Weston Park Cancer Centre

The skeleton is the most common organ to be affected by metastatic cancer and the site of disease that produces the greatest morbidity. Skeletal morbidity includes pain that requires radiotherapy, hypercalcemia, pathologic fracture, and spinal cord or nerve root compression. From randomized trials in advanced cancer, it can be seen that one of these major skeletal events occurs on average every 3 to 6 months. Additionally, metastatic disease may remain confined to the skeleton with the decline in quality of life and eventual death almost entirely due to skeletal complications and their treatment. The prognosis of metastatic bone disease is dependent on the primary site, with breast and prostate cancers associated with a survival measured in years compared with lung cancer, where the average survival is only a matter of months. Additionally, the presence of extraosseous disease and the extent and tempo of the bone disease are powerful predictors of outcome. The latter is best estimated by measurement of bone-specific markers, and recent studies have shown a strong correlation between the rate of bone resorption and clinical outcome, both in terms of skeletal morbidity and progression of the underlying disease or death. Our improved understanding of prognostic and predictive factors may enable delivery of a more personalized treatment for the individual patient and a more cost-effective use of health care resources.

BACKGROUND: Long-term hormone therapy has been the standard of care for advanced prostate cancer since the 1940s. STAMPEDE is a randomised controlled trial using a multiarm, multistage platform design. It recruits men with high-risk, locally advanced, metastatic or recurrent prostate cancer who are starting first-line long-term hormone therapy. We report primary survival results for three research comparisons testing the addition of zoledronic acid, docetaxel, or their combination to standard of care versus standard of care alone. METHODS: Standard of care was hormone therapy for at least 2 years; radiotherapy was encouraged for men with N0M0 disease to November, 2011, then mandated; radiotherapy was optional for men with node-positive non-metastatic (N+M0) disease. Stratified randomisation (via minimisation) allocated men 2:1:1:1 to standard of care only (SOC-only; control), standard of care plus zoledronic acid (SOC + ZA), standard of care plus docetaxel (SOC + Doc), or standard of care with both zoledronic acid and docetaxel (SOC + ZA + Doc). Zoledronic acid (4 mg) was given for six 3-weekly cycles, then 4-weekly until 2 years, and docetaxel (75 mg/m(2)) for six 3-weekly cycles with prednisolone 10 mg daily. There was no blinding to treatment allocation. The primary outcome measure was overall survival. Pairwise comparisons of research versus control had 90% power at 2·5% one-sided α for hazard ratio (HR) 0·75, requiring roughly 400 control arm deaths. Statistical analyses were undertaken with standard log-rank-type methods for time-to-event data, with hazard ratios (HRs) and 95% CIs derived from adjusted Cox models. This trial is registered at ClinicalTrials.gov (NCT00268476) and ControlledTrials.com (ISRCTN78818544). FINDINGS: 2962 men were randomly assigned to four groups between Oct 5, 2005, and March 31, 2013. Median age was 65 years (IQR 60-71). 1817 (61%) men had M+ disease, 448 (15%) had N+/X M0, and 697 (24%) had N0M0. 165 (6%) men were previously treated with local therapy, and median prostate-specific antigen was 65 ng/mL (IQR 23-184). Median follow-up was 43 months (IQR 30-60). There were 415 deaths in the control group (347 [84%] prostate cancer). Median overall survival was 71 months (IQR 32 to not reached) for SOC-only, not reached (32 to not reached) for SOC + ZA (HR 0·94, 95% CI 0·79-1·11; p=0·450), 81 months (41 to not reached) for SOC + Doc (0·78, 0·66-0·93; p=0·006), and 76 months (39 to not reached) for SOC + ZA + Doc (0·82, 0·69-0·97; p=0·022). There was no evidence of heterogeneity in treatment effect (for any of the treatments) across prespecified subsets. Grade 3-5 adverse events were reported for 399 (32%) patients receiving SOC, 197 (32%) receiving SOC + ZA, 288 (52%) receiving SOC + Doc, and 269 (52%) receiving SOC + ZA + Doc. INTERPRETATION: Zoledronic acid showed no evidence of survival improvement and should not be part of standard of care for this population. Docetaxel chemotherapy, given at the time of long-term hormone therapy initiation, showed evidence of improved survival accompanied by an increase in adverse events. Docetaxel treatment should become part of standard of care for adequately fit men commencing long-term hormone therapy. FUNDING: Cancer Research UK, Medical Research Council, Novartis, Sanofi-Aventis, Pfizer, Janssen, Astellas, NIHR Clinical Research Network, Swiss Group for Clinical Cancer Research.

BACKGROUND: Tamoxifen, taken for five years, is the standard adjuvant treatment for postmenopausal women with primary, estrogen-receptor-positive breast cancer. Despite this treatment, however, some patients have a relapse. METHODS: We conducted a double-blind, randomized trial to test whether, after two to three years of tamoxifen therapy, switching to exemestane was more effective than continuing tamoxifen therapy for the remainder of the five years of treatment. The primary end point was disease-free survival. RESULTS: Of the 4742 patients enrolled, 2362 were randomly assigned to switch to exemestane, and 2380 to continue to receive tamoxifen. After a median follow-up of 30.6 months, 449 first events (local or metastatic recurrence, contralateral breast cancer, or death) were reported--183 in the exemestane group and 266 in the tamoxifen group. The unadjusted hazard ratio in the exemestane group as compared with the tamoxifen group was 0.68 (95 percent confidence interval, 0.56 to 0.82; P<0.001 by the log-rank test), representing a 32 percent reduction in risk and corresponding to an absolute benefit in terms of disease-free survival of 4.7 percent (95 percent confidence interval, 2.6 to 6.8) at three years after randomization. Overall survival was not significantly different in the two groups, with 93 deaths occurring in the exemestane group and 106 in the tamoxifen group. Severe toxic effects of exemestane were rare. Contralateral breast cancer occurred in 20 patients in the tamoxifen group and 9 in the exemestane group (P=0.04). CONCLUSIONS: Exemestane therapy after two to three years of tamoxifen therapy significantly improved disease-free survival as compared with the standard five years of tamoxifen treatment.

