Holly Baker

Radiotherapy in the elderly and frail with glioblastoma

Lancet Oncology, The - In Press.Proof corrected by the author Available online since mercredi 7 octobre 2015

Extending aromatase inhibitor adjuvant therapy to 10 years

www.thelancet.com/oncology Vol 17 July 2016 e275 Postmenopausal women with hormone-receptor-positive early breast cancer could benefit by extending adjuvant therapy with aromatase inhibitors from 5 years to 10 years, a new double-blind, phase 3, placebo-controlled trial study suggests. Paul Goss (Massachusetts General Hospital Cancer Centre, MA, USA) and colleagues’ study enrolled postmenopausal women with primary breast cancer who had received 4·5-6·0 years of adjuvant therapy with an aromatase inhibitor, most of whom had previously been treated with tamoxifen and who were disease-free at the time of enrolment. 1918 patients were randomly assigned to receive 25 mg letrozole or placebo daily for a further 5 years. At a median follow-up of 6·3 years, 67 (7%) of 959 patients in the letrozole group had disease recurrence or contralaleral breast cancer compared with 98 (10%) of 959 patients in the placebo group. 5-year disease-free survival (the primary endpoint) was 95% (95% CI 93–96) in the letrozole group and 91% (89–93) in the placebo group, (0·66 hazard ratio [95% CI 0·48–0·91]; p=0·01). 5-year overall survival was similar between groups: 93% (95% CI 92–95) with letrozole and 94% (92–95) with placebo (HR 0·97, 95% CI 0·73–1·28; p=0·83). Except for bone-related toxic eff ects, which occurred more frequently in the letrozole group compared with the placebo group, the toxic eff ects were similar. Commenting on the study, Miguel Martin (Hospital General Universitario Gregorio Maranon, Madrid, Spain), said that “this [study] is very relevant clinically, is practicechanging, and should be discussed with our patients as a new option, taking into consideration the pros (reduction of contralateral breast cancers and local-regional and distant metastases) and the cons (lack of survival benefi t and negative bone eff ects of letrozole) of the therapy.” He continued, “Avoiding a contralateral breast cancer, regardless of the lack of benefit on survival, is a goal by itself.” Goss told The Lancet Oncology, “We are conducting deeper analyses to determine which patients should or should not continue [alignment therapy]. We have reduced recurrences or occurrences by 34% which is clinically very significant.” However, he concluded, “Extending a therapy clinically for 5 years is important and my opinion is that...a sober judgment by properly appointed guideline committees is needed” before such changes are instituted.

Surveillance benefit for pancreatic cancer in high-risk individuals

www.thelancet.com/oncology Published online May 6, 2016 http://dx.doi.org/10.1016/ S1470-2045(16)30130-9 1 Surveillance of CDNK2A mutation carriers facilitates detection of pancreatic ductal adenocarcinoma (PDAC) at an early, resectable stage, according to a new study. Hans Vasen (Leiden University Medical Centre, Leiden, Netherlands) and colleagues collected screening outcomes from expert centres in Leiden, Marburg, and Madrid that conduct prospective screening in families at a high risk of developing PDAC, to assess whether surveillance aids detection of PDAC and thus improves prognosis. Individuals were put on surveillance at 45 years of age in Leiden, and at age 40 years or 10 years before the youngest age of diagnosis in the family in Marburg and Madrid. Of the 411 asymptomatic individuals that participated, 214 had a family history of PDAC and 197 had a genetic defect associated with PDAC (178 had mutations in CDKN2A and 19 had mutations in PALB2 or BRCA1/2. PDAC was detected in 13 (7·3%) of 178 patients with CDKN2A mutations; the resection rate was 75% and 5-year survival was 24%. Of the 214 patients with a family history, three were found to have a PDAC, with a resection rate of 1·4%. Only one of 19 individuals with a BRCA1/2 mutation developed PDAC. Vasen commented, “Pancreatic cancer is a very aggressive tumour. Mean survival after diagnosis is only 6 months. If patients present with symptoms, the cancer is usually diagnosed at an advanced stage, and the tumour can be resected in only 15%.” He continued, “The study demonstrated that the yield of screening was relatively high in the group with a CDKN2A/p16-Leiden defect. Pancreatic cancer was detected in 7% of the individuals. The resection rate was much higher than the resection rate reported for sporadic pancreatic cancer (about 15%). Also, the survival of the patients was higher”. Philip Philip (Karmanos Cancer Center, Wayne State University, MI, USA) commented that, “The strengths of this study lie in the number of participants included, inclusion of participants known to have a significantly elevated risk of developing pancreatic cancer, and the demonstration that a multidisciplinary collaboration including geneticists, gastroenterologists, and surgeons is essential for the successful conduct of such complex screening strategies”. However, he continued, “con sideration must be given to applicability of such screening modality for the general population...most importantly issues related to false positivity”.

