NET-02: a randomised, non-comparative, phase II trial of nal-IRI/5-FU or docetaxel as second-line therapy in patients with progressive poorly differentiated extra-pulmonary neuroendocrine carcinoma.

Background: The prognosis for patients with poorly-differentiated extra-pulmonary neuroendocrine carcinoma (PD-EP-NEC) is poor. A recognised first-line (1L) treatment for advanced disease is etoposide/platinum-based chemotherapy with no standard second-line (2L) treatment. Methods: Patients with histologically-confirmed PD-EP-NEC (Ki-67 > 20%; Grade 3) received IV liposomal irinotecan (nal-IRI) (70 mg/m2 free base)/5-FU (2400 mg/m2)/folinic acid, Q14 days (ARM A), or IV docetaxel (75 mg/m2), Q21 days (ARM B), as 2L therapy. Primary endpoint was 6-month progression-free survival (PFS) rate (80% power to demonstrate one-sided 95% lower confidence interval excluded 15% (target level of efficacy: 30%)). Secondary endpoints: objective response rate (ORR), median PFS, overall survival (OS), toxicity and patient-reported quality-of-life (QoL) (ClinicalTrials.gov: NCT03837977). Findings: Of 58 patients (29 each arm); 57% male, 90% ECOG PS 0/1, 10% PS 2, 89.7% Ki-67 ≥ 55%, primary site: 70.7%-gastrointestinal, 18.9%-other, 10.3%-unknown, 91.4%/6.9%/1.7% were resistant/sensitive/intolerant to 1L platinum-based treatment, respectively. The primary end-point of 6-month PFS rate was met by ARM A: 29.6% (lower 95% Confidence-Limit (CL) 15.7), but not by ARM B: 13.8% (lower 95%CL:4.9). ORR, median PFS and OS were 11.1% (95%CI:2.4-29.2) and 10.3% (95%CI:2.2-27.4%); 3 months (95%CI:2-6) and 2 months (95%CI:2-2); and 6 months (95%CI:3-10) and 6 months (95%CI:3-9) in ARMS A and B, respectively. Adverse events ≥ grade 3 occurred in 51.7% and 55.2% (1 and 6 discontinuations due to toxicity in ARMS A and B), respectively. QoL was maintained in ARM A, but not ARM B. Interpretation: nal-IRI/5-FU/folinic acid, but not docetaxel, met the primary endpoint, with manageable toxicity and maintained QoL, with no difference in OS. ORR and median PFS were similar in both arms. This study provides prospective efficacy, toxicity and QoL data in the 2L setting in a disease group of unmet need, and represents some of the strongest evidence available to recommend systemic treatment to these patients. Funding: Servier.

Advance care planning in primary care for patients with gastrointestinal cancer: feasibility randomised trial.

BACKGROUND: Advance (anticipatory) care planning (ACP) requires discussions between patients and healthcare professionals about planning for future deterioration in health. ACP improves care coordination but uptake is limited and often deferred. AIM: To assess the feasibility and acceptability to patients, carers, and GPs of a primary care ACP intervention for people with incurable oesophageal, gastric, or pancreatic cancer. DESIGN AND SETTING: A 12-month feasibility randomised controlled trial (RCT) in a Scottish Cancer Network. METHOD: Patients aged ≥18 years starting palliative oncology treatment were randomised 1:1 to an ACP intervention or standard care. Patients in the intervention group received an oncologist letter supporting them to request a GP review along with a patient information leaflet about ACP. Pre-specified analyses with masking included trial recruitment and retention, ACP completion, and quality-of-life questionnaires (EuroQol EQ-5D-5L and ICECAP Supportive Care Measure) at baseline, 6, 12, 24, and 48 weeks. Qualitative interviews with purposive sampling explored patient, carer, and GP experiences. RESULTS: Of 99 eligible participants (269 screened), 46% were recruited (n = 46) and randomised; 25 to intervention and 21 to control. By 12 weeks, 45% (n = 9/20) of the individuals in the intervention and 59% (n = 10/17) in the control group had a documented ACP plan. By 24 weeks, 30% (n = 14) had died; in the remaining participants quality of life was maintained at 24 weeks except for physical symptoms. Social norms associating ACP with dying were prevalent among 23 participants interviewed. No psychological or clinical harms were identified. CONCLUSION: An RCT of ACP for people with incurable cancer in primary care is feasible. Patient, carer, and GP attitudes and behaviours determined acceptability and timing of care planning.

Daily functioning in glioma survivors: associations with cognitive function, psychological factors and quality of life.

Aim: Understanding and supporting quality of life (QoL) and daily functioning in glioma patients is a clinical imperative. In this study, we examined the relationship between cognition, psychological factors, measures of health-related QoL and functioning in glioma survivors. Materials & methods: We examined neuropsychological, self-reported cognition, mood and QoL correlates of work and non-work-related daily functioning in 23 glioma survivors, and carried out linear models of the best predictors. Results & conclusion: A total of 13/23 participants were working at the time of enrollment. The best model for worse work-related functioning (R2 = .83) included worse self-reported cognitive function, depression, loneliness and brain tumor symptoms. The best model for worse non-work-related functioning (R2 = .61) included worse self-reported cognitive functioning, anxiety, sleep disturbance and physical functioning. Neuropsychological variables were not among the most highly correlated with function. Worse cognitive, particularly self-reported and psychosocial outcomes may compromise optimal functioning in glioma survivors.

