Nationwide comprehensive gastro-intestinal cancer cohorts: the 3P initiative.

BACKGROUND: The increasing sub-classification of cancer patients due to more detailed molecular classification of tumors, and limitations of current trial designs, require innovative research designs. We present the design, governance and current standing of three comprehensive nationwide cohorts including pancreatic, esophageal/gastric, and colorectal cancer patients (NCT02070146). Multidisciplinary collection of clinical data, tumor tissue, blood samples, and patient-reported outcome (PRO) measures with a nationwide coverage, provides the infrastructure for future and novel trial designs and facilitates research to improve outcomes of gastrointestinal cancer patients. MATERIAL AND METHODS: All patients aged ≥18 years with pancreatic, esophageal/gastric or colorectal cancer are eligible. Patients provide informed consent for: (1) reuse of clinical data; (2) biobanking of primary tumor tissue; (3) collection of blood samples; (4) to be informed about relevant newly identified genomic aberrations; (5) collection of longitudinal PROs; and (6) to receive information on new interventional studies and possible participation in cohort multiple randomized controlled trials (cmRCT) in the future. RESULTS: In 2015, clinical data of 21,758 newly diagnosed patients were collected in the Netherlands Cancer Registry. Additional clinical data on the surgical procedures were registered in surgical audits for 13,845 patients. Within the first two years, tumor tissue and blood samples were obtained from 1507 patients; during this period, 1180 patients were included in the PRO registry. Response rate for PROs was 90%. The consent rate to receive information on new interventional studies and possible participation in cmRCTs in the future was >85%. The number of hospitals participating in the cohorts is steadily increasing. CONCLUSION: A comprehensive nationwide multidisciplinary gastrointestinal cancer cohort is feasible and surpasses the limitations of classical study designs. With this initiative, novel and innovative studies can be performed in an efficient, safe, and comprehensive setting.

Randomized phase III trial of S-1 versus capecitabine in the first-line treatment of metastatic colorectal cancer: SALTO study by the Dutch Colorectal Cancer Group.

BACKGROUND: Hand-foot syndrome (HFS) is a common side-effect of capecitabine. S-1 is an oral fluoropyrimidine with comparable efficacy to capecitabine in gastrointestinal cancers but associated with a lower incidence of HFS in Asian patients. This study compares the incidence of HFS between S-1 and capecitabine as first-line treatment in Western metastatic colorectal cancer (mCRC) patients. PATIENTS AND METHODS: Patients with previously untreated mCRC and planned treatment with fluoropyrimidine monochemotherapy were randomized 1 : 1 to receive either capecitabine (1250 mg/m2 orally for patients <70 years; 1000 mg/m2 for patients ≥70 years, twice daily on days 1-14) or S-1 (30 mg/m2 orally twice daily on days 1-14) in 3-weekly cycles, with bevacizumab optional in both groups. The primary endpoint was the incidence of any grade HFS, as assessed by both physicians and patients (diaries). Secondary endpoints included grade 3 HFS, other toxicities, relative dose intensity, progression-free survival, response rate and overall survival. RESULTS: A total of 161 patients were randomized in 27 centres. The incidence of any grade HFS as assessed by physicians was 73% in the capecitabine group (n = 80) and 45% in the S-1 group (n = 80) [odds ratio (95% confidence interval) 0.31 (0.16-0.60), P = 0.0005]. The incidence of grade 3 HFS was 21% and 4% (P = 0.003), respectively. Patient-assessed any grade HFS was 84% and 58%, respectively (P = 0.004). Grade 3 anorexia was more common in the S-1 group (3% versus 13%, P = 0.03). Median relative dose intensity was 88% in the capecitabine group and 95% in the S-1 group (P = 0.026). There were no statistically significant differences in median progression-free survival, response rate and overall survival rates. CONCLUSION: Treatment with S-1 in Western mCRC patients is associated with a significantly lower incidence of HFS compared with capecitabine, with comparable efficacy. CLINICALTRIALS.GOV REGISTRATION NUMBER: NCT01918852.

Prospective Dutch colorectal cancer cohort: an infrastructure for long-term observational, prognostic, predictive and (randomized) intervention research.