BACKGROUND: Abiraterone acetate plus prednisolone improves survival in men with relapsed prostate cancer. We assessed the effect of this combination in men starting long-term androgen-deprivation therapy (ADT), using a multigroup, multistage trial design. METHODS: We randomly assigned patients in a 1:1 ratio to receive ADT alone or ADT plus abiraterone acetate (1000 mg daily) and prednisolone (5 mg daily) (combination therapy). Local radiotherapy was mandated for patients with node-negative, nonmetastatic disease and encouraged for those with positive nodes. For patients with nonmetastatic disease with no radiotherapy planned and for patients with metastatic disease, treatment continued until radiologic, clinical, or prostate-specific antigen (PSA) progression; otherwise, treatment was to continue for 2 years or until any type of progression, whichever came first. The primary outcome measure was overall survival. The intermediate primary outcome was failure-free survival (treatment failure was defined as radiologic, clinical, or PSA progression or death from prostate cancer). RESULTS: A total of 1917 patients underwent randomization from November 2011 through January 2014. The median age was 67 years, and the median PSA level was 53 ng per milliliter. A total of 52% of the patients had metastatic disease, 20% had node-positive or node-indeterminate nonmetastatic disease, and 28% had node-negative, nonmetastatic disease; 95% had newly diagnosed disease. The median follow-up was 40 months. There were 184 deaths in the combination group as compared with 262 in the ADT-alone group (hazard ratio, 0.63; 95% confidence interval [CI], 0.52 to 0.76; P<0.001); the hazard ratio was 0.75 in patients with nonmetastatic disease and 0.61 in those with metastatic disease. There were 248 treatment-failure events in the combination group as compared with 535 in the ADT-alone group (hazard ratio, 0.29; 95% CI, 0.25 to 0.34; P<0.001); the hazard ratio was 0.21 in patients with nonmetastatic disease and 0.31 in those with metastatic disease. Grade 3 to 5 adverse events occurred in 47% of the patients in the combination group (with nine grade 5 events) and in 33% of the patients in the ADT-alone group (with three grade 5 events). CONCLUSIONS: Among men with locally advanced or metastatic prostate cancer, ADT plus abiraterone and prednisolone was associated with significantly higher rates of overall and failure-free survival than ADT alone. (Funded by Cancer Research U.K. and others; STAMPEDE ClinicalTrials.gov number, NCT00268476 , and Current Controlled Trials number, ISRCTN78818544 .).

The skeleton is the most common organ to be affected by metastatic cancer, and tumors arising from the breast, prostate, thyroid, lung, and kidney possess a special propensity to spread to bone. Breast carcinoma, the most prevalent malignancy, causes the greatest morbidity. Of great clinical importance is the observation that metastatic bone disease may remain confined to the skeleton. In these patients, the decline in quality of life and eventual death is due almost entirely to skeletal complications and their subsequent treatment. Bone pain is the most common complication of metastatic bone disease, resulting from structural damage, periosteal irritation, and nerve entrapment. Recent evidence suggests that pain caused by bone metastasis may also be related to the rate of bone resorption. Hypercalcemia occurs in 5-10% of all patients with advanced cancer but is most common in patients with breast carcinoma, multiple myeloma, and squamous carcinomas of the lung and other primary sites. Pathologic fractures are a relatively late complication of bone involvement. The clinical courses of breast and prostate carcinoma are relatively long, with a median survival of 2-3 years. For patients with breast carcinoma, good prognostic factors for survival after the development of bone metastases are good histologic grade, positive estrogen receptor status, bone disease at initial presentation, a long disease free interval, and increasing age. In addition, patients with disease that remains confined to the skeleton have a better prognosis than those with subsequent visceral involvement. For patients with prostate carcinoma, adverse prognostic features include poor performance status, involvement of the appendicular skeleton and visceral involvement, whereas for patients with multiple myeloma, the levels of serum beta2-microglobulin and lactate dehydrogenase and the immunologic phenotype are the most important factors. These prognostic factors may be useful in planning the rational use of bisphosphonates in the treatment of advanced cancer.

BACKGROUND: Based on previous findings, we hypothesised that radiotherapy to the prostate would improve overall survival in men with metastatic prostate cancer, and that the benefit would be greatest in patients with a low metastatic burden. We aimed to compare standard of care for metastatic prostate cancer, with and without radiotherapy. METHODS: We did a randomised controlled phase 3 trial at 117 hospitals in Switzerland and the UK. Eligible patients had newly diagnosed metastatic prostate cancer. We randomly allocated patients open-label in a 1:1 ratio to standard of care (control group) or standard of care and radiotherapy (radiotherapy group). Randomisation was stratified by hospital, age at randomisation, nodal involvement, WHO performance status, planned androgen deprivation therapy, planned docetaxel use (from December, 2015), and regular aspirin or non-steroidal anti-inflammatory drug use. Standard of care was lifelong androgen deprivation therapy, with up-front docetaxel permitted from December, 2015. Men allocated radiotherapy received either a daily (55 Gy in 20 fractions over 4 weeks) or weekly (36 Gy in six fractions over 6 weeks) schedule that was nominated before randomisation. The primary outcome was overall survival, measured as the number of deaths; this analysis had 90% power with a one-sided α of 2·5% for a hazard ratio (HR) of 0·75. Secondary outcomes were failure-free survival, progression-free survival, metastatic progression-free survival, prostate cancer-specific survival, and symptomatic local event-free survival. Analyses used Cox proportional hazards and flexible parametric models, adjusted for stratification factors. The primary outcome analysis was by intention to treat. Two prespecified subgroup analyses tested the effects of prostate radiotherapy by baseline metastatic burden and radiotherapy schedule. This trial is registered with ClinicalTrials.gov, number NCT00268476. FINDINGS: Between Jan 22, 2013, and Sept 2, 2016, 2061 men underwent randomisation, 1029 were allocated the control and 1032 radiotherapy. Allocated groups were balanced, with a median age of 68 years (IQR 63-73) and median amount of prostate-specific antigen of 97 ng/mL (33-315). 367 (18%) patients received early docetaxel. 1082 (52%) participants nominated the daily radiotherapy schedule before randomisation and 979 (48%) the weekly schedule. 819 (40%) men had a low metastatic burden, 1120 (54%) had a high metastatic burden, and the metastatic burden was unknown for 122 (6%). Radiotherapy improved failure-free survival (HR 0·76, 95% CI 0·68-0·84; p<0·0001) but not overall survival (0·92, 0·80-1·06; p=0·266). Radiotherapy was well tolerated, with 48 (5%) adverse events (Radiation Therapy Oncology Group grade 3-4) reported during radiotherapy and 37 (4%) after radiotherapy. The proportion reporting at least one severe adverse event (Common Terminology Criteria for Adverse Events grade 3 or worse) was similar by treatment group in the safety population (398 [38%] with control and 380 [39%] with radiotherapy). INTERPRETATION: Radiotherapy to the prostate did not improve overall survival for unselected patients with newly diagnosed metastatic prostate cancer. FUNDING: Cancer Research UK, UK Medical Research Council, Swiss Group for Clinical Cancer Research, Astellas, Clovis Oncology, Janssen, Novartis, Pfizer, and Sanofi-Aventis.

