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High-dose therapy followed by autologous stem-cell transplantation is standard of care for patients with relapsed or primary refractory Hodgkin's lymphoma. Roughly 50% of patients might be cured after autologous stem-cell transplantation; however, most patients with unfavourable risk factors progress after transplantation. We aimed to assess whether brentuximab vedotin improves progression-free survival when given as early consolidation after autologous stem-cell transplantation. We did this randomised, double-blind, placebo-controlled, phase 3 trial at 78 sites in North America and Europe. Patients with unfavourable-risk relapsed or primary refractory classic Hodgkin's lymphoma who had undergone autologous stem-cell transplantation were randomly assigned, by fixed-block randomisation with a computer-generated random number sequence, to receive 16 cycles of 1·8 mg/kg brentuximab vedotin or placebo intravenously every 3 weeks, starting 30–45 days after transplantation. Randomisation was stratified by best clinical response after completion of salvage chemotherapy (complete response vs partial response vs stable disease) and primary refractory Hodgkin's lymphoma versus relapsed disease less than 12 months after completion of frontline therapy versus relapse 12 months or more after treatment completion. Patients and study investigators were masked to treatment assignment. The primary endpoint was progression-free survival by independent review, defined as the time from randomisation to the first documentation of tumour progression or death. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01100502. Between April 6, 2010, and Sept 21, 2012, we randomly assigned 329 patients to the brentuximab vedotin group (n=165) or the placebo group (n=164). Progression-free survival by independent review was significantly improved in patients in the brentuximab vedotin group compared with those in the placebo group (hazard ratio [HR] 0·57, 95% CI 0·40–0·81; p=0·0013). Median progression-free survival by independent review was 42·9 months (95% CI 30·4–42·9) for patients in the brentuximab vedotin group compared with 24·1 months (11·5–not estimable) for those in the placebo group. We recorded consistent benefit (HR <1) of brentuximab vedotin consolidation across subgroups. The most frequent adverse events in the brentuximab vedotin group were peripheral sensory neuropathy (94 [56%] of 167 patients vs 25 [16%] of 160 patients in the placebo group) and neutropenia (58 [35%] vs 19 [12%] patients). At time of analysis, 28 (17%) of 167 patients had died in the brentuximab vedotin group compared with 25 (16%) of 160 patients in the placebo group. Early consolidation with brentuximab vedotin after autologous stem-cell transplantation improved progression-free survival in patients with Hodgkin's lymphoma with risk factors for relapse or progression after transplantation. This treatment provides an important therapeutic option for patients undergoing autologous stem-cell transplantation. Seattle Genetics and Takeda Pharmaceuticals International.

Doubts exist regarding optimal second-line treatment options for HIV-1-infected patients in resource-limited settings. We assessed safety and efficacy of dolutegravir compared with ritonavir-boosted lopinavir, plus two nucleoside reverse transcriptase inhibitors (NRTIs) in adults in whom previous first-line antiretroviral therapy with a non-nucleoside reverse transcriptase inhibitor (NNRTI) plus two NRTIs has failed. DAWNING is a phase 3b, open-label, parallel-group, non-inferiority, active-controlled trial done at 58 sites in 13 countries. Eligible adults were aged at least 18 years and, during at least 6 months of treatment with a first-line treatment containing an NNRTI and two NRTIs, had virological failure (confirmed HIV-1 RNA ≥400 copies per mL). Participants were randomly assigned by a central randomisation system to receive oral dolutegravir (50 mg once daily) or ritonavir-boosted lopinavir (800 mg lopinavir plus 200 mg ritonavir once daily or 400 mg plus 100 mg twice daily), plus two investigator-selected NRTIs (at least one fully active based on resistance testing at screening). The primary outcome was the proportion of participants achieving viral suppression (defined as plasma HIV-1 RNA <50 copies per mL) at week 48 using the snapshot algorithm and a non-inferiority margin of −12%. The primary analysis was done in an intention-to-treat-exposed (ITT-E) population of participants who received at least one dose of study medication, according to original group assignment. Safety was analysed in all participants who received at least one dose of study drug, according to which drug was received. The study was registered at ClinicalTrials.gov, number