Current landscape of cancer survivorship research in Australia.

AIM: Response to the substantial and long-term impacts that a cancer diagnosis and treatment has on the growing population of cancer survivors, requires priority-driven, impactful research. This study aimed to map Australian cancer survivorship research activities to identify gaps and opportunities for improvement and compare activities against identified survivorship research priorities. METHODS: An online survey was completed by Australian researchers regarding their cancer survivorship research, and the barriers they identified to conducting such research. Current research activity was compared to recently established Australian survivorship research priorities. RESULTS: Overall, 178 participants completed the online survey. The majority of the research undertaken utilized survey or qualitative designs and focused on breast cancer, adult populations, and those in early survivorship (<5 years post-treatment). Barriers to conducting survivorship research included funding, collaboration and networking, mentoring, and time constraints. There was moderate alignment with existing research priorities. Investigating models of care and health service delivery were the most frequently researched priorities. Research priorities that were less commonly investigated included patient navigation, patient-reported outcomes, multimorbidity, fear of cancer recurrence, and economic issues. CONCLUSION: This study provides the first snapshot of Australian survivorship research activity. Comparison to established priorities demonstrates health services research is receiving attention and highlights areas for potential pursuits, such as rare cancers or multimorbidity. Findings indicate the need for improved funding and infrastructure to support researchers in advancing the survivorship research agenda.

Implementing Optimal Care Pathways for Aboriginal and Torres Strait Islander People With Cancer: A Survey of Rural Health Professionals' Self-Rated Learning Needs.

Objective: In 2018, the Optimal Care Pathway (OCP) for Aboriginal and Torres Strait Islander people with cancer was developed in Australia to improve the cancer care experiences and outcomes of Aboriginal and Torres Strait Islander people. Methods: Our study examined health professionals' learning needs to meet the clinical practice requirements of the new OCP. An electronic questionnaire was distributed to 120 health professionals providing oncology care in two rural areas in Victoria, Australia. Questions included demographics, practice, cancer OCPs and implementation recommendations. Descriptive, chi-square and thematic analyses were undertaken. Results: Fifty-two health professionals from medicine (21%), nursing (37%) and allied health (37%) responded. All OCP sub-categories were selected, with a mean of 23 sub-categories identified as areas requiring additional learning. Aboriginal and Torres Strait Islander Perspectives, Treatment, and End of Life were the categories of higher interest. Care After Initial Treatment and Recovery was the category of lower interest. For respondents without cultural training, sub-categories involving practical tasks were of significant interest. Cultural education, connecting with Aboriginal and Torres Strait Islander services, putting learning into practice and respect emerged as themes. Conclusion: Strategies to address gaps included cultural safety training, person and family centred practice, and partnerships and connections with Aboriginal and Torres Strait Islander people and organisations across primary and tertiary sectors.

Defining research and infrastructure priorities for cancer survivorship in Australia: a modified Delphi study.

PURPOSE: The aim of this study was to establish research and infrastructure priorities for cancer survivorship. METHODS: A two-round modified online Delphi study was completed by Australian experts in cancer survivorship. Initial priorities were generated from the literature and organized into four research categories: physiological outcomes, psychosocial outcomes, population groups, and health services; and one research infrastructure category. In round 1 (R1), panelists ranked the importance of 77 items on a five-point scale (not at all important to very important). In round 2 (R2), panelists ranked their top 5 priorities within each category. Panelists also specified the type of research needed, such as biological, exploratory, intervention development, or implementation, for the items within each research category. RESULTS: Response rates were 76% (63/82) and 82% (68/82) respectively. After R1, 12 items were added, and 16 items combined or reworded. In R2, the highest prioritized research topics and the preferred type of research in each category were: biological research in cancer progression and recurrence; implementation and dissemination research for fear of recurrence; exploratory research for rare cancer types; and implementation research for quality of care topics. Data availability was listed as the most important priority for research infrastructure. CONCLUSIONS: This study has defined priorities that can be used to support coordinated action between researchers, funding bodies, and other key stakeholders. Designing future research which addresses these priorities will expand our ability to meet survivors' diverse needs and lead to improved outcomes.

Personalised cancer care in the era of precision medicine.

