A multicenter, open-label, randomized, phase II study of cediranib with or without lenalidomide in iodine 131-refractory differentiated thyroid cancer.

BACKGROUND: Multitargeted tyrosine kinase inhibitors (TKIs) of the vascular endothelial growth factor receptor (VEGFR) pathway have activity in differentiated thyroid cancer (DTC). Lenalidomide demonstrated preliminary efficacy in DTC, but its safety and efficacy in combination with VEGFR-targeted TKIs is unknown. We sought to determine the safety and efficacy of cediranib, a VEGFR-targeted TKI, with or without lenalidomide, in the treatment of iodine 131-refractory DTC. PATIENTS AND METHODS: In this multicenter, open-label, randomized, phase II clinical trial, 110 patients were enrolled and randomized to cediranib alone or cediranib with lenalidomide. The primary endpoint was progression-free survival (PFS). Secondary endpoints included response rate, duration of response, toxicity, and overall survival (OS). Patients (≥18 years of age) with DTC who were refractory to further surgical or radioactive iodine (RAI) therapy as reviewed at a multispecialty tumor board conference, and evidence of disease progression within the previous 12 months and no more than one prior line of systemic therapy were eligible. RESULTS: Of the 110 patients, 108 started therapy and were assessable for efficacy. The median PFS was 14.8 months [95% confidence interval (CI) 8.5-23.8 months] in the cediranib arm and 11.3 months (95% CI 8.7-18.9 months) in the cediranib with lenalidomide arm (P = 0.36). The 2-year OS was 64.8% (95% CI 43.3% to 86.4%) and 75.3% (95% CI 59.4% to 91.0%), respectively (P = 0.80). The serious adverse event rate was 41% in the cediranib arm and 46% in the cediranib with lenalidomide arm. CONCLUSIONS: Single-agent therapy with cediranib showed promising efficacy in RAI-refractory DTC similar to other VEGFR-targeted TKIs, while the addition of lenalidomide did not result in clinically meaningful improvements in outcomes.

Cross-Canada differences in early-stage breast cancer treatment and acute-care use.

Background: Chemotherapy has improved outcomes in early-stage breast cancer, but treatment practices vary, and use of acute care is common. We conducted a pan-Canadian study to describe treatment differences and the incidence of emergency department visits (edvs), edvs leading to hospitalization (edvhs), and direct hospitalizations (hs) during adjuvant chemotherapy. Methods: The cohort consisted of women diagnosed with early-stage breast cancer (stages i-iii) during 2007-2012 in British Columbia, Manitoba, Ontario, or Nova Scotia who underwent curative surgery. Parallel provincial analyses were undertaken using linked clinical, registry, and administrative databases. The incidences of edvs, edvhs, and hs in the 6 months after treatment initiation were examined for patients treated with adjuvant chemotherapy. Results: The cohort consisted of 50,224 patients. The proportion of patients who received chemotherapy varied by province, with Ontario having the highest proportion (46.4%), and Nova Scotia, the lowest proportion (38.0%). Age, stage, receptor status, comorbidities, and geographic location were associated with receipt of chemotherapy in all provinces. Ontario had the highest proportion of patients experiencing an edv (36.1%), but the lowest proportion experiencing h (6.4%). Conversely, British Columbia had the lowest proportion of patients experiencing an edv (16.0%), but the highest proportion experiencing h (26.7%). The proportion of patients having an edvh was similar across provinces (13.9%-16.8%). Geographic location was associated with edvs, edvhs, and hs in all provinces. Conclusions: Intra- and inter-provincial differences in the use of chemotherapy and acute care were observed. Understanding variations in care can help to identify gaps and opportunities for improvement and shared learnings.

A primer on the genetics of medullary thyroid cancer.

