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1.
Oral Oncol. 2019 Dec 11;101:104492. doi: 10.1016/j.oraloncology.2019.104492. [Epub ahead of print]

Management of recurrent and metastatic oral cavity cancer: Raising the bar a step higher.

Author information

1
Medical Oncology, Department of Oncology, Lausanne University Hospital (CHUV), Lausanne, Switzerland.
2
Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium; Department of Medical Oncology, Antwerp University Hospital, Edegem, Belgium. Electronic address: JanB.Vermorken@uza.be.

Abstract

In recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M-SCCHN), the armamentarium of systemic anti-cancer modalities continues to grow in parallel with innovations in and better integration of local approaches. The backbone of cytotoxic chemotherapy remains cisplatin with 5-fluorouracil or a taxane. In contrast to cisplatin, the tumoricidal activity of carboplatin monotherapy is debatable. Adding the epidermal growth factor receptor (EGFR) inhibitor cetuximab to a platinum/5-fluorouracil doublet (the so-called EXTREME regimen) produced a statistically but also clinically significant improvement of survival and became thus the standard first-line palliative treatment in adequately fit patients. Interestingly, three large randomized trials (EXTREME, SPECTRUM, and ZALUTE) evaluating different anti-EGFR monoclonal antibodies (cetuximab, panitumumab, and zalutumumab, respectively) demonstrated preferential anti-tumour efficacy in patients with primary cancer in the oral cavity. Modern immunotherapy with immunomodulating antibodies, dubbed immune checkpoint inhibitors, such as anti-programmed cell death protein-1 (anti-PD-1) inhibitors nivolumab and pembrolizumab, showed unprecedented activity in one first-line (KEYNOTE-048) and several second-line trials (CheckMate-141, KEYNOTE-012, KEYNOTE-055, and KEYNOTE-040). In a minority of also heavily-pretreated patients, these agents generate long-lasting responses without the typical chemotherapy-related toxicity, however, at a price of a low overall response rate, rare but potentially life-threatening immune-related adverse events, the risk of hyperprogression, and high costs. In oligometastatic disease, emerging data indicate long-term benefit with locally ablative techniques including metastasectomy and stereotactic radiotherapy of pulmonary but also hepatic and other distant lesions. In the frame of highly-individualized cancer care, a particularly intriguing approach is a combination of systemic and local therapies.

KEYWORDS:

Bevacizumab; Buparlisib; Cetuximab; Cisplatin; Epidermal growth factor receptor; Head and neck cancer; Immunotherapy; PI3K/AKT/mTOR pathway; Predictive biomarker; Vascular endothelial growth factor

2.
J Mol Diagn. 2019 Dec 11. pii: S1525-1578(19)30439-8. doi: 10.1016/j.jmoldx.2019.09.009. [Epub ahead of print]

Development and Analytical Validation of a DNA Dual-Strand Approach for the FDA-Approved Next-Generation Sequencing-Based Praxis Extended RAS Panel for Metastatic Colorectal Cancer Samples.

Author information

1
Department of Clinical Genomics Assay Development and Oncology.
2
Department of Clinical Genomics Assay Development and Oncology. Electronic address: aiyer@illumina.com.
3
Department of Biostatistics, Bioinformatics.
4
Department of Medical Affairs.
5
Department of Illumina, Inc., San Diego, California.

Abstract

A next-generation sequencing method was developed that can distinguish single-stranded modifications from low-frequency somatic mutations present on both strands of DNA in formalin-fixed paraffin-embedded (FFPE) colorectal cancer (CRC) samples. We applied this method for analytical validation of the Praxis Extended RAS Panel, a United States Food and Drug Administration (FDA)-approved companion diagnostic for panitumumab, on the Illumina MiSeqDx platform. Using the TruSeq amplicon workflow, both strands of DNA from the starting material were interrogated independently. Mutations were reported only if found on both strands; artifacts usually present on only one strand would not be reported. A total of 56 mutations were targeted within the KRAS and NRAS genes. A minimum read depth of 1800x per amplicon is required per sample, but averaged >30,000x at maximum multiplexing levels. Analytical validation studies were performed to determine the simultaneous detection of mutations on both strands, reproducibility, assay detection level, precision of the assay across various factors, and the impact of interfering substances. In conclusion, this assay can clearly distinguish single-stranded artifacts from low frequency mutations. Furthermore, the assay is accurate, precise, and reproducible, can achieve consistent detection of a mutation at 5% mutation frequency, exhibits minimal impact from tested interfering substances, and can simultaneously detect 56 mutations in a single run using 10 samples, plus controls.

3.
J Mol Diagn. 2019 Dec 11. pii: S1525-1578(19)30433-7. doi: 10.1016/j.jmoldx.2019.10.008. [Epub ahead of print]

Therapeutic Monitoring of Circulating DNA Mutations in Metastatic Cancer with Personalized Digital PCR.

Author information

1
Division of Oncology, Department of Medicine, Stanford University School of Medicine, Stanford, California.
2
Intermountain Healthcare, St. George,Utah.
3
Intermountain Healthcare, St. George,Utah. Electronic address: lincoln.nadauld@imail.org.
4
Division of Oncology, Department of Medicine, Stanford University School of Medicine, Stanford, California; Stanford Genome Technology Center, Stanford University, Palo Alto, California. Electronic address: genomics_ji@stanford.edu.