Long-Term Outcomes and Exploratory Analyses of the Randomized Phase III BILCAP Study.

PURPOSE: The BILCAP study described a modest benefit for capecitabine as adjuvant therapy for curatively resected biliary tract cancer (BTC), and capecitabine has become the standard of care. We present the long-term data and novel exploratory subgroup analyses. METHODS: This randomized, controlled, multicenter, phase III study recruited patients age 18 years or older with histologically confirmed cholangiocarcinoma or muscle-invasive gallbladder cancer after resection with curative intent and an Eastern Cooperative Oncology Group performance status of < 2. Patients were randomly assigned 1:1 to receive oral capecitabine (1,250 mg/m2 twice daily on days 1-14 of a 21-day cycle, for eight cycles) or observation. The primary outcome was overall survival (OS). This study is registered with EudraCT 2005-003318-13. RESULTS: Between March 15, 2006, and December 4, 2014, 447 patients were enrolled; 223 patients with BTC resected with curative intent were randomly assigned to the capecitabine group and 224 to the observation group. At the data cutoff of January 21, 2021, the median follow-up for all patients was 106 months (95% CI, 98 to 108). In the intention-to-treat analysis, the median OS was 49.6 months (95% CI, 35.1 to 59.1) in the capecitabine group compared with 36.1 months (95% CI, 29.7 to 44.2) in the observation group (adjusted hazard ratio 0.84; 95% CI, 0.67 to 1.06). In a protocol-specified sensitivity analysis, adjusting for minimization factors, nodal status, grade, and sex, the OS hazard ratio was 0.74 (95% CI, 0.59 to 0.94). We further describe the prognostic impact of R status, grade, nodal status, and sex. CONCLUSION: This long-term analysis supports the previous analysis, suggesting that capecitabine can improve OS in patients with resected BTC when used as adjuvant chemotherapy after surgery and should be considered as the standard of care.

NET-02 trial protocol: a multicentre, randomised, parallel group, open-label, phase II, single-stage selection trial of liposomal irinotecan (nal-IRI) and 5-fluorouracil (5-FU)/folinic acid or docetaxel as second-line therapy in patients with progressive poorly differentiated extrapulmonary neuroendocrine carcinoma (NEC).

INTRODUCTION: Poorly differentiated (PD), extrapulmonary (EP), neuroendocrine carcinomas (NECs) are rare but aggressive neuroendocrine neoplasms. First-line treatment for advanced disease is an etoposide and platinum-based chemotherapy combination. There is no established second-line treatment for patients with PD-EP-NEC, and this is an area of unmet need. METHODS AND ANALYSIS: NET-02 is a UK, multicentre, randomised (1:1), parallel group, open-label, phase II, single-stage selection trial of liposomal irinotecan (nal-IRI)/5-fluorouracil (5-FU)/folinic acid or docetaxel as second-line therapy in patients with progressive PD-EP-NEC. One hundred and two eligible participants will be randomised to receive either nal-IRI/5-FU/folinic acid or docetaxel. The primary objective is to determine the 6-month progression-free survival (PFS) rate. The secondary objectives of this study are to determine PFS, overall survival, objective response rate, toxicity, quality of life and whether neuron-specific enolase is predictive of treatment response. If either treatment is found to have a 6-month PFS rate of at least 25%, that treatment will be considered for a phase III trial. If both treatments meet this target, prespecified selection criteria will be applied to establish which treatment to take forward. ETHICS AND DISSEMINATION: This study has ethical approval from the Greater Manchester Central Research Ethics Committee (reference no. 18/NW/0031) and clinical trial authorisation from the Medicine and Healthcare Products Regulatory Agency. Results will be published in peer-reviewed journals and uploaded to the European Union Clinical Trials Register. TRIAL REGISTRATION NUMBERS: ISRCTN10996604, NCT03837977, EudraCT Number: 2017-002453-11.

Prognostic value of the neutrophil/lymphocyte ratio in enteropancreatic neuroendocrine tumors.

Accessible prognostic tools are needed to individualize treatment of neuroendocrine tumors (NETs). Data suggest neutrophil/lymphocyte ratios (NLRs) have prognostic value in some solid tumors, including NETs. In the randomized double-blind CLARINET study (NCT00353496; EudraCT 2005-004904-35), the somatostatin analog lanreotide autogel/depot increased progression-free survival (PFS) compared with placebo in patients with inoperable or metastatic intestinal and pancreatic NETs (grades 1-2, Ki-67 < 10%). The exploratory post-hoc analyses presented here evaluated the prognostic value of NLR in the CLARINET study cohort, in the context of and independently from treatment. Kaplan-Meier PFS plots were generated for patients with available NLR data, in subgroups based on NLR values, and 24-month survival rates were calculated. P values and hazard ratios for prognostic effects were generated using Cox models. 31216222 Baseline characteristics were balanced between lanreotide autogel/depot 120 mg (n = 100) and placebo (n = 101) arms. Irrespective of treatment, raw 24-month PFS rates were comparable across subgroups based on NLR tertiles [37.3% (low), 38.8% (middle), 38.8% (high); n = 67 per group] and NLR cutoff of 4 [38.1% (NLR ≤ 4; n = 176), 40.0% (NLR > 4; n = 25)]. Furthermore, NLRs were not prognostic in Cox models, irrespective of subgroups used. The therapeutic effect of lanreotide autogel/depot 120 mg was independent of NLRs (P > 0.1). These exploratory post-hoc analyses in patients with advanced intestinal and pancreatic NETs contrast with previous data suggesting NLR has prognostic potential in NETs. This may reflect the inclusion of patients with lower-grade tumors or use of higher NLR cutoff values in the current analysis.

