PracticeUpdate: Haematology & Oncology

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Vol 1. No 4. 2016

VOL. 1 • No. 4 • 2016

RESEARCH NEWS AND VIEWS FROM ELSEVIER

FORMERLY HAEMATOLOGY & ONCOLOGY NEWS

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Postmastectomy radiation improved local control but not overall survival in women with breast cancer

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OPINION

If I had to placemy chip 50 years down the future onwhat wewould know, I’d say it’s probably going to turn out to be viruses that we’re exposed too. They often end up integrating into our genome, unbeknownst to us. Dr Steven Toms 15

PROSTATE Special roundup of the 17th APCC in Melbourne

Patients treated with modern systemic therapy experienced excellent outcomes in local control and overall survival, regardless of whether they received radiation therapy.

CONFERENCE ASTRO 2016 A radiation boost is

recommended in patients with DCIS and ≥10 years life expectancy following breast-conserving surgery and whole breast radiotherapy Reduced radiation boost volume is recommended but craniospinal axis dose remains unchanged in average-risk paediatric medulloblastoma After 10 years, postmastectomy radiation is shown to improve local control but not overall survival in women with breast cancer and one to three positive nodes 10 FEATURE ARTICLE MicroRNAs in brain cancer treatment 15 8 9

Risk of neutropenia-related hospitalization in patients who received colony-stimulating factors with chemotherapy for breast cancer Journal of Clinical Oncology There was a low to modest benefit relative to neutropenia- related hospitalizations associated with G-CSF prophylaxis in breast cancer patients being treated with TC and TCH.

Dual block with lapatinib and trastuzumab vs single-agent trastuzumab combined with chemotherapy as neoadjuvant treatment of HER2-positive breast cancer: a meta-analysis of randomized trials Clinical Cancer Research Patients with HER2-positive breast cancer benefit from the neoadjuvant combination of lapatinib and trastuzumab, while hormone receptor- negative patients demonstrate the best results with taxane monotherapy. 5

Daratumumab, bortezomib, and dexamethasone for multiple myeloma The New England Journal of Medicine Daratumumab with bortezomib and dexamethasone led to significantly increased

Extramedullary disease in adult acute myeloid leukemia is common but lacks independent significance: analysis of patients in ECOG-ACRIN Cancer Research Group Trials, 1980–2008 Journal of Clinical Oncology EMD is relatively common, but not an independent prognostic factor in AML. They suggest that AML treatment decisions should be based on the presence of recognized AML prognostic factors, and not on the presence of EMD. 14

progression-free survival, but also resulted in more frequent adverse events compared with bortezomib/ dexamethasone alone.

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PROSTATE

EXPERT OPINION Future of immunotherapy and biomarkers in prostate cancer Interview with Gautam Jha, MD Dr Jha, Assistant Professor, University of Minnesota Medical Health in the US speaks with PracticeUpdate’s Farzanna Haffizulla, MD, FACP, FAMWA, on enhancing the immunotherapy response.

EDITORIAL Managing Editor Anne Neilson anne.neilson@elsevier.com Editor Carolyn Ng carolyn.ng@elsevier.com Designer Jana Sokolovskaja j.sokolovskaja@elsevier.com Medical Advisor Dr Barry M Dale Consultant Haematologist, Medical Oncologist

Dr Haffizulla : What about the future for immunotherapy? What’s on the horizon? What biomarkers might we be looking at, or other prognostic or predictive markers in immunotherapy? Dr Jha : One of the biggest drawbacks with immunotherapy, in general, is that there have not been good biomarkers. For example, at least with the PD-1 line of therapy, we look for PD-1 expression and, again, we know that it is dynamic, and it does not always correlate with response. Unfortunately, PD-1 hasn’t worked as well in prostate cancer as it has in many other cancer types. However, I think there is a big promise with immunotherapy; we have sipuleucel-T, which is already approved, and PROSTVAC, which is in later stages of development. Combining this with our checkpoint inhibitors like either ipilimumab or PD-1 inhibitors or, in fact, a new inhibitor. I have my own investigator-initiated trial with indoximod, which is an IDO inhibitor, which suppresses the inhibitory Tregs and would allow a much more enhanced response to sipuleucel-T. Those combined with other cytokines like IL-7 or IL-15 would be quite promising. So, this would make this modest response from sipuleucel-T or PROSTVAC into a much more enhanced response, which might last for a long period of benefit. Dr Haffizulla : Let’s talk about the role of immunotherapy in prostate cancer. Where we were, where we are, and where we’re going. We mentioned sipuleucel-T. Let’s talk some more about that particular vaccine and where we’ve come from that point. Dr Jha : Sipuleucel-T was the first landmark vaccine in that it was the first to get approved and was the first step in the right direction. Consistently, trial after trial, it was shown that it could improve survival, offering us a survival advantage of over 4 months, which was unheard of at that time. The important thing is that it is such a well-tolerated therapy. The only drug that worked before sipuleucel-T was docetaxel, which has substantial toxicity, as you know, and the survival advantage gained with that was barely 3 months or so. Dr Haffizulla : You want to minimise the toxicity and maxim- ise the efficacy, and, of course, you’re looking at cost, and you’re looking at the individual patient, and if this suits his particular clinical scenario. Dr Jha : Yes; there has to be an individualised approach, and it’s clear that vaccine therapy, especially sipuleucel-T, is not for everyone. It has been approved and tested in only a very spe- cific set of patients, patients who were castration-resistant