Daratumumab improves survival in multiple myeloma

Addition of daratumumab to lenalidomide and dexamethasone signifi cantly prolongs progressionfree survival among patients with relapsed or refractory multiple myeloma, a phase 3 trial showed. Meletios-Athanassios Dimopoulos (National and Kapodistrian University of Athens, Athens, Greece) and colleagues randomly assigned 286 patients to receive lenalidomide and dexamethasone plus daratumumab (daratumumab group) and 283 to receive lenalidomide and dexamethasone alone (control group). After a median follow-up of 13·5 months, 12-month progressionfree survival (the primary endpoint) was 83·2% (95% CI 78·3–87·2) in the daratumumab group versus 60·1% (54·0–65·7) in the control group (HR 0·37 [95% CI 0·27–0·52]; p<0·001). Overall response was 92·9% in the daratumumab group compared with 76·4% in the control group (p<0·001). Dimopoulos explained, “The difference observed as far as progression-free survival and response are concerned was overwhelming in favour of daratumumab– lenalidomide–dexamethasone.” Philip McCarthy (Roswell Park Cancer Institute, New York, NY, USA) commented that, “This study further demonstrates that daratumumab, as part of combination therapy, has pro found activity against relapsed and refractory multiple myeloma. [The drug] will likely be approved in combination treatment with lenalidomide for those patients failing one or more lines of prior therapy.” The most frequently observed grade 3 or 4 adverse events were neutropenia (51·9% of patients in the daratumumab group vs 37·0% of patients in the control group), thrombocytopenia (12·7% vs 13·5%), and anaemia (12·4% vs 19·6%). McCarthy continued: “Currently there does not appear to be a deleterious eff ect of prolonged daratumumab admini stration but long-term followup will be necessary to confi rm safety, as we do not know the longterm eff ects of daratumumab on the immune system, [and also] to determine if there is an overall survival benefi t.” McCarthy concluded that: “This study demonstrates the need for surrogate markers for long-term disease con trol. As more eff ective therapies are developed, it will be necessary to evaluate surrogate markers such as blood or bone marrow minimal residual disease negativity or immune recon stit ution/ profi ling before and after therapy.”

Cancer Drugs Fund failed to collect patient outcomes.

Lancet Oncology, The - In Press.Proof corrected by the author Available online since samedi 26 septembre 2015

High HLA-DP expression and graft-versus-host disease

Although transplantation can cure blood disorders, there remains a significant risk of graft-versus-host disease (GVHD). Researchers in the USA have found an association between high expression of HLA-DP variants and acute GVHD in patients receiving haematopoietic-cell transplantation for severe blood disorders. Effie Petersdorf (Fred Hutchinson Cancer Research Center, Seattle, WA, USA) and colleagues genotyped the HLA-DPB1 regulatory region variant rs9277534 in 3505 patients, and assessed the clinical outcomes of 1441 (71%) of 2029 recipients of transplants f r o m H L A A , B ,C , D R B 1 , D Q B 1 matched unrelated donors with only one HLA-DPB1 mismatch, and 588 (29%) recipients of transplants from an HLA-A,B,C,DRB1,DQB1,DPB1matched unrelated donor. The researchers found that transplant recipients with rs9277534G-linked HLA-DPB1 mismatches had higher risks of acute GVHD compared with recipients who had rs9277534A-linked mismatches (hazard ratio [HR] 1·54, 95% CI 1·25–1·89; p<0·001). Similarly, the risk of death due to causes other than disease recurrence was also higher for recipients with rs9277534Glinked HLA-DPB1 mismatches than for recipients with rs9277534A-linked HLA-DPB1 mismatches (HR 1·25, 95% CI 1·00–1·57; p=0·05). Katharina Fleischhauer (University Hospital Essen, Essen, Germany) said that this is an “elegant, innovative study, which for the fi rst time addresses the aspect of HLADPB1 expression levels, rather than matching for structural aminoacid polymorphism, in unrelated donor haematopoietic cell transplantation”. She added that “clinically, [these data] suggest that high-expression variant HLA-DPB1 mismatches... should be avoided in unrelated donor haematopoietic cell transplantation from donors with a low expression HLA-DPB1, to reduce the risk of severe acute GVHD”. According to Claudio Anasetti (Moffitt Cancer Center, Tampa, FL, USA), the study “uncovered structural polymorphisms in the intron regions of HLA-DPB1 genes as the basis for variability in alloreactivity against different DPB1 alleles”, which could “change the way we think about genetic matching and alloimmunity: intron sequences may be as important for patient outcome as exon sequences, by regulating gene expression”. Fleischhauer suggests that there are a number of questions that need to be addressed, including “confi rmation of the data in a validation cohort”.