Tyrosine Kinase Inhibitor Therapy in Locally Advanced Differentiated Thyroid Cancer: A Case Report.

A 73-year-old female presenting with haemoptysis and dyspnoea was found to have a locally advanced left thyroid mass and vocal cord palsy. A CT scan of the neck and thorax and endoscopy demonstrated invasion into the tracheal lumen. Histopathology of the intraluminal tracheal mass confirmed a papillary thyroid cancer (PTC). The tumour was deemed unresectable due to local extent and patient comorbidities. TKI therapy with lenvatinib was used for 14 months. On serial scanning, a marked reduction in tumour volume from 31 × 59 × 32 mm to 17 × 28 × 22 mm was noted. This subsequently allowed a successful surgical resection with a total thyroidectomy and central neck dissection with no evidence of residual macroscopic disease. Histopathology confirmed a well-differentiated PTC with features of tumour regression. In this case, TKI therapy in a locally advanced unresectable DTC reduced tumour size and infiltration to a degree that surgical resection of macroscopic disease was possible, without requiring airway resection. This raises the possibility that TKIs may have a neoadjuvant role in selected cases of locally advanced DTC to reduce tumour volume and therefore morbidity of subsequent surgical resection.

Capecitabine compared with observation in resected biliary tract cancer (BILCAP): a randomised, controlled, multicentre, phase 3 study.

BACKGROUND: Despite improvements in multidisciplinary management, patients with biliary tract cancer have a poor outcome. Only 20% of patients are eligible for surgical resection with curative intent, with 5-year overall survival of less than 10% for all patients. To our knowledge, no studies have described a benefit of adjuvant therapy. We aimed to determine whether adjuvant capecitabine improved overall survival compared with observation following surgery for biliary tract cancer. METHODS: This randomised, controlled, multicentre, phase 3 study was done across 44 specialist hepatopancreatobiliary centres in the UK. Eligible patients were aged 18 years or older and had histologically confirmed cholangiocarcinoma or muscle-invasive gallbladder cancer who had undergone a macroscopically complete resection (which includes liver resection, pancreatic resection, or, less commonly, both) with curative intent, and an Eastern Cooperative Oncology Group performance status of less than 2. Patients who had not completely recovered from previous surgery or who had previous chemotherapy or radiotherapy for biliary tract cancer were also excluded. Patients were randomly assigned 1:1 to receive oral capecitabine (1250 mg/m2 twice daily on days 1-14 of a 21-day cycle, for eight cycles) or observation commencing within 16 weeks of surgery. Treatment was not masked, and allocation concealment was achieved with a computerised minimisation algorithm that stratified patients by surgical centre, site of disease, resection status, and performance status. The primary outcome was overall survival. As prespecified, analyses were done by intention to treat and per protocol. This study is registered with EudraCT, number 2005-003318-13. FINDINGS: Between March 15, 2006, and Dec 4, 2014, 447 patients were enrolled; 223 patients with biliary tract cancer resected with curative intent were randomly assigned to the capecitabine group and 224 to the observation group. The data cutoff for this analysis was March 6, 2017. The median follow-up for all patients was 60 months (IQR 37-60). In the intention-to-treat analysis, median overall survival was 51·1 months (95% CI 34·6-59·1) in the capecitabine group compared with 36·4 months (29·7-44·5) in the observation group (adjusted hazard ratio [HR] 0·81, 95% CI 0·63-1·04; p=0·097). In a protocol-specified sensitivity analysis, adjusting for minimisation factors and nodal status, grade, and gender, the overall survival HR was 0·71 (95% CI 0·55-0·92; p=0·010). In the prespecified per-protocol analysis (210 patients in the capecitabine group and 220 in the observation group), median overall survival was 53 months (95% CI 40 to not reached) in the capecitabine group and 36 months (30-44) in the observation group (adjusted HR 0·75, 95% CI 0·58-0·97; p=0·028). In the intention-to-treat analysis, median recurrence-free survival was 24·4 months (95% CI 18·6-35·9) in the capecitabine group and 17·5 months (12·0-23·8) in the observation group. In the per-protocol analysis, median recurrence-free survival was 25·9 months (95% CI 19·8-46·3) in the capecitabine group and 17·4 months (12·0-23·7) in the observation group. Adverse events were measured in the capecitabine group only, and of the 213 patients who received at least one cycle, 94 (44%) had at least one grade 3 toxicity, the most frequent of which were hand-foot syndrome in 43 (20%) patients, diarrhoea in 16 (8%) patients, and fatigue in 16 (8%) patients. One (<1%) patient had grade 4 cardiac ischaemia or infarction. Serious adverse events were observed in 47 (21%) of 223 patients in the capecitabine group and 22 (10%) of 224 patients in the observation group. No deaths were deemed to be treatment related. INTERPRETATION: Although this study did not meet its primary endpoint of improving overall survival in the intention-to-treat population, the prespecified sensitivity and per-protocol analyses suggest that capecitabine can improve overall survival in patients with resected biliary tract cancer when used as adjuvant chemotherapy following surgery and could be considered as standard of care. Furthermore, the safety profile is manageable, supporting the use of capecitabine in this setting. FUNDING: Cancer Research UK and Roche.