NCT02227238, and viiv-studyregister.com, number 200304. Between Dec 11, 2014, and June 27, 2016, 968 adults were screened and 627 were randomly assigned to the dolutegravir group (n=312) or the ritonavir-boosted lopinavir group (n=315). Three patients in the ritonavir-boosted lopinavir group did not receive study medication and so 624 were included in the ITT-E population. At week 48, 261 (84%) of 312 participants in the dolutegravir group achieved viral suppression compared with 219 (70%) of 312 in the ritonavir-boosted lopinavir group (adjusted difference 13·8%; 95% CI 7·3–20·3). Non-inferiority was achieved on the basis of the 95% CI of the adjusted treatment difference having a lower bound greater than −12% (prespecified non-inferiority margin). Because the lower bound of the 95% CI is greater than zero (7·3%), superiority of dolutegravir was also concluded (p<0·0001). The safety profile for dolutegravir was favourable compared with that of ritonavir-boosted lopinavir. More grade 2–4 drug-related adverse events occurred with ritonavir-boosted lopinavir than dolutegravir (44 [14%] of 310 with ritonavir-boosted lopinavir vs 11 [4%] of 314 with dolutegravir), mainly driven by gastrointestinal disorders. When administered with two NRTIs, dolutegravir was superior to ritonavir-boosted lopinavir at 48 weeks and can be considered a suitable option for second-line treatment. ViiV Healthcare.

This randomized, phase III, open-label, multicenter study compared carfilzomib monotherapy against low-dose corticosteroids and optional cyclophosphamide in relapsed and refractory multiple myeloma (RRMM). Relapsed and refractory multiple myeloma patients were randomized (1:1) to receive carfilzomib (10-min intravenous infusion; 20 mg/m 2 on days 1 and 2 of cycle 1; 27 mg/m 2 thereafter) or a control regimen of low-dose corticosteroids (84 mg of dexamethasone or equivalent corticosteroid) with optional cyclophosphamide (1400 mg) for 28-day cycles. The primary endpoint was overall survival (OS). Three-hundred and fifteen patients were randomized to carfilzomib ( n =157) or control ( n =158). Both groups had a median of five prior regimens. In the control group, 95% of patients received cyclophosphamide. Median OS was 10.2 (95% confidence interval (CI) 8.4–14.4) vs 10.0 months (95% CI 7.7–12.0) with carfilzomib vs control (hazard ratio=0.975; 95% CI 0.760–1.249; P =0.4172). Progression-free survival was similar between groups; overall response rate was higher with carfilzomib (19.1 vs 11.4%). The most common grade ⩾3 adverse events were anemia (25.5 vs 30.7%), thrombocytopenia (24.2 vs 22.2%) and neutropenia (7.6 vs 12.4%) with carfilzomib vs control. Median OS for single-agent carfilzomib was similar to that for an active doublet control regimen in heavily pretreated RRMM patients.

In men with a detectable prostate-specific antigen (PSA) level after prostatectomy for prostate cancer, salvage prostate bed radiotherapy (PBRT) results in about 70% of patients being free of progression at 5 years. A three-group randomised trial was designed to determine whether incremental gains in patient outcomes can be achieved by adding either 4–6 months of short-term androgen deprivation therapy (ADT) to PBRT, or both short-term ADT and pelvic lymph node radiotherapy (PLNRT) to PBRT. The international, multicentre, randomised, controlled SPPORT trial was done at 283 radiation oncology cancer treatment centres in the USA, Canada, and Israel. Eligible patients (aged ≥18 years) were those who after prostatectomy for adenocarcinoma of the prostate had a persistently detectable or an initially undetectable and rising PSA of between 0·1 and 2·0 ng/mL. Patients with and without lymphadenectomy (N0/Nx) were eligible if there was no clinical or pathological evidence of lymph node involvement. Other eligibility criteria included pT2 or pT3 disease, prostatectomy Gleason score of 9 or less, and a Zubrod performance status of 0–1. Eligible patients were randomly assigned to receive PBRT alone at a dose of 64·8–70·2 Gy at 1·8 Gy per fraction daily (group 1), PBRT plus short-term ADT (group 2), or PLNRT (45 Gy at 1·8 Gy per fraction, and then a volume reduction made to the planning target volume for the remaining 19·8–25 ·2 Gy) plus PBRT plus short-term ADT (group 3). The primary endpoint was freedom from progression, in which progression was defined as biochemical failure according to the Phoenix definition (PSA ≥2 ng/mL over the nadir PSA), clinical failure (local, regional, or distant), or death from any cause. A planned interim analysis of 1191 patents with minimum potential follow-up time of 5 years applied a Haybittle-Peto boundary of p<0·001 (one sided) for comparison of 5-year freedom from progression rates between the treatment groups. This trial is registered with ClinicalTrials.gov, NCT00567580. The primary objectives of the trial have been completed, although long-term follow-up is continuing. Between March 31, 2008, and March 30, 2015, 1792 eligible patients were enrolled and randomly assigned to the three treatment groups (592 to group 1 [PBRT alone], 602 to group 2 [PBRT plus short-term ADT], and 598 to group 3 [PLNRT plus PBRT plus short-term ADT]). 