Abstract

As a high-performance solution for longitudinal monitoring of patients being treated for metastatic cancer, we developed and a single-color digital PCR (dPCR) assay that detects and quantifies specific cancer mutations present in circulating tumor DNA (ctDNA). This customizable assay has a high sensitivity of detection. One can detect a mutation allelic fraction of 0.1%, equivalent to three mutation-bearing DNA molecules among 3,000 genome equivalents. The objective of this study was to validate the use of personalized dPCR mutation assays to monitor patients with metastatic cancer. We compared our digital PCR results to serum biomarkers indicating disease progression or response. Patients had metastatic colorectal, biliary, breast, lung and melanoma cancers. Mutations occurred in essential cancer drivers such as BRAF, KRAS and PIK3CA. We monitored patients over multiple cycles of treatment up to a year. All patients had detectable ctDNA mutations. Our results correlated with serum markers of metastatic cancer burden including CEA, CA-19-9, and CA-15-3, and qualitatively corresponding to imaging studies. We observed corresponding trends among these patients receiving active treatment with chemotherapy or targeted agents. For example, in one patient under active treatment, we detected increasing quantities of ctDNA molecules over time, indicating recurrence of tumor. Our study demonstrates that personalized digital PCR enables longitudinal monitoring of patients with metastatic cancer and maybe a useful indicator for treatment response.

4.
J Cardiovasc Comput Tomogr. 2019 Dec 7. pii: S1934-5925(19)30614-8. doi: 10.1016/j.jcct.2019.12.005. [Epub ahead of print]

Left atrial tumor thrombus in metastatic thyroid cancer.

Author information

1
Royal Berkshire Hospital, Royal Berkshire NHS Foundation Trust, Reading, RG1 5AN, England, United Kingdom. Electronic address: mcks@fastmail.com.
2
Royal Berkshire Hospital, Royal Berkshire NHS Foundation Trust, Reading, RG1 5AN, England, United Kingdom.

KEYWORDS:

Cardiac CT; Left atrium; Metastasis; Thyroid cancer; Tumor thrombus

5.
J Med Econ. 2019 Dec 13:1. doi: 10.1080/13696998.2019.1705313. [Epub ahead of print]

Real-world incidence and burden of adverse events among non-metastatic prostate cancer patients treated with secondary hormonal therapies following androgen deprivation therapy.

Author information

1
Pharmerit International, Bethesda, MD, USA.
2
Bayer Healthcare Pharmaceuticals, Whippany, NJ, USA.
3
University of Maryland Greenebaum Comprehensive Cancer Center, Baltimore, MD, USA.
4
Baltimore VA Medical Center, Baltimore, MD, USA.

Abstract

Aims-To describe the incidence and identify prognostic factors of central nervous system (CNS) adverse events (AEs) and any AEs (CNS, skin rash, or fractures) and evaluate the healthcare resource utilization (HCRU), direct medical costs, and therapy discontinuation associated with these AEs among non-metastatic prostate cancer (nmPC) patients who received secondary hormone therapies.Methods and Results-nmPC patients who had initiated secondary hormonal therapy with enzalutamide, bicalutamide, or abiraterone ≥1 year after androgen deprivation therapy (ADT) were identified in the MarketScan database. Survival analyses were used to describe the incidence of CNS or any AEs. Annual HCRU and costs were compared across patient groups (CNS AE versus no CNS AE; any AE versus no AE) using propensity score weighted generalized linear models. Multivariate Cox proportional hazards models were used to identify AE predictors and compare risks of discontinuation.The analysis included 532 patients who initiated secondary hormonal therapies, among whom 201 (38%) and 244 (46%) experienced a CNS AE and any AE, respectively. Median times to CNS AE and any AE from therapy initiation were 17.90 and 11.00 months, respectively. Predictors of any AE were any AE in the baseline period (≤6 months before starting therapy), Charlson Comorbidity Index (CCI) score (1 vs 0), surgical castration, and older age. Predictors of CNS AEs were CNS AE in the baseline period and CCI score (1 vs 0). CNS and any AEs were associated with significantly higher HCRU. CNS AEs were associated with significantly higher incremental total medical costs ($18,522). CNS AEs and any AEs significantly increased therapy discontinuation risk by 48% and 38%, respectively.Conclusions-AEs increase the economic burden and therapy discontinuation among nmPC patients receiving secondary hormonal therapies subsequent to ADTs. These patients should be carefully evaluated for AEs to reduce therapy discontinuation, HCRU, and direct medical costs.

KEYWORDS:

C14; Enzalutamide; I10; abiraterone acetate; advanced prostate cancer; adverse events; bicalutamide; discontinuation; healthcare costs

6.
PLoS One. 2019 Dec 13;14(12):e0226356. doi: 10.1371/journal.pone.0226356. eCollection 2019.

MicroRNA-710 regulates multiple pathways of carcinogenesis in murine metastatic breast cancer.

Author information

1
MGH/MIT/HMS Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States of America.
2
College of Arts and Science, New York University, NY, United States of America.
3
Department of Health Sciences, CaNCURE Program, Northeastern University, Boston, MA.

Abstract

Prior research has shown that critical differences between non-metastatic and metastatic tumor cells are at the level of microRNA. Consequently, harnessing these molecules for the treatment of metastatic cancer could have significant clinical impact. In the present study, we set out to identify metastasis-specific microRNAs which drive metastatic colonization of distant organs. Using a murine model of metastatic breast cancer, we employed a directed approach in which we screened for microRNAs that are differentially expressed between the primary tumors and metastatic lesions but concordantly expressed in all of the metastatic lesions irrespective of the tissue that is colonized. Of the identified targets, we focused on miR-710, which was consistently and significantly downregulated in the metastatic lesions relative to the primary tumors. The level of downregulation was independent of the distant organ that is involved, suggesting that miR-710 plays a fundamental role in metastatic colonization. Computational target prediction suggested a pleiotropic role for miR-710 in apoptosis, migration and invasion, and stemness. Using a previously validated oligonucleotide delivery system, we introduced miR-710 mimics into 4T1 metastatic breast adenocarcinoma cells and assessed the resultant phenotypic effects. We demonstrated significant inhibition of cell viability, migration, and invasion. We also showed that the treatment profoundly enhanced cell senescence, reduced stemness, and influenced markers of epithelial to mesenchymal transition, as evidenced by enhanced E-cadherin and reduced vimentin expression. This knowledge represents a first step towards harnessing a similar approach to discover novel microRNA targets with therapeutic potential in metastasis.

