Category: Oncology

Hot Topics: Reports of Drug Side Effects Inconsistent

jackiewe Hot Topics in Research, Lung, Oncology, Pharmaceutical Sciences

Variation in toxicity reporting methods for early phase lung cancer treatment trials at oncology conferences

Simons EA, Smith DE, Gao D, Camidge DR. Variation in toxicity reporting methods for early phase lung cancer treatment trials at oncology conferences. Journal of Thoracic Oncology. https://doi.org/10.1016/j.jtho.2020.04.020.

Introduction

Phase I and II trials provide the initial human safety and tolerability data for new drugs. However, the methods for presenting toxicity data are not standardized. Clinicians often first encounter these data at professional conferences. We sought to characterize how the burden of adverse events (AE) is reported at the largest professional conference in clinical oncology.

Methods

We collected toxicity data from all lung cancer-associated phase I and II trial presentations and posters at the American Society for Clinical Oncology annual meetings 2017-2019. We captured AE features including the minimum incidence utilized for reporting; whether AEs shown were treatment-emergent or treatment-related, grouped by organ system or separated by individual descriptors; whether combined or separated across dose levels when a dose escalation component was included; and whether dose-limiting toxicities, serious AE, dose reduction rules and denominators for laboratory tests were described.

Results

209 trials were analyzed. There was wide variability in toxicity reporting practices. Six different thresholds for reporting AE of any grade were used. Treatment-related AEs were reported twice as frequently as treatment-emergent AEs. Toxicities were as likely to be reported across dose level as by dose level. Terms such as dose-limiting toxicity and serious AE were rarely defined. Dose reduction rules and denominators for laboratory tests were never defined.

Conclusion

Standardization of methods for reporting toxicities could improve the quality and ease of comparability of data on adverse effects in early phase therapeutic trials. A minimal AE data disclosure template is proposed.

Hot Topics: US Cancer Survivors Suffer Financial Hardship

jackiewe Hot Topics in Research, Oncology, Public Health

Medical Financial Hardship Intensity and Financial Sacrifice Associated with Cancer in the United States

Han X, Zhao J, Zheng Z, de Moor JS, Virgo KS, Yabroff KR. Medical financial hardship intensity and financial sacrifice associated with cancer in the united states. Cancer Epidemiol Biomarkers Prev. 2020. https://dx.doi.org/10.1158/1055-9965.EPI-19-0460.

Background: With rising costs of cancer care, this study aims to estimate the prevalence of, and factors associated with, medical financial hardship intensity and financial sacrifices due to cancer in the United States.

Methods: We identified 963 cancer survivors from the 2016 Medical Expenditures Panel Survey – Experiences with Cancer. Medical financial hardship due to cancer was measured in material (e.g., filed for bankruptcy), psychological (e.g., worry about paying bills and finances), and behavioral (e.g., delaying or forgoing care due to cost) domains. Nonmedical financial sacrifices included changes in spending and use of savings. Multivariable logistic models were used to identify characteristics associated with hardship intensity and sacrifices stratified by age group (18–64 or 65+ years).

Results: Among cancer survivors ages 18 to 64 years, 53.6%, 28.4%, and 11.4% reported at least one, two, or all three domains of hardship, respectively. Among survivors ages 65+ years, corresponding percentages were 42.0%, 12.7%, and 4.0%, respectively. Moreover, financial sacrifices due to cancer were more common in survivors ages 18 to 64 years (54.2%) than in survivors 65+ years (38.4%; P < 0.001). Factors significantly associated with hardship intensity in multivariable analyses included low income and educational attainment, racial/ethnic minority, comorbidity, lack of private insurance coverage, extended employment change, and recent cancer treatment. Most were also significantly associated with financial sacrifices.

Conclusions: Medical financial hardship and financial sacrifices are substantial among cancer survivors in the United States, particularly for younger survivors.

Impact: Efforts to mitigate financial hardship for cancer survivors are warranted, especially for those at high risk.