76 patients subsequently found to be ineligible were excluded from the analyses; thus, the evaluable patient population comprised 1716 patients. At the interim analysis (n=1191 patients; data cutoff May 23, 2018), the Haybittle-Peto boundary for 5-year freedom from progression was exceeded when group 1 was compared with group 3 (difference 17·9%, SE 2·9%; p<0·0001). The difference between groups 2 and 3 did not exceed the boundary (p=0·0063). With additional follow-up beyond the interim analysis (the final planned analysis; data cutoff May 26, 2021), at a median follow-up among survivors of 8·2 years (IQR 6·6–9·4), the 5-year freedom from progression rates in all 1716 eligible patients were 70·9% (95% CI 67·0–74·9) in group 1, 81·3% (78·0–84·6) in group 2, and 87·4% (84·7–90·2) in group 3. Per protocol criteria, freedom from progression in group 3 was superior to groups 1 and 2. Acute (≤3 months after radiotherapy) grade 2 or worse adverse events were significantly more common in group 3 (246 [44%] of 563 patients) than in group 2 (201 [36%] of 563; p=0·0034), which, in turn, were more common than in group 1 (98 [18%] of 547; p<0·0001). Similar findings were observed for grade 3 or worse adverse events. However, late toxicity (>3 months after radiotherapy) did not differ significantly between the groups, apart from more late grade 2 or worse blood or bone marrow events in group 3 versus group 2 (one-sided p=0·0060) attributable to the addition of PLNRT in this group. The results of this randomised trial establish the benefit of adding short-term ADT to PBRT to prevent progression in prostate cancer. To our knowledge, these are the first such findings to show that extending salvage radiotherapy to treat the pelvic lymph nodes when combined with short-term ADT results in meaningful reductions in progression after prostatectomy in patients with prostate cancer. National Cancer Institute.

Adjuvant radiotherapy has been shown to halve the risk of biochemical progression for patients with high-risk disease after radical prostatectomy. Early salvage radiotherapy could result in similar biochemical control with lower treatment toxicity. We aimed to compare biochemical progression between patients given adjuvant radiotherapy and those given salvage radiotherapy. We did a phase 3, randomised, controlled, non-inferiority trial across 32 oncology centres in Australia and New Zealand. Eligible patients were aged at least 18 years and had undergone a radical prostatectomy for adenocarcinoma of the prostate with pathological staging showing high-risk features defined as positive surgical margins, extraprostatic extension, or seminal vesicle invasion; had an Eastern Cooperative Oncology Group performance status of 0–1, and had a postoperative prostate-specific antigen (PSA) concentration of 0·10 ng/mL or less. Patients were randomly assigned (1:1) using a minimisation technique via an internet-based, independently generated allocation to either adjuvant radiotherapy within 6 months of radical prostatectomy or early salvage radiotherapy triggered by a PSA of 0·20 ng/mL or more. Allocation sequence was concealed from investigators and patients, but treatment assignment for individual randomisations was not masked. Patients were stratified by radiotherapy centre, preoperative PSA, Gleason score, surgical margin status, and seminal vesicle invasion status. Radiotherapy in both groups was 64 Gy in 32 fractions to the prostate bed without androgen deprivation therapy with real-time review of plan quality on all cases before treatment. The primary endpoint was freedom from biochemical progression. Salvage radiotherapy would be deemed non-inferior to adjuvant radiotherapy if freedom from biochemical progression at 5 years was within 10% of that for adjuvant radiotherapy with a hazard ratio (HR) for salvage radiotherapy versus adjuvant radiotherapy of 1·48. The primary analysis was done on an intention-to-treat basis. This study is registered with ClinicalTrials.gov, NCT00860652. Between March 27, 2009, and Dec 31, 2015, 333 patients were randomly assigned (166 to adjuvant radiotherapy; 167 to salvage radiotherapy). Median follow-up was 6·1 years (IQR 4·3–7·5). An independent data monitoring committee recommended premature closure of enrolment because of unexpectedly low event rates. 