Conflict of interest statement

Zdravka Medarova is Founder, and Scientific Advisory Board Member of TransCode Therapeutics, Inc. This does not alter her adherence to PLOS ONE policies on sharing data and materials.

7.
Int J Clin Oncol. 2019 Dec 13. doi: 10.1007/s10147-019-01599-4. [Epub ahead of print]

Prognostic significance of serum p53 antibody according to KRAS status in metastatic colorectal cancer patients.

Author information

1
Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto, 860-8556, Japan.
2
Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto, 860-8556, Japan. hdobaba@kumamoto-u.ac.jp.

Abstract

BACKGROUND:

Serum anti-p53 antibody is used clinically as a tumor marker of colorectal cancer. However, its prognostic significance in patients with metastatic colorectal cancer (mCRC) remains unclear. KRAS status may influence the host immune response against tumor progression. In the present study, we investigated the prognostic significance of serum anti-p53 in mCRC patients with wild-type KRAS and mutant KRAS treated with systemic chemotherapy.

METHODS:

A retrospective study of 150 mCRC patients in whom serum anti-p53 antibody was measured before first-line chemotherapy was conducted. The patients were divided into two groups, high p53 and low p53, based on their serum anti-p53 antibody levels. Associations between serum anti-p53 level and clinical outcomes were evaluated in conjunction with KRAS status.

RESULTS:

There were 97 (64.7%) patients with wild-type KRAS and 53 (35.3%) with mutant KRAS. In an analysis of all patients, there was no significant difference in overall survival (OS) between the high p53 and low p53 groups. In patients with mutant KRAS, those in the high p53 group exhibited significantly longer OS than those in the low p53 group (p = 0.017, log-rank test). In the multivariate analysis, serum p53 antibody level was an independent predictor of OS in mCRC patients (high vs. normal; hazard ratio 0.438, 95% confidence interval 0.178-0.974, p < 0.05).

CONCLUSIONS:

Serum anti-p53 antibody level may be an independent predictor of OS in mCRC patients with KRAS mutant tumors.

KEYWORDS:

KRAS status; Metastatic colorectal cancer; Serum anti-p53 antibody

8.
J Chin Med Assoc. 2019 Dec 12. doi: 10.1097/JCMA.0000000000000234. [Epub ahead of print]

Immunotherapy orchestrates radiotherapy in composing abscopal effects: A strategic review in metastatic head and neck cancer.

Author information

1
Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hung Hom, Hong Kong SAR, China.
2
Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan, ROC.
3
Department of Dentistry, School of Dentistry, National Yang-Ming University, Taipei, Taiwan, ROC.
4
School of Pharmaceutical Sciences, National Yang-Ming University, Taipei, Taiwan, ROC.
5
Institute of Pharmacology, National Yang-Ming University, Taipei, Taiwan, ROC.

Abstract

The treatment of metastatic head and neck squamous cell carcinoma (HNSCC) with a combination of radiotherapy (RT) and immunotherapy can augment treatment response and symptomatic relief. Combination therapy can also trigger a non-targeted tumor control event called the abscopal effect. This effect can be demonstrated by treatment with anti- programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) and anti- cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) antibodies in combination with hypofractionated RT. Individual studies and clinical trials have revealed that combination radio-immunotherapy improves overall treatment response by successful initiation of the abscopal effect, which extends the treatment effects to non-targeted lesions. Growing attention to the abscopal effect may inspire innovations in current radiotherapy toward more effective and less toxic radiobiological treatment modalities for advanced HNSCC. We review the latest findings on the abscopal effect with emphases on therapeutic modalities and potential applications for treating metastatic HNSCC.

9.
Clin Nucl Med. 2019 Dec 9. doi: 10.1097/RLU.0000000000002859. [Epub ahead of print]

68Ga-ZHER2 PET/CT Reveals HER2-Positive Metastatic Gastric Cancer With Better Image Quality Than 18F-FDG.

Author information

1
Jiangsu Institute of Atomic Medicine, Wuxi, China.

Abstract

A 40-year-old woman with suspected recurrent HER2-positive gastric cancer underwent both F-FDG PET/CT and Ga-ZHER2 PET/CT. Both scans revealed multiple lesions in bones and the left supraclavicular lymph node. Compared with F-FDG, Ga-ZHER2 PET/CT showed better image contrast, especially in the bone lesions.

10.
Int J Gynaecol Obstet. 2019 Dec 12. doi: 10.1002/ijgo.13084. [Epub ahead of print]

Prognostic value of distant metastatic sites in stage IV endometrial cancer: A SEER database study of 2948 women.

Author information

1
Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.

Abstract

OBJECTIVE:

To evaluate the prognosis of women with distant metastasis at the time of endometrial cancer (EC) diagnosis and identify prognostic factors according to metastatic site.

METHODS:

A retrospective cohort study of women diagnosed with EC according to the SEER database between 2010 and 2014. Univariate and multivariate Cox regression was used to identify variables associated with overall survival. Kaplan-Meier curves were used to compare survival among different groups.

RESULTS:

Overall, 2948 women with stage IV EC were identified. The most common distant metastatic site was the lung. Having a distant metastatic site independently predicted overall survival. Using brain metastasis as a reference, overall survival was longer for liver (P=0.049), lung (P=0.005), and bone (P=0.019) metastasis. Relative to no distant metastasis, overall survival was shorter for women with one (P<0.001) or two or more (P<0.001) sites of distant metastasis. Overall survival was independently influenced by tumor grade, insurance status, and surgery among women with only lung metastasis.