BACKGROUND: Advances in cancer treatment have not benefited all patients equally, underscoring the need for a personalised approach to care. OBJECTIVE: The aim of this article is to outline the key elements of personalised cancer care, including delivery of goal-directed care, self-management and self-management support, care integration, focus on access and equity, reduction in cost and promotion of health literacy and e-health literacy. DISCUSSION: Achievement of personalised cancer care requires a system-wide approach that targets the patient, healthcare provider and healthcare system with data informing practice. Primary care providers, including general practitioners (GPs) and practice nurses, play an important and growing part in the provision of personalised cancer care through support, advocacy, coordination, holistic care and health promotion. Cancer care systems can facilitate GPs' involvement in care through early input into multidisciplinary management, timely communication, rapid access to acute care and training opportunities.

Understanding Aboriginal Peoples' Cultural and Family Connections Can Help Inform the Development of Culturally Appropriate Cancer Survivorship Models of Care.

PURPOSE: To explore the cancer diagnosis, treatment, and survivorship experiences of Aboriginal people in the Gippsland region, Victoria, Australia, and identify factors critical to the development of a culturally appropriate cancer survivorship model of care. PATIENTS AND METHODS: Yarning circles were used to capture the stories of 15 people diagnosed with cancer and/or those of family members. Yarning circles were conducted in two locations in the Gippsland region. Sessions were facilitated by an Aboriginal Elder, audio recorded, and transcribed verbatim. Thematic analysis of the data were triangulated among three researchers and incorporated researcher reflexivity. RESULTS: Cultural connections and family were critical supports on the cancer journey. Putting the needs of the family first and caring for sick family members were more important than an individual's own health. There was "no time to grieve" for one's own cancer diagnosis and look after oneself. Cancer was a private experience; however, the constancy of deaths highlighted the importance of raising family awareness. Health professionals did not always understand the importance of people's cultural and family supports in their treatment and recovery. There were negatives attitudes in hospitals when family come to visit, seeing family as too large and overstaying visiting times. Health professionals did not seek family assistance with communication of information to family members whose literacy level was low, nor did they include family in treatment decision-making. Access to services depended on family support with transport, finances, and family responsibilities, often resulting in lapses in treatment and follow-up services. CONCLUSION: Understanding the importance of Aboriginal peoples' cultural and family connections can help to inform the development of culturally safe cancer survivorship models of care.

Circulating oestrogen receptor mutations and splice variants in advanced prostate cancer.

OBJECTIVE: To characterize circulating oestrogen receptor ( ER) mutants and splice variants in men with advanced prostate cancer. MATERIALS AND METHODS: Sequential blood samples were obtained from men with advanced prostate cancer, and from healthy controls. Blood-derived RNA samples were analysed using droplet digital PCR for the presence of six ERα mutations (E380Q, L536Q, Y537C, Y537S, Y537N and D538G), and six ERα and ERß splice variants (ERα-66, ERα-36, ERß1, ERß2, ERß4 & ERß5). RESULTS: A total of 94 samples were collected from 42 men with advanced prostate cancer. Four mutations (E380Q, L536Q, Y537S and D538G) and all six splice variants were detected in patient samples. Splice variants were detectable in non-cancer control samples. The presence of ER mutations was associated with bone metastases and castration resistance. ERß splice variant concentrations decreased after successive lines of treatment. CONCLUSIONS: The ER mutations were detectable in plasma from patients with advanced prostate cancer. ER splice variants were frequently detected in both men with and without prostate cancer.

Bevacizumab in Advanced Cervical Cancer: Issues and Challenges for Low- and Middle-Income Countries.

Bevacizumab became the first molecular antibody to show survival benefit in advanced cervical cancer. In the GOG-0240 (Paclitaxel and Cisplatin or Topotecan With or Without Bevacizumab in Treating Patients With Stage IVB, Recurrent, or Persistent Cervical Cancer) trial, it improved overall survival by a significant 3.7 months over platinum doublet chemotherapy alone. However, this discovery is not likely to improve the status of global cervical cancer because more than 85% of patients with cervical cancer live in low- and middle-income countries and cannot afford bevacizumab. This commentary looks at the options by which this drug can be made more affordable and cost-effective for patients in low- and middle-income countries. We also discuss other important questions related to its affordability and cost issues such as the optimal number of cycles and personalizing the treatment. Finally, we emphasize that although the unaffordability of bevacizumab in cervical cancer seems to be a very important issue, the best cost-effective strategy against cervical cancer is prevention with screening and vaccination.