Hot Topics: Cannabis Use in Teen Cancer Patients Increasing

jackiewe Hot Topics in Research, Oncology

Cannabis Use in Young Adult Cancer Patients

Donovan, K. A., Oberoi-Jassal, R., Chang, Y. D., Rajasekhara, S., Haas, M. F., Randich, A. L., & Portman, D. G. (2019). Cannabis use in young adult cancer patients. Journal of Adolescent and Young Adult Oncology,  http://doi.org/10.1089/jayao.2019.0039

Background: The use of cannabis by young adult (YA) cancer patients is likely to increase as medical cannabis becomes more available. Clinically relevant data on cannabis use are needed to establish benchmarks for use, to identify patients who are more likely to use cannabis, and to assess outcomes associated with use.

Objective: The current study sought to determine the rate of cannabis use in YA cancer patients ages 18 to 39, identify demographic and clinical correlates of use, and examine differences in moderate-to-severe symptoms between users and nonusers.

Methods: We conducted a retrospective review of objectively measured tetrahydrocannabinol (THC), self-reported cannabis use, and cancer-related symptomatology in YA cancer patients in active treatment referred for comprehensive supportive care.

Results: Approximately 30% of YA cancer patients tested positive for THC on urine drug testing. At the univariate level, cannabis users were more likely to be male, to have a lifetime history of smoking at least 100 cigarettes, and to be more recently diagnosed. Cannabis use was associated with moderate-to-severe symptomatology, including pain, nausea, lack of appetite, constipation, difficulty sleeping, and poorer overall well-being.

Conclusions: YAs referred for comprehensive supportive care may be managing their cancer-related symptoms with cannabis. Further research is needed to better understand patients’ perceptions of cannabis’s therapeutic and adverse effects, in patients who used cannabis before diagnosis, and in patients who commenced use in response to a cancer diagnosis.

Hot Topics: Steroid Implant Restores Sight

jackiewe Hot Topics in Research, Oncology, Surgery

Outcomes Associated With Sustained-Release Intraocular Fluocinolone Implants in a Case of Melanoma-Associated Retinopathy Treated Without Systemic Immunosuppression

Karatsai E, Robson AG, Taylor SRJ. Outcomes associated with sustained-release intraocular fluocinolone implants in a case of melanoma-associated retinopathy treated without systemic immunosuppression. 2019. https://doi.org/10.1001/jamaophthalmol.2019.0284.

Importance  Melanoma-associated retinopathy (MAR) is a paraneoplastic syndrome in which antiretinal antibodies crossreact with retinal ON-bipolar cells, resulting in night blindness and progressive visual field loss. Current therapeutic options include cytoreductive surgery in combination with immunoglobulin, corticosteroids, or plasmapheresis, but their effectiveness is limited and may be contraindicated, given the possible protective role of circulating autoantibodies against metastatic spread. We report 3-year follow-up of the first case (to our knowledge) of MAR treated with intravitreal long-acting steroid implants.

Objective  To report on a patient with MAR who was treated with intravitreal fluocinolone acetonide implants in the absence of systemic immunosuppression.

Design, Setting, and Participants  This is a 3-year follow-up of a 73-year-old woman with a history of surgical excision of a malignant melanoma of the left pinna who presented with visual symptoms of shimmering and nyctalopia. Fundus examination, fundus autofluorescence, and optical coherence tomography were normal, with no evidence of cystoid macular edema. Automated perimetry showed a reduction in visual field and full-field electroretinography (ERG) demonstrated findings consistent with generalized ON-bipolar cell dysfunction, typical of MAR. The patient was treated with bilateral fluocinolone acetonide intravitreal implants.

Main Outcomes and Measures  Visual acuity, visual field, and electroretinography testing for 3 years after treatment.

Results  Visual fields improved in this 73-year-old patient from 20/30 (Snellen measured as 6/9) OD and 20/16 (6/5) OS at baseline to 20/20 OU within 1 week of treatment. Detailed electroretinography monitoring indicated characteristic abnormalities that partly resolved after treatment, consistent with improved inner retinal ON-bipolar cell function. Bilateral cataracts developed approximately 2 years after injection; cataract surgery was performed uneventfully. At 3 years posttreatment, the patient remained visually stable and in systemic disease remission, with best-corrected visual acuity remaining at 20/20 OU.

Conclusions and Relevance  We report what is, to our knowledge, the first case of MAR treated with intravitreal slow-release corticosteroid implants, which shows improvements in visual symptoms, visual fields, and retinal function. Sustained-release intraocular steroid implants may offer an effective and safe alternative to systemic immunosuppression in MAR, although results from 1 case should be generalized with abundant caution.