Patients unfit for neoadjuvant therapy may still undergo resection of locally advanced esophageal or esophagogastric junctional cancer with acceptable oncological results.

Neoadjuvant chemotherapy (NA) is routinely offered to patients undergoing resection for locally advanced (≥cT3Nx or cTxN+) esophageal or esophagogastric junctional (EGJ) cancer in the United Kingdom. Patients with comorbidity precluding the use of NA can be considered for resection yet the effect of omitting NA on survival is unclear. METHODS: Retrospective review of prospectively collected clinical data from patients undergoing attempted curative therapy for ≥cT3Nx or cTxN+ esophageal or EGJ (Siewert type I-III) cancer between 2001 and 2013. RESULTS: NA was commenced in 289 patients and primarily comprised 2 cycles of cisplatin and 5-fluorouracil (264 patients, 91%). Surgery alone was planned for 82 patients with NA omitted due to comorbidity. Patients undergoing surgery alone were matched for clinical variables and stage with those undergoing NA but were significantly older (mean=8 y, P<0.001). NA was associated with an improved median overall survival of 28.7 months, compared with 20.9 months for patients undergoing surgery alone (P=0.008). Patients undergoing surgery alone had a 90-day postoperative mortality rate of 10% compared with 3% for those undergoing NA (P=0.011). In patients discharged postoperatively, the median overall survival benefit of NA was 2.7 months (P=0.048). Those 19% of patients experiencing a significant histologic response to NA demonstrated further improved survival. CONCLUSIONS: NA improves survival in patients undergoing resection for locally advanced esophageal or EGJ cancer; however, the median benefit is <3 months in patients discharged postoperatively. Patients precluded from NA achieve acceptable oncological results but experience a higher risk of perioperative mortality.

Sorafenib in combination with transarterial chemoembolisation in patients with unresectable hepatocellular carcinoma (TACE 2): a randomised placebo-controlled, double-blind, phase 3 trial.

BACKGROUND: Transarterial chemoembolisation (TACE) is the standard of care for patients with intermediate stage hepatocellular carcinoma, while the multikinase inhibitor sorafenib improves survival in patients with advanced disease. We aimed to determine whether TACE with sorafenib improves progression-free survival versus TACE with placebo. METHODS: We did a multicentre, randomised, placebo-controlled, phase 3 trial (TACE 2) in 20 hospitals in the UK for patients with unresectable, liver-confined hepatocellular carcinoma. Patients were eligible if they were at least aged 18 years, had Eastern Cooperative Oncology Group performance status of 1 or less, and had Child-Pugh A liver disease. Patients were randomised 1:1 by computerised minimisation algorithm to continuous oral sorafenib (400 mg twice-daily) or matching placebo combined with TACE using drug-eluting beads (DEB-TACE), which was given via the hepatic artery 2-5 weeks after randomisation and according to radiological response and patient tolerance thereafter. Patients were stratified according to randomising centre and serum α-fetoprotein concentration (<400 ng/mL and ≥400 ng/mL). Only the trial coordinator was unmasked to treatment allocation before patient progression during the study. The primary endpoint was progression-free survival defined as the interval between randomisation and progression according to Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v1.1) or death due to any cause, and was analysed by intention-to-treat. Safety was analysed by intention-to-treat. The trial has been completed and the final results are reported. The trial is registered at EudraCT, number 2008-005073-36, and ISRCTN, number ISRCTN93375053. FINDINGS: Between Nov 4, 2010, and Dec 7, 2015, the trial enrolled 399 patients and was terminated after a planned interim futility analysis. 86 patients failed screening and 313 remaining patients were randomly assigned: 157 to sorafenib and 156 to placebo. The median daily dose was 660 mg (IQR 389·2-800·0) sorafenib versus 800 mg (758·2-800·0) placebo, and median duration of therapy was 120·0 days (IQR 43·0-266·0) for sorafenib versus 162·0 days (70·0-323·5) for placebo. There was no evidence of difference in progression-free survival between the sorafenib group and the placebo group (hazard ratio [HR] 0·99 [95% CI 0·77-1·27], p=0·94); median progression-free survival was 238·0 days (95% CI 221·0-281·0) in the sorafenib group and 235·0 days (209·0-322·0) in the placebo group. The most common grade 3-4 adverse events were fatigue (29 [18%] of 157 patients in the sorafenib group vs 21 [13%] of 156 patients in the placebo group), abdominal pain (20 [13%] vs 12 [8%]), diarrhoea (16 [10%] vs four [3%]), gastrointestinal disorders (18 [11%] vs 12 [8%]), and hand-foot skin reaction (12 [8%] and none). At least one serious adverse event was reported in 65 (41%) of 157 patients in the sorafenib group and 50 (32%) of 156 in the placebo group, and 181 serious adverse events were reported in total, 95 (52%) in the sorafenib group and 86 (48%) in the placebo group. Three deaths occurred in each group that were attributed to DEB-TACE. Four deaths were attributed to study drug; three in the sorafenib group and one in the placebo group. INTERPRETATION: The addition of sorafenib to DEB-TACE does not improve progression-free survival in European patients with hepatocellular carcinoma. Alternative systemic therapies need to be assessed in combination with TACE to improve patient outcomes. FUNDING: Bayer PLC and BTG PLC.

