Geert-Jan Creemers

Sequential versus combination chemotherapy with capecitabine, irinotecan, and oxaliplatin in advanced colorectal cancer (CAIRO): a phase III randomised controlled trial

BACKGROUND The optimum use of cytotoxic drugs for advanced colorectal cancer has not been defined. Our aim was to investigate whether combination treatment is better than sequential administration of the same drugs in patients with advanced colorectal cancer. METHODS We randomly assigned 820 patients with advanced colorectal cancer to receive either first-line treatment with capecitabine, second-line irinotecan, and third-line capecitabine plus oxaliplatin (sequential treatment; n=410) or first-line treatment capecitabine plus irinotecan and second-line capecitabine plus oxaliplatin (combination treatment; n=410). The primary endpoint was overall survival. Analyses were done by intention to treat. This trial is registered with ClinicalTrials.gov with the number NCT00312000. FINDINGS 17 patients (nine in the sequential treatment group, eight in the combination group) were found to be ineligible and were excluded from the analysis. 675 (84%) patients died during the study: 336 in the sequential group and 339 in the combination group. Median overall survival was 16.3 (95% CI 14.3-18.1) months for sequential treatment and 17.4 (15.2-19.2) months for combination treatment (p=0.3281). The hazard ratio for combination versus sequential treatment was 0.92 (95% CI 0.79-1.08; p=0.3281). The frequency of grade 3-4 toxicity over all lines of treatment did not differ significantly between the two groups, except for grade 3 hand-foot syndrome, which occurred more often with sequential treatment than with combination treatment (13%vs 7%; p=0.004). INTERPRETATION Combination treatment does not significantly improve overall survival compared with the sequential use of cytotoxic drugs in advanced colorectal cancer. Thus sequential treatment remains a valid option for patients with advanced colorectal cancer.

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 studys 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.

Circulating tumour cells early predict progression-free and overall survival in advanced colorectal cancer patients treated with chemotherapy and targeted agents

BACKGROUND Early predictive markers for response are needed for advanced colorectal cancer (ACC) patients. We assessed the value of circulating tumour cells (CTC) in ACC patients treated with chemotherapy plus targeted agents (CAIRO2 phase III trial) and compared the results with computed tomography (CT) imaging. MATERIALS AND METHODS CTC were determined at baseline and at different time points during treatment. Patients were stratified into low (less than three CTC per 7.5 ml of blood) or high CTC (three or more CTC per 7.5 ml of blood). RESULTS A total of 467 patients were assessable for CTC analysis. Among them, 129 patients (29%) with high baseline CTC had a significantly decreased progression-free survival [PFS; hazard ratio (HR) 1.5] and overall survival (OS; HR 2.2) compared with 322 patients with low baseline CTC. This difference remained statistically significant during treatment. The sensitivity and specificity of high CTC at baseline for the prediction of progressive disease on CT imaging were 16.7% and 70.1%, respectively, and of high CTC at 1-2 weeks after the start of treatment 20.0% and 95.1%, respectively. The combined analysis of CTC and CT imaging provided a more accurate outcome assessment than either modality alone. CONCLUSIONS The CTC count before and during treatment independently predicts PFS and OS in ACC patients treated with chemotherapy plus targeted agents and provides additional information to CT imaging.

Randomized phase II study comparing efficacy and safety of combination-therapy trastuzumab and docetaxel vs. sequential therapy of trastuzumab followed by docetaxel alone at progression as first-line chemotherapy in patients with HER2+ metastatic breast cancer: HERTAX trial.

BACKGROUND Because chemotherapy for metastatic breast cancer (MBC) is associated with relevant toxicity, sequential monotherapy trastuzumab followed by cytotoxic therapy at disease progression might be an attractive approach. METHODS In a multicenter phase II trial, 101 patients with overexpression of human epidermal growth factor receptor 2 (HER2(+)) MBC were randomized between combination-therapy trastuzumab (Herceptin) plus docetaxel (H+D) and sequential therapy of single-agent trastuzumab followed at disease progression by docetaxel alone (H→D) as first-line chemotherapy for metastatic disease. The primary endpoint was progression-free survival (PFS) after completed sequential or combination therapy. RESULTS For the H+D group the median PFS was 9.4 vs. 9.9 months for the H→D group and 1-year PFS rates were 44% vs. 35%, respectively. However the overall response rates (ORRs) were 79% vs. 53%, respectively (P = .016), and overall survival was 30.5 vs. 19.7 months, respectively (P = .11). In the H→D group, response rates to monotherapy trastuzumab and subsequent docetaxel were 34% and 39%, respectively, with a median PFS during single-agent trastuzumab of 3.9 months. The incidence and severity of neuropathy were significantly higher in the H+D group. Retrospective analysis of trastuzumab treatment beyond progression (applied in 46% of patients in the H+D group and 37% in the H→D group) showed a correlation with longer overall survival in both treatment arms (36.0 vs. 18.0 months and 30.3 vs. 18.6 months, respectively). CONCLUSION First-line treatment in patients with MBC with H→D resulted in a similar PFS compared with H+D, but the response rate was lower and the overall survival nonsignificantly shorter.