Medullary thyroid cancer is a rare type of neuroendocrine tumour that arises from the parafollicular cells (C cells) of the thyroid gland. It accounts for 3%-5% of thyroid cancer cases. Close to 25% of cases are familial, and 75% are considered sporadic. Familial cases are associated with a germline RET mutation; 43%-65% of sporadic cases harbour a somatic event in the gene. Germline RET mutations are associated with the autosomal-dominant inherited multiple endocrine neoplasia (men) 2a and 2b syndromes and the isolated familial medullary thyroid cancer syndrome. More than 100 RET codon mutations have been reported to date, with genotype-phenotype correlations that include the extent and aggressiveness of the medullary thyroid cancer and the presence of other features of the men2 syndromes. The latter include pheochromocytoma-paraganglioma, hyperparathyroidism, cutaneous lichen amyloidosis, and Hirschsprung disease. In this narrative review, we focus on RET proto-oncogene physiology and pathogenesis induced by germline and somatic RET mutations, the genotype-phenotype correlation, and the management and follow-up of patients with germline-mutated medullary thyroid cancer.

Emergency department visits and unplanned hospitalizations in the treatment period for head and neck cancer patients treated with curative intent: A population-based analysis.

BACKGROUND: Mucosal head and neck squamous cell cancers are often managed with multimodality treatment which can be associated with significant toxicity. The objective of this study was to assess emergency department visits and unplanned hospitalizations for these patients during and immediately after their treatment. METHODS: A cohort of patients treated for head and neck squamous cell carcinoma was developed using administrative data. Emergency department visits and hospitalizations in the 90-day post-treatment period was determined. If a second treatment was initiated prior to the completion of 90 days, the attributable risk period was changed to the second treatment. RESULTS: Cohort of 3898 patients (1312 larynx/hypopharynx; 2586 oral cavity/oropharynx) from 2008 to 2012. The number of unplanned hospitalizations or ED visits (per 100 patient days) were 0.69 for surgery, 0.78 for surgery followed by concurrent chemoradiotherapy (CCRT), 0.55 for surgery followed by radiotherapy, 0.86 for CCRT, and 0.50 for radiation. Patients receiving CCRT had a statistically higher likelihood of treatment period events. The larynx/hypopharynx cancer subsite, higher comorbidity and more advanced stage of disease were all independent predictors of events. CONCLUSIONS: Patients undergoing treatment for head and neck cancer have significant unplanned hospitalizations and visits to the emergency department in the treatment period. Rates are higher in patients receiving CCRT. Quality improvement interventions should be used to improve these rates.

Factors associated with imaging in patients with early breast cancer after initial treatment.

Background: Overuse of surveillance imaging in patients after curative treatment for early breast cancer (ebc) was recently identified as one of the Choosing Wisely Canada initiatives to improve the quality of cancer care. We undertook a population-level examination of imaging practices in Ontario as they existed before the launch of that initiative. Methods: Patients diagnosed with ebc between 2006 and 2010 in Ontario were identified from the Ontario Cancer Registry. Records were linked deterministically to provincial health care databases to obtain comprehensive follow-up. We identified all advanced imaging exams [aies: computed tomography (ct), bone scan, positron-emission tomography] and basic imaging exams (bies: ultrasonography, chest radiography) occurring within the first 2 years after curative treatment. Poisson regression was used to assess associations between patient or provider characteristics and the rate of aies. Results: Of 30,006 women with ebc, 58.6% received at least 1 bie, and 30.6% received at least 1 aie in year 1 after treatment. In year 2, 52.7% received at least 1 bie, and 25.7% received at least 1 aie. The most common aies were chest cts and bone scans. The rate of aies increased with older age, higher disease stage, comorbidity, chemotherapy exposure, and prior staging investigations (p < 0.001). Imaging was ordered mainly by medical oncologists (38%), followed by primary care physicians (23%), surgeons (13%), and emergency room physicians (7%). Conclusions: Despite recommendations against its use, imaging is common in ebc survivors. Understanding the factors associated with aie use helps to identify areas for further research and is required to lower imaging rates and to improve survivorship care.

Experiences of Canadian oncologists with difficult patient deaths and coping strategies used.

OBJECTIVES: We aimed to explore and identify what makes patient death more emotionally difficult for oncologists and how oncologists cope with patient death. METHODS: A convenience sample of 98 Canadian oncologists (50 men, 48 women) completed an online survey that included a demographics section and a section about patient death. RESULTS: More than 80% of oncologists reported that patient age, long-term management of a patient, and unexpected disease outcomes contributed to difficult patient loss. Other factors included the doctor-patient relationship, identification with the patient, caregiver-related factors, oncologist-related factors, and "bad deaths." Oncologists reported varying strategies to cope with patient death. Most prevalent was peer support from colleagues, including nurses and other oncologists. Additional strategies included social support, exercise and meditation, faith, vacations, and use of alcohol and medications. CONCLUSIONS: Oncologists listed a number of interpersonal and structural factors that make patient death challenging for them to cope with. Oncologists reported a number of coping strategies in responding to patient death, including peer support, particularly from nursing colleagues. No single intervention will be suitable for all oncologists, and institutions wishing to help their staff cope with the emotional difficulty of patient loss should offer a variety of interventions to maximize the likelihood of oncologist participation.