Integrative analysis of copy number and gene expression in breast cancer using formalin-fixed paraffin-embedded core biopsy tissue: a feasibility study.

BACKGROUND: An absence of reliable molecular markers has hampered individualised breast cancer treatments, and a major limitation for translational research is the lack of fresh tissue. There are, however, abundant banks of formalin-fixed paraffin-embedded (FFPE) tissue. This study evaluated two platforms available for the analysis of DNA copy number and gene expression using FFPE samples. METHODS: The cDNA-mediated annealing, selection, extension, and ligation assay (DASL™) has been developed for gene expression analysis and the Molecular Inversion Probes assay (Oncoscan™), were used for copy number analysis using FFPE tissues. Gene expression and copy number were evaluated in core-biopsy samples from patients with breast cancer undergoing neoadjuvant chemotherapy (NAC). RESULTS: Forty-three core-biopsies were evaluated and characteristic copy number changes in breast cancers, gains in 1q, 8q, 11q, 17q and 20q and losses in 6q, 8p, 13q and 16q, were confirmed. Regions that frequently exhibited gains in tumours showing a pathological complete response (pCR) to NAC were 1q (55%), 8q (40%) and 17q (40%), whereas 11q11 (37%) gain was the most frequent change in non-pCR tumours. Gains associated with poor survival were 11q13 (62%), 8q24 (54%) and 20q (47%). Gene expression assessed by DASL correlated with immunohistochemistry (IHC) analysis for oestrogen receptor (ER) [area under the curve (AUC) = 0.95], progesterone receptor (PR)(AUC = 0.90) and human epidermal growth factor type-2 receptor (HER-2) (AUC = 0.96). Differential expression analysis between ER+ and ER- cancers identified over-expression of TTF1, LAF-4 and C-MYB (p ≤ 0.05), and between pCR vs non-pCRs, over-expression of CXCL9, AREG, B-MYB and under-expression of ABCG2. CONCLUSION: This study was an integrative analysis of copy number and gene expression using FFPE core biopsies and showed that molecular marker data from FFPE tissues were consistent with those in previous studies using fresh-frozen samples. FFPE tissue can provide reliable information and will be a useful tool in molecular marker studies. TRIAL REGISTRATION: Trial registration number ISRCTN09184069 and registered retrospectively on 02/06/2010.

The impact of bevacizumab in metastatic colorectal cancer with an intact primary tumor: Results from a large prospective cohort study.

BACKGROUND: Debate continues regarding the benefits versus risks of initial resection of the primary tumor in metastatic colorectal cancer (mCRC) patients with an asymptomatic primary tumor. Although the benefit of the anti-vascular endothelial growth factor agent bevacizumab alongside first-line chemotherapy in mCRC is established, the impact of bevacizumab on the intact primary tumor (IPT) is less well understood. METHODS: Data from an Australian mCRC registry were used to assess the impact of bevacizumab-based regimens in the presence of an IPT, to see if this differs from effects in resected primary tumor (RPT) patients and to understand the safety profile of bevacizumab in patients with IPT. Progression-free survival (PFS), overall survival (OS) and safety endpoints were analyzed. RESULTS: Of 1204 mCRC patients, 826 (69%) were eligible for inclusion. Bevacizumab use was similar in both arms (IPT (64%) versus RPT (70%)); compared with chemotherapy alone, bevacizumab use was associated with significantly longer PFS (IPT: 8.5 months vs 4.7 months, P = 0.017; RPT: 10.8 months vs 5.8 months, P < 0.001) and OS (IPT: 20 months vs 14.8 months, P = 0.005; RPT: 24.4 months vs 17.3 months, P = 0.004)).1 Bevacizumab use in an IPT was associated with more GI perforations (4.5% vs 1.8%, P = 0.210) but less frequent bleeding (1.5% vs 5.3%, P = 0.050) and thrombosis (1.5% vs 2.7%, P = 0.470), versus chemotherapy alone. Median survival was equivalent between patients that did or did not experience bevacizumab-related adverse events - 20.0 months versus 19.9 months, hazard ratio = 0.98, P = 0.623.1 CONCLUSIONS: The addition of bevacizumab significantly improved survival outcomes in mCRC with an IPT. The occurrence of bevacizumab-related adverse events did not significantly impact survival outcomes.