BACKGROUND: Systematic evaluation and validation of new prognostic and predictive markers, technologies and interventions for colorectal cancer (CRC) is crucial for optimizing patients' outcomes. With only 5-15% of patients participating in clinical trials, generalizability of results is poor. Moreover, current trials often lack the capacity for post-hoc subgroup analyses. For this purpose, a large observational cohort study, serving as a multiple trial and biobanking facility, was set up by the Dutch Colorectal Cancer Group (DCCG). METHODS/DESIGN: The Prospective Dutch ColoRectal Cancer cohort is a prospective multidisciplinary nationwide observational cohort study in the Netherlands (yearly CRC incidence of 15 500). All CRC patients (stage I-IV) are eligible for inclusion, and longitudinal clinical data are registered. Patients give separate consent for the collection of blood and tumor tissue, filling out questionnaires, and broad randomization for studies according to the innovative cohort multiple randomized controlled trial design (cmRCT), serving as an alternative study design for the classic RCT. Objectives of the study include: 1) systematically collected long-term clinical data, patient-reported outcomes and biomaterials from daily CRC practice; and 2) to facilitate future basic, translational and clinical research including interventional and cost-effectiveness studies for both national and international research groups with short inclusion periods, even for studies with stringent inclusion criteria. RESULTS: Seven months after initiation 650 patients have been enrolled, eight centers participate, 15 centers await IRB approval and nine embedded cohort- or cmRCT-designed studies are currently recruiting patients. CONCLUSION: This cohort provides a unique multidisciplinary data, biobank, and patient-reported outcomes collection initiative, serving as an infrastructure for various kinds of research aiming to improve treatment outcomes in CRC patients. This comprehensive design may serve as an example for other tumor types.

Response to influenza virus vaccination during chemotherapy in patients with breast cancer.

BACKGROUND: Patients receiving chemotherapy are at increased risk for influenza virus infection. Little is known about the preferred moment of vaccination during chemotherapy. PATIENTS AND METHODS: Breast cancer patients received influenza vaccination during FEC (5-fluorouracil, epirubicin and cyclophosphamide)-containing chemotherapy regimens. Patients were randomised for early (day 4) or late (day 16) vaccination during the chemotherapy cycle. Influenza virus-specific antibody titres were determined before and 3 weeks after vaccination by haemagglutination inhibition. RESULTS: We included 38 breast cancer patients (20 in the early and 18 in the late group) and 21 healthy controls. The overall patient group had significant lower responses to the vaccine compared with healthy controls. Patients vaccinated at day 4 tended to have higher antibody titres as compared with patients vaccinated at day 16, although the difference in post-vaccination titres is not statistically significant. Geometric mean titres post-vaccination for day 4 versus day 16 were 63.7 versus 29.5 (H3N2), 28.2 versus 19.6 (H1N1) and 29.8 versus 16.0 (B/Brisbane), respectively. CONCLUSIONS: Patients on chemotherapy have significantly lower responses to influenza virus vaccination compared with healthy controls. Vaccination early during the chemotherapy cycle induces better responses than does vaccination at day 16 of the cycle. Follow-up studies are needed to confirm this effect.

The relevance of geriatric assessment for older patients receiving palliative chemotherapy.

OBJECTIVES: No tools accurately discriminate between older patients who are fit and those who are frail to tolerate systemic palliative treatment. This study evaluates whether domains of geriatric assessment (GA) are associated with increased risk of chemotherapy intolerance in patients who were considered fit to start palliative chemotherapy after clinical evaluation by their treating clinician. MATERIALS AND METHODS: This prospective multicenter study included patients ≥70 years who started first line palliative systemic treatment. Before treatment initiation, patients completed GA including Activities of Daily Life (ADL), Instrumental Activities of Daily Life (IADL), Mini-Mental State Examination (MMSE), Mini Nutritional Assessment (MNA), Geriatric Depression Scale (GDS-15) and the Timed Up and Go Test (TUGT). Primary endpoint was treatment modification, defined as inability to complete the first three sessions of systemic treatment as planned. Secondary endpoint was treatment related toxicity ≥ grade 3 (CTCAE Version 4). The association between GA and endpoints were assessed using univariable and multivariable logistic regression analysis. RESULTS: Ninety-nine patients with median age of 77 (+/- 8) years underwent GA. 48% of the patients required treatment modification and grade 3 toxicity occurred in 53% of patients. One or more geriatric impairments were present in 71% of patients and 32% of patients were frail in two or more domains. Only TUGT was associated with treatment modifications (OR 2.9 [95% CI 1.3-6.5]) and grade 3 toxicities (OR 2.8 [95% CI 1.2-6.3]). CONCLUSION: Frailty was common in older patients who were considered fit to receive palliative chemotherapy. Treatment modification was necessary in half of the patients. Only TUGT was significantly associated with treatment modifications and grade 3 chemotherapy toxicities.