84 (50%) patients in the salvage radiotherapy group had radiotherapy triggered by a PSA of 0·20 ng/mL or more. 5-year freedom from biochemical progression was 86% (95% CI 81–92) in the adjuvant radiotherapy group versus 87% (82–93) in the salvage radiotherapy group (stratified HR 1·12, 95% CI 0·65–1·90; pnon-inferiority=0·15). The grade 2 or worse genitourinary toxicity rate was lower in the salvage radiotherapy group (90 [54%] of 167) than in the adjuvant radiotherapy group (116 [70%] of 166). The grade 2 or worse gastrointestinal toxicity rate was similar between the salvage radiotherapy group (16 [10%]) and the adjuvant radiotherapy group (24 [14%]). Salvage radiotherapy did not meet trial specified criteria for non-inferiority. However, these data support the use of salvage radiotherapy as it results in similar biochemical control to adjuvant radiotherapy, spares around half of men from pelvic radiation, and is associated with significantly lower genitourinary toxicity. New Zealand Health Research Council, Australian National Health Medical Research Council, Cancer Council Victoria, Cancer Council NSW, Auckland Hospital Charitable Trust, Trans-Tasman Radiation Oncology Group Seed Funding, Cancer Research Trust New Zealand, Royal Australian and New Zealand College of Radiologists, Cancer Institute NSW, Prostate Cancer Foundation Australia, and Cancer Australia.

Adjuvant radiotherapy reduces the risk of biochemical progression in prostate cancer patients after radical prostatectomy. We aimed to compare adjuvant versus early salvage radiotherapy after radical prostatectomy, combined with short-term hormonal therapy, in terms of oncological outcomes and tolerance. GETUG-AFU 17 was a randomised, open-label, multicentre, phase 3 trial done at 46 French hospitals. Men aged at least 18 years who had an Eastern Cooperative Oncology Group performance status of 1 or less, localised adenocarcinoma of the prostate treated with radical prostatectomy, who had pathologically-staged pT3a, pT3b, or pT4a (with bladder neck invasion), pNx (without pelvic lymph nodes dissection), or pN0 (with negative lymph nodes dissection) disease, and who had positive surgical margins were eligible for inclusion in the study. Eligible patients were randomly assigned (1:1) to either immediate adjuvant radiotherapy or delayed salvage radiotherapy at the time of biochemical relapse. Random assignment, by minimisation, was done using web-based software and stratified by Gleason score, pT stage, and centre. All patients received 6 months of triptorelin (intramuscular injection every 3 months). The primary endpoint was event-free survival. Efficacy and safety analyses were done on the intention-to-treat population. The trial is registered with ClinicalTrials.gov, NCT00667069. Between March 7, 2008, and June 23, 2016, 424 patients were enrolled. We planned to enrol 718 patients, with 359 in each study group. However, on May 20, 2016, the independent data monitoring committee recommended early termination of enrolment because of unexpectedly low event rates. At database lock on Dec 19, 2019, the overall median follow-up time from random assignment was 75 months (IQR 50–100), 74 months (47–100) in the adjuvant radiotherapy group and 78 months (52–101) in the salvage radiotherapy group. In the salvage radiotherapy group, 115 (54%) of 212 patients initiated study treatment after biochemical relapse. 205 (97%) of 212 patients started treatment in the adjuvant group. 5-year event-free survival was 92% (95% CI 86–95) in the adjuvant radiotherapy group and 90% (85–94) in the salvage radiotherapy group (HR 0·81, 95% CI 0·48–1·36; log-rank p=0·42). Acute grade 3 or worse toxic effects occurred in six (3%) of 212 patients in the adjuvant radiotherapy group and in four (2%) of 212 patients in the salvage radiotherapy group. Late grade 2 or worse genitourinary toxicities were reported in 125 (59%) of 212 patients in the adjuvant radiotherapy group and 46 (22%) of 212 patients in the salvage radiotherapy group. Late genitourinary adverse events of grade 2 or worse were reported in 58 (27%) of 212 patients in the adjuvant radiotherapy group versus 14 (7%) of 212 patients in the salvage radiotherapy group (p<0·0001). Late erectile dysfunction was grade 2 or worse in 60 (28%) of 212 in the adjuvant radiotherapy group and 17 (8%) of 212 in the salvage radiotherapy group (p<0·0001). Although our analysis lacked statistical power, we found no benefit for event-free survival in patients assigned to adjuvant radiotherapy compared with patients assigned to salvage radiotherapy. Adjuvant radiotherapy increased the risk of genitourinary toxicity and erectile dysfunction. A policy of early salvage radiotherapy could spare men from overtreatment with radiotherapy and the associated adverse events. French Health Ministry and Ipsen.

