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from funding agencies, will certainly open a new era for the development of bevacizumab in breast cancer. First, these randomised trials will enable a metaanalysis to be done. A meta-analysis will allow better understanding about which population derives more benefit, which chemotherapy backbone is the most appropriate, and will assess the effect of bevacizumab on outcome (disease-free survival and overall survival) in a large population of patients presenting with highrisk breast cancers. To what extent an improvement in pathological complete response translates into disease-free survival and overall survival benefit is still controversial in breast cancer, and this meta-analysis, based on a large number of patients, will certainly help. Second, neoadjuvant studies could allow the development of a molecular predictor for the efficacy of bevacizumab. The predictor could be cross-validated in different trials because four studies are now available. Several molecular predictors have already been proposed, including vascular cell adhesion molecule 1, intercellular adhesion molecule 1, E-selectin, and circulating VEGFR-2.8 Because most trials were done in a metastatic setting, no opportunity existed until now to test tissue-based biomarkers in samples obtained at baseline before therapy. Finally, neoadjuvant studies, where pretreatment and post-treatment samples are available, could allow the discovery of new mechanisms of action for bevacizumab. For example, bevacizumab has been reported to modulate the immune system through dendritic cells and regulatory T-cell functions, and could facilitate T-cell homing.9 If molecular analyses from neoadjuvant studies confirm an effect of bevacizumab on the immune system, they could generate a rationale for triple combination therapy of immunogenic chemotherapy, anti-PD1 agents, and bevacizumab. Overall, the study by Earl and colleagues,4 consistent with previous trials, suggests that bevacizumab could
improve pathological complete response in patients with breast cancer. These four trials could constitute the starting point of a new era for bevacizumab in breast oncology and could help to define which patients are more likely to benefit from bevacizumab, and which drug should optimally be combined with it. *Fabrice Andre, Elise Deluche, Herve Bonnefoi Department of Medical Oncology, Gustave Roussy, Villejuif, France (FA, ED); INSERM Unit U981 and Université Paris Sud, Faculté de Medecine Kremlin Bicetre, Kremlin Bicetre, France (FA); and Department of Medical Oncology, Institut Bergonie, Bordeaux, France (HB)
[email protected] FA reports grants from Novartis, AstraZeneca, and Eisai, outside the submitted work. ED and HB declare no competing interests. Copyright © Andre et al. Open Access article distributed under the terms of CC BY-NC-ND. 1
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Miles DW, Diéras V, Cortés J, Duenne A-A, Yi J, O’Shaughnessy J. First-line bevacizumab in combination with chemotherapy for HER2-negative metastatic breast cancer: pooled and subgroup analyses of data from 2447 patients. Ann Oncol 2013; 24: 2773–80. Cardoso F, Costa A, Norton L, et al. ESO-ESMO 2nd international consensus guidelines for advanced breast cancer (ABC2). Ann Oncol 2014; 25: 1871–88. Cameron D, Brown J, Dent R, et al. Adjuvant bevacizumab-containing therapy in triple-negative breast cancer (BEATRICE): primary results of a randomised, phase 3 trial. Lancet Oncol 2013; 14: 933–42. Earl HM, Hiller L, Dunn JA, et al. Efficacy of neoadjuvant bevacizumab added to docetaxel followed by fluorouracil, epirubicin, and cyclophosphamide, for women with HER2-negative early breast cancer (ARTemis): an open-label, randomised, phase 3 trial. Lancet Oncol 2015; published online May 12. http://dx.doi.org/10.1016/S1470-2045(15)70137-3. Bear HD, Tang G, Rastogi P, et al. Bevacizumab added to neoadjuvant chemotherapy for breast cancer. N Engl J Med 2012; 366: 310–20. Von Minckwitz G, Eidtmann H, Rezai M, et al. Neoadjuvant chemotherapy and bevacizumab for HER2-negative breast cancer. N Engl J Med 2012; 366: 299–309. Sikov WM, Berry DA, Perou CM, et al. Impact of the addition of carboplatin and/or bevacizumab to neoadjuvant once-per-week paclitaxel followed by dose-dense doxorubicin and cyclophosphamide on pathologic complete response rates in stage II to III triple-negative breast cancer: CALGB 40603 (Alliance). J Clin Oncol 2015; 33: 13–21. Jubb AM, Harris AL. Biomarkers to predict the clinical efficacy of bevacizumab in cancer. Lancet Oncol 2010; 11: 1172–83. Elamin YY, Rafee S, Toomey S, Hennessy BT. Immune effects of bevacizumab: killing two birds with one stone. Cancer Microenviron 2014; published online Oct 18. DOI: 10.1007/s12307-014-0160-8.
