Research Spotlight

Cella, D., B. Escudier, N. M. Tannir, T. Powles, F. Donskov, K. Peltola, M. Schmidinger, D. Y. C. Heng, P. N. Mainwaring, H. J. Hammers, J. L. Lee, B. J. Roth, F. Marteau, P. Williams, J. Baer, M. Mangeshkar, C. Scheffold, T. E. Hutson, S. Pal, R. J. Motzer and T. K. Choueiri (2018). “Quality of Life Outcomes for Cabozantinib Versus Everolimus in Patients With Metastatic Renal Cell Carcinoma: METEOR Phase III Randomized Trial.” J Clin Oncol: Jan 29:JCO2017752170. [Epub ahead of print].

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Purpose In the phase III METEOR trial (ClinicalTrials.gov identifier: NCT01865747), 658 previously treated patients with advanced renal cell carcinoma were randomly assigned 1:1 to receive cabozantinib or everolimus. The cabozantinib arm had improved progression-free survival, overall survival, and objective response rate compared with everolimus. Changes in quality of life (QoL), an exploratory end point, are reported here. Patients and Methods Patients completed the 19-item Functional Assessment of Cancer Therapy-Kidney Symptom Index (FKSI-19) and the five-level EuroQol (EQ-5D-5L) questionnaires at baseline and throughout the study. The nine-item FKSI-Disease-Related Symptoms (FKSI-DRS), a subset of FKSI-19, was also investigated. Data were summarized descriptively and by repeated-measures analysis (for which a clinically relevant difference was an effect size >/= 0.3). Time to deterioration (TTD) was defined as the earlier of date of death, radiographic progressive disease, or >/= 4-point decrease from baseline in FKSI-DRS. Results The QoL questionnaire completion rates remained >/= 75% through week 48 in each arm. There was no difference over time for FKSI-19 Total, FKSI-DRS, or EQ-5D data between the cabozantinib and everolimus arms. Among the individual FKSI-19 items, cabozantinib was associated with worse diarrhea and nausea; everolimus was associated with worse shortness of breath. These differences are consistent with the adverse event profile of each drug. Cabozantinib improved TTD overall, with a marked improvement in patients with bone metastases at baseline. Conclusion In patients with advanced renal cell carcinoma, relative to everolimus, cabozantinib generally maintained QoL to a similar extent. Compared with everolimus, cabozantinib extended TTD overall and markedly improved TTD in patients with bone metastases.

Bremova-Ertl, T., R. Schiffmann, M. C. Patterson, N. Belmatoug, T. Billette de Villemeur, S. Bardins, C. Frenzel, V. Malinova, S. Naumann, J. Arndt, E. Mengel, J. Reinke, R. Strobl and M. Strupp (2017). “Oculomotor and Vestibular Findings in Gaucher Disease Type 3 and Their Correlation with Neurological Findings.” Front Neurol Jan 15; 8:711.

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Objectives: To evaluate the function of the oculomotor and vestibular systems and to correlate these findings with the clinical status of patients with Gaucher disease type 3 (GD3). The goal of this cross-sectional and longitudinal study was to find oculomotor biomarkers for future clinical trials. Methods: Twenty-six patients with GD3 were assessed for eligibility and 21 were able to perform at least one task. Horizontal and vertical reflexive saccades, smooth pursuit, gaze-holding, optokinetic nystagmus, and horizontal vestibulo-ocular reflex (VOR) were examined by video-oculography/video-head impulse test and compared concurrently with 33 healthy controls. The Scale for the Assessment and Rating of Ataxia (SARA), the modified Severity Scoring Tool (mSST), and Grooved Pegboard Test (GPT) were administered to assess overall neurological function. Eleven patients were also re-assessed after 1 year. Results: Nine out of 17 patients exhibited gaze-holding deficits. One patient had upbeat nystagmus. Three patients presented with bilateral abducens palsy in combination with central oculomotor disorders, suggesting a bilateral involvement of the abducens nucleus. Horizontal angular VOR gain was reduced in all patients (0.66 +/- 0.37) compared with controls (1.1 +/- 0.11, p < 0.001). Most strongly correlated with clinical rating scales were peak velocity of downward saccades (SARA: rho = -0.752, p < 0.0005; mSST: rho = -0.611, p = 0.003; GPT: rho = -0.649, p = 0.005) and duration of vertical saccades (SARA: rho = 0.806, p < 0.001; mSST: rho = 0.700, p < 0.0005; GPT: rho = 0.558, p = 0.02) together with the VOR gain (SARA: rho = -0.63, p = 0.016; mSST: rho = -0.725, p = 0.003; GPT: rho = -0.666, p = 0.004). Vertical smooth pursuit gain decreased significantly at follow-up. Interpretation: This study shows neuronal degeneration of the brainstem and cerebellum with combined involvement of both supranuclear and nuclear oculomotor structures and the vestibular system in GD3. We also identified oculomotor parameters that correlate with the neurological status and can be used as biomarkers in future clinical trials.