but had either minimal symptomatic disease or were com- pletely asymptomatic. We’re talking about patients who were in extremely good health, had no visible disease, and were not taking an opiate for pain; so, essentially, these were the guys who had an anticipated survival of least a year or more. This is not a therapy that you would do at the end of the road, or in patients who have progressed on lines and lines and lines of therapy or someone who has a huge disease burden; you would not be benefiting the patient. In fact, you might be harming him by delaying more effective therapy. Dr Haffizulla : It makes me think about using these vaccines in prevention for patients who may have a very strong fam- ily history or may have other risk factors. What are your thoughts on using it in prevention? Dr Jha : It is quite interesting that you bring it up. Some call it a vaccine. Essentially, a vaccine is something that would enhance our immune response to fight the disease, but this one does not prevent the occurrence of disease. It would be great if we had something which could do that, and if it would be effective. The cost of this thing is so prohibitive that we have to select the right patients; the population who is going to benefit from this therapy. And this is a tremendous thing because it works and it is very well tolerated. Dr Haffizulla : Yes, because the way these vaccines are cre- ated, as you mentioned, are from the actual tumour itself, from the patients themselves, or from their peripheral blood mononuclear cells. Dr Jha : Yes. This is essentially using the antigen-presenting cells of the patient, and the dendritic cells, which are col- lected and are sensitised outside the patient’s body to es- sentially one of the proteins expressed on the cancer cells, prostatic acid phosphatase. This is not a tumour-based vaccine. There are some tumour- based vaccines, but none of them are far enough in develop- ment for prostate cancer. There are some being tested, but that arena is much more advanced in, say, kidney cancer melanoma. So, some tumour-based vaccines are in develop- ment, but not as much for the prostate. Dr Haffizulla : Let’s talk some more about the future of im- munotherapy. We just discussed sipuleucel-T and it being an effective adjunct to the therapeutic landscape already. What are your thoughts on what might be happening in the future? Dr Jha : With our improved understanding of immunotherapy, I feel things are changing, and we will start seeing more and more results. I feel that we could combine one of those checkpoint inhibitors, and all of the cytokines to enhance or augment the current immunotherapy. Things like sipuleucel-T or PROSTVAC, and checkpoint inhibitors like CTLA-4 or like PD-1. As I mentioned, I am working on a trial using an IDO inhibitor, which is an enzyme but inhibits or is quite immunosuppressive. In other words, an inhibition that will enhance or augment the response to immunotherapy. This would be quite compelling. Dr Haffizulla : So, really stepping back from the picture and looking at ways that we can have a vertical blockade and a horizontal blockade, more synergism really in the therapeutic paradigm. Dr Jha : Synergism, yes. Exactly.

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Account Manager Linnea Mitchell-Taverner l.mitchell-taverner@elsevier.com

DISCLAIMER PracticeUpdate Haematology&Oncology pro- vides highlights of key local and international conferences with timely and relevant news, expert opinions and journal article reviews for specialist medical professionals. The ideas and opinions expressed in this publication do not necessarily reflect those of the Publisher. Elsevier Australia will not assume responsibility for damages, loss, or claims of any kind arising from or related to the information contained in this publication, including any claims related to the products, drugs, or services mentioned herein. Please consult the full current Product Information before prescribing any medicationmentioned in this publication. For an annual print and/or digital subscription (6 issues) of PracticeUpdate Haematology & Oncology , please email news.au@elsevier. com or visit elseviermedcomms.com.au To share your feedback with us, please email news.au@elsevier.com Conference news, expert opinions and journal article reviews are sourced from PracticeUpdate.com PracticeUpdate provides professional research, expert insights, and education resources in a single online destination PracticeUpdate content is selected by medical experts in endocrinology for its relevance, timeliness, and importance. It is guided by world-renowned editorial and advisory boards that represent community practitioners and academic specialists with cross-disciplinary expertise. For in-depth insights which matter, discover PracticeUpdate.com today. ISSN – 2206-463X (Print) ISSN – 2206-4648 (Online)

New drugs and devices listing THERAPEUTIC GOODS ADMINISTRATION www.tga.gov.au Brentuximab vedotin (Adcetris) , Takeda – Hodgkin’s lymphoma Golimumab (Simponi) , Janssen-Cilag – axial spondyloarthritis Eftrenonacog alfa (Alprolix) , Biogen – haemophilia B Darunavir + cobicistat (Prezcobix) , Janssen-Cilag – HIV

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Scan this QR code, to watch this interview with Dr Jha.

Exenatide (Bydureon) , AstraZeneca – type 2 diabetes Pasireotide (Signifor LAR) , Novartis – acromegaly Please consult the full Product Information before prescribing.

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VOL. 1 • No. 4 • 2016

PROSTATE

Special roundup of the 17th APCC inMelbourne By Rajesh Nair, FRCS (Urol), FEBU, MSc and Homayoun (Homi) Zargar, MD, FRACS

The Asia-Pacific Prostate Cancer Conference (APCC) continues to host world leaders in all aspects of prostate cancer diagnosis, management and cutting- edge research. This exciting 4-day meeting, 31 August–3 September in Melbourne, remains one of the largest global multidisciplinary forums in prostate cancer, attracting over 750 delegates from more than 20 countries and showcasing over 20 international speakers. The meeting combined clinical urology, translational science and integrated nursing and allied health professions in a multidisciplinary environment. In this special feature, Dr Nair and Dr Zargar discuss clinically relevant new research topics presented at this uear APCC . C onference president Anthony Costello, MD, FRACS, FRCSI, MBBS, of the Royal Melbourne Hospital, opened the less significant tumours compared with sys- tematic biopsies alone.

