy. Adverse event rates were generally comparable across arms with the exception of known toxicities associated with anti-EGFR therapy. CONCLUSION: Panitumumab plus FOLFIRI significantly improved PFS and is well-tolerated as second-line treatment in patients with WT KRAS mCRC.

Commonly used prophylactic vaccines as an alternative for synthetically produced TLR ligands to mature monocyte-derived dendritic cells.

Currently dendritic cell (DC)-based vaccines are explored in clinical trials, predominantly in cancer patients. Murine studies showed that only maturation with Toll-like receptor (TLR) ligands generates mature DCs that produce interleukin-12 and promote optimal T-cell help. Unfortunately, the limited availability of clinical-grade TLR ligands significantly hampers the translation of these findings into DC-based vaccines. Therefore, we explored 15 commonly used preventive vaccines as a possible source of TLR ligands. We have identified a cocktail of the vaccines BCG-SSI, Influvac, and Typhim that contains TLR ligands and is capable of optimally maturing DCs. These DCs (vaccine DCs) showed high expression of CD80, CD86, and CD83 and secreted interleukin-12. Although vaccine DCs exhibited an impaired migratory capacity, this could be restored by addition of prostaglandin E(2) (PGE(2); vaccine PGE(2) DCs). Vaccine PGE(2) DCs are potent inducers of T-cell proliferation and induce Th1 polarization. In addition, vaccine PGE(2) DCs are potent inducers of tumor antigen-specific CD8(+) effector T cells. Finally, vaccine PGE(2)-induced DC maturation is compatible with different antigen-loading strategies, including RNA electroporation. These data thus identify a new clinical application for a mixture of commonly used preventive vaccines in the generation of Th1-inducing clinical-grade mature DCs.

Systemic treatment of advanced colorectal carcinoma.

For advanced colorectal cancer (ACC), 5-fluorouracil (5-FU) based chemotherapy has been the standard for some decades. Attempts have been made to improve its results by biochemical modulation and schedule modulation of 5-FU which, in combination with leucovorin (LV), has been regarded as standard chemotherapy for almost two decades. The oral preparations capecitabine and uracil+ftorafur combined with LV may be regarded as a useful alternative to 5-FU/LV for the first line treatment of ACC. Irinotecan is widely accepted as the standard second line treatment Oxaliplatin + 5-FU/LV has been used in the neo-adjuvant setting in patients with initially irresectable liver metastasis. Both irinotecan and oxaliplatin + 5-FU/LV are also used in first line treatment However, it is still an open question whether the concomitant use of irinotecan or oxaliplatin with 5-FU/LV is really superior to the sequential use of these drugs. In patients with ACC anecdotal responses have been documented in small-scale studies with different types of cancer vaccines, either alone, or in combination as radioimmunotherapy. Favourable results were reported for the monoclonal antibody C225 (cetuximab) against the epidermal growth factor receptor in patients with ACC refractory to irinotecan. Vascular endothelial growth factor (VEGF) is an important angiogenic factor in colorectal cancer and is a marker for poor prognosis. Preliminary results of treatment with anti-VEGF antibody in combination with 5-FU/LV have shown encouraging results.