BACKGROUND: We conducted a randomized trial of prophylactic cranial irradiation in patients with extensive small-cell lung cancer who had had a response to chemotherapy. METHODS: Patients between the ages of 18 and 75 years with extensive small-cell lung cancer were randomly assigned to undergo prophylactic cranial irradiation (irradiation group) or receive no further therapy (control group). The primary end point was the time to symptomatic brain metastases. Computed tomography or magnetic resonance imaging of the brain was performed when any predefined key symptom suggestive of brain metastases was present. RESULTS: The two groups (each with 143 patients) were well balanced regarding baseline characteristics. Patients in the irradiation group had a lower risk of symptomatic brain metastases (hazard ratio, 0.27; 95% confidence interval [CI], 0.16 to 0.44; P<0.001). The cumulative risk of brain metastases within 1 year was 14.6% in the irradiation group (95% CI, 8.3 to 20.9) and 40.4% in the control group (95% CI, 32.1 to 48.6). Irradiation was associated with an increase in median disease-free survival from 12.0 weeks to 14.7 weeks and in median overall survival from 5.4 months to 6.7 months after randomization. The 1-year survival rate was 27.1% (95% CI, 19.4 to 35.5) in the irradiation group and 13.3% (95% CI, 8.1 to 19.9) in the control group. Irradiation had side effects but did not have a clinically significant effect on global health status. CONCLUSIONS: Prophylactic cranial irradiation reduces the incidence of symptomatic brain metastases and prolongs disease-free and overall survival. (ClinicalTrials.gov number, NCT00016211 [ClinicalTrials.gov].).

BACKGROUND: The incidence of human papillomavirus (HPV)-positive oropharyngeal cancer, a disease affecting younger patients, is rapidly increasing. Cetuximab, an epidermal growth factor receptor inhibitor, has been proposed for treatment de-escalation in this setting to reduce the toxicity of standard cisplatin treatment, but no randomised evidence exists for the efficacy of this strategy. METHODS: ). The primary outcome was overall severe (grade 3-5) toxicity events at 24 months from the end of treatment. The primary outcome was assessed by intention-to-treat and per-protocol analyses. This trial is registered with the ISRCTN registry, number ISRCTN33522080. FINDINGS: Between Nov 12, 2012, and Oct 1, 2016, 334 patients were recruited (166 in the cisplatin group and 168 in the cetuximab group). Overall (acute and late) severe (grade 3-5) toxicity did not differ significantly between treatment groups at 24 months (mean number of events per patient 4·8 [95% CI 4·2-5·4] with cisplatin vs 4·8 [4·2-5·4] with cetuximab; p=0·98). At 24 months, overall all-grade toxicity did not differ significantly either (mean number of events per patient 29·2 [95% CI 27·3-31·0] with cisplatin vs 30·1 [28·3-31·9] with cetuximab; p=0·49). However, there was a significant difference between cisplatin and cetuximab in 2-year overall survival (97·5% vs 89·4%, hazard ratio 5·0 [95% CI 1·7-14·7]; p=0·001) and 2-year recurrence (6·0% vs 16·1%, 3·4 [1·6-7·2]; p=0·0007). INTERPRETATION: Compared with the standard cisplatin regimen, cetuximab showed no benefit in terms of reduced toxicity, but instead showed significant detriment in terms of tumour control. Cisplatin and radiotherapy should be used as the standard of care for HPV-positive low-risk patients who are able to tolerate cisplatin. FUNDING: Cancer Research UK.

BACKGROUND: We compared docetaxel plus doxorubicin and cyclophosphamide (TAC) with fluorouracil plus doxorubicin and cyclophosphamide (FAC) as adjuvant chemotherapy for operable node-positive breast cancer. METHODS: We randomly assigned 1491 women with axillary node-positive breast cancer to six cycles of treatment with either TAC or FAC as adjuvant chemotherapy after surgery. The primary end point was disease-free survival. RESULTS: At a median follow-up of 55 months, the estimated rates of disease-free survival at five years were 75 percent among the 745 patients randomly assigned to receive TAC and 68 percent among the 746 randomly assigned to receive FAC, representing a 28 percent reduction in the risk of relapse (P=0.001) in the TAC group. The estimated rates of overall survival at five years were 87 percent and 81 percent, respectively. Treatment with TAC resulted in a 30 percent reduction in the risk of death (P=0.008). The incidence of grade 3 or 4 neutropenia was 65.5 percent in the TAC group and 49.3 percent in the FAC group (P<0.001); rates of febrile neutropenia were 24.7 percent and 2.5 percent, respectively (P<0.001). Grade 3 or 4 infections occurred in 3.9 percent of the patients who received TAC and 2.2 percent of those who received FAC (P=0.05); no deaths occurred as a result of infection. Two patients in each group died during treatment. Congestive heart failure and acute myeloid leukemia occurred in less than 2 percent of the patients in each group. Quality-of-life scores decreased during chemotherapy but returned to baseline levels after treatment. CONCLUSIONS: Adjuvant chemotherapy with TAC, as compared with FAC, significantly improves the rates of disease-free and overall survival among women with operable node-positive breast cancer.

BACKGROUND: The goal of the current study was to compare the long-term (25-month) safety and efficacy of zoledronic acid with pamidronate in patients with bone lesions secondary to advanced breast carcinoma or multiple myeloma. METHODS: Patients (n = 1648) were randomized to receive 4 mg or 8 mg (reduced to 4 mg) zoledronic acid as a 15-minute infusion or to receive 90 mg pamidronate as a 2-hour infusion every 3-4 weeks for 24 months. The primary endpoint was the proportion of patients with at least 1 skeletal-related event (SRE), defined as pathologic fracture, spinal cord compression, radiation therapy, or surgery to bone. Secondary analyses included time to first SRE, skeletal morbidity rate, and multiple-event analysis. Hypercalcemia of malignancy (HCM) was included as an SRE in some secondary analyses. RESULTS: After 25 months of follow-up, zoledronic acid reduced the overall proportion of patients with an SRE and reduced the skeletal morbidity rate similar to pamidronate. Compared with pamidronate, zoledronic acid (4 mg) reduced the overall risk of developing skeletal complications (including HCM) by an additional 16% (P = 0.030). In patients with breast carcinoma, zoledronic acid (4 mg) was significantly more effective than pamidronate, reducing the risk of SREs by an additional 20% (P = 0.025) compared with pamidronate and by an additional 30% in patients receiving hormonal therapy (P = 0.009). Zoledronic acid (4 mg) and pamidronate were tolerated equally well. The most common adverse events included bone pain, nausea, and fatigue. CONCLUSIONS: Long-term follow-up data confirm that zoledronic acid was more effective than pamidronate in reducing the risk of skeletal complications in patients with bone metastases from breast carcinoma and was of similar efficacy in patients with multiple myeloma.