Use of physician services during the survivorship phase: a multi-province study of women diagnosed with breast cancer.

INTRODUCTION: Oncologists have traditionally been responsible for providing routine follow-up care for cancer survivors; in recent years, however, primary care providers (pcps) are taking a greater role in care during the follow-up period. In the present study, we used a longitudinal multi-province retrospective cohort study to examine how primary care and specialist care intersect in the delivery of breast cancer follow-up care. METHODS: Various databases (registry, clinical, and administrative) were linked in each of four provinces: British Columbia, Manitoba, Ontario, and Nova Scotia. Population-based cohorts of breast cancer survivors were identified in each province. Physician visits were identified using billings or claims data and were classified as visits to primary care (total, breast cancer-specific, and other), oncology (medical oncology, radiation oncology, and surgery), and other specialties. The mean numbers of visits by physician type and specialty, or by combinations thereof, were examined. The mean numbers of visits for each follow-up year were also examined by physician type. RESULTS: The results showed that many women (>64%) in each province received care from both primary care and oncology providers during the follow-up period. The mean number of breast cancer-specific visits to primary care and visits to oncology declined with each follow-up year. Interprovincial variations were observed, with greater surgeon follow-up in Nova Scotia and greater primary care follow-up in British Columbia. Provincial differences could reflect variations in policies and recommendations, relevant initiatives, and resources or infrastructure to support pcp-led follow-up care. CONCLUSIONS: Optimizing the role of pcps in breast cancer follow-up care might require strategies to change attitudes about pcp-led follow-up and to better support pcps in providing survivorship care.

A population-based assessment of primary care visits during adjuvant chemotherapy for breast cancer.

BACKGROUND: We used administrative health data to explore the impact of primary care physician (pcp) visits on acute-care service utilization by women receiving adjuvant chemotherapy for early-stage breast cancer (ebc). METHODS: Our population-based retrospective cohort study examined pcp visits and acute-care use [defined as an emergency room (er) visit or hospitalization] by women diagnosed with ebc between 2007 and 2009 and treated with adjuvant chemotherapy. Multivariate regression analysis was used to identify the effect of pcp visits on the likelihood of experiencing an acute-care visit. RESULTS: Patients receiving chemotherapy visited a pcp significantly more frequently than they had before their diagnosis [relative risk (rr): 1.48; 95% confidence interval (ci): 1.44 to 1.53; p < 0.001] and significantly more frequently than control subjects without cancer (rr: 1.51; 95% ci: 1.46 to 1.57; p < 0.001). More than one third of pcp visits by chemotherapy patients were related to breast cancer or chemotherapy-related side effects. In adjusted multivariate analyses, the likelihood of experiencing an er visit or hospitalization increased in the days immediately after a pcp visit (rr: 1.92; 95% ci: 1.76 to 2.10; p < 0.001). CONCLUSIONS: During chemotherapy treatment, patients visited their pcp more frequently than control subjects did, and they visited for reasons related to their breast cancer or to chemotherapy-related side effects. Visits to a pcp by patients receiving chemotherapy were associated with an increased frequency of er visits or hospitalizations in the days immediately after the pcp visit. Those results suggest an opportunity to institute measures for early detection and intervention in chemotherapy side effects.

Multigene expression profile testing in breast cancer: is there a role for family physicians?