Discontinuation of melanoma combination immunotherapy

Patients with advanced melanoma might continue to benefit from combination immunotherapy even after treatment is stopped because of adverse events, a new study suggests. Dirk Schadendorf (University Hospital Essen, Essen, Germany) and colleagues did a pooled analysis of randomised phase 2 and 3 trials in which 407 patients with unresectable stage III or stage IV melanoma had been randomly assigned to and received nivolumab plus ipilimumab every 3 weeks for four doses (induction phase), followed by nivolumab monotherapy every 2 weeks until disease progression or unacceptable toxicity. 176 (43%) patients discontinued treatment because of adverse events and, of these patients, 96 (24%) discontinued during the induction phase. 231 (57%) patients discontinued treatment for other reasons. After a minimum follow-up of 18 months, median progression-free survival was 8·4 months (95% CI 5·8–16·7) for patients who discontinued treatment during the induction phase and 10·8 months (5·9–23·0) for those who did not discontinue because of adverse events (hazard ratio 0·99, 95% CI 0·72–1·37; p=0·966). Similarly, no difference was noted in objective responses between these two groups (56 patients who discontinued treatment during induction achieved an objective response of 58·3% [95% CI 47·8–68·3] whereas 117 patients who discontinued treatment for other reasons achieved an objective response of 50·2% [43·6–56·8]; p=0·180). C o a u t h o r M i c h a e l Po s t o w (Memorial Sloan Kettering Cancer Center, New York, NY, USA) said, “Response rates, progression-free survival, and overall survival looked favourable, even in patients who discontinued immunotherapy early”. He continued, “Essentially, patients who have significant adverse events from combination immunotherapy may only need a short course of immunotherapy and be able to have a long period of disease control”. Vernon Sondak (Moffitt Cancer Center, Tampa, FL, USA) said that the results “provide some reassurance— namely, that even if patients have to stop treatment due to side-effects, they still stand a good chance of benefiting from the treatment they have already received.” He concluded that “This should encourage both patients and their oncologists to follow standard toxicity management algorithms, and to stop treatment when necessary without feeling concerned that doing so is jeopardising their chances of long-term benefit”.

Ipilimumab for relapse after allogeneic transplantation

www.thelancet.com/oncology Vol 17 September 2016 e374 Induction therapy with ipilimumab might produce durable responses for patients with relapse of haematological cancers after allogeneic haemaopoietic stem-cel l transplantation, a phase 1/1b multicentre study from the USA suggests. Matthew Davids (Dana-Farber Cancer Institute, Boston, MA, USA) and colleagues enrolled 28 patients to receive ipilimumab at a dose of 3 mg/kg or 10 mg/kg of bodyweight every 3 weeks for four doses, with additional doses every 12 weeks for 60 weeks in patients who displayed clinical benefit. Of six patients who received 3 mg/kg, none met the formal response criteria. Of 22 patients receiving a dose of 10 mg/kg, fi ve (23%) had an objective complete response; four with extramedullary acute myeloid leukaemia and one with myelodysplastic syndrome developing into acute myeloid leukaemia. Two (9%) patients had a partial response and six (27%) who did not meet response criteria had a reduction in the tumour burden. Four (18%) patients maintained a response for more than a year. Immune-related adverse events were observed in fi ve (18%) patients. One patient died 42 days after receiving the initial dose of ipilimumab. Graft-versus-host disease (GVHD) that precluded further therapy with ipilimumab was observed in four (14%) patients. Davids told The Lancet Oncology, “Patients who relapse after allogeneic transplantation have a particularly poor outcome. Donor lymphocyte infusion has been used to try to restore a graft-versus-tumour eff ect, but often has significant toxicity from GVHD”. He continued, “We hypothesised that ipilimumab could be a pharmacological way to restore a graft-versus-tumour eff ect with less risk of GVHD”. Daniel Weisdorf (University of Minnesota, Minneapolis, MN, USA) commented, “This was a well done, but small and preliminary study. It identifi ed some promise that this checkpoint inhibitor could unleash some graft-versus-tumour eff ect.” He continued, “Reproducibility and better defi nition of who could best benefi t are important, and consideration of whether such treatment could be valuable as prophylaxis of relapse for high-risk patients is also needed. But the phase 2 assessments in a similar population will come fi rst.” Davids concluded, “Our early phase data set the stage for larger studies of this approach in the post-allogeneic transplant setting, which if also positive, could change the treatment paradigm for patients in this dire situation.”