Gastrointestinal stromal tumours (GISTs) are rare tumours, with an estimated unadjusted incidence of around 1/100 000/year [1.Nilsson B. Bümming P. Meis-Kindblom J.M. et al.Gastrointestinal stromal tumors: the incidence, prevalence, clinical course, and prognostication in the preimatinib mesylate era–a population-based study in western Sweden.Cancer. 2005; 103: 821-829Crossref PubMed Scopus (1027) Google Scholar]. This only covers clinically relevant GISTs, since, if investigated, a much higher number of lesions ≤ 1 cm in diameter (microGISTs) can be found at histopathological examination of stomach tissue in middle-aged and elderly individuals. There is a slight prevalence in males. The median age is around 60–65 years, with a wide range. Occurrence in children is very rare. Paediatric GIST represents a clinically and molecularly distinct subset, marked by female predominance, absence of KIT/platelet-derived growth factor alpha (PDGFRA) mutations, frequent mutations or silencing of the four genes that encode the subunits of the succinate dehydrogenase (SDH) enzyme complex, gastric multicentric location and possible lymph node metastases [2.Pappo A.S. Janeway K.A. Pediatric gastrointestinal stromal tumors.Hematol Oncol Clin North Am. 2009; 23 (vii): 15-34Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar]. Some syndromes are linked to GISTs: •The Carney triad syndrome, marked by gastric GISTs, paraganglioma and pulmonary chondromas (these may occur at different ages) [3.Zhang L. Smyrk T.C. Young Jr, W.F. et al.Gastric stromal tumors in Carney triad are different clinically, pathologically, and behaviorally from sporadic gastric gastrointestinal stromal tumors: findings in 104 cases.Am J Surg Pathol. 2010; 34: 53-64Crossref PubMed Scopus (167) Google Scholar];•Carney–Stratakis syndrome, marked by a dyad of GIST and paraganglioma [4.Gaal J. Stratakis C.A. Carney J.A. et al.SDHB immunohistochemistry: a useful tool in the diagnosis of Carney–Stratakis and Carney triad gastrointestinal stromal tumors.Mod Pathol. 2011; 24: 147-151Crossref PubMed Scopus (162) Google Scholar, 5.Pasini B. McWhinney S.R. Bei T. et al.Clinical and molecular genetics of patients with the Carney–Stratakis syndrome and germline mutations of the genes coding for the succinate dehydrogenase subunits SDHB, SDHC, and SDHD.Eur J Hum Genet. 2008; 16: 79-88Crossref PubMed Scopus (363) Google Scholar]; and•Neurofibromatosis type 1(NF1), possibly leading to wild-type (WT), often multicentric GIST, predominantly located in the small bowel [6.Miettinen M. Fetsch J.F. Sobin L.H. Lasota J. Gastrointestinal stromal tumors in patients with neurofibromatosis 1: a clinicopathologic and molecular genetic study of 45 cases.Am J Surg Pathol. 2006; 30: 90-96Crossref PubMed Scopus (377) Google Scholar]. Families with germline autosomal dominant mutations of KIT are an extremely rare finding, presenting with multiple GISTs at an early age, possibly along with other associated features such as pigmented skin macules, urticaria pigmentosa and diffuse hyperplasia of the interstitial cells of Cajal in the gut wall. When small oesophagogastric or duodenal nodules < 2 cm in size are detected, endoscopic biopsy may be difficult and laparoscopic/laparotomic excision may be the only way to make a histological diagnosis. Many of these small nodules, if diagnosed as GISTs, will be either low-risk or entities whose clinical significance remains unclear. Therefore, the standard approach to patients with oesophagogastric or duodenal nodules < 2 cm is endoscopic ultrasound assessment and then follow-up, reserving excision for patients whose tumour increases in size or becomes symptomatic [IV, C]. As an option, the patient can choose to undergo a histological assessment, also depending on age, life expectancy and comorbidities. If follow-up is the choice, an evidence-based, optimal surveillance policy is lacking. A logical approach may be to have a short-term first control (e.g. at 3 months) and then, in the case of no evidence of growth, a more relaxed follow-up schedule may be selected. In a histologically proven small GIST, standard treatment is excision, unless major morbidity is expected. Alternatively, in the case of a likely low-risk GIST on biopsy, the decision can be made with the patient to follow up the lesion. However, an exception is the standard approach to rectal nodules represented by biopsy or excision after endorectal ultrasound assessment and pelvic magnetic resonance imaging (MRI), regardless of the tumour size and mitotic rate. In fact, the progression risk of a clinically significant GIST at this site is higher, its prognosis is significantly worse compared with most gastric GISTs and the local implications for surgery are more critical. A follow-up policy may be an option, to be discussed with the patient, in the case of small lesions and whenever the surgical risk is particularly high (comorbidities, age, etc.). The standard approach to tumours ≥2 cm in size is biopsy/excision, because they are associated with a higher risk of progression if confirmed as GIST [IV, C]. If there is an abdominal nodule not amenable to endoscopic assessment, laparoscopic/laparotomic excision is the standard approach. If there is a mass, especially if surgery is likely to be a multivisceral resection, multiple core needle biopsies are the standard approach. They should be obtained through endoscopic ultrasound guidance, or through an ultrasound/computed tomography (CT)-guided percutaneous approach. This may allow the surgeon to plan the best approach according to the histological diagnosis and avoid surgery for diseases which might not benefit (e.g. lymphomas, mesenteric fibromatosis and germ cell tumours). The risk of peritoneal contamination is negligible if the procedure is properly carried out. Moreover, lesions at risk in this regard (e.g. cystic masses) should be biopsied only in specialised centres. Immediate laparoscopic/laparotomic excision is an option on an individualised basis, especially if surgery is limited. If a patient presents with obvious metastatic disease, a biopsy of the metastatic focus is sufficient and the patient usually does not require a laparotomy for diagnostic purposes. The tumour sample should be fixed in 4% buffered formalin (Bouin fixative should not be used, since it prevents molecular analysis). Pathologically, the diagnosis of GIST relies on morphology and immunohistochemistry, the latter being positive for CD117 (KIT) and/or DOG1 (see Table 1) [7.Rubin B.P. Blanke C.D. Demetri G.D. et al.Protocol for the examination of specimens from patients with gastrointestinal stromal tumor.Arch Pathol Lab Med. 2010; 134: 165-170Crossref PubMed Google Scholar, 8.Novelli M. Rossi S. Rodriguez-Justo M. et al.DOG1 and CD117 are the antibodies of choice in the diagnosis of gastrointestinal stromal tumours.Histopathology. 