Development of T cell-mediated immunity after autologous stem cell transplantation: prolonged impairment of antigen-stimulated production of gamma-interferon.

The conditioning regimens for autologous SCT (auto-SCT) lead to impairment of the immune system and concomitant increase in susceptibility to infections. We studied the recovery of cellular immunity by in vitro analysis of T-cell proliferation and cytokine production profiles during the first 15 months after auto-SCT in patients with multiple myeloma and non-Hodgkin's lymphoma. PBMC were collected at 6, 9 and 15 months after transplantation and stimulated with a combination of CD2 and CD28 monoclonal antibodies, with PHA or with tetanus toxoid as recall antigen. A multiplex enzyme linked immunoassay was used to determine levels of Th1 cytokines IL-2, IFN-gamma and tumour-necrosis factor-alpha (TNF-alpha), Th2 cytokines IL-4, IL-5 and IL-13, the regulatory cytokine IL-10 and the proinflammatory cytokines IL-1alpha, IL-1beta, IL-6 and the chemokine IL-8. T-cell proliferation progressively increased from 6 to 15 months after auto-SCT. Overall, cytokine production increased after auto-SCT. Production of Th2 cytokines IL-5 and IL-13 was superior to production of Th1 cytokines IFN-gamma and TNF-alpha. We hypothesize that prolonged impairment of IFN-gamma production might contribute to the relatively high incidence of viral infections after auto-SCT.

Microarray profile of the humoral immune response to influenza vaccination in breast cancer patients treated with chemotherapy.

BACKGROUND: Patients treated with chemotherapy have an impaired response to influenza virus vaccination compared to healthy controls. Little is known about the broadness of the antibody response in these patients. METHODS: Breast cancer patients on FEC (5-fluorouracil, epirubicin and cyclophosphamide) chemotherapy regimens were vaccinated with influenza virus vaccine. Sera were obtained before and three weeks after vaccination. In addition to the determination of virus-specific antibody titres by hemagglutination inhibition assay, the broadness of the response was assessed by the use of a protein microarray and baseline titres were compared with an age-matched reference group. RESULTS: We included 38 breast cancer patients and found a wide variety in serum antibody response after vaccination. Patients with a history of influenza vaccination had higher pre-vaccination titres, which were comparable to the reference group. Increasing number of cycles of chemotherapy did not have a negative effect on influenza array antibody levels, nor on the HI antibody response. CONCLUSIONS: Overall there was a broad serum antibody response to the influenza virus vaccine in patients treated with chemotherapy for breast cancer.

Cost-effectiveness of capecitabine and bevacizumab maintenance treatment after first-line induction treatment in metastatic colorectal cancer.

AIM: Capecitabine and bevacizumab (CAP-B) maintenance therapy has shown to be more effective compared with observation in metastatic colorectal cancer patients achieving stable disease or better after six cycles of first-line capecitabine, oxaliplatin, bevacizumab treatment in terms of progression-free survival. We evaluated the cost-effectiveness of CAP-B maintenance treatment. METHODS: Decision analysis with Markov modelling to evaluate the cost-effectiveness of CAP-B maintenance compared with observation was performed based on CAIRO3 study results (n = 558). An additional analysis was performed in patients with complete or partial response. The primary outcomes were the incremental cost-effectiveness ratio (ICER) defined as the additional cost per life year (LY) and quality-adjusted life years (QALY) gained, calculated from EQ-5D questionnaires and literature and LYs gained. Univariable sensitivity analysis was performed to assess the influence of input parameters on the ICER, and a probabilistic sensitivity analysis represents uncertainty in model parameters. RESULTS: CAP-B maintenance compared with observation resulted in 0.21 QALYs (0.18LYs) gained at a mean cost increase of €36,845, yielding an ICER of €175,452 per QALY (€204,694 per LY). Varying the difference in health-related quality of life between CAP-B maintenance and observation influenced the ICER most. For patients achieving complete or partial response on capecitabine, oxaliplatin, bevacizumab induction treatment, an ICER of €149,300 per QALY was calculated. CONCLUSION: CAP-B maintenance results in improved health outcomes measured in QALYs and LYs compared with observation, but also in a relevant increase in costs. Despite the fact that there is no consensus on cost-effectiveness thresholds in cancer treatment, CAP-B maintenance may not be considered cost-effective.

