Preoperative chemoradiotherapy may improve the radical resection rate for resectable or borderline resectable pancreatic cancer, but the overall benefit is unproven.
In this randomized phase III ...trial in 16 centers, patients with resectable or borderline resectable pancreatic cancer were randomly assigned to receive preoperative chemoradiotherapy, which consisted of 3 courses of gemcitabine, the second combined with 15 × 2.4 Gy radiotherapy, followed by surgery and 4 courses of adjuvant gemcitabine or to immediate surgery and 6 courses of adjuvant gemcitabine. The primary end point was overall survival by intention to treat.
Between April 2013 and July 2017, 246 eligible patients were randomly assigned; 119 were assigned to preoperative chemoradiotherapy and 127 to immediate surgery. Median overall survival by intention to treat was 16.0 months with preoperative chemoradiotherapy and 14.3 months with immediate surgery (hazard ratio, 0.78; 95% CI, 0.58 to 1.05;
= .096). The resection rate was 61% and 72% (
= .058). The R0 resection rate was 71% (51 of 72) in patients who received preoperative chemoradiotherapy and 40% (37 of 92) in patients assigned to immediate surgery (
< .001). Preoperative chemoradiotherapy was associated with significantly better disease-free survival and locoregional failure-free interval as well as with significantly lower rates of pathologic lymph nodes, perineural invasion, and venous invasion. Survival analysis of patients who underwent tumor resection and started adjuvant chemotherapy showed improved survival with preoperative chemoradiotherapy (35.2
19.8 months;
029). The proportion of patients who suffered serious adverse events was 52% versus 41% (
096).
Preoperative chemoradiotherapy for resectable or borderline resectable pancreatic cancer did not show a significant overall survival benefit. Although the outcomes of the secondary end points and predefined subgroup analyses suggest an advantage of the neoadjuvant approach, additional evidence is required.
The benefit of neoadjuvant chemoradiotherapy in resectable and borderline resectable pancreatic cancer remains controversial. Initial results of the PREOPANC trial failed to demonstrate a ...statistically significant overall survival (OS) benefit. The long-term results are reported.
In this multicenter, phase III trial, patients with resectable and borderline resectable pancreatic cancer were randomly assigned (1:1) to neoadjuvant chemoradiotherapy or upfront surgery in 16 Dutch centers. Neoadjuvant chemoradiotherapy consisted of three cycles of gemcitabine combined with 36 Gy radiotherapy in 15 fractions during the second cycle. After restaging, patients underwent surgery followed by four cycles of adjuvant gemcitabine. Patients in the upfront surgery group underwent surgery followed by six cycles of adjuvant gemcitabine. The primary outcome was OS by intention-to-treat. No safety data were collected beyond the initial report of the trial.
Between April 24, 2013, and July 25, 2017, 246 eligible patients were randomly assigned to neoadjuvant chemoradiotherapy (n = 119) and upfront surgery (n = 127). At a median follow-up of 59 months, the OS was better in the neoadjuvant chemoradiotherapy group than in the upfront surgery group (hazard ratio, 0.73; 95% CI, 0.56 to 0.96;
= .025). Although the difference in median survival was only 1.4 months (15.7 months
14.3 months), the 5-year OS rate was 20.5% (95% CI, 14.2 to 29.8) with neoadjuvant chemoradiotherapy and 6.5% (95% CI, 3.1 to 13.7) with upfront surgery. The effect of neoadjuvant chemoradiotherapy was consistent across the prespecified subgroups, including resectable and borderline resectable pancreatic cancer.
Neoadjuvant gemcitabine-based chemoradiotherapy followed by surgery and adjuvant gemcitabine improves OS compared with upfront surgery and adjuvant gemcitabine in resectable and borderline resectable pancreatic cancer.
Children from multi-problem families have an increased risk for experiencing mental health problems. These families face problems in several domains that are often found to be chronic and ...intergenerational. Yet, the effects of mental health care for youths from multi-problem families are small at best, urging research on new treatment programs. The InConnection approach is an integrated care program to improve resilience of youths with mental health needs from multi-problem families by connecting professional expertise from multiple disciplines with the informal social network of the youth. Youths are asked to nominate a youth-initiated mentor (YIM) from the supportive adults in their network.