Robert Nam, MD, MSc, FRCS, of Sun- nybrook Health Sciences Centre, University of Toronto (Canada), shared a pilot study using MRI as a screening test for prostate cancer. Phillip Stricker, MBBS, FRACS, of St Vincent’s Hospital in Sydney, expanded on this concept, describing a nomogram devel- oped in Sydney incorporating MRI to predict significant prostate cancer. Dr Reiter then showed how 3D modelling with MRI could accurately predict final pathology from radical prostatectomy specimens. The strength and experience of Australian urologists and radiologists in PSMA PET im- aging was showcased throughout the meeting. Michael Hofman, MBBS, FRACP, FAANMS, of Peter MacCallum Cancer Centre in Mel- bourne, and Nathan Lawrentschuk, MBBS, PhD, FRACS, of Austin Hospital, Melbourne, delivered a state-of-the-art lecture on PET im- aging and presented their systematic review and meta-analysis of PSMA PET imaging for prostate cancer. A subsequent panel discus- sion was chaired by DeclanMurphy, MBBCH, BaO, FRACS, FRCS, of Peter MacCallum Cancer Centre and the Royal Melbourne Hospital, with case-based discussion focused on how best to integrate this technology into everyday practice. John Violet, MD, of Peter MacCallum Can- cer Centre, described the future of PSMA as a marker for targeted radiation delivery, as he discussed early outcomes for 177Lu-PSMA in the metastatic castration-resistant prostate cancer setting. Translational science, genomics and metastatic disease One of the novelties of the APCC meeting is the ability to bring research in basic science and clinicians under one roof. Peter Carroll, MD, MPH, of the University of California, started proceedings by integrating translation- al science and clinical practice, by reviewing commercially available tests for genetic profil- ing in prostate cancer. Clearly the future is the field of genomics and individualised cancer care. His description of current RNA and DNA-based genomic tools risk stratify patients before and after radical prostatectomy. Christopher Sweeny, MBBS, of the Dana Faber Cancer Institute (United States) and Bertrand Tombal, MD, PhD, of the Université catholique de Louvain (Belgium), reiterated this message in an informative presentation on precision medicine. They described inter- tumour heterogeneity in prostate cancer on a molecular and clinical level. The fascinat- ing descriptions of genomic and radiological variations seen between primary tumour and in metastatic disease served to remind all of the multiple targets that are yet to be studied, sequenced and targeted by drugs, particularly in those patients with metastatic-castration resistant disease. Nial Corcoran, PhD, FRACS, of the Royal Melbourne Hospital, explored the role of met- astatic prostate cancer further with a superb presentation exploring the role of bone biopsy in men with metastatic disease in genomic sequencing, and understanding the biology of metastases. The theme of advanced prostate

meeting alongside Lord Mayor of Melbourne, Robert Doyle. They reminded delegates of the cultural and scientific progress Melbourne has witnessed in medicine and science, and the progress that has been made in prostate cancer care worldwide. When discovered, therapeutic nihilism decreed prostate cancer a rare disease with no known cure. It is now the commonest cancer diagnosed in men with ever increasing therapeutic strategies and research. Perhaps the highlight lectures of the meeting included the 4th Patrick Walsh Lecture given by Martin Gleave of the University of British Columbia (Canada) titled ‘Two tales of precision oncology’. This exquisite lecture dissected some of the finer nuances in precision oncology in castration-resistance prostate cancer. Screening, biopsies and surveillance Stacey Loeb, MD, MSc, of NewYork Univer- sity, opened the plenary session with ‘Prostate cancer: a year in review’. This excellent session described key publications and presentations from the American Urological Association on prostate cancer. Perhaps it was the Euro- pean Urology paper, suggesting that men who ejaculated 21 or more times a month was at a lower risk of developing prostate cancer, 1 which raised the most eyebrows. Dr Loeb featured throughout the meeting with an informative talk on prostate biopsy complications, particularly sepsis, and the role of template-guided biopsies in the war against antibiotic resistance. She discussed the role of active surveillance and current protocols for selection and monitoring. What was apparent was the degree of variation in how active sur- veillance was performed globally, with some units incorporating PSA alone while others in- corporated repeat biopsy schedules and MRI. John Davies, MD, FACS, of MD Anderson Cancer Centre (United States) and Dr Zargar described the impact of reduced PSA screening guidelines issued by the US Preventive Ser- vices Task Force. The effects of such changes, although currently immature, show serious trends toward a reduction in radical treatment for prostate cancer. Dr Zargar, in particular, explored the ripple effect of such changes in Australia, where rates of PSA screening and radical prostatectomy have dropped synony- mously. Whether this translates to an increase in metastatic disease over time remains to be seen. Imaging in prostate cancer Rob Reiter, MD, MBA, of David Geffen School of Medicine, University of California, gave an overview of MRI in the United States for early detection of prostate cancer, signal- ling an era where MR targeted fusion biopsies detected more significant tumours and fewer