Analysis of docetaxel therapy in elderly (≥70 years) castration resistant prostate cancer patients enrolled in the Netherlands Prostate Study.

BACKGROUND: Prostate cancer truly is an age-associated disease. Due to the increased life expectancy and more sensitive diagnostic techniques in the Western world, prostate cancer is diagnosed more frequently and with rapidly increasing incidence and prevalence rates. However, age above 65 or 70 years has been an exclusion criterion in clinical trials for decades and the knowledge about chemotherapy tolerance in elderly is limited. METHODS: We performed a retrospective analysis of data acquired from the recently published Netherlands Prostate Study (NePro) to evaluate the influence of advanced age on docetaxel therapy in elderly men (>70 years) with castration resistant prostate cancer (CRPC) and bone metastases. Statistical analyses were performed stratified for age into four categories: <70 (n=315), 70-74 (n=150), 75-79 (n=85), and ≥80 years old (n=18). RESULTS: We analysed 568 patients (median age 68.1 years, range 46-89 years, 44.5% aged ≥70 years). There was no relation between dosage and age (p=0.60). We found no significant differences between the number of dose reductions, time to progression (TTP), overall survival, chemotherapy tolerance and toxicity up to the age of 80 years. However, when compared to younger men, men aged 80 years or above more frequently experienced grade 3/4 toxicity and were five times less likely to complete the first three treatment cycles at the intended dose (Odds ratio (OR) 5.34, p=0.0052) and showed decreased overall survival (15.3 months versus 24.5 months in <80 years group, p=0.020). CONCLUSION: In CRPC patients up to the age of 80 years, docetaxel chemotherapy is well tolerated, with toxicity levels and TTP comparable to those of younger patients. For chemotherapeutic treatment of patients above the age of 80 years an individual assessment should be made.

Influenza vaccination coverage in patients treated with chemotherapy: current clinical practice.

BACKGROUND: Influenza virus vaccination is recommended for patients treated with chemotherapy. Little is known about vaccination coverage in these patients. METHODS: Vaccination coverage in the Netherlands was analysed by questionnaires completed by general practitioners, within a catchment area of 1.3 million people, in the period 2010-2011. RESULTS: Of 433 eligible adult patients treated with chemotherapy for breast or colorectal cancer, 144 patients gave permission for us to approach their general practitioner with a questionnaire. General practitioners were asked about vaccination coverage, awareness of recommendations and their opinion about the responsibility for vaccination. We received 114 (79%) completed questionnaires. Sixty-seven out of 114 patients (59%) were vaccinated against influenza. Forty-four (66%) of these patients also had an indication for vaccination based on age (age ≥60 years). According to 48% of the general practitioners, the responsibility for vaccination belongs to the competence of the treating medical oncologist. CONCLUSION: Influenza vaccination coverage is limited to 59% of patients treated with chemotherapy. Guidelines for responsibility (general practitioner or medical oncologist) may increase the vaccination rate of cancer patients.

Serum antibody response to influenza virus vaccination during chemotherapy treatment in adult patients with solid tumours.