2010; 57: 259-270Crossref PubMed Scopus (147) Google Scholar]. A proportion of GISTs (in the range of 5%) are CD117-negative. The mitotic count has a prognostic value and should be expressed as the number of mitoses on a total area of 5 mm2 [which replaces the former 50 high-power field (HPF) area]. Mutational analysis for known mutations involving KIT and PDGFRA can confirm the diagnosis of GIST, if doubtful (particularly in rare CD117/DOG1-negative suspect GIST). Mutational analysis has a predictive value for sensitivity to molecular-targeted therapy and to prognostic value. Its inclusion in the diagnostic work-up of all GISTs should be considered standard practice [II, A] (with the possible exclusion of < 2 cm non-rectal GISTs, which are very unlikely ever to be candidates for medical treatment). Centralisation of mutational analysis in a laboratory enrolled in an external quality assurance programme and with expertise in the may be diagnosis is more for GIST, to confirm the diagnosis of GIST with an at a In GIST, for is to In GIST an syndrome should be Rossi S. M. et GIST is a for neurofibromatosis type 1 PubMed Scopus Google Scholar]. The of tissue is to allow molecular to be made at a for tumour to local and should be and for medical treatment or for medical treatment for medical treatment of of growth factor succinate in a of of growth factor succinate treatment is involving medical as as as should be carried in for and GISTs and/or expertise and a high number of patients The for node and of tumours the prognostic in GIST (see Table of for GIST from of of of to of KIT site in KIT or PDGFRA of and gastrointestinal stromal neurofibromatosis type growth factor tumour for from of with from in a GIST, gastrointestinal stromal neurofibromatosis type growth factor tumour for from of with from are the mitotic tumour size and tumour site GISTs have a prognosis small bowel or rectal is an prognostic factor and should be regardless of it or Mutational has not in risk at have a distinct GISTs have clinical and GIST with are associated with a prognosis and to risk have A risk by the of which the mitotic tumour size and tumour the prognostic in GISTs M. Lasota J. Gastrointestinal stromal tumors: on molecular and Pathol Lab Med. 2006; PubMed Google Scholar, M. Lasota J. Gastrointestinal stromal tumors: and prognosis at different Pathol. 2006; PubMed Scopus Google Scholar]. A all has on M. et and of a prognostic for after surgical of gastrointestinal stromal a 2009; Full Text Full Text PDF PubMed Scopus Google Scholar]. When these it is to that the mitotic and tumour size are that are through a of of GIST patients not with which the mitotic and tumour size as tumour is considered in to tumour site J. et of of gastrointestinal stromal tumour after an analysis of population-based Full Text Full Text PDF PubMed Scopus Google Scholar]. They have a that most the and the abdominal and pelvic is the of choice for and may be an rectal GISTs, and laboratory the work-up of the The of an tomography or is useful early of the tumour to molecular-targeted therapy is of The standard treatment of GISTs is surgical excision of the with no of clinically lymph If excision is the to follow the of surgery A] et of and surgery for gastric gastrointestinal stromal Google Scholar]. A approach is in patients have tumours, because of the risk of tumour which is associated with a very high risk of excision is the an excision whose are of tumour When surgery major and medical treatment is not the decision can be made with the patient to possible [IV, This is more for low-risk the of that surgery is associated with a worse If excision carried may be an option, the site of can be and major are not The risk of can be as by risk treatment with for 3 associated with a and in with 1 of therapy in patients in a M. et for stromal analysis of a Clin 34: PubMed Scopus (147) Google Scholar]. a that for a of 1 can in GISTs a diameter 3 cm with a et mesylate after of gastrointestinal stromal a 2009; Full Text Full Text PDF PubMed Scopus Google Scholar]. Therefore, therapy with for 3 is the standard treatment for patients with a significant risk of A is the risk is T. et treatment of GIST with or A on of the and the the the on GIST, the and the J 2009; Full Text Full Text PDF PubMed Scopus Google Scholar]. clinical are to of therapy in The benefit associated of may according to the type of being in patients with KIT mutations et of KIT and PDGFRA mutations on in patients with gastrointestinal stromal tumors with an analysis of a clinical PubMed Scopus Google Scholar, et and molecular features with after therapy of stromal the Clin PubMed Scopus Google Scholar]. Mutational analysis is to make a clinical decision There is a that PDGFRA GISTs should not be with the of sensitivity of this in and in [IV, the the of a higher of in the case of an KIT in GIST, to this in the for this [II, M. et mutations and for in patients with gastrointestinal stromal J 2006; Full Text Full Text PDF PubMed Scopus Google Scholar, et of and clinical in the North of mesylate for treatment of gastrointestinal stromal by and and Clin 2008; PubMed Scopus Google Scholar, Demetri G.D. et mutations and in patients with metastatic gastrointestinal stromal Clin PubMed Scopus Google Scholar]. may this which is not in the by regard to GIST, there is a on treatment in and GISTs [IV, This of sensitivity to and other in the as as which is often more of to sufficient and be to best in the rare In case of tumour at the of there is of tumour cells the peritoneal peritoneal can be to This the patient at a very high risk of peritoneal P. et of in patients with gastrointestinal stromal J 2010; PubMed Scopus Google Scholar]. 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BACKGROUND: It is unclear whether patients with early-stage Hodgkin's lymphoma and negative findings on positron-emission tomography (PET) after three cycles of chemotherapy with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) require radiotherapy. METHODS: Patients with newly diagnosed stage IA or stage IIA Hodgkin's lymphoma received three cycles of ABVD and then underwent PET scanning. Patients with negative PET findings were randomly assigned to receive involved-field radiotherapy or no further treatment; patients with positive PET findings received a fourth cycle of ABVD and radiotherapy. This trial assessing the noninferiority of no further treatment was designed to exclude a difference in the 3-year progression-free survival rate of 7 or more percentage points from the assumed 95% progression-free survival rate in the radiotherapy group. RESULTS: A total of 602 patients (53.3% male; median age, 34 years) were recruited, and 571 patients underwent PET scanning. The PET findings were negative in 426 of these patients (74.6%), 420 of whom were randomly assigned to a study group (209 to the radiotherapy group and 211 to no further therapy). At a median of 60 months of follow-up, there had been 8 instances of disease progression in the radiotherapy group, and 8 patients had died (3 with disease progression, 1 of whom died from Hodgkin's lymphoma); there had been 20 instances of disease progression in the group with no further therapy, and 4 patients had died (2 with disease progression and none from Hodgkin's lymphoma). In the radiotherapy group, 5 of the deaths occurred in patients who received no radiotherapy. The 3-year progression-free survival rate was 94.6% (95% confidence interval [CI], 91.5 to 97.7) in the radiotherapy group and 90.8% (95% CI, 86.9 to 94.8) in the group that received no further therapy, with an absolute risk difference of -3.8 percentage points (95% CI, -8.8 to 1.3). CONCLUSIONS: The results of this study did not show the noninferiority of the strategy of no further treatment after chemotherapy with regard to progression-free survival. Nevertheless, patients in this study with early-stage Hodgkin's lymphoma and negative PET findings after three cycles of ABVD had a very good prognosis either with or without consolidation radiotherapy. (Funded by Leukaemia and Lymphoma Research and others; RAPID ClinicalTrials.gov number, NCT00943423.).