CONCLUSION:

The findings showed that the prognosis of women with stage IV EC differs by distant metastatic site, and identified several predictors of poor survival. They may help clinicians to better predict prognosis for newly diagnosed cases of EC with distant metastasis.

KEYWORDS:

Distant metastasis; Endometrial cancer; Metastasis; Metastatic site; Prognosis; SEER; Stage IV

11.
Support Care Cancer. 2019 Dec 12. doi: 10.1007/s00520-019-05112-5. [Epub ahead of print]

Incidence of peripheral neuropathy associated with eribulin mesylate versus vinorelbine in patients with metastatic breast cancer: sub-group analysis of a randomized phase III study.

Author information

1
Department of Medical Oncology, Changzheng Hospital, Second Military Medical University, Shanghai, 200003, China.
2
Department of Neurology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
3
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
4
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China. xchu2009@hotmail.com.
5
Department of Medical Oncology, Fudan University Shanghai Cancer Center, No. 270 Dong'an Road, Shanghai, 200032, China. xchu2009@hotmail.com.

Abstract

BACKGROUND:

Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most significant neurologic complications of chemotherapy, impacting patient's behavior and quality of life. CIPN is mostly sensory, with rare incidences of autonomic dysfunction and other neuropathy.

METHODS:

We conducted a single-center sub-group analysis of patients with metastatic breast cancer enrolled in a phase III study (NCT02225470) set up to compare eribulin mesylate (1.4 mg/m2 on days 1 and 8 every 21 days) with vinorelbine (25 mg/m2 on days 1, 8, and 15 every 21 days). The analysis investigated incidence of peripheral neuropathy, time to onset of neuropathy, and safety.

RESULTS:

Our analysis included 110 women with a mean age of 50.7 (SD = 10.9). The median accumulated dose of eribulin was 11.2 mg/m2 and 125.0 mg/m2 for vinorelbine. Among patients in the eribulin group, a performance status (ECOG PS) of 2 was correlated with peripheral sensory neuropathy (p = 0.015), and accumulated eribulin dose (≥ 10 mg/m2) was associated with all neuropathy and peripheral sensory neuropathy (p = 0.003 and p = 0.007, respectively). In the vinorelbine group, patient age (≥ 65 years) was positively associated with all neuropathy (p = 0.043). The time to onset of neuropathy appeared to be longer for eribulin versus vinorelbine (35.3 vs. 34.6 weeks; p = 0.046), with a significantly higher incidence of autonomic neuropathy at weeks 2 and 10 observed among patients receiving vinorelbine (p = 0.008 and p = 0.043, respectively).

CONCLUSION:

Vinorelbine is associated with a higher incidence of autonomic neuropathy than eribulin in patients with metastatic breast cancer. Furthermore, the onset of neurotoxicity appears to occur earlier with vinorelbine than eribulin.

KEYWORDS:

Eribulin mesylate; Metastatic breast cancer; Peripheral neuropathy; Vinorelbine

12.
Rep Biochem Mol Biol. 2019 Jul;8(2):139-146.

Nutrient Deprivation Modulates the Metastatic Potential of Breast Cancer Cells.

Author information

1
School of Medicine, Shahroud University of Medical Sciences, Shahroud, Iran.
2
Cancer Prevention Research Center, Shahroud University of Medical Sciences, Shahroud, Iran.
3
Clinical Research Development Unit, Imam Hossein Hospital, Shahroud University of Medical Sciences, Shahroud, Iran.

Abstract

Background:

Breast cancer is the leading cause of cancer related death in women worldwide. The development of metastatic cancer is the main factor contributing to mortality. The molecular mechanisms underlying the metastatic process have yet to be clearly elucidated. However, the interplay between the tumor microenvironment and the cancer cells hold a critical role in influencing the progression of cancer metastasis. Within the microenvironment of solid tumors, the lack of sufficient vasculature leads to the development of nutrient deprived conditions. This study aimed to examine how nutrient deprivation influences factors involved in cancer progression and metastasis. Specifically, we examined how nutrient stress changes cancer cell migration, the gene expression, and cytokine production of metastasis-related factors in a human breast cancer cell line.

Methods:

MCF7 breast cancer cells were cultured in serum-free media for 24, 48, and 72 h. Cell migration was evaluated using a transwell migration assay. The transcriptional expression of metastatic related genes was examined via real-time PCR. Cytokine production was examined via enzyme-linked immunosorbent assay.

Results:

Nutrient deprivation of the MCF7 cells significantly reduced cell migration after 24 h. However, following 72 h of nutrient deprivation, there was significant increase in cell migration compared to the 24 h group. Transcriptional expression of markers involved in migration including, β-catenin, twist, vimentin, fibronectin, ICAM1, VCAM1, and VEGF were up regulated after 72 h of nutrient deprivation. The cytokines TGFβ1, IL-8, and MCP1 were differentially secreted.

Conclusion:

Nutrient deprivation is an environmental stress factor that can influence the behavior of cancer cells. Current treatments implement nutrient deprivation as a potential cancer treatment. Under short periods of nutrient deprivation, cancer cell migration is inhibited. However, our findings show that following extended lengths of nutrient deprivation, cancer cells are capable of adapting themselves to the environmental condition and restoring their migratory abilities. This, in part, may be a result of increased expression of metastasis-related genes. Further research is required to accurately identify how the expression of metastasis-related genes is modulated and controlled in response to nutrient deprivation and environmental stress.

