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Background The current treatment of ovarian cancer consists of cytoreductive surgery (CRS) and systemic chemotherapy. The aim of this study was to examine if hyperthermic intraperitoneal chemotherapy (HIPEC) is an alternative modality to treat this category of patients along with a second attempt of surgical resection and second- or third-line systemic chemotherapy afterward. Methods In an 8-year period (2006–2013), 120 women with advanced ovarian cancer (International Federation of Gynecology and Obstetrics [FIGO] III c and IV) who experienced disease recurrence after initial treatment with conservative or debulking surgery and systemic chemotherapy were randomized into two groups. Group A comprised 60 patients treated with CRS followed by HIPEC and then systemic chemotherapy. Group B comprised 60 patients treated with CRS only and systemic chemotherapy. Results The mean survival for group A was 26.7 versus 13.4 months in group B ( p  < 0.006). Three-year survival was 75 % for group A versus 18 % for group B ( p  < 0.01). In the HIPEC group, the mean survival was not different between patients with platinum-resistant disease versus platinum-sensitive disease (26.6 vs. 26.8 months). On the other hand, in the non-HIPEC group, there was a statistically significant difference between platinum-sensitive versus platinum-resistant disease (15.2 vs. 10.2 months, p  < 0.002). Complete cytoreduction was associated with longer survival. Patients with a peritoneal cancer index score of <15 appeared also to have longer survival. Conclusions The use of HIPEC along with the extent of the disease and the extent of cytoreduction play an important role in the survival of patients with recurrence in an initially advanced ovarian cancer.

Patients with platinum-sensitive relapsed ovarian cancer who had undergone complete resection were assigned to undergo surgery and then receive chemotherapy or to receive chemotherapy alone. The median overall survival was 54 months with surgery and chemotherapy, and 46 months with chemotherapy alone.

The role of surgery compared with reirradiation in the primary treatment of patients with resectable, locally recurrent nasopharyngeal carcinoma (NPC) who have previously received radiotherapy is a matter of debate. In this trial, we compared the efficacy and safety outcomes of salvage endoscopic surgery versus intensity-modulated radiotherapy (IMRT) in patients with resectable locally recurrent NPC. This multicentre, open-label, randomised, controlled, phase 3 trial was done in three hospitals in southern China. We included patients aged 18–70 years with a Karnofsky Performance Status score of at least 70 who were histopathologically diagnosed with undifferentiated or differentiated, non-keratinising, locally recurrent NPC with tumours confined to the nasopharyngeal cavity, the post-naris or nasal septum, the superficial parapharyngeal space, or the base wall of the sphenoid sinus. Eligible patients were randomly assigned (1:1) to receive either endoscopic nasopharyngectomy (ENPG group) or IMRT (IMRT group). Randomisation was done manually using a computer-generated random number code and patients were stratified by treatment centre. Treatment group assignment was not masked. The primary endpoint was overall survival, compared between the groups at 3 years. Efficacy analyses were done by intention to treat. Safety analysis was done in patients who received treatment according to the treatment they actually received. This trial was prospectively registered at the Chinese Clinical Trial Registry, ChiCTR-TRC-11001573, and is currently in follow-up. Between Sept 30, 2011, and Jan 16, 2017, 200 eligible patients were randomly assigned to receive either ENPG (n=100) or IMRT (n=100). At a median follow-up of 56·0 months (IQR 42·0–69·0), 74 patients had died (29 [29%] of 100 patients in the ENPG group and 45 [45%] of 100 patients in the IMRT group). The 3-year overall survival was 85·8% (95% CI 78·9–92·7) in the ENPG group and 68·0% (58·6–77·4) in the IMRT group (hazard ratio 0·47, 95% CI 0·29–0·76; p=0·0015). The most common grade 3 or worse radiation-related late adverse event was pharyngeal mucositis (in five [5%] of 99 patients who underwent ENPG and 26 [26%] of 101 patients who underwent IMRT). Five [5%] of the 99 patients who underwent ENPG and 20 [20%] of the 101 patients who underwent IMRT died due to late toxic effects specific to radiotherapy; attribution to previous radiotherapy or trial radiotherapy is unclear due to the long-term nature of radiation-related toxicity. Endoscopic surgery significantly improved overall survival compared with IMRT in patients with resectable locally recurrent NPC. These results suggest that ENPG could be considered as the standard treatment option for this patient population, although long-term follow-up is needed to further determine the efficacy and toxicity of this strategy. Sun Yat-sen University Clinical Research 5010 Program