BACKGROUND: Advanced biliary tract cancer has a poor prognosis. Cisplatin and gemcitabine is the standard first-line chemotherapy regimen, but no robust evidence is available for second-line chemotherapy. The aim of this study was to determine the benefit derived from second-line FOLFOX (folinic acid, fluorouracil, and oxaliplatin) chemotherapy in advanced biliary tract cancer. METHODS: as a 46-h continuous intravenous infusion). Randomisation was done following a minimisation algorithm using platinum sensitivity, serum albumin concentration, and stage as stratification factors. The primary endpoint was overall survival, assessed in the intention-to-treat population. Safety was also assessed in the intention-to-treat population. The study is complete and the final results are reported. This trial is registered with ClinicalTrials.gov, NCT01926236, and EudraCT, 2013-001812-30. FINDINGS: Between March 27, 2014, and Jan 4, 2018, 162 patients were enrolled and randomly assigned to ASC plus FOLFOX (n=81) or ASC alone (n=81). Median follow-up was 21·7 months (IQR 17·2-30·8). Overall survival was significantly longer in the ASC plus FOLFOX group than in the ASC alone group, with a median overall survival of 6·2 months (95% CI 5·4-7·6) in the ASC plus FOLFOX group versus 5·3 months (4·1-5·8) in the ASC alone group (adjusted hazard ratio 0·69 [95% CI 0·50-0·97]; p=0·031). The overall survival rate in the ASC alone group was 35·5% (95% CI 25·2-46·0) at 6 months and 11·4% (5·6-19·5) at 12 months, compared with 50·6% (39·3-60·9) at 6 months and 25·9% (17·0-35·8) at 12 months in the ASC plus FOLFOX group. Grade 3-5 adverse events were reported in 42 (52%) of 81 patients in the ASC alone group and 56 (69%) of 81 patients in the ASC plus FOLFOX group, including three chemotherapy-related deaths (one each due to infection, acute kidney injury, and febrile neutropenia). The most frequently reported grade 3-5 FOLFOX-related adverse events were neutropenia (ten [12%] patients), fatigue or lethargy (nine [11%] patients), and infection (eight [10%] patients). INTERPRETATION: The addition of FOLFOX to ASC improved median overall survival in patients with advanced biliary tract cancer after progression on cisplatin and gemcitabine, with a clinically meaningful increase in 6-month and 12-month overall survival rates. To our knowledge, this trial is the first prospective, randomised study providing reliable, high-quality evidence to allow an informed discussion with patients of the potential benefits and risks from second-line FOLFOX chemotherapy in advanced biliary tract cancer. Based on these findings, FOLFOX should become standard-of-care chemotherapy in second-line treatment for advanced biliary tract cancer and the reference regimen for further clinical trials. FUNDING: Cancer Research UK, StandUpToCancer, AMMF (The UK Cholangiocarcinoma Charity), and The Christie Charity, with additional funding from The Cholangiocarcinoma Foundation and the Conquer Cancer Foundation Young Investigator Award for translational research.