Parenthood in female survivors of Hodgkin’s lymphoma In The Lancet Oncology, Jurgen Brämswig and colleagues1 report pregnancy outcomes in 467 female long-term survivors of Hodgkin’s lymphoma who were younger than 18 years at diagnosis and treated in one of five concurrent clinical trials in Germany and Austria between 1978 and 1995. The investigators are to be congratulated www.thelancet.com/oncology Vol 16 June 2015
for this important contribution to the understanding of long-term pregnancy outcomes in female survivors of Hodgkin’s lymphoma. They have shown that the chance of these patients becoming a parent is similar to that in the female German population aged 16–39 years, and not significantly affected by potentially gonadotoxic
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Peter Schiazza/Cultura/Science Photo Library
chemotherapy. Only pelvic radiotherapy and being aged 40–44 years decreased the chance of having a live birth. In this study, treatment with either procarbazine or cyclophosphamide (in cumulative doses up to 11 400 mg/m² and 6000 mg/m², respectively), had little effect on the chance of becoming a parent. This contrasts with male survivors of childhood cancer who have been shown to be at significant risk of infertility and azoospermia after exposure to alkylating agents in a dose-dependent manner.2 Results of a previous study3 showed that procarbazine predisposed patients to premature menopause (now known as premature ovarian insufficiency) in a dose-dependent manner in patients aged 14–40 years (median 25 years) who had received treatment for Hodgkin’s lymphoma. 10 years after treatment, the actuarial risk of premature ovarian insufficiency was 64% after high cumulative doses (>8·4 g/m²) and 15% after low doses (≤4·2 g/m²) of procarbazine.3 By contrast, other Hodgkin’s lymphoma studies4 in adults have shown that despite intensive chemotherapy with procarbazine-containing regimens, pregnancy outcome is not significantly affected. Because no hormonal or pelvic ultrasound data is available in Brämswig and colleagues’ study, it is impossible to establish whether the decreased incidence of parenthood described in females who have received radiotherapy to their pelvis is due to premature ovarian insufficiency, radiation-induced uterine damage, or both. Patients who were pre-pubertal (aged <13 years) when they received treatment were likely to be at risk of substantial radiation-induced uterine damage, which is known to be associated with a high risk of miscarriage.5 Results of a study6 from the North American Childhood Cancer Survivor Study (CCSS) have shown that young cancer survivors had an increased risk of clinical infertility (ie, >1 year of attempts at conception without success) compared with that in sibling controls. Patients with a lymphoma diagnosis or radiotherapy to a field that included the pelvis were at particular risk. The survivors in the CCSS study had a slightly increased time to first pregnancy and were less likely to receive medical treatment for infertility than were sibling controls. Some studies have shown that survivors of childhood cancer are less likely to be married, and a Swedish qualitative study7 has shown that young adult childhood cancer survivors are hesitant about becoming parents because of anticipated physical and psychological consequences 602
of having had cancer. Brämswig and colleagues’ results1 therefore will be reassuring to both clinicians and adult survivors of childhood Hodgkin’s lymphoma. With excellent overall survival for young people with Hodgkin’s lymphoma, the emphasis in European studies is now on treatment de-escalation and particularly the avoidance of involved field radiotherapy in selected patients. Radiotherapy is known to predispose patients many years later to second malignant neoplasms within the radiation field,8 and breast cancer screening is now recommended for young patients who have received radiotherapy to a field that includes the breast tissue.9 This study emphasises that female survivors most at risk of not being able to be a parent are those who receive pelvic radiotherapy. For patients who are prepubertal or pubertal who are likely to need pelvic radiotherapy (or those who are post-pubertal but are without a partner and too young to undergo hormonal stimulation to freeze oocytes), fertility preservation counselling and ovarian tissue cryopreservation should be considered before treatment starts.10 Cryopreservation of ovarian cortical tissue with later replacement has resulted in at least 40 live births, but is still regarded as experimental in most countries. This important study has shown that overall pregnancy outcome in young female patients treated with both chemotherapy and radiation for Hodgkin’s lymphoma is positive; patients most at risk for not achieving parenthood are those that receive radiotherapy to their pelvis. Current challenges remain to avoid radiotherapy without compromising survival in selected patients with Hodgkin’s lymphoma, and, for those in whom radiotherapy cannot be avoided, to provide fertility preservation counselling and consider ovarian tissue cryopreservation under the auspices of a clinical trial. W Hamish Wallace University of Edinburgh and Royal Hospital for Sick Children, Edinburgh EH9 1LF, UK
[email protected] I declare no competing interests. 1
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Brämswig J, Riepenhausen M, Schellong G. Parenthood in adult female survivors successfully treated for Hodgkin’s lymphoma during childhood and adolescence: a prospective, longitudinal study. Lancet Oncol 2015; 16: 667–75. Green DM, Liu W, Kutteh WH, et al. Cumulative alkylating agent exposure and semen parameters in adult survivors of childhood cancer: a report from the St Jude Lifetime Cohort Study. Lancet Oncol 2014; 15: 1215–23. De Bruin ML, Huisbrink J, Hauptmann M, et al. Treatment-related risk factors for premature menopause following Hodgkin lymphoma. Blood 2008; 111: 101–08.