BACKGROUND: Family physicians (fps) play a role in aspects of personalized medicine in cancer, including assessment of increased risk because of family history. Little is known about the potential role of fps in supporting cancer patients who undergo tumour gene expression profile (gep) testing. METHODS: We conducted a mixed-methods study with qualitative and quantitative components. Qualitative data from focus groups and interviews with fps and cancer specialists about the role of fps in breast cancer gep testing were obtained during studies conducted within the pan-Canadian canimpact research program. We determined the number of visits by breast cancer patients to a fp between the first medical oncology visit and the start of chemotherapy, a period when patients might be considering results of gep testing. RESULTS: The fps and cancer specialists felt that ordering gep tests and explaining the results was the role of the oncologist. A new fp role was identified relating to the fp-patient relationship: supporting patients in making adjuvant therapy decisions informed by gep tests by considering the patient's comorbid conditions, social situation, and preferences. Lack of fp knowledge and resources, and challenges in fp-oncologist communication were seen as significant barriers to that role. Between 28% and 38% of patients visited a fp between the first oncology visit and the start of chemotherapy. CONCLUSIONS: Our findings suggest an emerging role for fps in supporting patients who are making adjuvant treatment decisions after receiving the results of gep testing. For success in this new role, education and point-of-care tools, together with more effective communication strategies between fps and oncologists, are needed.

Impact of early palliative care on caregivers of patients with advanced cancer: cluster randomised trial.

Background: Early palliative care improves the quality of life (QoL) and satisfaction with care of patients with advanced cancer, but little is known about its effect on caregivers. Here, we report outcomes of caregiver satisfaction with care and QoL from a trial of early palliative care. Patients and methods: Twenty-four medical oncology clinics were cluster-randomised, stratified by tumour site (lung, gastrointestinal, genitourinary, breast and gynaecological), to early palliative care team referral, or to standard oncology care with palliative care only as needed. Caregivers of patients with advanced cancer (clinical prognosis of 6-24 months, Eastern Cooperative Oncology Group 0-2) in both trial arms completed validated measures assessing satisfaction with care (FAMCARE-19) and QoL [SF-36v2 Health Survey; Caregiver QoL-Cancer (CQoL-C)], at baseline and monthly for 4 months. We used a multilevel linear random-intercept mixed-effect model to test whether there was improvement in the intervention group relative to the control group over 3 and 4 months. Results: A total of 182 caregivers completed baseline measures (94 intervention, 88 control); 151 caregivers (77 intervention, 74 control) completed at least one follow-up assessment. Satisfaction with care improved in the palliative intervention group compared with controls over 3 months (P = 0.007) and 4 months (P = 0.02). There was no significant improvement in the intervention group compared with controls for CQoL-C (3 months: P = 0.92, 4 months: P = 0.51), Physical Component Summary of the SF-36v2 Health Survey (3 months: P = 0.83, 4 months: P = 0.20), or Mental Component Summary of the SF-36v2 Health Survey (3 months: P = 0.87, 4 months: P = 0.60). Conclusion: Early palliative care increased satisfaction with care in caregivers of patients with advanced cancer. ClinicalTrials.gov identifier: NCT01248624.

Adjuvant Chemotherapy for Stage II Colon Cancer: Practice Patterns and Effectiveness in the General Population.

AIMS: Although guidelines do not recommend adjuvant chemotherapy (ACT) for stage II colon cancer, many state that ACT may be considered in high-risk disease. Here we describe practice patterns and outcomes associated with ACT in the general population. MATERIALS AND METHODS: All cases of colon cancer diagnosed in Ontario 2002-2008 were identified using the Ontario Cancer Registry, which was linked to electronic treatment records. Pathology reports were obtained for a 25% random sample of cases. High-risk disease was defined as: T4 tumours, <12 lymph nodes, poorly differentiated histology, lymphovascular invasion. Modified Poisson regression was used to evaluate factors associated with ACT. The Cox proportional hazards model was used to explore the association between ACT and cancer-specific (CSS) and overall survival. RESULTS: The study population included 2488 patients with stage II colon cancer; 1175 (47%) with high-risk disease. ACT was delivered to 18% of all patients and 24% of patients with high-risk disease. ACT rates were higher among younger patients (51% age 20-49 years versus 16% age 70-79, P < 0.001) and varied considerably across geographic regions (range 10-39%, P < 0.001). Among all patients with stage II colon cancer, ACT was not associated with improved CSS (hazard ratio 1.41, 95% confidence interval 1.09-1.82) or overall survival (hazard ratio 1.16, 95% confidence interval 0.94-1.42). Stratified survival analysis for patients with high-risk disease did not show benefit to ACT (CSS hazard ratio 1.14, 95% confidence interval 0.84-1.55; overall survival hazard ratio 1.02, 95% confidence interval 0.79-1.31). CONCLUSION: ACT use varies across age groups and geographic regions. ACT is not associated with improved survival among patients with stage II colon cancer including those with high-risk disease.