BACKGROUND: Cultured meat forms part of the emerging field of cellular agriculture. Still an early stage field it seeks to deliver products traditionally made through livestock rearing in novel forms that require no, or significantly reduced, animal involvement. Key examples include cultured meat, milk, egg white and leather. Here, we focus upon cultured meat and its technical, socio-political and regulatory challenges and opportunities. SCOPE AND APPROACH: The paper reports the thinking of an interdisciplinary team, all of whom have been active in the field for a number of years. It draws heavily upon the published literature, as well as our own professional experience. This includes ongoing laboratory work to produce cultured meat and over seventy interviews with experts in the area conducted in the social science work. KEY FINDINGS AND CONCLUSIONS: Cultured meat is a promising, but early stage, technology with key technical challenges including cell source, culture media, mimicking the in-vivo myogenesis environment, animal-derived and synthetic materials, and bioprocessing for commercial-scale production. Analysis of the social context has too readily been reduced to ethics and consumer acceptance, and whilst these are key issues, the importance of the political and institutional forms a cultured meat industry might take must also be recognised, and how ambiguities shape any emergent regulatory system.

BACKGROUND: Whole brain radiotherapy (WBRT) and dexamethasone are widely used to treat brain metastases from non-small cell lung cancer (NSCLC), although there have been no randomised clinical trials showing that WBRT improves either quality of life or overall survival. Even after treatment with WBRT, the prognosis of this patient group is poor. We aimed to establish whether WBRT could be omitted without a significant effect on survival or quality of life. METHODS: The Quality of Life after Treatment for Brain Metastases (QUARTZ) study is a non-inferiority, phase 3 randomised trial done at 69 UK and three Australian centres. NSCLC patients with brain metastases unsuitable for surgical resection or stereotactic radiotherapy were randomly assigned (1:1) to optimal supportive care (OSC) including dexamethasone plus WBRT (20 Gy in five daily fractions) or OSC alone (including dexamethasone). The dose of dexamethasone was determined by the patients' symptoms and titrated downwards if symptoms improved. Allocation to treatment group was done by a phone call from the hospital to the Medical Research Council Clinical Trials Unit at University College London using a minimisation programme with a random element and stratification by centre, Karnofsky Performance Status (KPS), gender, status of brain metastases, and the status of primary lung cancer. The primary outcome measure was quality-adjusted life-years (QALYs). QALYs were generated from overall survival and patients' weekly completion of the EQ-5D questionnaire. Treatment with OSC alone was considered non-inferior if it was no more than 7 QALY days worse than treatment with WBRT plus OSC, which required 534 patients (80% power, 5% [one-sided] significance level). Analysis was done by intention to treat for all randomly assigned patients. The trial is registered with ISRCTN, number ISRCTN3826061. FINDINGS: Between March 2, 2007, and Aug 29, 2014, 538 patients were recruited from 69 UK and three Australian centres, and were randomly assigned to receive either OSC plus WBRT (269) or OSC alone (269). Baseline characteristics were balanced between groups, and the median age of participants was 66 years (range 38-85). Significantly more episodes of drowsiness, hair loss, nausea, and dry or itchy scalp were reported while patients were receiving WBRT, although there was no evidence of a difference in the rate of serious adverse events between the two groups. There was no evidence of a difference in overall survival (hazard ratio 1·06, 95% CI 0·90-1·26), overall quality of life, or dexamethasone use between the two groups. The difference between the mean QALYs was 4·7 days (46·4 QALY days for the OSC plus WBRT group vs 41·7 QALY days for the OSC group), with two-sided 90% CI of -12·7 to 3·3. INTERPRETATION: Although the primary outcome measure result includes the prespecified non-inferiority margin, the combination of the small difference in QALYs and the absence of a difference in survival and quality of life between the two groups suggests that WBRT provides little additional clinically significant benefit for this patient group. FUNDING: Cancer Research UK, Medical Research Council Clinical Trials Unit at University College London, and the National Health and Medical Research Council in Australia.

BACKGROUND: In the Suppression of Ovarian Function Trial (SOFT) and the Tamoxifen and Exemestane Trial (TEXT), the 5-year rates of recurrence of breast cancer were significantly lower among premenopausal women who received the aromatase inhibitor exemestane plus ovarian suppression than among those who received tamoxifen plus ovarian suppression. The addition of ovarian suppression to tamoxifen did not result in significantly lower recurrence rates than those with tamoxifen alone. Here, we report the updated results from the two trials. METHODS: Premenopausal women were randomly assigned to receive 5 years of tamoxifen, tamoxifen plus ovarian suppression, or exemestane plus ovarian suppression in SOFT and to receive tamoxifen plus ovarian suppression or exemestane plus ovarian suppression in TEXT. Randomization was stratified according to the receipt of chemotherapy. RESULTS: In SOFT, the 8-year disease-free survival rate was 78.9% with tamoxifen alone, 83.2% with tamoxifen plus ovarian suppression, and 85.9% with exemestane plus ovarian suppression (P=0.009 for tamoxifen alone vs. tamoxifen plus ovarian suppression). The 8-year rate of overall survival was 91.5% with tamoxifen alone, 93.3% with tamoxifen plus ovarian suppression, and 92.1% with exemestane plus ovarian suppression (P=0.01 for tamoxifen alone vs. tamoxifen plus ovarian suppression); among the women who remained premenopausal after chemotherapy, the rates were 85.1%, 89.4%, and 87.2%, respectively. Among the women with cancers that were negative for HER2 who received chemotherapy, the 8-year rate of distant recurrence with exemestane plus ovarian suppression was lower than the rate with tamoxifen plus ovarian suppression (by 7.0 percentage points in SOFT and by 5.0 percentage points in TEXT). Grade 3 or higher adverse events were reported in 24.6% of the tamoxifen-alone group, 31.0% of the tamoxifen-ovarian suppression group, and 32.3% of the exemestane-ovarian suppression group. CONCLUSIONS: Among premenopausal women with breast cancer, the addition of ovarian suppression to tamoxifen resulted in significantly higher 8-year rates of both disease-free and overall survival than tamoxifen alone. The use of exemestane plus ovarian suppression resulted in even higher rates of freedom from recurrence. The frequency of adverse events was higher in the two groups that received ovarian suppression than in the tamoxifen-alone group. (Funded by Pfizer and others; SOFT and TEXT ClinicalTrials.gov numbers, NCT00066690 and NCT00066703 , respectively.).

BACKGROUND: Data from randomized, controlled trials of zoledronic acid were retrospectively analyzed to assess the effect of pathologic fractures on survival in patients with malignant bone disease. METHODS: A Cox regression model was used to estimate the effect of fractures (time-dependent variable) on survival in patients with stage III multiple myeloma or bone metastases from solid tumors enrolled in 3 large trials. Patients were randomized to receive zoledronic acid, pamidronate, or placebo every 3-4 weeks for up to 24 months (prostate cancer, breast cancer, and multiple myeloma) or up to 21 months (lung and other solid tumors). RESULTS: A total of 3049 patients with multiple myeloma (n = 513), breast (n = 1130), prostate (n = 640), or lung cancer or other solid tumors (n = 766) were included in this analysis. Patients with multiple myeloma had the highest fracture incidence (43%), followed by breast (35%), prostate (19%), and lung cancer (17%). In all tumor types except lung, pathologic fracture was associated with a significant increase in risk of death, and breast cancer patients had the greatest increased risk. After adjustment for baseline characteristics, including performance status and prior skeletal complications, breast cancer patients who developed a pathologic fracture on study had a significant 32% increased risk of death relative to patients without a fracture (hazard ratio = 1.32; P < .01); patients with multiple myeloma or prostate cancer had a >20% increased risk of death. CONCLUSIONS: These results suggest that fractures are associated with increased risk of death in patients with malignant bone disease. Therefore, preventing fractures is an important goal of therapy.