Chemoradiotherapy for grade 2 glioma improves survival

www.thelancet.com/oncology Vol 17 May 2016 e186 Long-term results of a phase 3 trial showed that combination chemotherapy plus radiotherapy improves overall survival of patients with grade 2 glioma, compared to radiotherapy alone. These findings are in contrast with the interim report of the study, which suggested improved progression-free survival, but not overall survival. Jan Buckner and colleagues enrolled 254 patients with grade 2 astrocytoma, oligoastrocytoma, or oligodendroglioma; 128 patients were randomly assigned to receive radiotherapy alone, and 126 to radiotherapy plus procarbazine, lomustine, and vincristine (PCV). All patients received therapy after tumour biopsy or resection. At median fol low-up of 11·9 years, overall survival was longer in patients who received combination chemotherapy plus radiotherapy (13·3 years, 95% CI 10·6–not reached) compared with patients who received radiotherapy alone (7·8 years, 6·1–9·8; HR for death 0·59, 95% CI 0·42–0·83, p=0·003). 10-year progression-free survival was 51% (95% CI 42–59) for patients given radiotherapy plus chemotherapy, versus 21% (14–28) for the group who received radiation alone. Arnab Chakravarti, an author on the paper, (Ohio State University, Columbus, OH, USA), told The Lancet Oncology, “We [also] sought to identify prognostic molecular biomarkers associated with clinical outcome [and] potential predictive biomarkers. The correlative molecular studies revealed that patients with IDH1 mutations...had signifi cantly improved outcomes compared with those that did not. Further, the results shed some insight into which patients may benefi t most from the addition of PCV to radiotherapy versus radiotherapy alone; these trended in favour of those low-grade glioma patients who had IDH1 mutations, although not defi nitive with the same size at hand”. Martin van den Bent (Erasmus MC, Rotterdam, Netherlands) commented, “This is a practice-changing paper... For [patients with] low-grade glioma, optimal postoperative treatment consists of radiotherapy followed by chemotherapy”. He continued, “[However], the question remains whether the subset of IDH mutated, 1p/19q intact patients also benefit, and what test is most informative for benefi t from PCV chemotherapy”. Chakravarti notes that “further studies are ongoing...to not only identify other prognostic and predictive biomarkers using high-throughput trans-omics studies, but also to identify underlying molecular and genetic mechanisms of treatment resistance in low-grade gliomas”.

Use of antidepressants and breast cancer recurrence

www.thelancet.com/oncology Vol 17 January 2016 e11 The use of antidepressants, together with tamoxifen, is not associated with increased risk of breast cancer recurrence, a new study suggests. Reina Haque (Kaiser Permanente Research, Pasadena, CA, USA) and colleagues assessed health records of 16 887 patients with early-stage breast cancer diagnosed between 1996 and 2007, who were treated with tamoxifen and andtidepressants. Patients were followed-up to Dec 31, 2009, for breast cancer recurrence. The researchers analysed the percentage of days of overlap of tamoxifen and an antidepressant, and the risk of subsequent cancer. 8099 (48%) of 16 887 patients used antidepressants, of which 2946 (36%) women developed subsequent breast cancer (defined as recurrence in the same breast, metastases, or contralateral breast cancer occuring ≥6 months after initial surgery). No significant increase in risk was noted with increasing overlap of paroxetine and tamoxifen use in the first year of tamoxifen treatment (hazard ratio 1·06 [95% CI 0·98–1·14, p=0·09] for 25% overlap; 1·13 [0·98–1·30, p=0·09] for 50% overlap; and 1·20 [0·97–1·49, p=0·09] for 75% overlap); no signifi cant diff erences were noted by the fi fth year. Similarly, no associations were noted with other antidepressants. Haque told The Lancet Oncology, “Tamoxifen is recommended for 5 years, but has notable side-eff ects, including depression. Since hormone replacement therapy is not recommended to alleviate these symptoms in breast cancer survivors, antidepressants have been increasingly prescribed for relief”. She continued, “Given that thousands of breast cancer survivors struggle with depression and other side-eff ects while on tamoxifen, our study should help alleviate concerns physicians have about prescribing antidepressants to their patients to help improve their quality of life.” Stacie Dusetzina (University of North Carolina at Chapel Hill, Chapel Hill, NC, USA) commented that, “only a small number of women were exposed to only one drug (3% had only paroxetine, while 23% had multiple types of drugs). Previous studies have shown that many women switch from antidepressants that are strong inhibitors [of CYP2D6 enzyme, which metabolises tamoxifen to its active form] to weak inhibitors, which could theoretically reduce the risk for recurrence among those who were prev iously using a strong inhibitor.” Dusetzina concluded, “it would likely be prudent to avoid strong inhibitor antidepressants when selecting a new treatment for women who are taking tamoxifen”.