Reliable gene expression profiling of formalin-fixed paraffin-embedded breast cancer tissue (FFPE) using cDNA-mediated annealing, extension, selection, and ligation whole-genome (DASL WG) assay.

BACKGROUND: The difficulties in using formalin-fixed and paraffin-embedded (FFPE) tumour specimens for molecular marker studies have hampered progress in translational cancer research. The cDNA-mediated, annealing, selection, extension, and ligation (DASL) assay is a platform for gene expression profiling from FFPE tissue and hence could allow analysis of large collections of tissue with associated clinical data from existing archives, therefore facilitating the development of novel biomarkers. METHOD: RNA isolated from matched fresh frozen (FF) and FFPE cancer specimens was profiled using both the DASL whole-genome (WG) platform, and Illumina BeadArray's, and results were compared. Samples utilized were obtained from the breast cancer tumour bank held at the Cambridge University Hospitals NHS Foundation Trust. RESULTS: The number of reliably detected probes was comparable between the DASL and BeadArray platforms, indicating that the source of RNA did not result in a significant difference in the detection rates (Mean probes- 17114 in FFPE & 17400 in FF). There was a significant degree of correlation between replicates within the FF and FFPE sample sets (r (2) = 0.96-0.98) as well as between the two platforms (DASL vs. BeadArray r (2) = range 0.83-0.89). Hierarchical clustering using the most informative probes showed that replicate and matched samples were grouped into the same sub-cluster, regardless of whether RNA was derived from FF or FFPE tissue. CONCLUSION: Both FF and FFPE material generated reproducible gene expression profiles, although there was more noise in profiles from FFPE specimens. We have shown that the DASL WG platform is suitable for profiling formalin-fixed paraffin-embedded samples, but robust bioinformatics analysis is required.

Continuous versus intermittent docetaxel for metastatic castration resistant prostate cancer.

Docetaxel (DTX) is a standard chemotherapeutic agent for metastatic castration resistant prostate cancer (mCRPC). However, given a number of toxicities associated with DTX, considerable debate exists regarding the optimal number of DTX cycles to be administered in this setting. In clinic, it is a usual practice to continue DTX until toxicities or disease progression precludes its administration. Therefore, we undertook a comprehensive review of the literature on intermittent versus continuous chemotherapy administration in this setting. Although there is no head-to-head comparison of these two approaches, our review discovered many studies which show that intermittent approach is a very feasible and attractive option with lower toxicities and better quality of life. Because of the availability of many newer agents that can be used post-docetaxel, stopping DTX early seems to be more appropriate with introduction of docetaxel or newer agents upon progression. This review summarizes the data from available studies regarding the feasibility and controversies of intermittent docetaxel in prostate cancer.

Computational pathology of pre-treatment biopsies identifies lymphocyte density as a predictor of response to neoadjuvant chemotherapy in breast cancer.