Casali, Paolo Giovanni; Bielack, Stefan S.; Abecassis, N.; Aro, Hannu; Bauer, Sebastian; Biagini, Roberto; Bonvalot, Sylvie; Boukovinas, Ioannis P.; Bovee, Judith V. M. G.; Brennan, Bernadette M. D.; Brodowicz, Thomas; Broto, Javier Martín; Brugières, Laurence; Buonadonna, Angela; De Álava, Enrique; Dei Tos, Angelo; García-Del-Muro, Xavier F.; Dileo, Palma; Dhooge, Catharina R. M.; Eriksson, Mikael; Fagioli, Franca; Fedenko, Alexander; Ferraresi, Virginia; Ferrari, Andrea; Ferrari, Stefano; Frezza, Anna Maria; Gaspar, Nathalie; Gasperoni, Silvia; Gelderblom, Hans J.; Gil, Thierry; Grignani, Giovanni; Gronchi, Alessandro; Haas, Rick LM.; Hassan, A. Bass; Hecker-Nolting, Stefanie; Hohenberger, Peter; Issels, Rolf Dieter; Joensuu, Heikki T.; Jones, Robin; Judson, Ian Robert; Jutte, Paul; Kaal, Suzanne E. J.; Kager, L. H.; Kasper, Bernd; Kopeckova, Kateřina; Krákorová, Dagmar; Ladenstein, Ruth Lydia; Le Cesne, Axel; López Pousa, Antonio; Lugowska, Iwona; Merimsky, Ofer; Montemurro, Michael; Morland, Bruce J.; Pantaleo, Maria Abbondanza; Piana, Raimondo; Picci, Piero; Piperno-Neumann, Sophie; Reichardt, Peter; Robinson, Martin H.; Rutkowski, Piotr; Safwat, Akmal Ahmed; Schöffski, Patrick; Sleijfer, Stefan; Stacchiotti, Silvia; Strauss, Sandra J.; Sundby Hall, Kirsten; Unk, Mojca; Van Coevorden, Frits; Van Der Graaf, Winette T. A.; Whelan, Jeremy S.; Wardelmann, Eva; Zaikova, Olga; Blay, Jean-Yves

BACKGROUND: Second-line chemotherapy for patients with oesophagogastric adenocarcinoma refractory to platinum and fluoropyrimidines has not shown benefits in health-related quality of life (HRQoL). We assessed whether the addition of docetaxel to active symptom control alone can improve survival and HRQoL for patients. METHODS: For this open-labelled, multicentre trial, we recruited patients aged 18 years or older from 30 UK centres. Patients were eligible if they had an advanced, histologically confirmed adenocarcinoma of the oesophagus, oesophagogastric junction, or stomach that had progressed on or within 6 months of treatment with a platinum-fluoropyrimidine combination. Patients could have an Eastern Cooperative Oncology Group performance status of 0-2. We randomly assigned patients using a central, computerised minimisation procedure to receive docetaxel plus active symptom control, or active symptom control alone (1:1; stratified by disease status, disease site, duration of response to previous chemotherapy, and performance status). Docetaxel was given at a dose of 75 mg/m(2) by intravenous infusion every 3 weeks for up to six cycles. The primary endpoint was overall survival, analysed by intention to treat. This is the report of the planned final analysis. This study is an International Standardised Randomised Controlled Trial, number ISRCTN13366390. FINDINGS: Between April 21, 2008, and April 26, 2012, we recruited 168 patients, allocating 84 to each treatment group. After a median follow-up of 12 months [IQR 10-21]) and 161 (96%) deaths (80 in the docetaxel group, 81 in the active symptom control group), median overall survival in the docetaxel group was 5.2 months (95% CI 4.1-5.9) versus 3.6 months (3.3-4.4) in the active symptom control group (hazard ratio 0.67, 95% CI 0.49-0.92; p=0.01). Docetaxel was associated with higher incidence of grade 3-4 neutropenia (12 [15%] patients vs no patients), infection (15 [19%] patients vs two [3%] patients), and febrile neutropenia (six [7%] patients vs no patients). Patients receiving docetaxel reported less pain (p=0.0008) and less nausea and vomiting (p=0.02) and constipation (p=0.02). Global HRQoL was similar between the groups (p=0.53). Disease specific HRQoL measures also showed benefits for docetaxel in reducing dysphagia (p=0.02) and abdominal pain (p=0.01). INTERPRETATION: Our findings suggest that docetaxel can be recommended as an appropriate second-line treatment for patients with oesophagogastric adenocarcinoma that is refractory to treatment with platinum and fluoropyrimidine. FUNDING: Cancer Research UK.

BACKGROUND: Most patients with extensive stage small-cell lung cancer (ES-SCLC) who undergo chemotherapy, and prophylactic cranial irradiation, have persistent intrathoracic disease. We assessed thoracic radiotherapy for treatment of this patient group. METHODS: We did this phase 3 randomised controlled trial at 42 hospitals: 16 in Netherlands, 22 in the UK, three in Norway, and one in Belgium. We enrolled patients with WHO performance score 0-2 and confirmed ES-SCLC who responded to chemotherapy. They were randomly assigned (1:1) to receive either thoracic radiotherapy (30 Gy in ten fractions) or no thoracic radiotherapy. All underwent prophylactic cranial irradiation. The primary endpoint was overall survival at 1 year in the intention-to-treat population. Secondary endpoints included progression-free survival. This study is registered with the Nederlands Trial Register, number NTR1527. FINDINGS: We randomly assigned 498 patients between Feb 18, 2009, and Dec 21, 2012. Three withdrew informed consent, leaving 247 patients in the thoracic radiotherapy group and 248 in the control group. Mean interval between diagnosis and randomisation was 17 weeks. Median follow-up was 24 months. Overall survival at 1 year was not significantly different between groups: 33% (95% CI 27-39) for the thoracic radiotherapy group versus 28% (95% CI 22-34) for the control group (hazard ratio [HR] 0.84, 95% CI 0.69-1.01; p=0.066). However, in a secondary analysis, 2-year overall survival was 13% (95% CI 9-19) versus 3% (95% CI 2-8; p=0.004). Progression was less likely in the thoracic radiotherapy group than in the control group (HR 0.73, 95% CI 0.61-0.87; p=0.001). At 6 months, progression-free survival was 24% (95% CI 19-30) versus 7% (95% CI 4-11; p=0.001). We recorded no severe toxic effects. The most common grade 3 or higher toxic effects were fatigue (11 vs 9) and dyspnoea (three vs four). INTERPRETATION: Thoracic radiotherapy in addition to prophylactic cranial irradiation should be considered for all patients with ES-SCLC who respond to chemotherapy. FUNDING: Dutch Cancer Society (CKTO), Dutch Lung Cancer Research Group, Cancer Research UK, Manchester Academic Health Science Centre Trials Coordination Unit, and the UK National Cancer Research Network.