Anti-tumour effects of lanreotide for pancreatic and intestinal neuroendocrine tumours: the CLARINET open-label extension study.

In the CLARINET study, lanreotide Autogel (depot in USA) significantly prolonged progression-free survival (PFS) in patients with metastatic pancreatic/intestinal neuroendocrine tumours (NETs). We report long-term safety and additional efficacy data from the open-label extension (OLE). Patients with metastatic grade 1/2 (Ki-67 ≤ 10%) non-functioning NET and documented baseline tumour-progression status received lanreotide Autogel 120 mg (n = 101) or placebo (n = 103) for 96 weeks or until death/progressive disease (PD) in CLARINET study. Patients with stable disease (SD) at core study end (lanreotide/placebo) or PD (placebo only) continued or switched to lanreotide in the OLE. In total, 88 patients (previously: lanreotide, n = 41; placebo, n = 47) participated: 38% had pancreatic, 39% midgut and 23% other/unknown primary tumours. Patients continuing lanreotide reported fewer adverse events (AEs) (all and treatment-related) during OLE than core study. Placebo-to-lanreotide switch patients reported similar AE rates in OLE and core studies, except more diarrhoea was considered treatment-related in OLE (overall diarrhoea unchanged). Median lanreotide PFS (core study randomisation to PD in core/OLE; n=101) was 32.8 months (95% CI: 30.9, 68.0). A sensitivity analysis, addressing potential selection bias by assuming that patients with SD on lanreotide in the core study and not entering the OLE (n=13) had PD 24 weeks after last core assessment, found median PFS remaining consistent: 30.8 months (95% CI: 30.0, 31.3). Median time to further PD after placebo-to-lanreotide switch (n=32) was 14.0 months (10.1; not reached). This OLE study suggests long-term treatment with lanreotide Autogel 120 mg maintained favourable safety/tolerability. CLARINET OLE data also provide new evidence of lanreotide anti-tumour benefits in indolent and progressive pancreatic/intestinal NETs.

Integrated collaborative care for major depression comorbid with a poor prognosis cancer (SMaRT Oncology-3): a multicentre randomised controlled trial in patients with lung cancer.

BACKGROUND: The management of depression in patients with poor prognosis cancers, such as lung cancer, creates specific challenges. We aimed to assess the efficacy of an integrated treatment programme for major depression in patients with lung cancer compared with usual care. METHODS: Symptom Management Research Trials (SMaRT) Oncology-3 is a parallel-group, multicentre, randomised controlled trial. We enrolled patients with lung cancer and major depression from three cancer centres and their associated clinics in Scotland, UK. Participants were randomly assigned in a 1:1 ratio to the depression care for people with lung cancer treatment programme or usual care by a database software algorithm that used stratification (by trial centre) and minimisation (by age, sex, and cancer type) with allocation concealment. Depression care for people with lung cancer is a manualised, multicomponent collaborative care treatment that is systematically delivered by a team of cancer nurses and psychiatrists in collaboration with primary care physicians. Usual care is provided by primary care physicians. The primary outcome was depression severity (on the Symptom Checklist Depression Scale [SCL-20], range 0-4) averaged over the patient's time in the trial (up to a maximum of 32 weeks). Trial statisticians and data collection staff were masked to treatment allocation, but patients and clinicians could not be masked to the allocations. Analyses were by intention to treat. This trial is registered with Current Controlled Trials, number ISRCTN75905964. FINDINGS: 142 participants were recruited between Jan 5, 2009, and Sept 9, 2011; 68 were randomly allocated to depression care for people with lung cancer and 74 to usual care. 43 (30%) of 142 patients had died by 32 weeks, all of which were cancer-related deaths. No intervention-related serious adverse events occurred. 131 (92%) of 142 patients provided outcome data (59 in the depression care for people with lung cancer group and 72 in the usual care group) and were included in the intention-to-treat primary analysis. Average depression severity was significantly lower in patients allocated to depression care for people with lung cancer (mean score on the SCL-20 1·24 [SD 0·64]) than in those allocated to usual care (mean score 1·61 [SD 0·58]); difference -0·38 (95% CI -0·58 to -0·18); standardised mean difference -0·62 (95% CI -0·94 to -0·29). Self-rated depression improvement, anxiety, quality of life, role functioning, perceived quality of care, and proportion of patients achieving a 12-week treatment response were also significantly better in the depression care for people with lung cancer group than in the usual care group. INTERPRETATION: Our findings suggest that major depression can be treated effectively in patients with a poor prognosis cancer; integrated depression care for people with lung cancer was substantially more efficacious than was usual care. Larger trials are now needed to estimate the effectiveness and cost-effectiveness of this care programme in this patient population, and further adaptation of the treatment will be necessary to address the unmet needs of patients with major depression and even shorter life expectancy. FUNDING: Cancer Research UK and Chief Scientist Office of the Scottish Government.