KEYWORDS:

Cancer cell migration; Epithelial mesenchymal transition; Nutrient deprivation

PMID:
31832437
13.
BMJ Open. 2019 Dec 11;9(12):e031019. doi: 10.1136/bmjopen-2019-031019.

Cost-effectiveness analysis of pembrolizumab plus chemotherapy for previously untreated metastatic non-small cell lung cancer in the USA.

Zeng X1,2, Wan X2,3, Peng L2,3, Peng Y2,3, Ma F4, Liu Q2,3, Tan C5,3.

Author information

1
PET-CT Center, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China.
2
Institute of Clinical Pharmacy, Central South University, Changsha, Hunan, China.
3
Department of Pharmacy, Second Xiangya Hospital of Central South University, Changsha, Hunan, China.
4
Department of Oncology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China.
5
Institute of Clinical Pharmacy, Central South University, Changsha, Hunan, China tanchongqing@csu.edu.cn.

Abstract

OBJECTIVES:

Evaluating the cost-effectiveness of pembrolizumab plus standard chemotherapy in the first-line setting for patients with metastatic non-small cell lung cancer (NSCLC) from the US payer perspective.

DESIGN:

A Markov model was constructed to analyse the cost-effectiveness of pembrolizumab plus chemotherapy in the first-line treatment of metastatic NSCLC. Health outcomes were estimated in quality-adjusted life-years (QALYs). The cost information was from Medicare in 2018. One-way and probabilistic sensitivity analyses examined the impact of uncertainty and assumptions on the results.

SETTING:

The US payer perspective.

PARTICIPANTS:

A hypothetical US cohort of patients with previously untreated metastatic nonsquamous NSCLC without EGFR or ALK mutations.

INTERVENTIONS:

Pembrolizumab plus chemotherapy versus chemotherapy.

PRIMARY OUTCOME MEASURES:

Costs, QALYs, incremental cost-effectiveness ratio (ICER) of pembrolizumab plus chemotherapy expressed as cost per QALY gained compared with chemotherapy RESULTS: The base case analysis demonstrated that pembrolizumab plus chemotherapy provided an additional 0.78 QALYs at incremental cost of $151 409, resulting in an ICER of $194 372/QALY. ICER for pembrolizumab plus chemotherapy was >$149 680/QALY in all of our univariable and probabilistic sensitivity analyses.

CONCLUSIONS:

Pembrolizumab in addition to chemotherapy provides modest incremental benefit at high incremental cost per QALY for the treatment of previously untreated metastatic NSCLC.

KEYWORDS:

chemotherapy; health economics; immunology

Conflict of interest statement

Competing interests: None declared.

14.
BMC Cancer. 2019 Dec 12;19(1):1209. doi: 10.1186/s12885-019-6369-7.

A systematic review of lenvatinib and sorafenib for treating progressive, locally advanced or metastatic, differentiated thyroid cancer after treatment with radioactive iodine.

Author information

1
Liverpool Reviews & Implementation Group (LRiG), Department of Health Services Research, Institute of Population Health Sciences, University of Liverpool, Whelan Building, Liverpool, L69 3GB, UK. nigel.fleeman@liverpool.ac.uk.
2
Liverpool Reviews & Implementation Group (LRiG), Department of Health Services Research, Institute of Population Health Sciences, University of Liverpool, Whelan Building, Liverpool, L69 3GB, UK.
3
The Clatterbridge Cancer Centre NHS Foundation Trust, Bebington, Wirral, UK.

Abstract

BACKGROUND:

Treatment with radioactive iodine is effective for many patients with progressive, locally advanced or metastatic, differentiated thyroid cancer. However, some patients become refractory to treatment. These types of patients are considered to have radioactive iodine refractory differentiated thyroid cancer (RR-DTC).

METHODS:

We searched Embase, MEDLINE, PubMed and the Cochrane Library from January 1999 through January 2017. Reference lists of included studies and ongoing trial registries were also searched. Reports of randomized controlled trials (RCTs), prospective observational studies, and systematic reviews/indirect comparisons were eligible for inclusion. In the absence of direct clinical trial evidence comparing lenvatinib versus sorafenib, we assessed the feasibility of conducting an indirect comparison to obtain estimates of the relative efficacy and safety of these two treatments.

RESULTS:

Of 2364 citations, in total, 93 papers reporting on 2 RCTs (primary evidence), 9 observational studies and 13 evidence reviews (supporting evidence) were identified. Compared to placebo, RCT evidence demonstrated improvements with lenvatinib or sorafenib in median progression-free survival (PFS) and objective tumour response rate (ORR). Overall survival (OS) was confounded by high treatment crossover (≥75%) in both trials. Adverse events (AEs) were more common with lenvatinib or sorafenib than with placebo but the most common AEs associated with each drug differed. Primarily due to differences in the survival risk profiles of patients in the placebo arms of the RCTs, we considered it inappropriate to indirectly compare the effectiveness of lenvatinib versus sorafenib. ORR and AE findings for lenvatinib and sorafenib from the supporting evidence were broadly in line with RCT evidence. Health-related quality of life (HRQoL) data were limited.

CONCLUSIONS:

Lenvatinib and sorafenib are more efficacious than placebo (a proxy for best supportive care) for treating RR-DTC. Uncertainty surrounds the extent of the impact on OS and HRQoL. Lenvatinib could not reliably be compared with sorafenib. Choice of treatment is therefore likely to depend on an individual patient's circumstances.

KEYWORDS:

Clinical effectiveness; Lenvatinib; Sorafenib; Systematic review; Thyroid cancer; Tyrosine kinase inhibitor

15.
JAMA Oncol. 2019 Dec 12. doi: 10.1001/jamaoncol.2019.4636. [Epub ahead of print]

Association Between New Unconfirmed Bone Lesions and Outcomes in Men With Metastatic Castration-Resistant Prostate Cancer Treated With Enzalutamide: Secondary Analysis of the PREVAIL and AFFIRM Randomized Clinical Trials.