ObjectiveSorafenib is the standard systemic therapy for advanced hepatocellular carcinoma (HCC). Survival benefits of resection/local ablation for early HCC are compromised by 70% 5-year recurrence rates. The phase 3 STORM trial comparing sorafenib with placebo as adjuvant treatment did not achieve its primary endpoint of improving recurrence-free survival (RFS). The biomarker companion study BIOSTORM aims to define (A) predictors of recurrence prevention with sorafenib and (B) prognostic factors with B level of evidence.DesignTumour tissue from 188 patients randomised to receive sorafenib (83) or placebo (105) in the STORM trial was collected. Analyses included gene expression profiling, targeted exome sequencing (19 known oncodrivers), immunohistochemistry (pERK, pVEGFR2, Ki67), fluorescence in situ hybridisation (VEGFA) and immunome. A gene signature capturing improved RFS in sorafenib-treated patients was generated. All 70 RFS events were recurrences, thus time to recurrence equalled RFS. Predictive and prognostic value was assessed using Cox regression models and interaction test.ResultsBIOSTORM recapitulates clinicopathological characteristics of STORM. None of the biomarkers tested (related to angiogenesis and proliferation) or previously proposed gene signatures, or mutations predicted sorafenib benefit or recurrence. A newly generated 146-gene signature identifying 30% of patients captured benefit to sorafenib in terms of RFS (p of interaction=0.04). These sorafenib RFS responders were significantly enriched in CD4+ T, B and cytolytic natural killer cells, and lacked activated adaptive immune components. Hepatocytic pERK (HR=2.41; p=0.012) and microvascular invasion (HR=2.09; p=0.017) were independent prognostic factors.ConclusionIn BIOSTORM, only hepatocytic pERK and microvascular invasion predicted poor RFS. No mutation, gene amplification or previously proposed gene signatures predicted sorafenib benefit. A newly generated multigene signature associated with improved RFS on sorafenib warrants further validation.Trial registration number NCT00692770.

Rucaparib, a poly(ADP-ribose) polymerase inhibitor, has anticancer activity in recurrent ovarian carcinoma harbouring a BRCA mutation or high percentage of genome-wide loss of heterozygosity. In this trial we assessed rucaparib versus placebo after response to second-line or later platinum-based chemotherapy in patients with high-grade, recurrent, platinum-sensitive ovarian carcinoma. In this randomised, double-blind, placebo-controlled, phase 3 trial, we recruited patients from 87 hospitals and cancer centres across 11 countries. Eligible patients were aged 18 years or older, had a platinum-sensitive, high-grade serous or endometrioid ovarian, primary peritoneal, or fallopian tube carcinoma, had received at least two previous platinum-based chemotherapy regimens, had achieved complete or partial response to their last platinum-based regimen, had a cancer antigen 125 concentration of less than the upper limit of normal, had a performance status of 0–1, and had adequate organ function. Patients were ineligible if they had symptomatic or untreated central nervous system metastases, had received anticancer therapy 14 days or fewer before starting the study, or had received previous treatment with a poly(ADP-ribose) polymerase inhibitor. We randomly allocated patients 2:1 to receive oral rucaparib 600 mg twice daily or placebo in 28 day cycles using a computer-generated sequence (block size of six, stratified by homologous recombination repair gene mutation status, progression-free interval after the penultimate platinum-based regimen, and best response to the most recent platinum-based regimen). Patients, investigators, site staff, assessors, and the funder were masked to assignments. The primary outcome was investigator-assessed progression-free survival evaluated with use of an ordered step-down procedure for three nested cohorts: patients with BRCA mutations (carcinoma associated with deleterious germline or somatic BRCA mutations), patients with homologous recombination deficiencies (BRCA mutant or BRCA wild-type and high loss of heterozygosity), and the intention-to-treat population, assessed at screening and every 12 weeks thereafter. This trial is registered with ClinicalTrials.gov, number NCT01968213; enrolment is complete. Between April 7, 2014, and July 19, 2016, we randomly allocated 564 patients: 375 (66%) to rucaparib and 189 (34%) to placebo. Median progression-free survival in patients with a BRCA-mutant carcinoma was 16·6 months (95% CI 13·4–22·9; 130 [35%] patients) in the rucaparib group versus 5·4 months (3·4–6·7; 66 [35%] patients) in the placebo group (hazard ratio 0·23 [95% CI 0·16–0·34]; p<0·0001). In patients with a homologous recombination deficient carcinoma (236 [63%] vs 118 [62%]), it was 13·6 months (10·9–16·2) versus 5·4 months (5·1–5·6; 0·32 [0·24–0·42]; p<0·0001). In the intention-to-treat population, it was 10·8 months (8·3–11·4) versus 5·4 months (5·3–5·5; 0·36 [0·30–0·45]; p<0·0001). Treatment-emergent adverse events of grade 3 or higher in the safety population (372 [99%] patients in the rucaparib group vs 189 [100%] in the placebo group) were reported in 209 (56%) patients in the rucaparib group versus 28 (15%) in the placebo group, the most common of which were anaemia or decreased haemoglobin concentration (70 [19%] vs one [1%]) and increased alanine or aspartate aminotransferase concentration (39 [10%] vs none). Across all primary analysis groups, rucaparib significantly improved progression-free survival in patients with platinum-sensitive ovarian cancer who had achieved a response to platinum-based chemotherapy. ARIEL3 provides further evidence that use of a poly(ADP-ribose) polymerase inhibitor in the maintenance treatment setting versus placebo could be considered a new standard of care for women with platinum-sensitive ovarian cancer following a complete or partial response to second-line or later platinum-based chemotherapy. Clovis Oncology.