Various locoregional treatments exist for PET–CT-detected pelvic nodal oligorecurrences in patients with prostate cancer. We aimed to assess whether elective nodal radiotherapy (ENRT) to the pelvis would be superior to metastasis-directed therapy (MDT). PEACE V–STORM is a phase 2, open-label, randomised, controlled trial conducted in 21 hospitals in Australia, Belgium, Italy, Norway, Spain, and Switzerland. Eligible participants were aged 18 years or older, with WHO performance status 0–1 and a histologically confirmed initial diagnosis of adenocarcinoma of the prostate, with a PET-detected pelvic nodal oligorecurrence (up to five nodes) following radical local treatment. Patients were randomly assigned (1:1) to MDT or ENRT. Randomisation was done online by minimisation with randomisation factor 0·80 and was stratified by type of PET tracer (choline vs prostate-specific membrane antigen) and type of MDT used (salvage lymph node dissection vs stereotactic body radiotherapy or simultaneous integrated boost). Participants and researchers were not masked to treatment assignment. Patients in the MDT group had salvage lymph node dissection or stereotactic body radiotherapy (30 Gy in three fractions every other day), with 6 months of androgen deprivation therapy. Patients in the ENRT group received a 45 Gy dose in 25 fractions to the pelvis with a simultaneous integrated boost of 65 Gy to the PET-positive nodes or salvage lymph node dissection, with 6 months of androgen deprivation therapy. The primary endpoint was metastasis-free survival, defined as the time between randomisation and the appearance of a metastatic recurrence (any M1) on PET imaging or death due to any cause, and was analysed per modified intention to treat. This study is registered with ClinicalTrials.gov, NCT03569241, and the Swiss National Clinical Trials Portal, SNCTP000002947, and is active, not recruiting. Between June 11, 2018, and April 30, 2021, 198 patients were screened for eligibility, 196 of whom were randomly assigned to MDT (n=99) or ENRT (n=97), with 190 evaluable patients (MDT n=97 and ENRT n=93). All patients were male. Data on race and ethnicity were not collected. Median follow-up was 50 months (IQR 42–58). 4-year metastasis-free survival was 63% (80% CI 56–69) in the MDT group and 76% (69–81) in the ENRT group (HR 0·62 [80% CI 0·44–0·86]; p=0·063). The most common grade 3 adverse events were urinary incontinence (six [6%] of 97 in the MDT group vs nine [10%] in the ENRT group) and diarrhoea (one [1%] in the MDT group vs two [2%] in the ENRT group). No treatment-related deaths occurred. To our knowledge, this is the first randomised trial for metachronous PET-detected nodal recurrences comparing two local treatment approaches (MDT and ENRT) in combination with 6 months of androgen deprivation therapy. By showing an improved metastasis-free survival with ENRT, this trial establishes ENRT as a potential standard treatment approach, awaiting a phase 3 trial confirming these results. Movember Foundation, Kom Op Tegen Kanker, Stichting tegen Kanker.