Approach to evaluation of fever in ambulatory cancer patients receiving chemotherapy: A systematic review.

PURPOSE: To define the optimal model of care for patients receiving outpatient chemotherapy who experience a fever. Fever is a common symptom in patients receiving chemotherapy, but the approach to evaluation of fever is not standardized. METHODS: We conducted a search for existing guidelines and a systematic review of the primary literature from database inception to November 2015. Full-text reports and conference abstracts were considered for inclusion. The search focused on the following topics: the relationship between temperature and poor outcome; predictors for the development of febrile neutropenia (FN); the timing, location, and personnel involved in fever assessment; and the provision of information to patients receiving chemotherapy. RESULTS: Eight guidelines and 38 studies were included. None of the guidelines were directly relevant to the target population because they dealt primarily with the management of FN after diagnosis. The primary studies tended to include fever as one of many symptoms assessed in the setting of chemotherapy. Temperature level was a weak predictor of poor outcomes. We did not find validated prediction models for identifying patients at risk of FN among patients receiving chemotherapy. Several studies presented approaches to symptom management that included fever among the symptoms, but results were not mature enough to merit widespread adoption. CONCLUSION: Despite the frequency and risks of fever in the setting of chemotherapy, there is limited evidence to define who needs urgent assessment, where the assessment should be performed, and how quickly. Future research in this area is greatly needed to inform new models of care.

Approach to fever assessment in ambulatory cancer patients receiving chemotherapy: a clinical practice guideline.

BACKGROUND: This guideline was prepared by the Fever Assessment Guideline Development Group, a group organized by the Program in Evidence-Based Care at the request of the Cancer Care Ontario Systemic Treatment Program. The mandate was to develop a standardized approach (in terms of definitions, information, and education) for the assessment of fever in cancer patients receiving chemotherapy. METHODS: The guideline development methods included a search for existing guidelines, literature searches in medline and embase for systematic reviews and primary studies, internal review by content and methodology experts, and external review by targeted experts and intended users. RESULTS: The search identified eight guidelines that had partial relevance to the topic of the present guideline and thirty-eight primary studies. The studies were mostly noncomparative prospective or retrospective studies. Few studies directly addressed the topic of fever except as one among many symptoms or adverse effects associated with chemotherapy. The recommendations concerning fever definition are supported mainly by other existing guidelines. No evidence was found that directly pertained to the assessment of fever before a diagnosis of febrile neutropenia was made. However, some studies evaluated approaches to symptom management that included fever among the symptoms. Few studies directly addressed information needs and resources for managing fever in cancer patients. CONCLUSIONS: Fever in patients with cancer who are receiving systemic therapy is a common and potentially serious symptom that requires prompt assessment, but currently, evidence to inform best practices concerning when, where, and by whom that assessment is done is very limited.

A phase II study of the HSP90 inhibitor AUY922 in chemotherapy refractory advanced pancreatic cancer.

OBJECTIVES: AUY922 is a novel heat shock protein inhibitor with preclinical activity in pancreatic cancer. This phase II study evaluated the efficacy of AUY922 in patients with advanced pancreatic cancer previously treated with chemotherapy. METHODS: In this single-arm, Simon two-stage phase II trial, patients with metastatic or locally advanced pancreatic ductal adenocarcinoma who had progressed on at least one line of chemotherapy and were of good performances status (ECOG 0 or 1) were treated with AUY922 at a dose of 70 mg/m(2) IV weekly. The primary endpoint was disease control rate (objective response and stable disease ≥16 weeks). RESULTS: Twelve patients were accrued, all of whom received treatment. At least possibly related ≥grade 3 adverse events included fatigue (8 %) and AST elevation (8 %). Ten patients were evaluable for response with 1 (10 %) having stable disease and 9 (90 %) progressive disease. The median progression-free survival was 1.6 months, and the median overall survival was 2.9 months. CONCLUSIONS: AUY922 was not associated with significant efficacy in previously treated patients with advanced pancreatic cancer.