The APCC faculty

cancer was explored further with Professor Sweeny elaborating on the CHAARTED 2 and STAMPEDE 3 trials, both acknowledging the survival advantage gained in introducing taxane chemotherapy in addition to andro- gen deprivation at the time of high volume metastatic disease. Small cell neuroendocrine prostate cancers were also discussed. These are not as uncommon as once thought and Eric Small, MD, of the University of Cali- fornia, described their relative resistance to abiraterone and enzalutamide. Almost synonymous to the discussion of metastatic prostate cancer management was a debate of prostatectomy versus radiotherapy for localised disease by Robert Nam, MD, FRCSC, of Sunnybrook Health Sciences Centre, University of Toronto (Canada). He presented Canadian data examining long-term outcomes and meta-analyses favouring surgery particularly with reference to side effects. Jas- preet Sandhu, MD, of the Memorial Sloan Kettering Cancer Centre in New York, then outlined many of the continence and erectile function outcomes following radical prosta- tectomy and some of the strategies utilised in improving continence outcomes. Perhaps the highlight lectures of the meeting included the 4th Patrick Walsh Lecture given by Martin Gleave, MD, FRCSC, FACS, of the University of British Columbia (Canada) titled ‘Two tales of precision oncology’. This exquisite lecture dissected some of the finer nuances in precision oncology in castration- resistance prostate cancer. Peter Wiklund, MD, of Karolinska Uni- versity Hospital (Sweden) gave the ERUS Lecture examining the role of surgery in high-risk and metastatic prostate cancer. He was subsequently supported in the programme by George Thalman, MD of the University of Bern (Switzerland), Phil Dundee, MD of the Royal Melbourne Hospital, and John Yax- ley, MD of Wesley Urology Clinic, Brisbane, examining the indications and techniques, and evidence for and against extended pelvic lymph node dissection. Open versus robotic prostatectomy: the Brisbane experience No conference is without controversy, and Geoff Couglin, MBBS, FRACS of Wesley Urology Clinic, Brisbane, and Dr Yaxley

presented one particular debate that engaged the audience. They reported the early onco- logical and functional outcomes of open versus robotic prostatectomy of a randomised con- trolled multicentre phase 3 study published in The Lancet recently. 4 Urinary function and sexual function were similar at 12 weeks post prostatectomy. Posi- tive surgical margin rates were also similar at 10% versus 15% in the open versus robotic groups, respectively. Robot-assisted radical prostatectomy is associated with clinical out- comes similar to those achieved with open rad- ical prostatectomy. Yet, secondary outcomes show a different picture: the robotic group demonstrated less blood loss, less postopera- tive pain, and a shorter hospital stay. Whilst highly commendable, this study did not control for individual surgical experience and trainee involvement, and the outcome pa- rameters recorded at 12 weeks represented too short a follow-up period to allow for meaningful comparison. If anything, this study allows one to view robotic surgery in a favourable light; a lesser experienced surgeon is able to deliver functional and oncological outcomes that an experienced open surgeon can deliver by adopt- ing robotic techniques. References 1. Rider JR, Wilson KM, Sinnott JA, et al. . Eur Urol 2016 Mar 28[Epub ahead of print] 2. Sweeney CJ, Chen YH, Carducci M, et al. N Engl J Med 2015;373:737-746 3. James ND, Sydes MR, Clarke NW, et al. Lancet 2016;373:737-746 4. Yaxley JW, Coughlin GD, Lancet 2016;388:1057-66 Dr Nair is a UK-trained urological surgeon undergoing advanced fellowship training in robotics and uro-oncology

at the Royal Melbourne Hospital. Dr Zargar is a urological surgeon with fellowship training in uro-oncology, and

advanced laparoscopic and robotic surgery. He is Consultant Urologist at the Royal Melbourne Hospital and Senior Clinical Lecturer, Department of Surgery, University of Melbourne.

PRACTICEUPDATE HAEMATOLOGY & ONCOLOGY

BREAST

Low to modest reductions in neutropenia-related hospitalisations observed with colony-stimulating factors Comment by Lee Schwartzberg, MD, FACP G rowth factor support with granulocyte-colony stimulat- ing factor (G-CSF) reduces

cancer setting with three common regimens: TC, TCH, and non-dose dense AC. The investigators found that the TC and TCH regimens plus G-CSF, overwhelmingly adminis- tered as long-acting pegfilgrastim, were associated with a reduction in hospitalisation. In contrast, women taking AC, a regimen considered

But, which patients receiving inter- mediate-risk regimens, with a 10% to 20% risk of febrile neutropenia, deserve G-CSF prophylaxis and what are the clinical and economic benefits of the intervention? This retrospective claims-based study adds an important analysis of use of growth factor in the breast

low risk by guidelines, did not derive benefit from growth factor. In the TC/TCH groups, the re- duction in hospitalisation benefit was pronounced in older patients (>65 years of age) who received prophylaxis. This finding is very much in keeping with guidelines, which suggest, for intermediate-risk regimens, that patient risk factors are very important to consider. Risk factors include age, comorbidi- ties, prior history of neutropenia, and prior chemotherapy. While for the overall group analysed in this study the strict cost–benefit ratio was modest, the clinician who ap- plies the principles of judiciously using growth factor support with moderate-risk regimens will reduce the adverse events associated with chemotherapy in breast cancer and likely do so in a cost-effective, re- sponsible manner.

the incidence of febrile neutropenia, hospitalisation, and death in patients at high risk of myelosuppression from chemotherapy, which is com- monly considered at a threshold lev- el of >20% risk without prophylaxis.