BACKGROUND: There is a need to improve prediction of response to chemotherapy in breast cancer in order to improve clinical management and this may be achieved by harnessing computational metrics of tissue pathology. We investigated the association between quantitative image metrics derived from computational analysis of digital pathology slides and response to chemotherapy in women with breast cancer who received neoadjuvant chemotherapy. METHODS: We digitised tissue sections of both diagnostic and surgical samples of breast tumours from 768 patients enrolled in the Neo-tAnGo randomized controlled trial. We subjected digital images to systematic analysis optimised for detection of single cells. Machine-learning methods were used to classify cells as cancer, stromal or lymphocyte and we computed estimates of absolute numbers, relative fractions and cell densities using these data. Pathological complete response (pCR), a histological indicator of chemotherapy response, was the primary endpoint. Fifteen image metrics were tested for their association with pCR using univariate and multivariate logistic regression. RESULTS: Median lymphocyte density proved most strongly associated with pCR on univariate analysis (OR 4.46, 95 % CI 2.34-8.50, p < 0.0001; observations = 614) and on multivariate analysis (OR 2.42, 95 % CI 1.08-5.40, p = 0.03; observations = 406) after adjustment for clinical factors. Further exploratory analyses revealed that in approximately one quarter of cases there was an increase in lymphocyte density in the tumour removed at surgery compared to diagnostic biopsies. A reduction in lymphocyte density at surgery was strongly associated with pCR (OR 0.28, 95 % CI 0.17-0.47, p < 0.0001; observations = 553). CONCLUSIONS: A data-driven analysis of computational pathology reveals lymphocyte density as an independent predictor of pCR. Paradoxically an increase in lymphocyte density, following exposure to chemotherapy, is associated with a lack of pCR. Computational pathology can provide objective, quantitative and reproducible tissue metrics and represents a viable means of outcome prediction in breast cancer. TRIAL REGISTRATION: ClinicalTrials.gov NCT00070278 ; 03/10/2003.

Intensive cisplatin/oral etoposide for epithelial ovarian cancer: the Cambridge Gynae-Oncology Centre experience: too toxic for relapse?

Intensive cisplatin and oral etoposide for relapsed epithelial ovarian cancer (EOC), commonly known as the van der Burg (VDB) protocol, has been reported to improve response rates and progression-free survival. We report on all patients with relapsed EOC treated on the VDB protocol at the Cambridge Gynae-Oncology Centre. From the institutional databases, we identified all patients treated since 2001. We extracted demographic, clinical, treatment, and toxicity data and outcomes. We used Cox regression to identify predictors of survival. A total of 35 patients were treated on the VDB protocol. Toxicity was significant, with grade 3/4 fatigue, nausea and vomiting affecting 46, 46 and 29% of patients, respectively. Six patients had grade 3/4 infection and four (11%) deaths occurred on treatment. Efficacy was encouraging, with a radiological response rate of 43%, a median progression-free survival of 5.8 months and a median overall survival of 14.1 months. No significant difference in efficacy was seen between platinum-resistant and sensitive patients. We report significant activity of the VDB protocol in a routine clinical setting. However, the high rates of serious toxicity and treatment-related deaths among patients treated with palliative intent proved unacceptable. The Cambridge Gynae-Oncology Centre no longer uses this regimen in women with relapsed EOC.

Cheaper Options in the Prevention of Chemotherapy-Induced Nausea and Vomiting.

Chemotherapy-induced nausea and vomiting (CINV) is a common challenge in oncology practice for which there are expensive guideline-based treatment options. Although supportive care in cancer adds significantly to the overall cost, the discussion of unaffordability of anticancer treatment frequently only revolves around the targeted drugs and immunotherapies. In this review, we highlight the available cost-saving strategies and recent updates in preventing CINV in patients with cancer. This is the first work, to our knowledge, to review specifically the less expensive alternatives in CINV prevention, which is particularly important for those working in resource-limited settings. Whereas patients in these settings often cannot afford expensive antiemetics, we now have the science to offer cheaper, more affordable options without necessarily compromising efficacy.

Epirubicin, Cisplatin, and Capecitabine for Primary Platinum-Resistant or Platinum-Refractory Epithelial Ovarian Cancer: Results of a Retrospective, Single-Institution Study.