Author information

1
Division of Medical Oncology and Urology, Duke Cancer Institute Center for Prostate and Urologic Cancers, Duke University, Durham, North Carolina.
2
Biostatistics, Pfizer Inc, Cambridge, Massachusetts.
3
Biostatistics, Pfizer Inc, San Francisco, California.
4
Clinical Development, Pfizer Inc, San Francisco, California.
5
Biostatistics, Astellas Pharma Inc, Northbrook, Illinois.
6
Clinical Development, Astellas Pharma Inc, Northbrook, Illinois.
7
Division of Urology, Cliniques Universitaires Saint-Luc, Brussels, Belgium.
8
Medical Oncology, Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, New York.
9
Division of Clinical Studies, The Institute of Cancer Research, The Royal Marsden National Health Service Foundation Trust, London, United Kingdom.
10
Genitourinary Oncology Service, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, New York.
11
Division of Hematology/Medical Oncology, OHSU Knight Cancer Institute, Oregon Health & Science University, Portland.

Abstract

Importance:

For men with metastatic castration-resistant prostate cancer (mCRPC) whose condition is responding to enzalutamide, new unconfirmed bone lesions detected at posttreatment scinitigraphy may reflect an osteoblastic reaction that represents healing, known as pseudoprogression, which can lead to premature discontinuation of therapy.

Objective:

To determine the association between new unconfirmed lesions detected on a follow-up bone scintigram (bone scan) and outcomes in enzalutamide-treated men with mCRPC.

Design, Setting, and Participants:

This post hoc, retrospective secondary analysis of 1672 enzalutamide-treated men from 2 phase 3, randomized mCRPC studies (PREVAIL and AFFIRM) before or after treatment with docetaxel was conducted from April 12, 2018, to July 25, 2019. Participants were men from the enzalutamide groups of the 2 studies with a decrease in prostate-specific antigen level at any time or with stable disease or soft-tissue disease responding to treatment based onradiologic findings.

Intervention:

Enzalutamide, 160 mg once daily.

Main Outcomes and Measures:

The clinical significance of new lesions detected on the first (early) or second (late) posttreatment bone scan, without an unfavorable change in prostate-specific antigen level or soft-tissue progression, was investigated. Associations of new unconfirmed lesions with radiographic progression-free survival, overall survival, decrease in prostate-specific antigen level, objective response in soft tissue, and quality of life were evaluated.

Results:

Among the 643 men (median age, 72 years [range, 43-93 years]) in PREVAIL, early and late unconfirmed lesions were observed in 177 men (27.5%) with stable disease or disease responding to enzalutamide. Among the 404 men (median age, 70 years [range, 41-88 years]) in AFFIRM, early and late unconfirmed lesions were observed in 73 men (18.1%) with stable disease or disease responding to enzalutamide. In PREVAIL, men with new unconfirmed lesions had median radiographic progression-free survival (hazard ratio [HR], 1.37 [95% CI, 0.81-2.30]; P = .23) and median overall survival (HR, 1.25 [95% CI, 0.85-1.83]) in the chemotherapy-naive setting similar to men those of men without such new lesions. In AFFIRM, the median overall survival (HR, 1.94 [95% CI, 1.10-3.44]) was reduced among men with unconfirmed bone lesions, but the median radiographic progression-free survival was not reduced (HR, 1.21 [95% CI, 0.83-1.75]; P = .32). Quality of life over time was similar regardless of the presence of new unconfirmed lesions detected on a follow-up bone scan in either setting.

Conclusions and Relevance:

These results suggest that new unconfirmed lesions detected on follow-up bone scans may represent pseudoprogression in men with mCRPC and are indicative of a favorable treatment response to enzalutamide. The detection of new unconfirmed bone lesions in men with mCRPC that responded to treatment with enzalutamide after docetaxel appears to be associated with worse overall survival and may represent true progression, thus highlighting the need for improved functional bone metastasis imaging.

Trial Registration:

ClinicalTrials.gov identifier: NCT01212991 and NCT00974311.

16.
PLoS One. 2019 Dec 12;14(12):e0225938. doi: 10.1371/journal.pone.0225938. eCollection 2019.

Comprehensive value assessment of drugs using a multi-criteria decision analysis: An example of targeted therapies for metastatic colorectal cancer treatment.

Author information

1
School of Pharmacy and Institute of Clinical Pharmacy and Pharmaceutical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
2
Department of Pharmacy, National Cheng Kung University Hospital, Tainan, Taiwan.
3
Department of Internal Medicine, National Cheng Kung University Hospital, Tainan, Taiwan.
4
Department of Internal Medicine, Tainan Municipal Hospital, Tainan, Taiwan.

Abstract

OBJECTIVE:

This study is aimed toward establishing a decision-making model with multiple criteria for appraisal and reimbursement to compare the attitudes of different stakeholders toward various dimensions and criteria and to evaluate the five targeted therapies (bevacizumab, cetuximab, panitumumab, aflibercept, and regorafenib) for metastatic colorectal cancer.

METHOD:

This study is a multi-criteria decision analysis (MCDA) using a model that includes three dimensions and nine criteria. Both the overall and individual scores of the respective targeted therapies in different dimensions and criteria were calculated. A sensitivity analysis was carried out in order to evaluate the robustness of the research results. An interview-based questionnaire survey was applied to obtain the performance information for the targeted therapies and the weights of the dimensions and criteria.