Risk of neutropenia-related hospitalization in patients who received colony-stimulating factors with chemotherapy for breast cancer Journal of Clinical Oncology Take-home message • The authors evaluated 4815 patients with breast cancer who received docetaxel and cyclophosphamide (TC), docetaxel, carboplatin, and trastuzumab (TCH), and doxorubicin and cyclophosphamide (AC) to determine if granulocyte–colony stimulating factor (G-CSF) prophylaxis improved neutropenia-related hospitalizations. Results showed that G-CSF given within 5 days of starting chemotherapy was associated with reduced risk of neutropenia-related hospitalization in patients taking TC (adjusted OR, 0.29) and in those taking THC (adjusted OR, 0.19) but not in those taking AC (adjusted OR, 1.21). • There was a low to modest benefit relative to neutropenia-related hospitalizations associated with G-CSF prophylaxis in breast cancer patients being treated with TC and TCH. Abstract

or infection-related hospitalization within 21 days of initiating chemotherapy. Multivariable regressions and number-needed-to-treat analyses were used. RESULTS A total of 4,815 patients received TC (2,849 PP; 1,966 no PP); 2,292 patients received TCH (1,444 PP; 848 no PP); and 1,638 patients received AC (857 PP; 781 no PP) regimen. PP was associated with reduced risk of neutropenia-related hospitalization for TC (2.0% PP; 7.1% no PP; adjusted odds ratio [AOR], 0.29; 95% CI, 0.22 to 0.39) and TCH (1.3% PP; 7.1% no PP; AOR, 0.19; 95% CI, 0.12 to 0.30), but not AC (4.7% PP; 3.8% no PP; AOR, 1.21; 95% CI, 0.75 to 1.93) regimens. For the TC regimen, 20 patients (95% CI, 16 to 26) would have to be treated for 21 days to avoid one neutropenia-related hospitalization; with the TCH regimen, 18 patients (95% CI, 13 to 25) would have to be treated. CONCLUSION Primary G-CSF prophylaxis was associated with low-to-modest benefit in lowering neutropenia- related hospitalization in patients with breast cancer who received TC and TCH regimens. Further evaluation is needed to better understand which patients benefit most from G-CSF prophylaxis in this setting. J Clin Oncol 2016 Sep 19;[Epub ahead of print], Agiro A, Ma Q, Acheson AK, et al.

database for 14 commercial US health plans. This retrospective analysis included patients with breast cancer who began first-cycle chemotherapy from 2008 to 2013 using docetaxel and cyclophosphamide (TC); docetaxel, carboplatin, and trastuzumab (TCH); or doxo- rubicin and cyclophosphamide (conventional-dose AC) regimens. Primary prophylaxis (PP) was defined as G-CSF administration within 5 days of beginning chemotherapy. Outcome was neutropenia, fever,

Dr Schwartzberg is Senior Partner

PURPOSE To describe outcomes after granulocyte colony-stimulating factor (G-CSF) prophylaxis in pa- tients with breast cancer who received chemotherapy regimens with low-to-intermediate risk of induction of neutropenia-related hospitalization. PATIENTS AND METHODS We identified 8,745 patients age ≥ 18 years from a medical and pharmacy claims

and Medical Director, The West Clinic, Memphis, Tennessee.

Dual block with lapatinib and trastuzumab effective as neoadjuvant treatment of HER2-postive breast cancer Comment by Lee Schwartzberg, MD, FACP A ddition of lapatinib, a small-molecule HER2 inhibitor, to trastuzumab with chemotherapy led to improvement lapatinib, and finds that its biggest impact is in the ER− subgroup and those patients receiving single-agent taxane. In an era when combina- tion chemotherapy is typically delivered with

anti-HER2 agents, the incremental benefit of lapatinib is small and nonsignificant. However, given the growing use of single-agent taxane plus trastuzumab in lower-risk patients or patients with more comorbidities, one can conjecture a setting in which adding lapatinib instead of more cytotoxic chemotherapy would make sense in the neoadjuvant/adjuvant set- ting. It would be interesting to see a prospec- tive trial test this idea.

in the pathologic complete response rate in the neoadjuvant setting but not disease-free survival benefit in the adjuvant setting. This meta-analysis teases out the relative benefit of

Advances in genomic testing and computational biology for breast cancer

672 (58.2%) hormone receptor- positive, 534 (46.2%) received taxanes alone, and 621 (53.8%) anthracyclines plus taxanes or the docetaxel-carboplatin regi- men. Overall, the dual block was associated with a significant 13% absolute improvement in pCR rate compared with single-agent tras- tuzumab (summary risk difference, SRD 0.13; 95% CI, 0.08–0.19). The activity was greater in hormone receptor-negative patients who received chemotherapy with taxanes alone (SRD 0.25; 95% CI, 0.13–0.37), compared to hor- mone receptor-positive or hor- mone receptor-negative disease treated with anthracyclines plus taxanes or the docetaxel-carbo- platin regimen (SRD 0.09; 95% CI, 0.02–0.15; Pinteraction = 0.05). CONCLUSIONS On the basis of ΔpCR data, the dual block with trastuzumab and lapatinib plus chemotherapy is a very active treatment only in HER2(+) and hormone receptor-negative breast cancer treated with taxane monochemotherapy. Clin Cancer Res 2016;22:4594- 4603, Clavarezza M, Puntoni M, Gennari A, et al.

• This meta-analysis assessed neoadjuvant combination of lapa- tinib and trastuzumab vs trastuzumab alone in HER2-positive breast cancer. The combination was associated with a 13% absolute improvement in pathologic complete response com- pared with trastuzumab alone (summary risk difference, 0.13). Interestingly, in hormone receptor-negative patients, there was greater activity with trastuzumab alone compared with the hormone receptor-positive or hormone receptor-negative patients treated with the dual block. • The authors conclude that patients with HER2-positive breast cancer benefit from the neoadjuvant combination of lapatinib and trastuzumab, while hormone receptor–negative patients demonstrate the best results with taxane monotherapy. Abstract

INTERVIEW WITH KIMBERLY BLACKWELL, MD

Dr Blackwell discusses the latest advances in genomic testing and gene expression profiles, in- cluding results of the MINDACT trial and immune

checkpoint inhibitors. Dr Blackwell is Professor of Medicine and Assis- tant Professor in Radiation Oncol- ogy, Duke Department of Medicine, North Carolina.

