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Editorial Improved relative survival of patients with B-cell non-Hodgkin in Queensland, 1993e2012

Ian N Olver

Monoclonal -based are improving outcomes for patients with a range of cancers

nti-, including monoclonal anti- A fi bodies to speci c cell surface protein , is proving to be a successful strategy in the emerging era of personalised medicine. This issue of the Journal includes the report of a retrospective study of the impact of one of the first therapeutic monoclonal , , on population data, including clinical registry data, and would thus the relative survival of patients with improve data accuracy and completeness. non-Hodgkin lymphoma in Queens- Rituximab was one of the early successes in immunotherapy, but a land between 1993 and 2012.1 Rituximab binds the CD20 anti- range of further monoclonal antibodies have since been success- gen that is found on 90% of B cells, making it easier for other fully applied to treating other cancers. For example, immune system cells to eliminate the cancerous cells (antibody- binds and downregulates the HER2 protein, the expression of dependent cell-mediated immunity). which is amplified in 20% of breast cancers and in some gastric Wright, Hapgood and their co-authors report that adding ritux- cancers, promoting cancer cell growth. Added to imab to improved the 5-year overall survival of patients after surgery, trastuzumab increased the 10-year overall survival with diffuse large lymphoma (from 49% to 62%) or follicular rate for women with operable HER2-positive breast cancer from lymphoma (from 73% to 86%), consistent with results reported 75% to 84%.3 from randomised clinical trials.1 Survival of patients with Hodgkin fi lymphoma did not change during the same period.1 Before the Bispeci c monoclonal antibodies combine two monoclonal anti- introduction of rituximab in 2003, nothing had improved the out- bodies to two different targets. , used to treat relapsed comes of intermediate grade lymphoma therapy since the intro- acute lymphocytic leukaemia, binds to CD19 on leukaemic cells and duction of CHOP (cyclophosphamide, doxorubicin, vincristine, CD3 on immune T cells, facilitating destruction of the leukaemic prednisone) in the 1970s. cells by the T cells. Long term survival (longer than 30 months) of patients treated with blinatumomab has been reported.4 The population figures reported by Wright and colleagues lack detail regarding, for example, staging; as they recognise, prog- Monoclonal antibodies can also be conjugated with a cytotoxic nostic factors and comorbid conditions may also influence out- drug or radioactive isotope that they deliver to the cancer cells; in comes. The influence of rurality and socio-economic status was T-DM1, for example, trastuzumab is bound to the cytotoxic agent examined, but the only statistically significant association was that emtansine (DM1). As HER2 is overexpressed only by cancer cells, survival of rural patients with diffuse large B-cell lymphoma was the toxin specifically targets these cells, and a meta-analysis found inferior to that of urban patients.1 However, the study was un- that T-DM1 was associated with improved overall survival of derpowered for achieving definitive findings. Patients in rural patients with metastatic breast cancer.5 Ibritumomab tiuxetan, the J 0 (4) 209 MJA areas have previously been reported to have poorer outcomes than conjugate of an antibody to B-lymphocyte CD20 with -90, urban residents, but the differences may be influenced by other is employed as an adjunct in the treatment of relapsed or factors, such as the lower socio-economic status of rural regions.2 refractory non-Hodgkin lymphoma.6

The study by Wright and colleagues shows that a small study Some other treatments do not target the j population size makes subgroup analysis problematic. The major cancer cells themselves. , for example, targets 2018 August 20 challenge of population studies is ensuring that outcomes are vascular endothelial growth factor, blocking angiogenesis and attributable to the treatment of interest and not to confounding preventing the new blood vessels forming around the tumour that factors, such as comorbid conditions and unrecognised changes in are needed for its growth and spread. Bevacizumab improves the the study population. Better digitisation of our health data would overall survival of patients with colorectal cancer or non- facilitate linkage of clinical data with demographic and other squamous lung cancer.7,8

157 Cancer Research Institute, University of South Australia, Adelaide, SA. [email protected] j doi: 10.5694/mja18.00626 j See Research, p. 166 Editorial