The randomized phase 3 ENDEAVOR study ( N =929) compared carfilzomib and dexamethasone (Kd) with bortezomib and dexamethasone (Vd) in relapsed multiple myeloma (RMM). We performed a subgroup analysis from ENDEAVOR in patients categorized by number of prior lines of therapy or by prior treatment. Median progression-free survival (PFS) for patients with one prior line was 22.2 months for Kd vs 10.1 months for Vd, and median PFS for patients with ⩾2 prior lines was 14.9 months for Kd vs 8.4 months for Vd. For patients with prior bortezomib exposure, the median PFS was 15.6 months for Kd vs 8.1 months for Vd, and for patients with prior lenalidomide exposure the median PFS was 12.9 months for Kd vs 7.3 months for Vd. Overall response rates (Kd vs Vd) were 81.9 vs 65.5% (one prior line), 72.0 vs 59.7% (⩾2 prior lines), 71.2 vs 60.3% (prior bortezomib) and 70.1 vs 59.3% (prior lenalidomide). The safety profile in the prior lines subgroups was qualitatively similar to that in the broader ENDEAVOR population. In RMM, outcomes are improved when receiving treatment with carfilzomib compared with bortezomib, regardless of the number of prior therapy lines or prior exposure to bortezomib or lenalidomide.

Background. There is an urgent need for alternative rescue therapies in invasive infections caused by methicillin-resistant Staphylococcus aureus (MRSA). We assessed the clinical efficacy and safety of the combination of fosfomycin and imipenem as rescue therapy for MRSA infective endocarditis and complicated bacteremia. Methods. The trial was conducted between 2001 and 2010 in 3 Spanish hospitals. Adult patients with complicated MRSA bacteremia or endocarditis requiring rescue therapy were eligible for the study. Treatment with fosfomycin (2 g/6 hours IV) plus imipenem (1 g/6 hours IV) was started and monitored. The primary efficacy endpoints were percentage of sterile blood cultures at 72 hours and clinical success rate assessed at the test-of-cure visit (45 days after the end of therapy). Results. The combination was administered in 12 patients with endocarditis, 2 with vascular graft infection, and 2 with complicated bacteremia. Therapy had previously failed with vancomycin in 9 patients, daptomycin in 2, and sequential antibiotics in 5. Blood cultures were negative 72 hours after the first dose of the combination in all cases. The success rate was 69%, and only 1 of 5 deaths was related to the MRSA infection. Although the combination was safe in most patients (94%), a patient with liver cirrhosis died of multiorgan failure secondary to sodium overload. There were no episodes of breakthrough bacteremia or relapse. Conclusions. Fosfomycin plus imipenem was an effective and safe combination when used as rescue therapy for complicated MRSA bloodstream infections and deserves further clinical evaluation as initial therapy in these infections.

Screw loosening due to broken pedicles is a common complication resulting from the insertion of screws either with inadequate diameters or into an osteoporotic pedicle. In this novel in vitro study, we tried to clarify the contribution of the pedicle to screw fixation and subsequent salvage strategies using longer or larger-diameter screws in broken pedicles. Sixty L4 fresh-frozen lumbar vertebrae harvested from mature pigs were designed as the normal-density group (n = 30) and decalcified as the osteoporosis group (n = 30). Three modalities were randomly assigned as intact pedicle (n = 30), semi-pedicle (n = 15), and non-pedicle (n = 15) in each group. Three sizes of polyaxial screws (diameter × length of 6.0 mm × 45 mm, 6.0 mm × 50 mm, and 6.5 mm × 45 mm) over five trials were used in each modality. The associations between bone density, pedicle modality and screw pullout strength were analyzed. After decalcification for 4 weeks, the area bone mineral density decreased to approximately 56% ( p  < 0.05) of the normal-density group, which was assigned as the osteoporosis group. An appropriate screw trajectory and insertional depth were confirmed using X-ray imaging prior to pullout testing in both groups. The pullout forces of larger-diameter screws (6.5 mm × 45 mm) and longer screws (6.0 mm × 50 mm) were significantly higher ( p  < 0.05) in the semi- and non-pedicle modalities in the normal-density group, whereas only longer screws (6.0 mm × 50 mm) had a significantly higher ( p  < 0.05) pullout force in the non-pedicle modalities in the osteoporosis group. The pedicle plays an important role in both the normal bone density group and the osteoporosis group, as revealed by analyzing the pullout force percentage contributed by the pedicle. Use of a longer screw would be a way to salvage a broken pedicle of osteoporotic vertebra.