Integrated collaborative care for comorbid major depression in patients with cancer (SMaRT Oncology-2): a multicentre randomised controlled effectiveness trial.

BACKGROUND: Medical conditions are often complicated by major depression, with consequent additional impairment of quality of life. We aimed to compare the effectiveness of an integrated treatment programme for major depression in patients with cancer (depression care for people with cancer) with usual care. METHODS: SMaRT Oncology-2 is a parallel-group, multicentre, randomised controlled effectiveness trial. We enrolled outpatients with major depression from three cancer centres and their associated clinics in Scotland, UK. Participants were randomly assigned in a 1:1 ratio to the depression care for people with cancer intervention or usual care, with stratification (by trial centre) and minimisation (by age, primary cancer, and sex) with allocation concealment. Depression care for people with cancer is a manualised, multicomponent collaborative care treatment that is delivered systematically by a team of cancer nurses and psychiatrists in collaboration with primary care physicians. Usual care is provided by primary care physicians. Outcome data were collected up until 48 weeks. The primary outcome was treatment response (≥50% reduction in Symptom Checklist Depression Scale [SCL-20] score, range 0-4) at 24 weeks. Trial statisticians and data collection staff were masked to treatment allocation, but participants could not be masked to the allocations. Analyses were by intention to treat. This trial is registered with Current Controlled Trials, number ISRCTN40568538. FINDINGS: 500 participants were enrolled between May 12, 2008, and May 13, 2011; 253 were randomly allocated to depression care for people with cancer and 247 to usual care. 143 (62%) of 231 participants in the depression care for people with cancer group and 40 (17%) of 231 in the usual care group responded to treatment: absolute difference 45% (95% CI 37-53), adjusted odds ratio 8·5 (95% CI 5·5-13·4), p<0·0001. Compared with patients in the usual care group, participants allocated to the depression care for people with cancer programme also had less depression, anxiety, pain, and fatigue; and better functioning, health, quality of life, and perceived quality of depression care at all timepoints (all p<0·05). During the study, 34 cancer-related deaths occurred (19 in the depression care for people with cancer group, 15 in the usual care group), one patient in the depression care for people with cancer group was admitted to a psychiatric ward, and one patient in this group attempted suicide. None of these events were judged to be related to the trial treatments or procedures. INTERPRETATION: Our findings suggest that depression care for people with cancer is an effective treatment for major depression in patients with cancer. It offers a model for the treatment of depression comorbid with other medical conditions. FUNDING: Cancer Research UK and Chief Scientist Office of the Scottish Government.

Lanreotide in metastatic enteropancreatic neuroendocrine tumors.

BACKGROUND: Somatostatin analogues are commonly used to treat symptoms associated with hormone hypersecretion in neuroendocrine tumors; however, data on their antitumor effects are limited. METHODS: We conducted a randomized, double-blind, placebo-controlled, multinational study of the somatostatin analogue lanreotide in patients with advanced, well-differentiated or moderately differentiated, nonfunctioning, somatostatin receptor-positive neuroendocrine tumors of grade 1 or 2 (a tumor proliferation index [on staining for the Ki-67 antigen] of <10%) and documented disease-progression status. The tumors originated in the pancreas, midgut, or hindgut or were of unknown origin. Patients were randomly assigned to receive an extended-release aqueous-gel formulation of lanreotide (Autogel [known in the United States as Depot], Ipsen) at a dose of 120 mg (101 patients) or placebo (103 patients) once every 28 days for 96 weeks. The primary end point was progression-free survival, defined as the time to disease progression (according to the Response Evaluation Criteria in Solid Tumors, version 1.0) or death. Secondary end points included overall survival, quality of life (assessed with the European Organization for Research and Treatment of Cancer questionnaires QLQ-C30 and QLQ-GI.NET21), and safety. RESULTS: Most patients (96%) had no tumor progression in the 3 to 6 months before randomization, and 33% had hepatic tumor volumes greater than 25%. Lanreotide, as compared with placebo, was associated with significantly prolonged progression-free survival (median not reached vs. median of 18.0 months, P<0.001 by the stratified log-rank test; hazard ratio for progression or death, 0.47; 95% confidence interval [CI], 0.30 to 0.73). The estimated rates of progression-free survival at 24 months were 65.1% (95% CI, 54.0 to 74.1) in the lanreotide group and 33.0% (95% CI, 23.0 to 43.3) in the placebo group. The therapeutic effect in predefined subgroups was generally consistent with that in the overall population, with the exception of small subgroups in which confidence intervals were wide. There were no significant between-group differences in quality of life or overall survival. The most common treatment-related adverse event was diarrhea (in 26% of the patients in the lanreotide group and 9% of those in the placebo group). CONCLUSIONS: Lanreotide was associated with significantly prolonged progression-free survival among patients with metastatic enteropancreatic neuroendocrine tumors of grade 1 or 2 (Ki-67 <10%). (Funded by Ipsen; CLARINET ClinicalTrials.gov number, NCT00353496; EudraCT 2005-004904-35.).