The most recent successes with monoclonal antibodies have been 1 Wright F, Hapgood G, Loganathan A, et al. Relative survival of patients with lymphoma the checkpoint inhibitors — including , , in Queensland according to histological subtype. Med J Aust 2018; 209: 166-172. , and — that block proteins on T 2 Mannetje A, De Roos AJ, Boffetta P, et al Occupation and risk of non-Hodgkin lymphoma and its subtypes: a pooled analysis from the InterLymph consortium. Environ Health cells or cancer cells which prevent the T cells targeting cancer cells. Perspect 2016; 124: 396-405. Ipilimumab binds to cytotoxic T-lymphocyte-associated protein 4 3 Perez EA, Romond EH, Suman VJ, et al. Trastuzumab plus adjuvant (CTLA-4) on T lymphocytes, allowing an immune response in chemotherapy for human epidermal growth factor receptor 2-positive breast cancer: patients with advanced ; a pooled analysis found 3- planned joint analysis of overall survival form NSABP B-31 and NCCTG N9831. year survival to be 22%.9 Nivolumab and pembrolizumab block J Clin Oncol 2014; 32: 3744-3752. T cell programmed cell death protein 1 (PD-1), which helps pre- 4 Zugmaier G, Gökbuget N, Klinger M, et al. Long-term survival and T-cell kinetics in vent autoimmunity, but also inhibits their attacking cancer cells. relapsed/refractory ALL patients who achieved MRD response after blinatumomab These drugs have improved survival in patients with melanoma, treatment. Blood 2015; 126: 2578-2584. have shown promise in the treatment of non-small cell lung 5 Shen K, Ma X, Zhu C, et al. Safety and efficacy of in advanced cancer, and are being investigated for treating other cancers, human epidermal growth factor receptor 2-postive breast cancer: a meta-analysis. Sci Rep 2016; 6: 23262. including renal cancer and Hodgkin lymphoma.10 Side effects, 6 Auger-Quittet S, Duny Y, Daures J-P, Quittet P. Outcomes after 90yttrium-ibritumomab however, include autoimmune effects in a range of organs. Ate- tiuxetan-BEAM in diffuse large B-cell lymphoma: a meta-analysis. Cancer Med 2014; 3: zolizumab, which blocks programmed death-ligand 1 (PD-L1) 927-938. receptors on cancer cells, is being used to treat lung and bladder 7 Botrel TE, Clark L, Paladini L, Clark O. Efficacy and safety of bevacizumab plus 11 cancers. chemotherapy compared to chemotherapy alone in previously untreated advanced or metastatic colorectal cancer. BMC Cancer 2016; 16: 667. 1 As the study by Wright, Hapgood and their co-authors indicates, 8 Greiller L, Tomasini P, Barlesi F. Bevacizumab in the treatment of nonsquamous non-small rituximab is having an impact at the population level. Newer cell lung cancer: evidence and experience. Ther Adv Respir Dis 2016; 10: 485-491. monoclonal antibodies are being tested for treating an increasing 9 Letendre P, Monga V, Mihem M, Zakharia Y. Ipilimumab: from preclinical development to range of cancers, and it is expected that there will be further im- future clinical perspectives in melanoma. Future Oncol 2017; 13: 625-636. provements in cancer survival at the population level. 10 Medina PJ, Adams VR. PD-1 pathway inhibitors: immune-oncology agents for restoring antitumour immune responses. Pharmacotherapy 2016; 36: 317-334. Competing interests: No relevant disclosures. 11 Ning YM, Suzman D, Maher VE, et al. FDA approval summary: atezolizumab Provenance: Commissioned; externally peer reviewed. n for the treatment of patients with progressive advanced urothelial carcinoma after platinum-containing chemotherapy. Oncologist 2017; ª 2018 AMPCo Pty Ltd. Produced with Elsevier B.V. All rights reserved. 22: 743-749. - 20 August 2018 j MJA 209 (4)

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