Blum, J. L., N. Robert, J. Andersen, A. Favret, P. Ward, C. Osborne and J. Pippen (2018). “Use of Biomarkers to Guide Decisions on Adjuvant Systemic Therapy in Early-Stage Invasive Breast Cancer.” J Clin Oncol 36(4): 428-429.

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Although we agree with the decision of the ASCO Guideline Panel members to update the use of biomarkers to guide decisions on adjuvant systemic therapy for women with early-stage invasive breast cancer1 on the basis of the published results of the MINDACT (Microarray in Node-Negative and 1 to 3 Positive Lymph Node Disease May Avoid Chemotherapy) trial, we take exception with two issues. One is the language used in most of the detailed recommendations in the update, which state that physicians “should” or “should not” use specific tests in specific situations. We believe that the use of directive language, such as should and should not, goes beyond the concept of recommended guidelines and becomes a directive to clinicians. We note that recommendation 1.2.1 includes language that states that physicians “may” use the 70-gene signature assay and does not use the more directive should or should not language. Second, we agree that the 70-gene assay may provide some utility for decision making for patients with breast cancer with estrogen receptor (ER)–positive, human epidermal growth factor receptor 2–negative, lymph node–positive disease with one to three positive lymph nodes. However, we note that this recommendation is based on a small prospective data set of 731 women with lymph node–positive disease with one to three positive lymph nodes and high clinical and low genomic risk who were randomly assigned to receive chemotherapy or not. Although the entire high clinical and low genomic risk group included 1,550 women randomly assigned to receive chemotherapy or not, this group included both patients with positive and patients with negative lymph nodes. The outcome data provided for the entire group as noted in Figure 2 and Table 3 of the report included one half of the patients who had lymph node–negative disease. Moreover, follow-up for this study is still short at only 5 years, and the results may change with later follow-up. (Excerpt from text.)

Block, T. M., H. Alter, N. Brown, A. Brownstein, C. Brosgart, K. M. Chang, P. J. Chen, C. Cohen, H. El-Serag, J. Feld, R. Gish, J. Glenn, T. F. Greten, J. T. Guo, Y. Hoshida, K. V. Kowdley, W. Li, A. S. Lok, B. McMahon, A. Mehta, R. Perrillo, C. M. Rice, J. Rinaudo, R. F. Schinazi and K. Shetty (2018). “Research priorities for the discovery of a cure for chronic hepatitis B: Report of a workshop.” Antiviral Res 150: 93-100.

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In early 2017, the Hepatitis B Foundation invited 30 experts in the fields of hepatitis B and liver cancer research to identify projects they deemed important to the goal of finding a cure for chronic hepatitis B and D and the diseases with which these viral infections are associated. They were also asked to identify general categories of research and to prioritize sub-project topics within those areas. The experts generally agreed on broadly defined areas of research, but there was usually little difference between the highest and lowest scoring projects; for the most part, all programs described in this document were considered valuable and necessary. An executive summary of this discussion was recently published (Alter et al., Hepatology 2017). The present manuscript reports the areas of research identified by the workshop participants, provides a brief rationale for their selection, and attempts to express differences among the priorities assigned to each area of research, when such distinctions were expressed.

Alsahhar, J. S., R. Idriss and R. Bahirwani (2018). “A Rare Case of Cutaneous Metastases Secondary To Hepatocellular Carcinoma.” Clin Gastroenterol Hepatol. Jan 15. [Epub ahead of print].

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A 54-year-old man presented with a 2-month history of an abdominal rash, initially small papules over the epigastrium that spread medially and subsequently becoming painful. His past medical history included decompensated hepatitis C cirrhosis with hepatocellular carcinoma (HCC) CLC stage B diagnosed one year prior to presentation (3 lesions, largest measuring 5 cm). He underwent chemoembolization followed by cyberknife radiation 6 months prior to current presentation. Physical examination revealed a Sister Mary Joseph’s nodule surrounded by erythematous tender subcutaneous nodules (Figure a). His serum alpha-fetoprotein (AFP) was 1000 ng/ml. Given the high suspicion for metastases, punch biopsy of a nodule was performed revealing anastomosing cords of highly atypical cells with enlarged hyper-chromatic pleomorphic nuclei and atypical mitoses, consistent with high grade adenocarcinoma of hepatobiliary origin (Figure b+c). The patient died of liver failure two weeks after presentation. [Excerpt from text.]