Patterns of metachronous metastases after curative treatment of colorectal cancer.

BACKGROUND This study aimed to provide information on timing, anatomical location, and predictors for metachronous metastases of colorectal cancer based on a large consecutive series of non-selected patients. METHODS All patients operated on with curative intent for colorectal cancer (TanyNanyM0) between 2003 and 2008 in the Dutch Eindhoven Cancer Registry were included (N=5671). By means of active follow-up by the Cancer Registry staff within ten hospitals, data on development of metastatic disease were collected. Median follow-up was 5.0 years. RESULTS Of the 5671 colorectal cancer patients, 1042 (18%) were diagnosed with metachronous metastases. Most common affected sites were the liver (60%), lungs (39%), extra-regional lymph nodes (22%), and peritoneum (19%). 86% of all metastases was diagnosed within three years and the median time to diagnosis was 17 months (interquartile range 10-29 months). Male gender (HR=1.2, 95%CI 1.03-1.32), an advanced primary T-stage (T4 vs. T3 HR=1.6, 95%CI 1.32-1.90) and N-stage (N1 vs. N0 HR=2.8, 95%CI 2.42-3.30 and N2 vs. N0 HR=4.5, 95%CI 3.72-5.42), high-grade tumour differentiation (HR=1.4, 95%CI 1.17-1.62), and a positive (HR=2.1, 95%CI 1.68-2.71) and unknown (HR=1.7, 95%CI 1.34-2.22) resection margin were predictors for metachronous metastases. CONCLUSIONS Different patterns of metastatic spread were observed for colon and rectal cancer patients and differences in time to diagnosis were found. Knowledge on these patterns and predictors for metachronous metastases may enhance tailor-made follow-up schemes leading to earlier detection of metastasized disease and increased curative treatment options.

Impact of chemotherapy on health status and symptom burden of colon cancer survivors: A population-based study

BACKGROUND This population-based study assessed the impact of chemotherapy on general and disease-specific health status of resected colon cancer survivors up to 10 years post-diagnosis. PATIENTS AND METHODS Colon cancer survivors diagnosed between 1998 and 2007 were selected from the Eindhoven Cancer Registry. Survivors completed the SF-36 and the EORTC colorectal module (EORTC-QLQ-CR38). Comparisons to a normative population were conducted. Multiple linear regression analyses investigated the association between treatment and health status. RESULTS Eight hundred and forty eight survivors were evaluated: 29% had chemotherapy (CT); 71% without chemotherapy (nCT). Survivors had similar SF-36 scores and scored better than the normative population on several domains. On the EORTC-QLQ-CR38, male nCT survivors had more sexual problems than CT survivors (p=0.01). Among the sexually active respondents, the survivors reported sex to be less enjoyable than the normative population (p=0.02). In multivariate analyses, CT predicted better physical function, and less male sexual dysfunction and weight loss problems than nCT. CONCLUSIONS Overall, CT survivors have general health status scores comparable to nCT survivors and the normative population up to 10 years since initial diagnosis. Sex-related problems among survivors suggest more attention on this often sensitive issue is required in clinical management.

Prolonged time to surgery after neoadjuvant chemoradiotherapy increases histopathological response without affecting survival in patients with esophageal or junctional cancer

Objective:To determine the relation between time to surgery (TTS) after neoadjuvant chemoradiotherapy (nCRT) and pathologically complete response (pCR), surgical outcome, and survival in patients with esophageal cancer. Background:Standard treatment for potentially curable esophageal cancer is nCRT plus surgery after 4 to 6 weeks. In rectal cancer patients, evidence suggests that prolonged TTS is associated with a higher pCR rate and possibly with better survival. Methods:We identified patients treated with nCRT plus surgery for esophageal cancer between 2001 and 2011. TTS (last day of radiotherapy to day of surgery) varied mainly for logistical reasons. Minimal follow-up was 24 months. The effect of TTS on pCR rate, postoperative complications, and survival was determined with (ordinal) logistic, linear, and Cox regression, respectively. Results:In total, 325 patients were included. Median TTS was 48 days (p25–p75 = 40–60). After 45 days, TTS was associated with an increased probability of pCR [odds ratio (OR) = 1.35 per additional week of TSS, P = 0.0004] and a small increased risk of postoperative complications (OR = 1.20, P < 0.001). Prolonged TTS had no effect on disease-free and overall survivals (HR = 1.00 and HR = 1.06 per additional week of TSS, P = 0.976 and P = 0.139, respectively). Conclusions:Prolonged TTS after nCRT increases the probability of pCR and is associated with a slightly increased probability of postoperative complications, without affecting disease-free and overall survivals. We conclude that TTS can be safely prolonged from the usual 4 to 6 weeks up to at least 12 weeks, which facilitates a more conservative wait-and-see strategy after neoadjuvant chemoradiotherapy to be tested.