OBJECTIVE: Primary platinum-resistant epithelial ovarian cancer (EOC) is an area of unmet medical need. There is limited evidence from small studies that platinum-based combinations can overcome "resistance" in a proportion of patients. We investigated the efficacy and toxicity of platinum-based combination chemotherapy in the platinum-resistant and platinum-refractory setting. METHODS: Epirubicin, cisplatin, and capecitabine (ECX) combination chemotherapy was used at our institution for the treatment of relapsed EOC. From the institutional database, we identified all patients with primary platinum-refractory or platinum-resistant relapse treated with ECX as second-line therapy between 2001 and 2012. We extracted demographic, clinical, treatment, and toxicity data and outcomes. We used logistic and Cox regression models to identify predictors of response and survival respectively. RESULTS: Thirty-four 34 patients (8 refractory, 26 resistant) were treated with ECX. Response Evaluation Criteria In Solid Tumors (RECIST) response rate was 45%, median progression-free survival (PFS) was 6.4 months, and overall survival (OS) was 10.6 months. Platinum-resistant patients had better outcomes than did platinum-refractory patients (response rate, 54% vs 0%, P = 0.047; PFS 7.2 vs 1.8 months, P < 0.0001; OS 14.4 vs 3 months, P < 0.001). In regression models, time to progression after first-line treatment and platinum-refractory status were the strongest predictors of response and PFS or OS, respectively. Patients with time to progression after first-line treatment longer than 3 months showed PFS and OS of 7.9 and 14.7 months, respectively. Toxicity was manageable, with only 13% of cycles administered at reduced doses. CONCLUSIONS: Epirubicin, cisplatin, and capecitabine seems to be active in platinum-resistant relapsed EOC with manageable toxicity. Further prospective investigation of platinum-anthracycline combinations is warranted in patients who relapse 3 to 6 months after first-line platinum-taxane treatment.

Novel quality indicators for metastatic colorectal cancer management identify significant variations in these measures across treatment centers in Australia.

AIMS: Defining multidisciplinary quality of care indicators (QCIs) for metastatic colorectal cancer (mCRC) could improve understanding of variations in routine practice care. This may identify areas of below-average performance, which could then be addressed by clinicians to improve the quality of care delivered. This study aimed to define a panel of QCIs in mCRC and, based on these QCIs, to evaluate quality of care across multiple Australian sites. METHODS: A panel of clinicians with expertise in colorectal cancer defined evidence-based or best practice-based QCIs relevant to the routine multidisciplinary management of mCRC patients through structured consensus discussion. Related data were extracted from the Treatment of Recurrent and Advanced Colorectal Cancer (TRACC) registry, a prospectively maintained database recording comprehensive details on consecutive mCRC patients across multiple Australian hospitals. Variations in QCIs across sites were explored. RESULTS: Of 13 QCIs defined, data related to 10 were reliably extracted from TRACC. Analysis of data on 1276 patients across 10 sites demonstrated low rates of screening for hereditary nonpolyposis colorectal cancer in young patients and significant variation in surveillance-detected recurrences, lung resection rates and palliative chemotherapy use. Exploratory analyses suggested correlation between liver resection rates and survival. CONCLUSIONS: We have defined a novel set of mCRC QCIs and have demonstrated wide variation in the quality of care of mCRC across multiple Australian sites. With further validation to confirm a direct correlation between QCI and patient outcomes, these QCIs could be applied to improve the quality of care received by all mCRC patients.

Effects of the addition of gemcitabine, and paclitaxel-first sequencing, in neoadjuvant sequential epirubicin, cyclophosphamide, and paclitaxel for women with high-risk early breast cancer (Neo-tAnGo): an open-label, 2×2 factorial randomised phase 3 trial.