Surgical resection and peri-operative chemotherapy for colorectal cancer liver metastases: A population-based study.

BACKGROUND: Most literature describing surgery for colorectal cancer (CRC) liver metastases (LM) comes from high volume centres. Here, we report management and outcomes achieved in routine clinical practice. METHODS: All cases of CRC in Ontario who underwent resection of LM in 1994-2009 were identified using the population-based Ontario Cancer Registry. Electronic treatment records identified chemotherapy delivery. Temporal trends are described for 3 periods: 1994-1999, 2000-2004, 2005-2009. We describe volume of resected CRCLM as a ratio of incident cases per CRCLM resection. Overall (OS) and cancer-specific survival (CSS) are measured from time of LM resection. RESULTS: 2717 patients underwent resection of CRCLM. Between 1994 and 2009 there was a 78% increase in case volume; from one resection for every 48 incident cases to one resection for every 27 incident cases, p < 0.001. Use of peri-operative chemotherapy increased over study periods from 44% (306/700), to 52% (429/830), to 65% (777/1187, p < 0.001). Chemotherapy utilization rates varied across geographic regions (range 43%-69%, p < 0.001). Post-operative mortality rates at 30 and 90 days were 2.5% and 4.3% respectively. Five year OS during the study periods was 36% (95% CI 32-39%), 40% (95% CI 36-43%), and 46% (95% CI 43-49%) (p < 0.001); CSS was 38% (95% CI 35-42%), 42% (95% CI 38-45%), 49% (95% CI 44-53%) (p < 0.001). The temporal improvement in OS/CSS persisted on adjusted analyses. CONCLUSIONS: Outcomes of patients with resected CRCLM in routine practice is comparable to those reported from high volume centres. Survival improved over the study period despite a greater proportion of patients with CRC undergoing liver resection.

Guidelines on the use of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in patients with peritoneal surface malignancy arising from colorectal or appendiceal neoplasms.

To meet the needs of patients, Canadian surgical and medical oncology leaders in the treatment of peritoneal surface malignancies (psms), together with patient representatives, formed the Canadian HIPEC Collaborative Group (chicg). The group is dedicated to standardizing and improving the treatment of psm in Canada so that access to treatment and, ultimately, the prognosis of Canadian patients with psm are improved. Patients with resectable psm arising from colorectal or appendiceal neoplasms should be reviewed by a multidisciplinary team including surgeons and medical oncologists with experience in treating patients with psm. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy should be offered to appropriately selected patients and performed at experienced centres. The aim of this publication is to present guidelines that we recommend be applied across the country for the treatment of psm.

Does routine symptom screening with ESAS decrease ED visits in breast cancer patients undergoing adjuvant chemotherapy?

BACKGROUND: In 2007, the provincial cancer agency in Ontario, Canada initiated a wide-scale program to screen for symptoms in the cancer population using the Edmonton Symptom Assessment Scale (ESAS). The purpose of this study is to evaluate the impact of screening with ESAS on emergency department (ED) visit rates in women with breast cancer receiving adjuvant chemotherapy. PATIENTS AND METHODS: This retrospective cohort study used linked administrative health care data from across the province of Ontario, Canada. The cohort included all women aged ≥18 who were diagnosed with stage I-III breast cancer between January 2007 and December 2009 and received adjuvant chemotherapy within 6 months of diagnosis. Using an adjusted recurrent event model, we examined the association of screening with ESAS at a clinic visit on the ED visit rate. RESULTS: The relative rate of ED visits was 0.57 when prior ESAS screening occurred compared to when it did not. The relative rate of ED visits was 0.83 when the prior number of ESAS screens was modeled as a continuous variable. Alternatively stated, the rate of ED visits was 43 % lower among patients previously screened with ESAS compared to those not previously screened. For each additional prior ESAS assessment, there was a 17 % decreased rate of ED visits. CONCLUSIONS: Our results demonstrate that screening with ESAS is associated with decreased ED visits. To our knowledge, this is the first report on the effectiveness of routinely documenting a patient reported outcome on ED visits, in a real-world setting.

Continuous versus intermittent chemotherapy strategies in metastatic colorectal cancer: a systematic review and meta-analysis.