No improvement in median survival for patients with metastatic gastric cancer despite increased use of chemotherapy

BACKGROUND Gastric cancer often presents in a metastasized stage. We conducted a population-based study to evaluate trends in systemic treatment and survival of metastatic noncardia gastric cancer. PATIENTS AND METHODS All patients with noncardia adenocarcinoma of the stomach, diagnosed between 1990 and 2011 in the Eindhoven Cancer Registry area in the Netherlands were included (N = 4797). We conducted multivariable logistic regression analysis to evaluate trends in administration of palliative chemotherapy and multivariable proportional hazards regression analyses to evaluate trends in crude overall survival. RESULTS The proportion of patients presenting with metastatic gastric cancer increased from 24% in 1990 to 44% in 2011 (P < 0.0001). The use of palliative chemotherapy increased, from 5% in 1990 to 36% in 2011, with a strong increase in particular after 2006 (P < 0.0001). Younger patients [<50 years: adjusted odds ratio (ORadj) 3.9, P < 0.001; 50-59 years: ORadj 1.7, P = 0.01] and patients with a high socioeconomic status (ORadj 1.7, P = 0.01) more often received chemotherapy. In contrast, older patients (70-79 years: ORadj 0.3, P < 0.001; 80+ years: ORadj 0.02, P < 0.001), patients with comorbidity (ORadj 0.6, P = 0.03), linitis plastica (ORadj 0.5, P = 0.03) and multiple distant metastases (ORadj 0.5, P = 0.01) were less often treated with chemotherapy. A large hospital variation was observed in the administration of palliative chemotherapy (9%-27%). Median overall survival remained constant between 15 [95% confidence interval (CI) 11.9-17.7] and 17 (95% CI 15.0-20.0) weeks (P = 0.10). CONCLUSIONS The increased administration of chemotherapy in patients with metastatic gastric cancer did not lead to an increase in population-based overall survival. Identification of the subgroup of patients which benefits from palliative chemotherapy is of utmost importance to avoid unnecessary treatment.

The effect of socioeconomic status on staging and treatment decisions in esophageal cancer.

Background: Optimal treatment choice for patients with esophageal cancer (EC) is complex and largely determined by tumor characteristics, comorbidity, and age. Goals: This study describes the role of patient characteristics, among which is socioeconomic status (SES), in EC treatment. Study: Patients diagnosed with primary EC between 1990 and 2008 in the southern part of the Netherlands were identified using the Eindhoven Cancer Registry. Multivariable logistic and proportional hazard regression analyses were used to identify determinants of treatment and survival. Results: We included 1914 patients, and 37% of them underwent intentionally curative treatment. Low-SES patients were diagnosed at older age (16% vs. 9%, age more than or equal to 80) and with more advanced tumor stages (13% vs. 10%, stage T4) than high-SES patients. Age less than 60 compared with 70 to 79 years [adjusted odds ratio, 4.51; 95% confidence interval (CI), 2.98-6.84] and high SES compared with low SES (adjusted odds ratio 1.59; 95% CI, 1.07-2.37) were independent predictors for curative treatment. Probability of death for high-SES patients undergoing palliative treatment was decreased compared with low-SES patients (hazard ratio, 0.84; 95% CI, 0.71-0.99). Conclusions: SES is an important factor in treatment choice of EC. As health care is equally accessible to the whole population in the Netherlands, this suggests that both patient-related and physician-related factors are involved in this phenomenon.

Weekly docetaxel in metastatic breast cancer patients: No superior benefits compared to three-weekly docetaxel

BACKGROUND In anthracycline-pretreated metastatic breast cancer (MBC) patients, it is unknown whether weekly single-agent docetaxel is preferable to 3-weekly docetaxel regarding its toxicity and efficacy profile. PATIENTS AND METHODS In this multicenter, randomised, open-label phase III trial, 162 patients were randomised to weekly docetaxel (group A) or 3-weekly docetaxel (group B). The primary end-point was tolerability; secondary end-points were efficacy and quality of life (QoL). RESULTS Group A (weekly docetaxel, n=79) experienced less haematological toxicity, with just 1.3% versus 16.9% febrile neutropenia in group B (3-weekly docetaxel, n=77) (p=0.001). Not this difference, but fatigue and general malaise foremost led to more patient withdrawals in group A (24 versus 12 patients, p=0.032), less patients completing treatment (29 versus 43 patients, p=0.014) and reduced dose-intensity (15.6 versus 26mg/m(2)/week, 58% versus 70% of projected dose, p=0.017). As a result, 3-weekly docetaxel was related to better overall survival in multivariate analysis (hazard ratio 0.70, p=0.036), although in univariate analysis efficacy was similar in both groups. Reported QoL was similar in both groups, but less effective treatment with more general toxicity led to less completed QoL forms in group A (65.4% versus 50%, p=0.049). CONCLUSION Weekly docetaxel is less well tolerated than a 3-weekly schedule, due to more non-haematological toxicity, despite less febrile neutropenia. Also, no efficacy benefits can be demonstrated for weekly docetaxel, which may even be inferior based on multivariate analysis. Therefore, a 3-weekly schedule should be preferred in the setting of MBC.