This quasi-experimental study compared the effectiveness of the InConnection approach to treatment as usual in a sample of 107 families (n = 66 intervention group, n = 41 control group) with n = 115 youths receiving treatment (cases). Youths (n = 102 reports, M
= 15.59 years), parents (n = 85 reports) and case managers (n = 107 reports) responded to questionnaires four times over 15 months. Using these data, we measured youth resilience as the primary outcome, seven secondary outcomes, and three intermediate outcomes.
Latent growth models showed only one significant change in outcomes over time across conditions, namely a decrease in case manager-reported child unsafety, and only two condition effects, which were both parent-reported. Parents in the InConnection group reported improvements over time in youth's emotional and behavioral problems and their own positive parenting, whereas control parents reported no changes (ps ≤ 0.013).
The treatment conditions were not effective in improving most of the youth and parental outcomes over time, except for child safety reported by the case manager. The InConnection approach only outperformed care as usual on two parent-reported outcomes. Future research should examine for whom and under what circumstances the InConnection approach works more convincingly.
Netherlands Trial Register NL7565. Retrospectively registered on 05/03/2019.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Summary 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.
The optimal first‐line palliative systemic treatment strategy for metastatic esophagogastric cancer is not well defined. The aim of our study was to explore real‐world use of first‐line systemic ...treatment in esophagogastric cancer and assess the effect of treatment strategy on overall survival (OS), time to failure (TTF) of first‐line treatment and toxicity. We selected synchronous metastatic esophagogastric cancer patients treated with systemic therapy (2010–2016) from the nationwide Netherlands Cancer Registry (n = 2,204). Systemic treatment strategies were divided into monotherapy, doublet and triplet chemotherapy, and trastuzumab‐containing regimens. Data on OS were available for all patients, on TTF for patients diagnosed from 2010 to 2015 (n = 1,700), and on toxicity for patients diagnosed from 2010 to 2014 (n = 1,221). OS and TTF were analyzed using multivariable Cox regression, with adjustment for relevant tumor and patient characteristics. Up to 45 different systemic treatment regimens were found to be administered, with a median TTF of 4.6 and OS of 7.5 months. Most patients (45%) were treated with doublet chemotherapy; 34% received triplets, 10% monotherapy and 10% a trastuzumab‐containing regimen. The highest median OS was found in patients receiving a trastuzumab‐containing regimen (11.9 months). Triplet chemotherapy showed equal survival rates compared to doublets (OS: HR 0.92, 95%CI 0.83–1.02; TTF: HR 0.92, 95%CI 0.82–1.04) but significantly more grade 3–5 toxicity than doublets (33% vs. 21%, respectively). In conclusion, heterogeneity of first‐line palliative systemic treatment in metastatic esophagogastric cancer patients is striking. Based on our data, doublet chemotherapy is the preferred treatment strategy because of similar survival and less toxicity compared to triplets.
What's new?
Metastatic esophagogastric cancer can't be cured, but palliative therapy can improve patients’ quality of life and survival. However, there's no consensus regarding the optimal first‐line palliative systemic therapy for metastatic esophagogastric cancer. Here, the authors evaluated real‐world use of first‐line systemic treatments. The retrospective study included a cohort of 2,204 metastatic patients and found 45 different treatment regimens administered. Patients that received doublet and triplet chemotherapy had similar survival, with triplet patients experiencing higher toxicity. Monotherapy produced significantly worse overall survival and only modest reduction in toxicity. These findings support doublet therapy as the optimal first‐line treatment strategy.
Background
Increasing evidence suggests that severe skeletal muscle index (SMI) loss (sarcopenia) is associated with poor overall survival in metastatic colorectal cancer patients, but its mechanisms ...are unknown. We recently found, using data of the randomized phase 3 CAIRO3 study, that SMI loss was related with shorter time to disease progression and overall survival during first‐line maintenance treatment with capecitabine + bevacizumab (CAP‐B) or observation and during more intensive capecitabine + oxaliplatin + bevacizumab (CAPOX‐B) reintroduction treatment. As a potential risk factor for reduced survival, we explored whether sarcopenia and SMI loss were associated with dose‐limiting toxicities (DLTs) during CAP‐B and CAPOX‐B.