With a median follow-up of 13 years, a randomized comparison of radiotherapy with or without antiandrogen therapy in patients with a rising PSA level after prostatectomy showed that 2 years of antiandrogen therapy resulted in a significantly higher overall survival rate. Patients with localized prostatic cancer are often treated with radical prostatectomy. More than 30% of such patients will subsequently have recurrence. This recurrence manifests first as a rising serum level of prostate-specific antigen (PSA), 1 – 3 termed biochemical recurrence. Large, retrospective studies suggest that salvage radiation therapy after biochemical recurrence may be associated with long-term freedom from cancer recurrence. 4 , 5 However, 50% of the patients who are treated with salvage radiation therapy will have further disease progression, particularly when there are aggressive disease features. 4 – 7 The combination of radiation therapy and either androgen-deprivation therapy or antiandrogen therapy prolongs survival among some . . .

Cervical cancer that relapses after platinum-containing chemotherapy is often refractory to salvage therapy. Cemiplimab, a fully human antibody to PD-1, was compared with single-agent chemotherapy with pemetrexed, gemcitabine, irinotecan, topotecan, or vinorelban. Among 608 patients, median overall survival was 8.5 months with chemotherapy and 12.0 months with cemiplimab.

In this trial, omission of radiotherapy after breast-conserving surgery led to an increased incidence of local recurrence but no difference in distant recurrence as the first event or breast cancer–specific or overall survival.

Olaparib is a poly(ADP-ribose) polymerase inhibitor and cediranib is an anti-angiogenic agent with activity against VEGF receptor (VEGFR) 1, VEGFR2, and VEGFR3. Both oral agents have antitumour activity in women with recurrent ovarian cancer, and their combination was active and had manageable toxicities in a phase 1 trial. We investigated whether this combination could improve progression-free survival (PFS) compared with olaparib monotherapy in women with recurrent platinum-sensitive ovarian cancer. In our randomised, open-label, phase 2 study, we recruited women (aged ≥18 years) who had measurable platinum-sensitive, relapsed, high-grade serous or endometrioid ovarian, fallopian tube, or primary peritoneal cancer, or those with deleterious germline BRCA1/2 mutations from nine participating US academic medical centres. We randomly allocated participants (1:1) according to permuted blocks, stratified by germline BRCA status and previous anti-angiogenic therapy, to receive olaparib capsules 400 mg twice daily or the combination at the recommended phase 2 dose of cediranib 30 mg daily and olaparib capsules 200 mg twice daily. The primary endpoint was progression-free survival analysed in the intention-to-treat population. The phase 2 trial is no longer accruing patients. An interim analysis was conducted in November, 2013, after 50% of expected events had occurred and efficacy results were unmasked. The primary analysis was performed on March 31, 2014, after 47 events (66% of those expected). The trial is registered with ClinicalTrials.gov, number NCT01116648. Between Oct 26, 2011, and June 3, 2013, we randomly allocated 46 women to receive olaparib alone and 44 to receive the combination of olaparib and cediranib. Median PFS was 17·7 months (95% CI 14·7–not reached) for the women treated with cediranib plus olaparib compared with 9·0 months (95% CI 5·7–16·5) for those treated with olaparib monotherapy (hazard ratio 0·42, 95% CI 0·23–0·76; p=0·005). Grade 3 and 4 adverse events were more common with combination therapy than with monotherapy, including fatigue (12 patients in the cediranib plus olaparib group vs five patients in the olaparib monotherapy group), diarrhoea (ten vs none), and hypertension (18 vs none). Cediranib plus olaparib seems to improve PFS in women with recurrent platinum-sensitive high-grade serous or endometrioid ovarian cancer, and warrants study in a phase 3 trial. The side-effect profile suggests such investigations should include assessments of quality of life and patient-reported outcomes to understand the effects of a continuing oral regimen with that of intermittent chemotherapy. American Recovery and Reinvestment Act grant from the National Institutes of Health (NIH) (3 U01 CA062490-16S2); Intramural Program of the Center for Cancer Research; and the Division of Cancer Treatment and Diagnosis, National Cancer Institute, NIH.