Hot Topics: YouTube Misinforms About Prostate Cancer

jackiewe Hot Topics in Research, Oncology

Dissemination of Misinformative and Biased Information about Prostate Cancer on YouTube
Loeb S, Sengupta S, Butaney M, et al. Dissemination of misinformative and biased information about prostate cancer on YouTube. Eur Urol. https://doi.org/10.1016/j.eururo.2018.10.056.
YouTube is a social media platform with more than 1 billion users and >600 000 videos about prostate cancer. Two small studies examined the quality of prostate cancer videos on YouTube, but did not use validated instruments, examine user interactions, or characterize the spread of misinformation. We performed the largest, most comprehensive examination of prostate cancer information on YouTube to date, including the first 150 videos on screening and treatment. We used the validated DISCERN quality criteria for consumer health information and the Patient Education Materials Assessment Tool, and compared results for user engagement. The videos in our sample had up to 1.3 million views (average 45 223) and the overall quality of information was moderate. More videos described benefits (75%) than harms (53%), and only 50% promoted shared decision-making as recommended in current guidelines. Only 54% of the videos defined medical terms and few provided summaries or references. There was a significant negative correlation between scientific quality and viewer engagement (views/month p = 0.004; thumbs up/views p = 0.015). The comments section underneath some videos contained advertising and peer-to-peer medical advice. A total of 115 videos (77%) contained potentially misinformative and/or biased content within the video or comments section, with a total reach of >6 million viewers.
Patient summary
Many popular YouTube videos about prostate cancer contained biased or poor-quality information. A greater number of views and thumbs up on YouTube does not mean that the information is trustworthy.

Hot Topics: Health-Related Quality of Life Not Sufficiently Measured in Oncology Studies

jackiewe Hot Topics in Research, Oncology, Research and Scholarly Communication

Evaluating Progression-Free Survival as a Surrogate Outcome for Health-Related Quality of Life in Oncology: A Systematic Review and Quantitative Analysis
Kovic B, Jin X, Kennedy S, et al. Evaluating progression-free survival as a surrogate outcome for health-related quality of life in oncology: A systematic review and quantitative analysis. JAMA Internal Medicine. 2018. http://doi.org/10.1001/jamainternmed.2018.4710.
Importance  Progression-free survival (PFS) has become a commonly used outcome to assess the efficacy of new cancer drugs. However, it is not clear if delay in progression leads to improved quality of life with or without overall survival benefit.
Objective  To evaluate the association between PFS and health-related quality of life (HRQoL) in oncology through a systematic review and quantitative analysis of published randomized clinical trials. Eligible trials addressed oral, intravenous, intraperitoneal, or intrapleural chemotherapy or biological treatments, and reported PFS or health-related quality of life.
Data Sources  For this systematic review and quantitative analysis of randomized clinical trials of patients with cancer, we searched Medline, Embase, and the Cochrane Central Register of Controlled Trials from January 1, 2000, through May 4, 2016.
Study Selection  Paired reviewers independently screened citations, extracted data, and assessed risk of bias of included studies.
Data Extraction and Synthesis  We examined the association of difference in median PFS duration (in months) between treatment groups with difference in global, physical, and emotional HRQoL scores between groups (standardized to a range of 0-100, with higher scores representing better HRQoL) using weighted simple regressions.
Main Outcome and Measure  The association between PFS duration and HRQoL.
Results  Of 35 960 records screened, 52 articles reporting on 38 randomized clinical trials involving 13 979 patients across 12 cancer types using 6 different HRQoL instruments were included. The mean (SD) difference in median PFS between the intervention and the control arms was 1.91 (3.35) months. The mean (SD) differences in change of HRQoL adjusted to per-month values were −0.39 (3.59) for the global domain, 0.26 (5.56) for the physical domain, and 1.08 (3.49) for the emotional domain. The slope of the association between the difference in median PFS and the difference in change for global HRQoL (n = 30 trials) was 0.12 (95% CI, −0.27 to 0.52); for physical HRQoL (n = 20 trials) it was −0.20 (95% CI, −0.62 to 0.23); and for emotional HRQoL (n = 13 trials) it was 0.78 (95% CI, −0.05 to 1.60).
Conclusions and Relevance  We failed to find a significant association between PFS and HRQoL in cancer clinical trials. These findings raise questions regarding the assumption that interventions prolonging PFS also improve HRQoL in patients with cancer. Therefore, to ensure that patients are truly obtaining important benefit from cancer therapies, clinical trial investigators should measure HRQoL directly and accurately, ensuring adequate duration and follow-up.