RESULTS:

Overall, the clinical dimension had the highest weight, followed by the economic dimension, and finally, the social dimension. In the clinical dimension, the "comparative efficacy" criterion had the highest weight; in the economic dimension, the "cost-effectiveness" criterion" was given the greatest importance; in the social dimension, the "social concern and patient needs" criterion was given more emphasis. The overall values ranked from high to low as follows: cetuximab (overall score 3.3666), bevacizumab (3.3043), panitumumab (3.2030), aflibercept (2.8923) and regorafenib (2.8366).

CONCLUSIONS:

A comprehensive value assessment system combining "multi-dimensional criteria," "multi-perspectives," and an "integrative assessment" is necessary to evaluate the value of medicines. The results showed not only the order of weights of different dimensions or criteria, but also the rankings of the value of the targeted therapies.

Conflict of interest statement

The authors have declared that no competing interests exist.

17.
Endocrinol Diabetes Metab Case Rep. 2019 Dec 12;2019. pii: EDM190063. doi: 10.1530/EDM-19-0063. [Epub ahead of print]

Denosumab-induced hypocalcaemia in metastatic castrate-resistant prostate cancer.

Author information

1
Barwon Health, Geelong University Hospital, Geelong, Victoria, Australia.

Abstract

Summary:

Denosumab is a fully human MAB that acts as a potent anti-resorptive by inhibiting activation of osteoclasts by inhibiting the receptor activator of nuclear factor-kappa B (RANK) ligand. Hypocalcaemia has been reported as one of the serious adverse sequelae of use of denosumab. We present a case of refractory hypocalcaemia following administration of a single dose of denosumab in a patient with metastatic castrate-resistant prostate cancer. The patient's serum calcium and vitamin D concentrations and renal function were normal prior to denosumab administration. Serum alkaline phosphatase (ALP) level was however elevated pre-morbidly consistent with known bone metastases. The patient was treated with high-dose oral and IV calcium without any appreciable response in serum calcium. During his 30-day hospital admission, he demonstrated disease progression with development of new liver metastases and bone marrow involvement. Normocalcaemia was not achieved despite 1 month of aggressive therapy. Given the patient was asymptomatic and prognosis guarded, he was eventually discharged for ongoing supportive care under the palliative care team.

Learning points:

Denosumab is a potent anti-resorptive therapy and hypocalcaemia is one of the known adverse effects. Serum calcium and vitamin D concentrations must be replete prior to administration of denosumab to reduce the risk of hypocalcaemia. Denosumab has been proven to be more effective than zoledronic acid in preventing skeletal-related adverse effects in patients with metastatic castrate-resistant prostate cancer.

KEYWORDS:

2019; Adenocarcinoma; Adult; Albumin; Alkaline phosphatase; Australia; Bone; C-telopeptide ; Calcitriol; Calcium (serum); Calcium (urine); Calcium carbonate; Calcium citrate*; Calcium gluconate; Cholecalciferol; Cramps; December; Denosumab; Dexamethasone; Fatigue; Hydrochlorothiazide; Hypocalcaemia; Iatrogenic disorder; Liver function; Magnesium; Male; Oncology; PTH; Pancytopaenia; Paraesthesia; Phosphate (serum); Pro-collagen 1*; Prostate cancer; Unique/unexpected symptoms or presentations of a disease; White

18.
Expert Rev Respir Med. 2019 Dec 12:1-12. doi: 10.1080/17476348.2020.1701439. [Epub ahead of print]

Atezolizumab in combination with bevacizumab, paclitaxel and carboplatin for the first-line treatment of patients with metastatic non-squamous non-small cell lung cancer, including patients with EGFR mutations.

Author information

1
Lung Clinic Grosshansdorf, Airway Research Center North, German Center for Lung Research, Grosshansdorf, Germany.
2
Product Development Oncology, Genentech Inc, South San Francisco, CA, USA.
3
Thoracic Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
4
Thoracic Oncology Program, AdventHealth Cancer Institute, Orlando, FL, USA.

Abstract

Introduction: Cancer immunotherapy has revolutionized the treatment of patients with advanced or metastatic non-small cell lung cancer (NSCLC). However, specific patient groups (e.g. patients with activating epidermal growth factor receptor [EGFR] mutations) do not appear to derive benefit from immune checkpoint inhibitor (ICI) monotherapy. Combining ICIs, such as atezolizumab, with chemotherapy and/or targeted therapies may help to address this unmet need.Areas covered: Atezolizumab is an anti-programmed death-ligand 1 therapy for several tumor types. We review its clinical efficacy and safety in the treatment of advanced or metastatic NSCLC, with a specific focus on the combination of atezolizumab with bevacizumab, carboplatin, and paclitaxel (ABCP). Data from IMpower150 show that the ABCP regimen provided clinical benefit to patients with non-squamous NSCLC, including those with EGFR mutations.Expert opinion: Combining ICIs with chemotherapy has proven to be superior to chemotherapy alone. However, tumor resistance to ICIs will likely increase as these drugs enter earlier lines of therapy, underscoring a need for effective treatments when immunotherapy fails. Data suggest that the ABCP regimen may circumvent ICI resistance mechanisms. Continued investigation into the regimen's mechanisms, improved patient profiling/selection, and treatment personalization will drive further development/discoveries.

KEYWORDS:

Atezolizumab; bevacizumab

19.
J Immunother Cancer. 2019 Dec 11;7(1):347. doi: 10.1186/s40425-019-0825-4.

Chemotherapy accelerates immune-senescence and functional impairments of Vδ2pos T cells in elderly patients affected by liver metastatic colorectal cancer.