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Behringer K, Thielen I, Mueller H,et al. Fertility and gonadal function in female survivors after treatment of early unfavorable Hodgkin lymphoma (HL) within the German Hodgkin Study Group HD14 trial. Ann Oncol 2012; 23: 1818–25. Critchley HOD, Wallace WHB. Impact of cancer treatment on uterine function. J Natl Cancer Inst Monogr 2005; 34: 64–68. Barton SE, Najita JS, Ginsburg ES, et al. Infertility, infertility treatment, and achievement of pregnancy in female survivors of childhood cancer: a report from the Childhood Cancer Survivor Study cohort. Lancet Oncol 2013; 14: 873–81. Nilsson J, Jervaeus A, Lampic C, et al. “Will I be able to have a baby?” Results from online focus group discussions with childhood cancer survivors in Sweden. Hum Reprod 2014; 29: 2704–11.
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Wallace WHB, Thompson L, Anderson RA. Long term follow-up of survivors of childhood cancer: summary of updated SIGN guidance. BMJ 2013; 346: f1190. Mulder RL, Kremer LCM, Hudson MM. Recommendations for breast cancer surveillance for female survivors of childhood, adolescent, and young adult cancer given chest radiation: a report from the International Late Effects of Childhood Cancer Guideline Harmonization Group. Lancet Oncol 2013; 14: e621–29. Wallace WHB, Smith AG, Kelsey TW, Edgar AE, Anderson RA. Fertility preservation for girls and young women with cancer: population-based validation of criteria for ovarian tissue cryopreservation. Lancet Oncol 2014; 15: 1129–36.
Although most patients with renal cell carcinoma have localised tumours that can be cured with surgery, many patients experience disease relapse caused by local recurrence or distant metastases. The occurrence of metastatic disease is the single most important surrogate event predictive of death from this disease. Currently, no consensus has been established for standardised follow-up protocols to detect early asymptomatic metastatic relapse, therefore, an obvious rationale exists for the identification of clinical, genetic, or molecular biomarkers that enable the identification of patients at risk for relapse. A plethora of potential clinical, genetic, and molecular biomarkers for recurrence prognostication have been published in recent years.1,2 Classic prognostication models like those from Frank and colleagues3 or Sorbellini and colleagues4 used only standard clinicopathological factors as prognostic factors to predict recurrence. Klatte and colleagues5 developed a model that combined clinicopathological features with several molecular markers and showed a concordance index of 0·904%. The same group also created a prognostic model based on clinicopathological parameters and the loss of chromosome 9p,6 which had a concordance index of 0·89. However, both studies were based on a modest sample size and the results were not validated. In The Lancet Oncology, Brian Rini and colleagues7 describe the identification and validation of a 16-gene signature (recurrence score) that showed improved recurrence prognostication in patients with localised clear-cell renal cell carcinoma when compared with a model based on clinicopathological features alone. The authors showed that the concordance index increased from 0·74 when the Leibovich score alone www.thelancet.com/oncology Vol 16 June 2015
was used to 0·81 with the inclusion of their 16-gene signature. The authors used extensive genetic tests and straightforward methods to analyse both a large development cohort and an external multicentric validation cohort. These clear strengths, combined with the fact that the authors re-reviewed pathologies before patients were included in the study, distinguish this investigation from previous studies. Rini and colleagues’ findings also provide insight into the biology of renal cell carcinoma. Genes that were found to be prognostically relevant are members of vascular, immune response, inflammation, cell cycle progression, and proliferation pathways. These results concur with previous findings suggesting that hypoxic renal cell carcinomas display more aggressive features than vascularised tumours.8,9 As existing targeted treatment strategies mainly tackle angiogenesis pathways, these treatments might preferentially target vascularised tumours and be ineffective in the treatment of the highly aggressive hypoxic renal cell carcinomas. Although Rini and colleagues’ study is extensive, it has some limitations that need further assessment. Due to reclassification of pathology or insufficient tissue, a total of 1371 (59%) of 2313 patients were excluded from model development for clinical or pathological reasons. Furthermore, the retrospective analysis included patients who were treated between 1985 and 2003 in the development cohort, and between 1995 and 2007 in the validation cohort. Follow-up was not standardised across all institutions, and no centralised review and confirmation of recurrence sites could be done during these long periods. Additionally, other prognostic models that use only classical clinicopathological features have shown concordance indices of 0·80–0·82,
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Prognostication in localised renal cell carcinoma
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