BACKGROUND: An important goal of intermittent strategies of delivering systemic treatment as first-line treatment of metastatic colorectal cancer (mCRC) is to maintain efficacy while improving patients' quality of life (QoL). Given the varying impact on efficacy demonstrated in individual randomized, controlled trials (RCTs), a systematic review and meta-analysis of RCTs of these intermittent strategies was carried out. DESIGN: Relevant databases were systematically searched for the period 2000-2014. RCTs that compared a continuous versus intermittent strategy of delivering systemic treatment were identified by a systematic review. Overall survival (OS) hazard ratios (HRs) were extracted from the most recently reported trial results. The results of identified trials were clinically homogeneous so the data were pooled using Review Manager software (RevMan 5.1). RESULTS: Eleven RCTs were identified (n = 4 854). For the eight (n = 4508) trials with available HRs, the treatment patients received after induction was: none (five trials, n = 3036), fluoropyrimidine (one trial, n = 620), and biologic (two trials, n = 852). There were no statistically significant survival differences observed between the continuous and intermittent chemotherapy strategies. There was no statistically significant difference observed between continuous and intermittent strategies [HR = 1.03, 95% confidence interval (CI) 0.96-1.10, P = 0.38)]. Subgroup analyses demonstrated results were generally robust across induction and maintenance regimens. One subgroup analysis of the three trials (CAIRO3, OPTIMOX2, COIN, n = 2403) with combination treatment induction and no maintenance until progression revealed a statistically, but nonclinically significant benefit for continuous treatment (HR = 1.10, 95% CI 1.00-1.20, P = 0.049). QoL life was either the same in both arms in two trials (n = 912) or improved in the intermittent strategy arm in one trial (n = 1630). CONCLUSION: Intermittent strategies of delivering systemic treatment of mCRC do not result in a clinically significant reduction in OS compared with a continuous strategy of delivery, and should be part of an informed discussion of treatment options with patients with mCRC.

Induction gemcitabine plus concurrent gemcitabine and radiotherapy for locally advanced unresectable or resected pancreatic cancer.

AIMS: To determine the efficacy of induction gemcitabine followed by biweekly gemcitabine concurrent with radiotherapy for locally advanced pancreatic cancer. MATERIALS AND METHODS: Between March 2001 and August 2009, 90 patients with unresectable (78) or resected (12) pancreatic cancer were treated with a standard treatment policy of induction gemcitabine (seven doses of weekly gemcitabine at 1000 mg/m(2)) followed by concurrent radiotherapy (52.5 Gy) and biweekly gemcitabine (40 mg/m(2)). RESULTS: After induction gemcitabine, 17.8% of patients did not proceed to chemoradiotherapy, due to either disease progression, performance status deterioration or gemcitabine toxicity. Of the patients who received chemoradiotherapy, 68.9% completed the course of 52.5 Gy, whereas 79.7% received more than 45 Gy. Chemoradiotherapy was stopped early due to treatment toxicity in 22.9% of patients. On intention to treat analysis, the median overall survival was 12.7 months in the locally advanced group and 18.2 months in the resected group. On multivariate analysis for the unresectable patients, a larger gross tumour volume was a significant poor prognostic factor for overall survival and local progression-free survival. CONCLUSION: This large series confirms, in a standard practice setting, similar efficacy and tolerability of treatment as previously reported in our phase I-II study. The benefit to patients with a gross tumour volume >48 cm(3) may be limited.

How may clinical research improve healthcare outcomes?

Healthcare outcomes such as overall survival or quality of life are the end results of a complex interaction between the patient, treatment and the healthcare system. Research may identify superior interventions but their dissemination and changing the behaviour of healthcare providers is challenging. Demonstrating and measuring the benefits of clinical research on healthcare outcomes is an important issue but there is remarkably little empiric work to date in this area. In this chapter we explore benefits that may arise in healthcare from contributing to clinical research, and consider the mechanisms which may be relevant. Improvements in infrastructure, the processes of care and workforces are important. Complex adaptive systems theory provides a framework for considering the many feedback loops that relate research, health outcomes and the behaviour of healthcare providers. Given the costs of research, additional studies to examine the impact of research on healthcare outcomes and to explore the mechanisms are justified and highly desirable.