Hot Topics: Nuclear Medicine Imaging Targets Cancer

jackiewe Hot Topics in Research, Oncology, Radiology

A Tumor-Imaging Method Targeting Cancer-Associated Fibroblasts
Loktev A, Lindner T, Mier W, et al. A tumor-imaging method targeting cancer-associated fibroblasts. Journal of Nuclear Medicine. 2018;59(9):1423-1429. http://dx.doi.org/10.2967/jnumed.118.210435.
The tumor stroma, which accounts for a large part of the tumor mass, represents an attractive target for the delivery of diagnostic and therapeutic compounds. Here, the focus is notably on a subpopulation of stromal cells, known as cancer-associated fibroblasts, which are present in more than 90% of epithelial carcinomas, including pancreatic, colon, and breast cancer. Cancer-associated fibroblasts feature high expression of fibroblast activation protein (FAP), which is not detectable in adult normal tissue but is associated with a poor prognosis in cancer patients. Methods: We developed an iodinated and a DOTA-coupled radiotracer based on a FAP-specific enzyme inhibitor (FAPI) and evaluated them in vitro using uptake, competition, and efflux studies as well as confocal microscopy of a fluorescence-labeled variant. Furthermore, we performed imaging and biodistribution studies on tumor-bearing animals. Finally, proof of concept was realized by imaging patients with 68Ga-labeled FAPI. Results: Both FAPIs showed high specificity, affinity, and rapid internalization into FAP-expressing cells in vitro and in vivo. Biodistribution studies on tumor-bearing mice and on the first cancer patients demonstrated high intratumoral uptake of the tracer and fast body clearance, resulting in high-contrast images and negligible exposure of healthy tissue to radiation. A comparison with the commonly used radiotracer 18F-FDG in a patient with locally advanced lung adenocarcinoma revealed that the new FAP ligand was clearly superior. Conclusion: Radiolabeled FAPIs allow fast imaging with very high contrast in tumors having a high stromal content and may therefore serve as pantumor agents. Coupling of these molecules to DOTA or other chelators allows labeling not only with 68Ga but also with therapeutic isotopes such as 177Lu or 90Y.

Hot Topics: Childhood Cancer Tumor Pathway Discovered Through Zebrafish

jackiewe Hot Topics in Research, Oncology, Pediatrics

PAX3-FOXO1 transgenic zebrafish models identify HES3 as a mediator of rhabdomyosarcoma tumorigenesis
Kendall GC, Watson S, Xu L, et al. PAX3-FOXO1 transgenic zebrafish models identify HES3 as a mediator of rhabdomyosarcoma tumorigenesis. eLife. 2018;7:e33800. https://doi.org/10.7554/eLife.33800.
Alveolar rhabdomyosarcoma is a pediatric soft-tissue sarcoma caused by PAX3/7-FOXO1fusion oncogenes and is characterized by impaired skeletal muscle development. We developed human PAX3-FOXO1 -driven zebrafish models of tumorigenesis and found that PAX3-FOXO1 exhibits discrete cell lineage susceptibility and transformation. Tumors developed by 1.6–19 months and were primitive neuroectodermal tumors or rhabdomyosarcoma. We applied this PAX3-FOXO1 transgenic zebrafish model to study how PAX3-FOXO1 leverages early developmental pathways for oncogenesis and found that her3 is a unique target. Ectopic expression of the her3 human ortholog, HES3, inhibits myogenesis in zebrafish and mammalian cells, recapitulating the arrested muscle development characteristic of rhabdomyosarcoma. In patients, HES3 is overexpressed in fusion-positive versus fusion-negative tumors. Finally, HES3 overexpression is associated with reduced survival in patients in the context of the fusion. Our novel zebrafish rhabdomyosarcoma model identifies a new PAX3-FOXO1 target, her3/HES3, that contributes to impaired myogenic differentiation and has prognostic significance in human disease.