Methods
Sarcopenia status and SMI loss were assessed by using consecutive computed tomography scans. DLTs were defined as any dose delay/reduction/discontinuation of systemic treatment because of reported CTCAE (version 3.0) toxicities at the start or during treatment. Poisson regression models were used to study whether sarcopenia and body mass index (BMI) at the start of treatment and SMI and BMI loss during treatment were associated with DLTs.
Results
One hundred eighty‐two patients (mean age 63.0 ± 8.8 years, 37% female) received CAP‐B, and 232 patients (mean age 63.0 ± 9.0 years, 34% female) received CAPOX‐B. At the start of CAP‐B and CAPOX‐B, 54% and 46% of patients were sarcopenic, respectively. Mean BMI was lower in sarcopenic patients, although patients were on average still overweight (sarcopenic vs. non‐sarcopenic at the start of CAP‐B 25.0 ± 3.9 vs. 26.7 ± 4.1 and CAPOX‐B 25.8 ± 3.8 vs. 27.1 ± 3.8 kg/m2). Sarcopenia at the start of CAP‐B was not associated with DLTs relative risk 0.87 (95% confidence interval 0.64–1.19), whereas patients with >2% SMI loss had a significantly higher risk of DLTs 1.29 (1.01–1.66). At the start of subsequent CAPOX‐B, 25% of patients received a dose reduction, and the risk of dose reduction was significantly higher for patients with preceding SMI loss 1.78 (1.06–3.01) or sarcopenia 1.75 (1.08–2.86). After the received dose reductions, sarcopenia or SMI loss was not significantly associated with a higher risk of DLTs during CAPOX‐B sarcopenia vs. non‐sarcopenic: 0.86 (0.69–1.08) and SMI loss vs. stable/gain: 0.83 (0.65–1.07). In contrast, BMI (loss) at the start or during either treatment was not associated with an increased risk of DLTs.
Conclusions
In this large longitudinal study in metastatic colorectal cancer patients during palliative systemic treatment, sarcopenia and/or muscle loss was associated with an increased risk of DLTs. BMI was not associated with DLTs and could not detect sarcopenia or SMI loss. Prospective (randomized) studies should reveal whether normalizing chemotherapeutic doses to muscle mass or muscle mass preservation (by exercise and nutritional interventions) increases chemotherapeutic tolerance and improves survival.
Background
Addition of trastuzumab to first-line palliative chemotherapy in gastroesophageal cancer patients with HER2 overexpression has shown to improve survival. Real-world data on HER2 assessment ...and administration of trastuzumab are lacking. The aim of this study was to assess HER2 testing, trastuzumab administration, and overall survival (OS) in a nationwide cohort of metastatic gastroesophageal cancer patients.
Methods
Data of patients with synchronous metastatic gastroesophageal adenocarcinoma diagnosed in 2010–2016 that received palliative systemic treatment (
n
= 2846) were collected from the Netherlands Cancer Registry and Dutch Pathology Registry. The ToGA trial criteria were used to determine HER2 overexpression. Proportions of HER2 tested patients were analyzed between hospital volume categories using Chi-square tests, and over time using trend analysis. OS was tested using the Kaplan Meier method with log rank test.
Results
HER2 assessment increased annually, from 18% in 2010 to 88% in 2016 (
P
< 0.01). Median OS increased from 6.9 (2010–2013) to 7.9 months (2014–2016;
P
< 0.05). Between the hospitals, the proportion of tested patients varied between 29–100%, and was higher in high-volume hospitals (
P
< 0.01). Overall, 77% of the HER2 positive patients received trastuzumab. Median OS was higher in patients with positive (8.8 months) and negative (7.4 months) HER2 status, compared to non-tested patients (5.6 months;
P
< 0.05).