Author information

1
Unit of Clinical and Experimental Immunology, Humanitas Clinical and Research Center - IRCCS, Via Alessandro Manzoni, 56, Rozzano, Milan, Italy.
2
Department of Medical Biotechnologies and Translational Medicine (BioMeTra), University of Milan, Milan, Italy.
3
Department of Hepatobiliary and General Surgery, Humanitas University, Humanitas Clinical and Research Center - IRCCS, Rozzano, Milan, Italy.
4
Central Laboratory for Advanced Diagnosis and Biomedical Research, Palermo, Italy.
5
Department of Biomedicine, Neurosciences and Advances Diagnostics (Bi.N.D.), University of Palermo, Palermo, Italy.
6
Unit of Clinical and Experimental Immunology, Humanitas Clinical and Research Center - IRCCS, Via Alessandro Manzoni, 56, Rozzano, Milan, Italy. joanna.mikulak@humanitasresearch.it.
7
Department of Medical Biotechnologies and Translational Medicine (BioMeTra), University of Milan, Milan, Italy. joanna.mikulak@humanitasresearch.it.
8
Unit of Clinical and Experimental Immunology, Humanitas Clinical and Research Center - IRCCS, Via Alessandro Manzoni, 56, Rozzano, Milan, Italy. domenico.mavilio@unimi.it.
9
Department of Medical Biotechnologies and Translational Medicine (BioMeTra), University of Milan, Milan, Italy. domenico.mavilio@unimi.it.

Abstract

Human (gamma delta) γδ T cells are unconventional innate-like lymphocytes displaying a broad array of anti-tumor activities with promising perspectives in cancer immunotherapy. In this context, Vδ2pos T cells represent the preferential target of several immunotherapy protocols against solid tumors. However, the impact of both aging and chemotherapy (CHT) on Vδ2pos T cells is still unknown. The present study evaluates with multi-parametric flow cytometry the frequencies, terminal differentiation, senescence and effector-functions of peripheral blood and tumor infiltrating Vδ2pos T cells purified from liver metastases (CLM) of patients affected by colorectal cancer (CRC) compared to those of sex- and age-matched healthy donors. The peripheral blood of CLM patients underwent CHT is characterized by decreased amounts of Vδ2pos T cells showing a relative increase of terminally-differentiated CD27neg/CD45RApos (TEMRA) cells. The enrichment of this latter subset is associated with an increased expression of the senescent marker CD57. The acquisition of CD57 on TEMRA Vδ2pos T cells is also coupled with impairments in cytotoxicity and production of TNF-α and IFN-γ. These features resemble the acquisition of an immune-senescent profile by Vδ2pos T cells from CLM patients that received CHT, a phenomenon that is also associated with the loss of the co-stimulatory marker CD28 and with the induced expression of CD16. The group of CLM patients underwent CHT and older than 60 years old showed higher frequencies of CD57pos and TEMRA Vδ2pos T cells. Similar results were found for tumor infiltrating Vδ2pos T cell subset purified from CLM specimens of patients treated with CHT. The toxicity of CHT regimens also affects the homeostasis of Vδ2pos T cells by inducing higher frequencies of circulating CD57pos TEMRA subset in CLM underwent CHT and younger than 60 years old. Taken together, our data demonstrate that the enrichment of senescent Vδ2pos T cells in CLM patients is not only induced by patients' aging but also by the toxicity of CHT that further accelerates the accumulation of CD57pos TEMRA cells highly dysfunctional in their anti-tumor activities. These results are important to both predict the clinical outcome of CLM and to optimize those protocols of cell cancer immunotherapy employing unconventional Vδ2pos T cells.

KEYWORDS:

Cancer; Chemotherapy; Immune-senescence/Aging; γδ T cells

20.
World J Surg Oncol. 2019 Dec 11;17(1):214. doi: 10.1186/s12957-019-1746-x.

Clinical outcomes of complete cytoreduction with concurrent liver resection followed by hyperthermic intraperitoneal chemotherapy for synchronous peritoneal and liver metastatic colorectal cancer.

Author information

1
Division of Colon and Rectal Surgery, Department of Surgery, Gangnam Severance Hospital, Yonsei University College of Medicine, 20, Eonju-ro 63-gil, Gangnam-gu, Seoul, 06229, Korea.
2
Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea.
3
Division of Colon and Rectal Surgery, Department of Surgery, Gangnam Severance Hospital, Yonsei University College of Medicine, 20, Eonju-ro 63-gil, Gangnam-gu, Seoul, 06229, Korea. whitenoja@yuhs.ac.

Abstract

BACKGROUND:

This study aimed to evaluate the clinical outcomes of concurrent liver resection with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in colorectal cancer patients with synchronous liver and peritoneal metastases.

METHODS:

Patients with colorectal liver and peritoneal metastasis who underwent complete cytoreduction and hyperthermic intraperitoneal chemotherapy with concurrent liver surgery between September 2014 and July 2018 were included. Perioperative outcomes, overall survival, and progression-free survival were analyzed retrospectively.

RESULTS:

In total, 22 patients were included. The median peritoneal cancer index was 13 (range, 0-26), and the median number of liver metastases was 3 (range, 1-13). The mean total operative time was 11.4 ± 2.6 h. Minor postoperative complications (Clavien-Dindo grade I-II) were reported in 10 patients (45.5%), and major postoperative complications (grade III-V) were reported in five patients (22.7%), including one mortality patient. The median overall survival since diagnosis with metastasis was 27.4 months. The median overall survival since surgical intervention and the progression-free survival were 16.7 months and 7.1 months, respectively.

CONCLUSIONS:

This short-term follow-up study showed that, in an experienced center, combined resection with hyperthermic intraperitoneal chemotherapy for colorectal liver and peritoneal metastases was feasible and safe with acceptable oncologic outcomes.

KEYWORDS:

Colorectal cancer; Cytoreductive surgery; Hyperthermic intraperitoneal chemotherapy; Liver metastases; Liver resection; Peritoneal metastases

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