Physical activity monitoring: a responsive and meaningful patient-centered outcome for surgery, chemotherapy, or radiotherapy?

CONTEXT: In surgical and clinical oncology, there is a growing need for patient-centered outcomes that are responsive, meaningful, and fit for purpose. OBJECTIVES: The aim of this study was to validate physical activity (PA) monitoring as a responsive outcome measure at different stages of disease and treatment, by verifying correlations between PA, performance score, and quality of life (QoL). METHODS: Daily life PA of 162 cancer patients, monitored by a device that records time sitting/lying, time standing, time walking, number of steps taken, and walking cadence, was compared with 20 healthy volunteers. In a subgroup of patients, functional status and QoL were assessed using the World Health Organization/Eastern Cooperative Oncology Group and the Karnofsky Performance Status scores and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30) questionnaire. RESULTS: The PA of patients with resectable gastrointestinal cancer did not differ significantly from controls. In contrast, patients with advanced cancer took 45% fewer steps and spent an extra 2.8 hours/day lying/sitting (P=0.001). Patients undergoing neoadjuvant chemotherapy and surgery (5-6 weeks after operation) experienced a similar reduction in PA. There were significant correlations between PA and the physical and role domains as well as fatigue subscale of the EORTC QLQ-C30 scale. CONCLUSION: Objective PA scores correlate significantly with disease stage, functional status, and QoL of patients with cancer. Therefore, activity monitoring can make meaningful objective estimates of patient function in response to cancer and its treatment and may provide surrogate outcomes of QoL.

Thoughts of death and suicide reported by cancer patients who endorsed the "suicidal thoughts" item of the PHQ-9 during routine screening for depression.

BACKGROUND: Patients with serious medical illnesses, such as cancer, are at increased risk of suicide but are also often facing death. The Patient Health Questionnaire-9 (PHQ-9) is widely used to screen patients for depression. It includes an item that asks about thoughts of death and hurting yourself (Item-9). OBJECTIVE: To describe the nature of thoughts of death and suicide reported in clinical interviews carried out to further assess suicidal ideation of cancer outpatients who had endorsed the "suicidal thoughts item" (Item-9) of the PHQ-9 during routine depression screening. METHOD: Secondary analysis of anonymized service data (with ethical approval) derived from the routine clinical administration of self-report questionnaires and telephone interviews to outpatients attending a Cancer Centre in the UK. RESULTS: Complete data were available on 330/463 (71%) of patients who had endorsed Item-9. In a subsequent structured telephone interview, approximately one-third of these patients denied any thoughts that they would be better off dead, another third acknowledged having thoughts that they would be better off dead, but not of suicide, and the remaining third reported clear thoughts of committing suicide. CONCLUSION: Only one-third of cancer outpatients who endorse the "suicidal thoughts item" of the PHQ-9 report suicidal thoughts at a subsequent interview. Services planning to set up depression screening with the PHQ-9 need to carefully consider the relative benefits and burden to their service and patients of including Item-9 and interviewing all those who endorse it.

Screening for major depression in cancer outpatients: the diagnostic accuracy of the 9-item patient health questionnaire.

BACKGROUND: Systematic screening for depression has been recommended for patients who have medical conditions like cancer. The 9-item Patient Health Questionnaire (PHQ-9) is becoming widely used, but its diagnostic accuracy has not yet been tested in a cancer patient population. In this article, the authors report on the performance of the PHQ-9 as a screening instrument for major depressive disorder (MDD) in patients with cancer. METHODS: Data obtained from a depression screening service for patients who were attending clinics of a Regional Cancer Centre in Edinburgh, United Kingdom were used. Patients had completed both the PHQ-9 and a 2-stage procedure to identify cases of MDD. Performance of the PHQ-9 in identifying cases of MDD was determined using receiver operating characteristic (ROC) analysis. RESULTS: Data were available on 4264 patients. When scored as a continuous measure, the PHQ-9 performed well with an area under the ROC curve of 0.94 (95% confidence interval [CI], 0.93-0.95). A cutoff score of ≥ 8 provided a sensitivity of 93% (95% CI, 89%-95%), a specificity of 81% (95% CI, 80%-82%), a positive predictive value (PPV) of 25%, and a negative predictive value (NPV) of 99% and could be considered optimum in a screening context. The PHQ-9 did not perform as well when it was scored using an algorithm with a sensitivity of 56% (95% CI, 55%-57%), a specificity of 96% (95% CI, 95%-97%), a PPV of 52%, and an NPV of 97%. CONCLUSIONS: The PHQ-9 scored as a continuous measure with a cutoff score of ≥ 8 performed well in identifying MDD in cancer patients and should be considered as a screening instrument in this population.

Better off dead: suicidal thoughts in cancer patients.