Conclusion
Increased determination of HER2 and administration of trastuzumab have changed daily practice management of metastatic gastroesophageal cancer patients receiving palliative systemic therapy, and possibly contributed to their improved survival. Further increase in awareness of HER2 testing and trastuzumab administration may improve quality of care and patient outcomes.
Fluoropyrimidine treatment can result in severe toxicity in up to 30% of patients and is often the result of reduced activity of the key metabolic enzyme dihydropyrimidine dehydrogenase (DPD), mostly ...caused by genetic variants in the gene encoding DPD (DPYD). We assessed the effect of prospective screening for the four most relevant DPYD variants (DPYD*2A rs3918290, c.1905+1G>A, IVS14+1G>A, c.2846A>T rs67376798, D949V, c.1679T>G rs55886062, DPYD*13, I560S, and c.1236G>A rs56038477, E412E, in haplotype B3) on patient safety and subsequent DPYD genotype-guided dose individualisation in daily clinical care.
In this prospective, multicentre, safety analysis in 17 hospitals in the Netherlands, the study population consisted of adult patients (≥18 years) with cancer who were intended to start on a fluoropyrimidine-based anticancer therapy (capecitabine or fluorouracil as single agent or in combination with other chemotherapeutic agents or radiotherapy). Patients with all tumour types for which fluoropyrimidine-based therapy was considered in their best interest were eligible. We did prospective genotyping for DPYD*2A, c.2846A>T, c.1679T>G, and c.1236G>A. Heterozygous DPYD variant allele carriers received an initial dose reduction of 25% (c.2846A>T and c.1236G>A) or 50% (DPYD*2A and c.1679T>G), and DPYD wild-type patients were treated according to the current standard of care. The primary endpoint of the study was the frequency of severe (National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03 grade ≥3) overall fluoropyrimidine-related toxicity across the entire treatment duration. We compared toxicity incidence between DPYD variant allele carriers and DPYD wild-type patients on an intention-to-treat basis, and relative risks (RRs) for severe toxicity were compared between the current study and a historical cohort of DPYD variant allele carriers treated with full dose fluoropyrimidine-based therapy (derived from a previously published meta-analysis). This trial is registered with ClinicalTrials.gov, number NCT02324452, and is complete.
Between April 30, 2015, and Dec 21, 2017, we enrolled 1181 patients. 78 patients were considered non-evaluable, because they were retrospectively identified as not meeting inclusion criteria, did not start fluoropyrimidine-based treatment, or were homozygous or compound heterozygous DPYD variant allele carriers. Of 1103 evaluable patients, 85 (8%) were heterozygous DPYD variant allele carriers, and 1018 (92%) were DPYD wild-type patients. Overall, fluoropyrimidine-related severe toxicity was higher in DPYD variant carriers (33 39% of 85 patients) than in wild-type patients (231 23% of 1018 patients; p=0·0013). The RR for severe fluoropyrimidine-related toxicity was 1·31 (95% CI 0·63–2·73) for genotype-guided dosing compared with 2·87 (2·14–3·86) in the historical cohort for DPYD*2A carriers, no toxicity compared with 4·30 (2·10–8·80) in c.1679T>G carriers, 2·00 (1·19–3·34) compared with 3·11 (2·25–4·28) for c.2846A>T carriers, and 1·69 (1·18–2·42) compared with 1·72 (1·22–2·42) for c.1236G>A carriers.
Prospective DPYD genotyping was feasible in routine clinical practice, and DPYD genotype-based dose reductions improved patient safety of fluoropyrimidine treatment. For DPYD*2A and c.1679T>G carriers, a 50% initial dose reduction was adequate. For c.1236G>A and c.2846A>T carriers, a larger dose reduction of 50% (instead of 25%) requires investigation. Since fluoropyrimidines are among the most commonly used anticancer agents, these findings suggest that implementation of DPYD genotype-guided individualised dosing should be a new standard of care.
Dutch Cancer Society.
Highlights • One fifth of operated colorectal cancer patients will develop metachronous metastases. • Colon and rectal cancer patients have different patterns of metastatic spread. • Median time to ...diagnosis depends on site of metastasis. • The risk for metastases is associated with patient and tumour characteristics.
Summary 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.
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