BACKGROUND: Anthracyclines and taxanes have been the standard neoadjuvant chemotherapies for breast cancer in the past decade. We aimed to assess safety and efficacy of the addition of gemcitabine to accelerated paclitaxel with epirubicin and cyclophosphamide, and also the effect of sequencing the blocks of epirubicin and cyclophosphamide and paclitaxel (with or without gemcitabine). METHODS: In our randomised, open-label, 2×2 factorial phase 3 trial (Neo-tAnGo), we enrolled women (aged >18 years) with newly diagnosed breast cancer (tumour size >20 mm) at 57 centres in the UK. Patients were randomly assigned via a central randomisation procedure to epirubicin and cyclophosphamide then paclitaxel (with or without gemcitabine) or paclitaxel (with or without gemcitabine) then epirubicin and cyclophosphamide. Four cycles of each component were given. The primary endpoint was pathological complete response (pCR), defined as absence of invasive cancer in the breast and axillary lymph nodes. This study is registered with EudraCT (2004-002356-34), ISRCTN (78234870), and ClinicalTrials.gov (NCT00070278). FINDINGS: Between Jan 18, 2005, and Sept 28, 2007, we randomly allocated 831 participants; 207 received epirubicin and cyclophosphamide then paclitaxel; 208 were given paclitaxel then epirubicin and cyclophosphamide; 208 had epirubicin and cyclophosphamide followed by paclitaxel and gemcitabine; and 208 received paclitaxel and gemcitabine then epirubicin and cyclophosphamide. 828 patients were eligible for analysis. Median follow-up was 47 months (IQR 37-51). 207 (25%) patients had inflammatory or locally advanced disease, 169 (20%) patients had tumours larger than 50 mm, 413 (50%) patients had clinical involvement of axillary nodes, 276 (33%) patients had oestrogen receptor (ER)-negative disease, and 191 (27%) patients had HER2-positive disease. Addition of gemcitabine did not increase pCR: 70 (17%, 95% CI 14-21) of 404 patients in the epirubicin and cyclophosphamide then paclitaxel group achieved pCR compared with 71 (17%, 14-21) of 408 patients who received additional gemcitabine (p=0·98). Receipt of a taxane before anthracycline was associated with improved pCR: 82 (20%, 95% CI 16-24) of 406 patients who received paclitaxel with or without gemcitabine followed by epirubicin and cyclophosphamide achieved pCR compared with 59 (15%, 11-18) of 406 patients who received epirubicin and cyclophosphamide first (p=0·03). Grade 3 toxicities were reported at expected levels: 173 (21%) of 812 patients who received treatment and had full treatment details had grade 3 neutropenia, 66 (8%) had infection, 41 (5%) had fatigue, 41 (5%) had muscle and joint pains, 37 (5%) had nausea, 36 (4%) had vomiting, 34 (4%) had neuropathy, 23 (3%) had transaminitis, 16 (2%) had acute hypersensitivity, and 20 (2%) had a rash. 86 (11%) patients had grade 4 neutropenia and 3 (<1%) had grade 4 infection. INTERPRETATION: Although addition of gemcitabine to paclitaxel and epirubicin and cyclophosphamide chemotherapy does not improve pCR, sequencing chemotherapy so that taxanes are received before anthracyclines could improve pCR in standard neoadjuvant chemotherapy for breast cancer. FUNDING: Cancer Research UK, Eli Lilly, Bristol-Myers Squibb.

Safety and efficacy of vemurafenib in end stage renal failure.

BACKGROUND: Serine-threonine inhibitors, such as vemurafenib, are being used increasingly in cancer treatment, and the toxicity and therapeutic benefit need to be balanced carefully both before and during treatment. CASE PRESENTATION: A patient with metastatic melanoma and end stage renal failure who was on peritoneal dialysis was treated with the serine-threonine kinase inhibitor, vemurafenib. After 5 months of treatment, a substantial response to vemurafenib was observed using imaging, but when he developed a prolonged QTc interval (common toxicity criteria (CTC) grade 3), treatment was interrupted. Vemurafenib was restarted at a reduced dose when the QTc interval returned to normal. The patient has had a significant response to vemurafenib and continued on treatment for 12 months after beginning the therapy. CONCLUSION: This is the first reported case of end stage renal failure in a patient who is taking vemurafenib. Although the patient developed QTc prolongation, it appears to be asymptomatic, and was managed with dose reduction. This case highlights the need for closer QTc monitoring at the start and during treatment.

Epirubicin as adjuvant therapy in breast cancer.

The past two decades have seen the introduction of routine adjuvant chemotherapy for early breast cancer. Since the cyclophosphamide, methotrexate and 5-fluorouracil (CMF) regimen was shown to improve disease-free and overall survival, adjuvant chemotherapy has become standard for many women. Anthracyclines, which are active in metastatic breast cancer, were then incorporated into adjuvant regimens and the meta-analysis of anthracycline trials has shown these regimens to be superior to CMF. Epirubicin (Ellence, Pharmacia), the 4'-epimer of doxorubicin, produces similar response rates to doxorubicin in the metastatic setting, and has been shown to have a better toxicity profile. In this review, the data relating to the efficacy of epirubicin in the adjuvant setting, including data from the recently presented National Epirubicin Adjuvant Trial, will be discussed.