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strontium and samarium are myelosuppressive, which limits their clinical utility. Radium-223, as a short-range α-emitting radio pharmaceutical, provides meaningful benefi t without proportional haematological toxic eff ects. From a pragmatic clinical perspective, this profi le broadens its potential clinical application by allowing the development of combinations with other agents and permitting repetitive dosing. The investigators should be credited for selecting men likely to benefi t, and showing that, in addition to prolongation of survival, patients benefi tted from a reduction in cancer-associated symptoms.

The absence of dose-limiting haematological toxic eff ects, and the lack of a proportional decrease in serum concentration of prostate-specifi c antigen (PSA) raises intriguing questions about the mechanisms of action of radium-223. The bone marrow is a frequent site in which prostate cancer cells are detected, and serum PSA concentration is a marker associated with cancer cell load within individual patients. The short range of α-particles possibly accounts for the reduced haematological toxic eff ects (the bone marrow is spared) but might not extend to areas where some cancers reside. Attributing the clinical benefi ts to radiation-induced cytoreduction in the absence of a decrease in serum PSA concentration is challenging.

Other clinically eff ective therapeutics studied in men with castrate-resistant prostate cancer share the radium-223 response profi le. For example, sipuleucel-T (Provenge, Dendreon Corporation, WA, USA), an approved prostate cancer vaccine, and cabozantinib, a VEGFR2/cMET-inhibiting tyrosine kinase inhibitor, have remarkable eff ects on bone scan results, serum alkaline phosphatase concentration, and bone pain, but less eff ect on serum PSA concentration.5–7 The small reduction in serum PSA concentration compels

us to consider alternative hypotheses to account for the clinical effi cacy of radium-223. Although speculative, plausible mechanisms include selective killing of non-PSA-expressing clones within range of the α-particles or indirect eff ects on tumour lethality through the modulation of the tumour microenvironment. What has become clear is that serum PSA concentration is neither predictive nor prognostic in the setting of metastatic castrate-resistant prostate cancer. An urgent need exists to identify, and build on, the mechanisms that explain the clinical effi cacy of these agents, to identify predictive and companion markers that can be used to select who will benefi t from radium-223, and to continue to monitor its effi cacy .

Christopher J LogothetisUniversity of Texas, M D Anderson Cancer Center, Genitourinary Medical Oncology, Holcombe Blvd, Houston, TX 77030, USAclogothe@mdanderson.org

I have received grants, personal fees, and non-fi nancial support from Astellas Pharma, Novartis, Bristol-Myers Squibb, Johnson & Johnson, Exelixis, and Pfi zer.

1 Parker C, Nilsson S, Heinrich D, et al, for the ALSYMPCA Investigators. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med 2013; 369: 213–23.

2 Sartor O, Coleman R, Nilsson S, et al. Eff ect of Radium-223 dichloride on symptomatic skeletal events in patients with castration-resistant prostate cancer and bone metastases: results from a phase 3, double-blind, randomised trial. Lancet Oncol 2014; published May 14, 2014. http://dx.doi.org/10.1016/S1470-2045(14)70183-4.

3 Logothetis CJ, Basch E, Molina A,et al. Eff ect of abiraterone acetate and prednisone compared with placebo and prednisone on pain control and skeletal-related events in patients with AA-301 randomised trial. Lancet Oncology 2012; 13: 1210–17.

4 Porter AT. Strontium 89 (Metastron) in the treatment of prostate cancer metastatic to bone. Eur Urol 1994; 26 (suppl 1): 20–25.

5 Smith MR, Saad F, Coleman R, et al. Denosumab and bone-metastasis-free survival in men with castration-resistant prostate cancer: results of a phase 3, randomised, placebo-controlled trial. Lancet 2012; 379: 39–46.

6 Fizazi K, Carducci M, Smith M, et al. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet 2011; 377: 813–22.

7 Smith DC, Smith MR, Sweeney C, et al. Cabozantinib in patients with advanced prostate cancer: results of a phase II randomized discontinuation trial. J Clin Oncol 2013; 31: 412–19.

Carboplatin for early triple-negative breast cancer?Anthracycline/taxane-based primary systemic therapy with or without trastuzumab is the backbone of treatment for patients with stage II–III HER2-positive and triple-receptor-negative breast cancer, respectively. This approach leads to a pathological complete response (no residual invasive cancer in the breast or axilla) in 30–50% of patients.1 The introduction

of trastuzumab, and recently dual therapy with trastuzumab and pertuzumab, or trastuzumab and lapatinib, has further improved pathological complete response in patients with HER2-positive breast cancer to around 60%.2–4 By contrast, no substantial progress has been made in treatment of patients with early triple-negative breast cancer in the past decade.