5-year results of the UK Standardisation of Breast Radiotherapy (START) trials suggested that lower total doses of radiotherapy delivered in fewer, larger doses (fractions) are at least as safe and effective as the historical standard regimen (50 Gy in 25 fractions) for women after primary surgery for early breast cancer. In this prespecified analysis, we report the 10-year follow-up of the START trials testing 13 fraction and 15 fraction regimens. From 1999 to 2002, women with completely excised invasive breast cancer (pT1–3a, pN0–1, M0) were enrolled from 35 UK radiotherapy centres. Patients were randomly assigned to a treatment regimen after primary surgery followed by chemotherapy and endocrine treatment (where prescribed). Randomisation was computer-generated and stratified by centre, type of primary surgery (breast-conservation surgery or mastectomy), and tumour bed boost radiotherapy. In START-A, a regimen of 50 Gy in 25 fractions over 5 weeks was compared with 41·6 Gy or 39 Gy in 13 fractions over 5 weeks. In START-B, a regimen of 50 Gy in 25 fractions over 5 weeks was compared with 40 Gy in 15 fractions over 3 weeks. Eligibility criteria included age older than 18 years and no immediate surgical reconstruction. Primary endpoints were local-regional tumour relapse and late normal tissue effects. Analysis was by intention to treat. Follow-up data are still being collected. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN59368779. START-A enrolled 2236 women. Median follow-up was 9·3 years (IQR 8·0–10·0), after which 139 local-regional relapses had occurred. 10-year rates of local-regional relapse did not differ significantly between the 41·6 Gy and 50 Gy regimen groups (6·3%, 95% CI 4·7–8·5 vs 7·4%, 5·5–10·0; hazard ratio [HR] 0·91, 95% CI 0·59–1·38; p=0·65) or the 39 Gy (8·8%, 95% CI 6·7–11·4) and 50 Gy regimen groups (HR 1·18, 95% CI 0·79–1·76; p=0·41). In START-A, moderate or marked breast induration, telangiectasia, and breast oedema were significantly less common normal tissue effects in the 39 Gy group than in the 50 Gy group. Normal tissue effects did not differ significantly between 41·6 Gy and 50 Gy groups. START-B enrolled 2215 women. Median follow-up was 9·9 years (IQR 7·5–10·1), after which 95 local-regional relapses had occurred. The proportion of patients with local-regional relapse at 10 years did not differ significantly between the 40 Gy group (4·3%, 95% CI 3·2–5·9) and the 50 Gy group (5·5%, 95% CI 4·2–7·2; HR 0·77, 95% CI 0·51–1·16; p=0·21). In START-B, breast shrinkage, telangiectasia, and breast oedema were significantly less common normal tissue effects in the 40 Gy group than in the 50 Gy group. Long-term follow-up confirms that appropriately dosed hypofractionated radiotherapy is safe and effective for patients with early breast cancer. The results support the continued use of 40 Gy in 15 fractions, which has already been adopted by most UK centres as the standard of care for women requiring adjuvant radiotherapy for invasive early breast cancer. Cancer Research UK, UK Medical Research Council, UK Department of Health.