HER2 biosimilars in clinical practice: an interviewwith Dr William Gradishar INTERVIEW WITH WILLIAM GRADISHAR, MD, FACP

trastuzumab versus trastuzumab alone in HER2+ breast cancer. EXPERIMENTAL DESIGN Trials were identified by Medline (PubMed), ISI Web of Science (Science Cita- tion Index Expanded), Embase, Cochrane library, and reference lists of published studies, review articles, editorials, and by hand- searched reports from major cancer meeting reports. RESULTS Six randomized trials including 1,155 patients were identified, of whom 483 (41.8%) were hormone receptor-negative,

PURPOSE (Neo)adjuvant treat- ment with chemotherapy plus trastuzumab reduces recurrence and death risk in HER2-positive (HER2+) breast cancer. Rand- omized trials assessed HER2 dual block by adding lapatinib to trastuzumab and chemotherapy in the neoadjuvant setting using pathologic complete response (pCR) as the outcome measure. We conducted a meta-analysis of randomized trials testing neoadju- vant dual block with lapatinib and

Dr Gradishar discusses the Heritage trial on the trastuzumab biomimilar for HER2+ metastatic breast cancer and shares his thoughts on using biosimilars in practice. Dr Gradishar is Betsy Bram-

sen Professor of Breast Oncology in the Division of Hematology and Medical Oncology, Department of Medicine, at the Feinberg School Medicine at Northwestern Univer- sity in Chicago, Illinois.

VOL. 1 • No. 4 • 2016

MINIMUM PRODUCT INFORMATION: PALEXIA ® SR (tapentadol hydrochloride) INDICATION: Moderate to severe chronic pain unresponsive to non-narcotic analgesia. CONTRAINDICATIONS: Known hypersensitivity to tapentadol or any component of Palexia SR; conditions in which mu-opioid receptor agonist activity is contraindicated e.g. significant respiratory depression and acute or severe bronchial asthma or hypercapnia; confirmed or suspected paralytic ileus; acute intoxication with alcohol; hypnotics, centrally acting analgesics or psychotropic drugs; patients who are receiving MAO inhibitors or who have taken them within the last 14 days. PRECAUTIONS: Monitor for signs of abuse and addiction; repeated administration may lead to tolerance; withdrawal symptoms could occur after abrupt discontinuation; not recommended in patients with increased intracranial pressure, impaired consciousness, or coma and severe renal or severe hepatic impairment; caution in patients with impaired respiratory functions, patients with head injury, brain tumours, a history of seizures or any condition that increases risk of seizures, moderate hepatic impairment or biliary tract disease, including acute pancreatitis. Use in pregnancy (Category C). Should not be used during breastfeeding. Not recommended for children <18 years old. May impair ability to drive or operate machinery. INTERACTIONS: Care should be taken when combining with mixed opioid agonist/antagonists or partial mu-opioid agonists; additive CNS depression with concomitant administration of other mu-opioid receptor agonist PBS Information: Restricted benefit. Chronic severe disabling pain not responding to non-narcotic analgesics. Authority required for increased maximum quantities and/or repeats. Refer to PBS schedule for full restricted benefit and authority information. Before prescribing, please review the Product Information available at www.seqirus.com.au/PI.

For Chronic Pain Patients Pain relief as effective as oxycodone CR with significantly less constipation, nausea and vomiting (p<0.001)* 1,2 *Meta-analysis to assess non-inferior efficacy and superior GI tolerability (constipation) in moderate to severe chronic pain; PALEXIA SR 100–250 mg BD vs. oxycodone CR 20–50 mg BD That’s just one of the ways PALEXIA SR helps you do more for your patients with moderate to severe chronic pain

analgesics, general anaesthetics, phenothiazines, other tranquilisers, sedatives, hypnotics or other CNS depressants (including alcohol and illicit drugs) – reduction of dose of one or both agents should be considered; contraindicated in patients who are receiving MAO inhibitors or who have taken them within the last 14 days; isolated case reports of serotonin syndrome when used in combination with serotonergic drugs (see full PI). ADVERSE EFFECTS: Very common ( ≥ 1/10): dizziness, somnolence, headache, nausea, constipation; Common ( ≥ 1/100 to <1/10): Decreased appetite, anxiety, depressed mood, sleep disorder, nervousness, restlessness, disturbance in attention, tremor, muscle contractions involuntary, flushing, dyspnoea, vomiting, diarrhoea, dyspepsia, pruritus, hyperhidrosis, rash, asthenia, fatigue, feeling of body temperature change, mucosal dryness, oedema. Postmarketing: suicidal ideation, angioedema, anaphylaxis and anaphylactic shock. DOSAGE AND ADMINISTRATION: To be taken orally twice daily, whole with sufficient liquid, approximately every twelve hours, with or without food. Initiation of therapy in patients currently not taking opioid analgesics: start with 50 mg Palexia SR twice daily. Initiation of therapy in patients currently taking opioid analgesics: nature, administration and mean daily dose of previous medication should be taken into account. Titration and maintenance: titrate individually to a level that provides adequate analgesia and minimises side effects under close supervision of prescribing physician; titration regimen in increments of 50 mg twice daily every 3 days shown to be appropriate in most patients in clinical trials. Total daily doses >500 mg not recommended. Discontinuation of treatment: taper dose gradually to prevent symptoms of withdrawal. Renal Impairment: not recommended in severe renal impairment. Hepatic Impairment: initiate at 50 mg once daily in moderate hepatic impairment; not recommended in severe hepatic impairment. Elderly patients more likely to have decreased renal and hepatic function – care in dose selection. Not recommended for use in children <18 years old. Based on approved Product Information dated 17 September 2015. REFERENCES: 1. Palexia SR Approved Product Information, 17 September 2015. 2. Lange B et al. Adv Ther 2010;27(6):381–99. PALEXIA ® SR is a registered trademark of Grünenthal Pty Ltd. PALEXIA ® SR is distributed by Seqirus (Australia) Pty Ltd under licence from Grünenthal Pty Ltd. Seqirus (Australia) Pty Ltd ABN 66 120 398 067, 63 Poplar Road Parkville, Victoria 3052. www.seqirus.com.au. Medical Information: 1800 642 865. Seqirus ™ is a trademark of Seqirus UK Limited or its affiliates. Date of preparation: September 2016. AUS/PALX/0616/0225. SEQP11124/HO/DPS. Ward6.