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Unfortunately, no molecular target for this subtype of breast cancer has been established. Chemotherapy is the only systemic option to prevent systemic relapse, and patients with triple-negative breast cancer often have poor clinical outcomes.5 However, nearly half of patients will have a near pathological complete response or a pathological complete response after a regimen of third-generation primary systemic therapy with anthracycline, cyclophosphamide, and taxane, and these patients have an excellent prognosis. There is an urgent need to provide new drugs to patients with this subtype of breast cancer. Findings from two large, randomised phase 3 studies of bevacizumab-based primary systemic therapy showed modest increases in pathological complete responses for patients with stage II–III breast cancer, but no eff ects in daily clinical practice.6,7

Platinum salts (ie, cisplatin and carboplatin) are active in early and advanced triple-negative breast cancer, especially in patients with BRCA1/2 mutation.8 A preclinical model showed synergism between platinum salts and trastuzumab in HER2-positive breast cancer.9 However, this fi nding was not replicated in a phase 3 trial of patients with metastatic HER2-positive breast cancer.10

In the GeparSixto trial, von Minckwitz and colleagues11 tested the role of carboplatin in 588 patients with stage II–III HER2-positive or triple-negative breast cancer. The trial tested a new complex regimen including weekly paclitaxel and liposomal doxorubicin for 18 weeks. Bevacizumab, trastuzumab, and lapatinib were added according to HER2 status. The addition of carboplatin did not improve the proportion of HER2-positive patients who achieved pathological complete response (52·9% with carboplatin vs 48·9% without). However, it signifi cantly increased the proportion of patients with triple-negative breast cancer who achieved a pathological complete response (53·2% with carboplatin vs 42·7% without). The addition of carboplatin to the complex regimen used in this trial came with substantial haematological and non-haematological toxic eff ects, frequent dose reductions (69%) and early treatment discontinuation (48%), and lower drug dose delivery (70%).

Sikov and colleagues12 recently presented the results of the CALGB 40603 trial. The addition of four cycles

of carboplatin (total drug dose intensity) every 3 weeks to weekly paclitaxel signifi cantly increased the proportion of patients who achieved a pathological complete response from to 41% to 54% in patients with stage II–III triple-negative breast cancer. The benefi t also came with a high incidence of adverse events and increase in the discontinuation rate.

The GeparSixto and CALGB 40603 trials raise several clinical questions. Is the magnitude of the increase in the proportion of patients who achieved a pathological complete response (10–15%) high enough to improve progression-free survival and overall survival? In general, pathological complete response in patients with triple-negative breast cancer is associated with signifi cant improvement in long-term outcomes, including overall survival. Trastuzumab-based primary regimens led to a higher proportion of pathological complete responses than did non-trastuzumab regimens. The absolute increase in pathological complete response (19%) was associated with increase in progression-free survival and overall survival.13 What is the best schedule—every 3 weeks, or weekly? There is no preclinical or clinical data to suggest that one scheme is better than the other. However, a weekly carboplatin schedule was associated with increased incidence of serious adverse events and treatment discontinuation.12 Additionally, the taxane/anthracycline scheme used in the GeparSixto trial was complex and diff erent to other regimens in current use. Therefore, dosing every 3 weeks as per the CALGB 40603 trial would be clinically feasible. The fi nal and most important questions are whether all patients with stage II–III triple-negative breast cancer need to be exposed to carboplatin, with its serious toxic eff ects and unacceptably high rate of treatment discontinuation; and whether every subgroup of patients with triple-negative breast cancer would equally benefi t from a platinum salt.14,15 15–20% of patients treated with anthracycline-based regimen alone have a pathological complete response. The addition of a taxane after anthracycline-based chemotherapy increases this to 30–40%. Should doctors consider carboplatin only for those patients with triple-negative breast cancer with residual disease after an anthracycline-based or taxane-based regimen either before surgery in patients with clinical or radiological residual disease, or after surgery for patients with substantial residual cancer burden? This approach will avoid overtreatment in the 40% of patients that achieve axillary and breast pathological

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complete response after standard therapy, and will also minimise morbidity and cost. Finally, the role of genomic signatures and other new technologies, including next-generation sequencing, should provide new therapeutic targets and establish molecular markers or genomic signatures to personalise the treatment of patients with triple-negative breast cancer. New therapeutic options are urgently needed, especially for patients with primary chemotherapy-resistant early and advanced triple-negative breast cancer.

Vicente ValeroUniversity of Texas MD Anderson Cancer Center, Department of Breast Medical Oncology, Houston, TX 77030, USAvvalero@mdanderson.org

I declare no competing interests.

1 Cortazar P, Zhang L, Untch M, et al. Pathological complete response and long-term clinical benefi t in breast cancer: the CTNeoBC pooled analysis. Lancet 2014, published online Feb 14. http://dx.doi.org/10.1016/S0140-6736(13)62422-8.

