Mahesh Iddawela

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.

Ipilimumab-induced thrombocytopenia in a patient with metastatic melanoma.

A 57-year-old man with metastatic melanoma developed grade 4 thrombocytopenia during treatment with ipilimumab (anti-CTLA-4 antibody). Bone marrow examination confirmed increased megakaryocytes, which supported a diagnosis of drug-induced, immune-mediated thrombocytopenia and he received 1 mg/kg prednisolone and 1 g/kg intravenous immunoglobulin. There was a delayed response to treatment, with the first evidence of rise in platelet count seen after 9 days. This was followed by a complete and sustained resolution of thrombocytopenia. Hematological toxicity has rarely been associated with ipilimumab and to our knowledge this is the first report of isolated grade 4 thrombocytopenia. This case demonstrates the importance of monitoring full blood count in all patients receiving ipilimumab.

A central review of histopathology reports after breast cancer neoadjuvant chemotherapy in the neo-tango trial

Background:Neo-tAnGo, a National Cancer Research Network (NCRN) multicentre randomised neoadjuvant chemotherapy trial in early breast cancer, enroled 831 patients in the United Kingdom. We report a central review of post-chemotherapy histopathology reports on the surgical specimens, to assess the presence and degree of response.Methods:A central independent two-reader review (EP and HME) of histopathology reports from post-treatment surgical specimens was performed. The quality and completeness of pathology reporting across all centres was assessed. The reviews included pathological response to chemotherapy (pathological complete response (pCR); minimal residual disease (MRD); and lesser degrees of response), laterality, the number of axillary metastases and axillary nodes, and the type of surgery. A consensus was reached after discussion.Results:In all, 825 surgical reports from 816 patients were available for review. Out of 4125 data items there were 347 discrepant results (8.4% of classifications), which involved 281 patients. These involved grading of breast response (169 but only 9 involving pCR vs MRD); laterality (6); presence of axillary metastasis (35); lymph node counts (108); and type of axillary surgery (29). Excluding cases with pCR, only 45% of reports included any comment regarding response in the breast and 30% in the axillary lymph nodes.Conclusion:We found considerable variability in the completeness of reporting of surgical specimens within this national neoadjuvant breast cancer trial. This highlights the need for consensus guidelines among trial groups on histopathology reporting, and the participation of histopathologists throughout the development and analysis of neoadjuvant trials.

Considerations for the processing and analysis of GoldenGate-based two-colour Illumina platforms

Illumina’s GoldenGate technology is a two-channel microarray platform that allows for the simultaneous interrogation of about 1 500 locations in the genome. GoldenGate has proved a flexible platform not only in the choice of those 1 500 locations, but also in the choice of the property being measured at them. It retains the desirable properties of Illumina’s BeadArrays in that the probes (in this case ‘beads’) are randomly arranged across the microarray, there are multiple instances of each probe and many samples can be processed simultaneously. As for other Illumina technologies, however, these properties are not exploited as they might be. Here we review the various common adaptations of the GoldenGate platform, review the analysis methods that are associated with each adaptation and then, with the aid of a number of example data sets we illustrate some of the improvements that can be made over the default analysis.

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.

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.

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.

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

BackgroundThe 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.MethodRNA 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.ResultsThe 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 (r2 = 0.96–0.98) as well as between the two platforms (DASL vs. BeadArray r2 = 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.ConclusionBoth 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.

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.

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

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.