BACKGROUND: Higher rates of hospitalization and mortality are described in oncology patients with influenza virus infection compared to the general population. Yearly influenza vaccination is recommended for patients treated with chemotherapy. The optimal moment to administer the vaccine during a treatment cycle has not been studied extensively. PATIENTS AND METHODS: During the influenza season 2011-2012 we conducted a multicenter randomized controlled trial (OFLUVAC, NTR2858, no sponsoring) in the Netherlands. Patients receiving adjuvant chemotherapy for breast or colorectal cancer were randomized between early (day 5 after chemotherapy) and late (day 16 after chemotherapy) vaccination with the influenza virus vaccine (Influvac(®) 2011/2012-Vaxigrip(®) 2011/2012). Influenza virus-specific antibody titres were determined before, 3 and 12 weeks after vaccination by haemagglutination inhibition. RESULTS: Thirty-eight breast cancer patients (early=21; late=17) and 18 colorectal cancer patients (early=8; late=10) were analyzed. In breast cancer patients overall serologic responses were adequate. A statistically significant higher response in patients who received early compared to late vaccination in the chemotherapy cycle was observed. Geometric mean titres post vaccination on day 5 versus day 16 were 69.3 versus 27.4 (H3N2), 76.4 versus 17.5 (H1N1) and 34.4 versus 26.0 (B/Brisbane), respectively. In colorectal cancer patients overall serologic responses were adequate, no significant difference was found between early and late vaccination. Geometric mean titres post vaccination on day 5 versus day 16 were 170.1 versus 192.4 (H3N2), 233.0 versus 280.8 (H1N1) and 62.6 versus 75.9 (B/Brisbane), respectively. CONCLUSION: Overall antibody response to the influenza virus vaccine in patients treated with chemotherapy for breast or colorectal cancer patients is adequate. Breast cancer patients seem to mount the best antibody response when vaccinated early after a chemotherapy cycle (≤day 5). No difference was found between early and late vaccination in colorectal cancer patients.

Vaccination responses and lymphocyte subsets after autologous stem cell transplantation.

Twenty autologous stem cell transplant recipients were vaccinated with three doses of Diphtheria-Tetanus-Poliomyelitis vaccine and conjugated Haemophilus influenzae type b (Hib) vaccine. Pneumococcal vaccination consisted of two doses of conjugated vaccine followed by a single dose of polysaccharide vaccine, at 6, 8 and 14 months after transplantation, respectively. Mean anti-tetanus, anti-Hib and anti-pneumococcal IgG antibodies significantly increased after each vaccination. Response rates after the full vaccination schedule were 94%, 78% and 61% for Hib, conjugated 7-valent pneumococcal vaccine and non-conjugated 23-valent pneumococcal vaccine, respectively. Three months after transplantation, CD16(+)CD56(+) NK cells were in the normal range and remained so. The total number of T lymphocytes at 3 months was and remained in the normal range. The mean CD4/CD8 ratio was 0.43 at 3 months post aSCT and, while gradually increasing, remained subnormal. The mean number of CD19(+) B lymphocytes significantly increased during the study period. Patients with CD19 counts <0.10 x 10(9)L(-1) required at least two Hib vaccinations to show a response, while the majority of patients with CD19 counts > or = 0.20 x 10(9)L(-1) showed a response to Hib after one vaccination only. Thus, a minimum threshold level of CD19(+) cells appears to be required for adequate responses to vaccination.

Influenza virus vaccination and booster in B-cell chronic lymphocytic leukaemia patients.

Background: Influenza vaccination is recommended for patients with B-cell chronic lymphocytic leukaemia (CLL). Because response rates are often low, we decided to evaluate antibody response to single and booster vaccinations with influenza A and B virus vaccine in these patients. Methods: Twenty patients with B-CLL received two subunit virus vaccine injections 21 days apart. Antibody titres were determined before and 21 days after the single and booster vaccinations. The serological response was expressed using the following criteria: (1) response rate, i.e. the proportion of subjects with at least a 4-fold titre increase; (2) the protection rate, i.e. the proportion of subjects exceeding the threshold of 100 (influenza A) or 200 (influenza B); and (3) the mean fold increase (MFI), i.e. the difference between the log-adjusted geometric mean titres of pre- and post-vaccination sera. Results: Response rates were 5% for influenza A and 15% for B after the single vaccination and 15% for A and 30% for B after the booster vaccination. Protection rates were 0% for influenza A and 25% for B after the single vaccination; they were 5% (H1N1) and 10% (H3N2) for influenza A and 30% for B after the booster. The MFI+/-S.D. (range) after the booster vaccination was 0.26+/-0.33 (0-1.00), 0.17+/-0.34 (0-1.00) and 0.35+/-0.34 (0-1.20) for H1N1, H3N2 and influenza B, respectively. Conclusion: In this study with B-CLL patients, immune response to influenza vaccination was poor. Thus, single and booster vaccinations with influenza virus vaccine do not appear to be of great value to patients with B-cell CLL.