2 Baselga J, Bradbury I, Eidtmann H, et al. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial. Lancet 2012; 379: 633–40.

3 Schneeweiss A, Chia S, Hickish T, et al. Pertuzumab plus trastuzumab in combination with standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer: a randomized phase II cardiac safety study (TRYPHAENA). Ann Oncol 2013; 24: 2278–84.

4 Gianni L, Pienkowski T, Im YH, et al. Effi cacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, infl ammatory, or early HER2-positive breast breast cancer cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. Lancet Oncol 2012; 13: 25–32.

5 Liedtke C, Mazouni C, Hess KR, et al. Response to neoadjuvant therapy and long-term survival in patients with triple-negative breast cancer. J Clin Oncol 2008; 26: 1275–81.

6 Bear HD, Tang G, Rastogi P, et al. Bevacizumab added to neoadjuvant chemotherapy for breast cancer. N Engl J Med 2012; 336: 310–20.

7 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.

8 Byrski T, Gronwald J, Huzarski T, et al. Pathologic complete response rates in young women with BRCA1-positive breast cancers after neoadjuvant chemotherapy. J Clin Oncol 2010; 28: 375–79.

9 Pegram MD, Konecny GE, O’Callaghan C, et al. Rational combinations of trastuzumab with chemotherapeutic drugs used in the treatment of breast cancer. J Natl Cancer Inst 2004; 96: 739–49.

10 Valero V, Forbes J, Pegram MD, et al. Multicenter Phase III randomized trial comparing docetaxel and trastuzumab with docetaxel, carboplatin, and trastuzumab as fi rst-line chemotherapy for patients with HER2-gene-amplifi ed metastatic breast cancer (BCIRG 007 study): two highly active therapeutic regimens. J Clin Oncol 2011; 29: 149–56.

11 von Minckwitz G, Schneeweiss A, Loibl S, et al. Neoadjuvant carboplatin in patients with triple-negative and HER2-positive early breast cancer (GeparSixto; GBG 66): a randomised phase 2 trial. Lancet Oncol 2014; published online May 1. http://dx.doi.org/1016/S1470-2045(14)70160-3.

12 Sikov, WM, Berry DA, Perou CM et al. Impact of the addition of carboplatin and/or bevacizumab to neoadjuvant weekly paclitaxel followed by dose-dense AC on pathologic complete response rates in triple-negative breast cancer: CALGB/Alliance 40603. San Antonio Breast Cancer Symposium; San Antonio, TX, USA; Dec 10–14, 2013. S5-01.

13 Gianni L, Eiermann W, Semiglazov V, et al. Neoadjuvant chemotherapy with trastuzumab followed by adjuvant trastuzumab versus neoadjuvant chemotherapy alone, in patients with HER2-positive locally advanced breast cancer (the NOAH trial): a randomised controlled superiority trial with a parallel HER2-negative cohort. Lancet 2010; 375: 377–84.

14 Lehmann BD, Bauer JA, Chen X, et al. Identifi cation of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. J Clin Invest 2011; 121: 2750–67.

15 Mayer IA, Abramson VG, Lehmann BD, Pietenpol JA. New strategics for triple negative breast cancer-decifering tumor hererogeneity. Clin Cancer Res 2014; 20: 782–90.

Lymphoma-directed conditioning for aggressive lymphomaPublished Online

May 12, 2014http://dx.doi.org/10.1016/

S1470-2045(14)70232-3

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Treatment of patients with aggressive B-cell and T-cell lymphomas who relapse or who are refractory after fi rst-line immunochemotherapy is diffi cult. Although autologous stem-cell transplantation is deemed to be the standard of care for these patients according to the PARMA trial,1 the CORAL trial2 showed that even this approach often has a poor outcome, with treatment failure in more than 80% of patients. How best to achieve remission and consolidate treatment with stem-cell transplantation is still unclear, as is how patients should be conditioned before transplantation. In The Lancet Oncology, Bertram Glass and colleagues3 show the eff ects of a myeloablative lymphoma-directed conditioning regimen for allogeneic stem-cell transplantation on disease control in these patients. Even though 23 (55%) of 42 patients

in each group were refractory to chemotherapy, at 1 year progression-free survival was 45% (95% CI 34–55) and overall survival was 52% (95% CI 41–62). As expected, refractory disease was an independent adverse prognostic factor for progression-free survival: patients with refractory disease showed a trend to poorer overall survival at 3 years than did those with sensitive or untested response but not signifi cantly so (38·3% vs 45·8%; p=0·134), which shows further eff orts should be made to tackle the problem.

Allogeneic stem-cell transplantation is underused for treatment of aggressive lymphomas, and this study is the fi rst clinical trial done in this setting. In the past, allogeneic stem-cell transplantation has been associated with very high non-relapse mortality,4 mainly because of the highly toxic myeloablative