Hot Topics: Animal Model May Show How to Reduce Chemotherapy Pain

jackiewe Hot Topics in Research, Oncology, Pharmaceutical Sciences

Chemotherapy-induced pain is promoted by enhanced spinal adenosine kinase levels through astrocyte-dependent mechanisms
Wahlman C, Doyle TM, Little JW, et al. Chemotherapy-induced pain is promoted by enhanced spinal adenosine kinase levels through astrocyte-dependent mechanisms. Pain. doi: 10.1097/j.pain.0000000000001177
Development of chemotherapy-induced neuropathic pain (CINP) compromises the use of chemotherapy and greatly impacts thousands of lives. Unfortunately, there are no Food and Drug Administration–approved drugs to prevent or treat CINP. Neuropathological changes within CNS, including neuroinflammation and increased neuronal excitability, are driven by alterations in neuro-glia communication; but, the molecular signaling pathways remain largely unexplored. Adenosine is a potent neuroprotective purine nucleoside released to counteract the consequences of these neuropathological changes. Adenosine signaling at its adenosine receptors (ARs) is dictated by adenosine kinase (ADK) in astrocytes, which provides a cellular sink for the removal of extracellular adenosine. We now demonstrate that chemotherapy (oxaliplatin) in rodents caused ADK overexpression in reactive astrocytes and reduced adenosine signaling at the A3AR subtype (A3AR) within the spinal cord. Dysregulation of ADK and A3AR signaling was associated with increased proinflammatory and neuroexcitatory interleukin-1β expression and activation of nucleotide-binding oligomerization domain-like receptor protein 3 inflammasome, but not putative oxaliplatin-associated GSK3β transcriptional regulation. Intrathecal administration of the highly selective A3AR agonist MRS5698 attenuated IL-1β production and increased the expression of potent anti-inflammatory and neuroprotective IL-10. The effects of MRS5698 were blocked by attenuating IL-10 signaling in rats with intrathecal neutralizing IL-10 antibody and in IL-10−/− knockout mice. These findings provide new molecular insights implicating astrocyte-based ADK-adenosine axis and nucleotide-binding oligomerization domain-like receptor protein 3 in the development of CINP and IL-10 in the mechanism of action of A3AR agonists. These findings strengthen the pharmacological rationale for clinical evaluation of A3AR agonists already in advanced clinical trials as anticancer agents as an adjunct to chemotherapy.

Hot Topics: Mass Spectroscopy “Cancer Pen” Could Quickly Detect Tumors

jackiewe Hot Topics in Research, Oncology, Uncategorized

Nondestructive tissue analysis for ex vivo and in vivo cancer diagnosis using a handheld mass spectrometry system
Zhang J, Rector J, Lin JQ, et al. Nondestructive tissue analysis for ex vivo and in vivo cancer diagnosis using a handheld mass spectrometry system. Science Translational Medicine. 2017;9(406). http://dx.doi.org/10.1126/scitranslmed.aan3968
Conventional methods for histopathologic tissue diagnosis are labor- and time-intensive and can delay decision-making during diagnostic and therapeutic procedures. We report the development of an automated and biocompatible handheld mass spectrometry device for rapid and nondestructive diagnosis of human cancer tissues. The device, named MasSpec Pen, enables controlled and automated delivery of a discrete water droplet to a tissue surface for efficient extraction of biomolecules. We used the MasSpec Pen for ex vivo molecular analysis of 20 human cancer thin tissue sections and 253 human patient tissue samples including normal and cancerous tissues from breast, lung, thyroid, and ovary. The mass spectra obtained presented rich molecular profiles characterized by a variety of potential cancer biomarkers identified as metabolites, lipids, and proteins. Statistical classifiers built from the histologically validated molecular database allowed cancer prediction with high sensitivity (96.4%), specificity (96.2%), and overall accuracy (96.3%), as well as prediction of benign and malignant thyroid tumors and different histologic subtypes of lung cancer. Notably, our classifier allowed accurate diagnosis of cancer in marginal tumor regions presenting mixed histologic composition. Last, we demonstrate that the MasSpec Pen is suited for in vivo cancer diagnosis during surgery performed in tumor-bearing mouse models, without causing any observable tissue harm or stress to the animal. Our results provide evidence that the MasSpec Pen could potentially be used as a clinical and intraoperative technology for ex vivo and in vivo cancer diagnosis.