PURPOSE: Cancer is associated with an increased risk of suicide and attempted suicide. However, we do not know how many cancer patients have thoughts that they would be better off dead or thoughts of hurting themselves. This study aimed to determine the prevalence of such thoughts in cancer outpatients and which patients are most likely to have them. PATIENTS AND METHODS: A survey of consecutive patients who attended the outpatient clinics of a regional cancer center in Edinburgh, United Kingdom. Patients completed the Patient Health Questionnaire-9 (PHQ-9), which included Item 9 that asks patients if they have had thoughts of being better off dead or of hurting themselves in some way in the previous 2 weeks. Those who reported having had such thoughts for at least several days in this period were labeled as positive responders. Patients also completed the Hospital Anxiety and Depression Scale (HADS) and a pain scale. The participating patients' cancer diagnoses and treatments were obtained from the cancer center clinical database. RESULTS: Data were available on 2,924 patients; 7.8% (229 of 2,924; 95% CI, 6.9% to 8.9%) were positive responders. Clinically significant emotional distress, substantial pain, and--to a lesser extent--older age, were associated with a positive response. There was strong evidence of interactions between these effects, and emotional distress played the most important role. CONCLUSION: A substantial number of cancer outpatients report thoughts that they would be better off dead or thoughts of hurting themselves. Management of emotional distress and pain should be a central aspect of cancer care.

Management of depression for people with cancer (SMaRT oncology 1): a randomised trial.

BACKGROUND: Major depressive disorder severely impairs the quality of life of patients with medical disorders such as cancer, but evidence to guide its management is scarce. We aimed to assess the efficacy and cost of a nurse-delivered complex intervention that was designed to treat major depressive disorder in patients who have cancer. METHODS: We did a randomised trial in a regional cancer centre in Scotland, UK. 200 outpatients who had cancer with a prognosis of greater than 6 months and major depressive disorder (identified by screening) were eligible and agreed to take part. Their mean age was 56.6 (SD 11.9) years, and 141 (71%) were women. We randomly assigned 99 of these participants to usual care, and 101 to usual care plus the intervention, with minimisation for sex, age, diagnosis, and extent of disease. The intervention was delivered by a cancer nurse at the centre over an average of seven sessions. The primary outcome was the difference in mean score on the self-reported Symptom Checklist-20 depression scale (range 0 to 4) at 3 months after randomisation. Analysis was by intention to treat. This trial is registered as ISRCTN84767225. FINDINGS: Primary outcome data were missing for four patients. For 196 patients for whom we had data at 3 months, the adjusted difference in mean Symptom Checklist-20 depression score, between those who received the intervention and those who did not, was 0.34 (95% CI 0.13-0.55). This treatment effect was sustained at 6 and 12 months. The intervention also improved anxiety and fatigue but not pain or physical functioning. It cost an additional pound sterling 5278 (US$10 556) per quality-adjusted life-year gained. INTERPRETATION: The intervention-Depression Care for People with Cancer-offers a model for the management of major depressive disorder in patients with cancer and other medical disorders who are attending specialist medical services that is feasible, acceptable, and potentially cost effective.

Neoadjuvant chemotherapy for carcinoma of the oesophagus and oesophago-gastric junction: a six-year experience.

BACKGROUND: Oesophageal cancer is a major clinical problem with a generally poor prognosis. As a result there has been interest in combining surgery with neoadjuvant chemotherapy to try and improve outcomes, although the current evidence for benefit is inconsistent. We aimed to compare, in a non-randomised study, the post-operative complication rate and short and long-term survival of patients who underwent surgical resection for carcinoma of the oesophagus and types I and II carcinoma of the oesophago-gastric junction with or without neo-adjuvant chemotherapy. METHODS: Details of all resections for oesophageal/junctional (types I and II) adenocarcinoma or squamous cell carcinoma between April 2000 and July 2006 were collected prospectively. Data from patients with T3 and/or N1 disease who underwent either neoadjuvant chemotherapy (NAC) or not (non-NAC) were compared. Data were analysed using Kaplan-Meier plots, Mann-Whitney U-test, Cox Regression modelling, and Chi-squared test with Yates' correction where sample sizes <10. RESULTS: 167 patients were included (89 NAC and 78 non-NAC). The in-hospital post-operative mortality rate of the NAC group (n = 2 deaths; 2.2%) was significantly lower (p = 0.045) than the non-NAC group (n = 6 deaths; 7.7%). Most deaths were due to cardio-respiratory complications; however, there was no significant difference in rates of chest infections, anastomotic leaks, wound infections, re-operations, readmission to ITU or overall complications between the two groups. Although both the two-year survival rate (60.7%) and long-term survival of NAC patients (median survival = 793 days; 95% CI = 390-1196) was greater than non-NAC patients (two-year survival rate = 48.7%; median survival = 554 days; 95% CI = 246-862 respectively), these differences were not statistically significant. CONCLUSION: This non-randomised study demonstrated that NAC was associated with a significant reduction in post-operative inpatient mortality rate. Whether this can be explained by a decreased co-morbidity in NAC patients or a protective phenomenon associated with NAC remains unclear. This study also demonstrated a greater two-year survival rate and overall median survival time following NAC but this was not statistically significant.