CONFERENCE COVERAGE

58th annual meeting of the American Society for Radiation Oncology (ASTRO)

25–28 SEPTEMBER • BOSTON, UNITED STATES

With 11,000 attendees from the radiology community, the 2016 ASTRO annual meeting showcased the latest in radiation therapy techniques and technologies. The PracticeUpdate Editorial Team reports from Boston on some of the highlighted clinical trial data presented at the meeting.

A radiation boost is recommended in patients with DCIS and ≥10 years life expectancy following breast-conserving surgery and whole breast radiotherapy A supplemental boost of radiation has been shown to improve local control and provide an incremen- tal benefit in decreasing breast cancer recurrence for patients with ductal carcinoma in situ (DCIS) who receive whole breast radiation therapy fol- lowing lumpectomy. This finding of a retrospective analysis was reported at the ASTRO 2016. M eena Savur Moran, MD, of Yale School of Medicine, NewHaven, Connecticut, explained that patients with DCIS undergoing breast conservation therapy typically receive a lumpectomy, followed by whole breast radiotherapy. Many then receive an additional boost of radiation of four to eight fractions to the surgical bed. While multiple clinical trials have demonstrated a modest but statistically significant reduction in ipsilateral breast tumour re- currence from a radiation boost after whole breast radiotherapy for invasive breast cancer, no phase 3 studies have evaluated radiation boost for DCIS. Ten academic institutions from the US, Canada, and France provided de-identified data for 4131 cases of DCIS, the largest cohort of patients with DCIS treated with or without boost to date. Eligible patients included those with pure DCIS (ie, no microinvasion) who received whole breast radiotherapy with or without radiation boost and reached at 5 years of follow-up. They received either electron or photo radiation boost. The

The benefit in reducing in-breast recurrence was demon- strated across all age subgroups. Furthermore, treatment with the DCIS boost was an independent predictor of decreasing ipsilateral breast tumour recurrence on multivariate analyses that controlled for grade, necrosis, margin status, age, tumour size, and tamoxifen use. On subset analysis, though the boost did not convey a statisti- cally significant benefit in the subset of patients with positive margins, it did independently predict for reducing ipsilateral breast tumour recurrence in all age groups with negative mar- gins (all P < 0.02). Dr Moran explained that only 4% of partici- pants comprised the subset of patients with positive margins. It is highly likely, therefore, that the positive margin subset was underpowered to show a statistically significant benefit. Dr Moran stated, “Our findings suggest that adding several additional fractions of radiation directed to the lumpectomy cavity after whole breast radiation for DCIS provides an incre- mental benefit in decreasing local relapse, similar in magni- tude to the benefit of 4% at 20 years of the boost for invasive cancers.” “While these small numbers may not seem substantial, the boost data in invasive disease have highlighted the clinical importance that small decreases in local relapse provide for patients. Ultimately, these small decreases in ipsilateral breast tumour recurrence reduced the number of mastectomies for recurrence by approximately 40% in patients who had received a boost vs those who did not.”

median boost dose was 14 Gy. Records documenting patients receiving a brachytherapy boost, those with unknown boost status, and those who receive partial breast radiation were not included in the analysis. Among 4131 cases included in the analysis, 2661 patients received a radiation boost and 1470 did not. Radiation boosts were more common for patients with positive margins follow- ing breast-conserving surgery, those with unknown oestrogen receptor status, and individuals with documented necrosis. Median follow-up was 9 years. Patients with DCIS who received a radiation boost following whole breast radiotherapy experienced a reduction in local recurrence. Ipsilateral breast tumour-free survival for boost versus no boost, was 97.1 versus 96.3% at 5 years, 94.1 versus 92.5% at 10 years, and 91.6 versus 88.0% at 15 years following treatment, respectively (P = 0.013). Dr Moran remarked, “Many radiation oncologists routinely deliver a boost after whole breast radiotherapy for DCIS. We anticipated a similar benefit to that of invasive cancers. But we haven’t had consistent data to demonstrate this benefit in DCIS.” She continued, “Our study has demonstrated that a radiation boost provides an albeit small but significant long-term benefit in reducing breast tumour recurrence for patients with DCIS. The results support consideration of a boost in patients with DCIS who undergo whole breast radiotherapy and have life expectancies of 10 or more years.”

PRACTICEUPDATE HAEMATOLOGY & ONCOLOGY

ASTRO 2016

Adding several additional fractions of radiation directed to the lumpectomy cavity after whole breast radiation for DCIS provides an incremental benefit in decreasing local relapse, similar inmagnitude to the benefit of 4% at 20 years of the boost for invasive cancers.

Onmultivariate analysis, we identified younger age (<40 years) and higher- grade diseasewere associatedwith higher risk of locoregional recurrence and death. These patients, therefore, may bemore likely to benefit from radiation therapy. >10

Our results confirm that radiosurgery to the surgical cavity is a viable treatment option to improve local control, with less impact on cognitive function and quality of life than whole brain radiotherapy in resected metastatic brain disease. >11

Reduced radiation boost volume is recommended but craniospinal axis dose remains unchanged in average-risk paediatric medulloblastoma A Children’s Oncology Group trial has found that survival is not compromised from smaller radiation volume to the posterior fossa. The authors uphold standard doses for craniospinal irradiation, however.

This outcome was reported at the ASTRO 2016. J eff M. Michalski, MD, MBA, of Washington University, St. Louis, Missouri, explained that in this largest trial of average-risk paediatric medulloblastoma, survival rates fol- lowing reduced radiation therapy boost volumes were compara- ble to standard treatment volumes for the primary tumour site. Lower doses of craniospinal axis irradiation were associated with higher event rates and worse survival. Findings from this phase 3 randomised trial indicate that physicians can adopt smaller boost volumes for posterior fossa radiotherapy but should maintain the standard radiotherapy dose for craniospinal irradiation. The most common type of brain malignancy in children, medulloblastoma is an aggressive tumour that originates in the lower, rear area of the brain but tends to spread to the upper brain and spine. As a result, the standard of care following surgical resection for these children has included systemic chemotherapy and irradiation to both the posterior fossa (pri- mary site) and craniospinal axis. Complications of craniospinal irradiation, however, include considerable negative effects on neurocognition, endocrinologic function, and hearing. We were disappointed to find that a lower dose of irradiation was associated with an increased rate of failure in the younger children. Reducing the treatment by just three fractions from 23.4 to 18 Gy was associated with a higher rate of events and diminished overall survival.

reduced dose of involved-field radiotherapy (n = 227). The 226 patients age 3 to 7 years were also randomised to a standard irradiation dose of 23.4 Gy to the craniospinal axis (n = 110) or a reduced dose of 18 Gy (n = 116). Following maximum surgery and within 31 days following resection, patients began 6 weeks of radiotherapy. After a 1-month break, they began to receive alternating cycles of cisplatin- and cytoxan-based chemotherapy. Primary outcomes included the amount of time from study entry to disease progression, disease recurrence, death from any cause, or a second malignant neoplasm. Researchers compared rates of overall survival, event-free survival, local failure, and distant failure. After a median of >6.5 years, reduction in the volume of radiotherapy boost to the posterior fossa did not compromise overall or event-free or survival in this cohort of paediatric patients with average-risk medulloblastoma. Overall survival at 5 years was 84.1 ± 2.8% for patients who received the reduced volume with involved-field radiotherapy and 85.2 ± 2.6% for patients who received the standard volume of radiation to the posterior fossa. Event-free survival at 5 years was 82.2 ± 2.9% for involved-field radiotherapy and 80.8 ± 3.0% for radiation to the posterior fossa. Rates of local failure did not vary significantly between treatment arms. Local failure at 5 years was 1.9 ± 0.1% for involved-field radiation and 3.7 ± 1.3% for radiation to the posterior fossa. Dr Michalski commented, “This trial – the largest of its kind to date – indicates that it is safe to adopt a limited posterior fossa boost for patients receiving radiation therapy for average risk medulloblastoma. These children can experience similar positive outcomes with lower chances of the radiation affecting surrounding brain tissue.” He added, “Additional data are needed, however, to address the appropriate volume for patients with higher-risk disease or metastasis at the time of diagnosis.” While reduced radiation volume to the posterior fossa did not impact survival rates, a low dose of craniospinal irradiation was associated with lower rates of event-free and overall survival in the youngest patients. Overall survival at 5 years was 78.1 ± 4.4% for those age 3 to 7 years who received low-dose irradiation therapy to the craniospinal axis versus 85.9 ± 3.8% for the standard dose to this axis. Event-free survival at 5 years was 72.1 ± 4.8% for children who received a low dose to the craniospinal axis, versus 82.6 ± 4.2% for those who received a standard dose to the axis. Rates of distant failure did not differ between groups. Isolated distant failure at 5 years was 12.8 ± 3.2% for low-dose radiation to the craniospinal axis and 8.2 ± 2.8% for standard-dose radiation to the axis. Dr Michalski concluded, “Unfortunately, we were disap- pointed to find that a lower dose of irradiation was associated with an increased rate of failure in the younger children. Re- ducing the treatment by just three fractions from 23.4 to 18 Gy was associated with a higher rate of events and diminished overall survival. Patients with average risk medulloblastoma should continue to receive a standard dose of 23.4 Gy to the craniospinal axis unless enrolled in a clinical trial.”

Researchers from the National Cancer Institute-supported Chil- dren’s Oncology Group set out to assess outcomes from a reduced ra- diation boost volume to the posterior fossa among paediatric average-risk medulloblastoma patients and a lower craniospinal dose, specifically in younger children. While several single-institution trials have found limited posterior fossa boost to be comparable to whole posterior fossa boost, this was the first trial that was sufficiently pow- ered to state definitively that the two approaches confer similar results in terms of survival. The findings are based on data from 464 patients age 3 to 21 years with average-risk medulloblastoma. Eli- gible patients had complete or near- complete resection of their primary tumours and no evidence of anaplasia or spread of the cancer beyond the posterior fossa. Patients were randomised to a standard radiation boost volume to the posterior fossa (n = 237) or a

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