Dynamic monitoring of PD-L1 and Ki67 in circulating tumor cells of metastatic non-small cell lung cancer patients treated with pembrolizumab.

Programmed cell death protein ligand-1 (PD-L1) expression in non-small cell lung cancer (NSCLC) tumors guides treatment selection. PD-L1 expression in circulating tumor cells (CTCs) may provide further information. We have explored PD-L1 and marker of proliferation Ki-67 (Ki67; also known as MKI67) in CTCs in longitudinal samples of 47 advanced NSCLC patients receiving pembrolizumab. A triple immunofluorescence, against cytokeratin, PD-L1, and Ki67, was performed on peripheral blood mononuclear cells, at baseline, post-first cycle, post-third, and primary resistance (PMR). Patients displaying PMR (progression at first evaluation) were classified as progressive disease (PD) and those with clinical benefit as disease control (DC). CTCs were categorized as PD-L1high/low/medium/negative and Ki67+ or Ki67- . CTC evaluation revealed a significant increase in the PD-L1low CTC rate at PMR compared to baseline (2.5% at baseline vs. 36.5% at PMR), whereas a reduction in the PD-L1high CTC rate was observed (31.5% vs. 0%, respectively). Investigation of CTC status between PD and DC patients showed that PD patients more frequently increased total and PD-L1low CTCs after first cycle compared to DC (83% of PD vs. 37% of DC and 67% of PD vs. 8% of DC, respectively). Progression-free survival (PFS) was longer in patients with decreased total and PD-L1low CTCs after first cycle compared to those with increased CTCs (median PFS: not reached vs. 2 months). PD-L1+ patients presenting a high Ki67 index (% Ki67+ CTCs > 30%) before treatment had a shorter PFS compared to those with a low Ki67 (≤ 30%), and overall survival (OS) was shorter in PD-L1+ patients harboring Ki67+ CTCs compared to those not presenting (median OS: 11.8 months vs. 33.1 months, respectively). In sequential samples of patients with a durable benefit, a low Ki67 index was observed. Our results suggest that monitoring PD-L1 and Ki67 expression in CTCs of NSCLC patients treated with pembrolizumab may be predictive for pembrolizumab efficacy.

Tyrosine Kinase Inhibitors for Radioactive Iodine Refractory Differentiated Thyroid Cancer.

Patients with differentiated thyroid cancer usually present with early-stage disease and undergo surgery followed by adjuvant radioactive iodine ablation, resulting in excellent clinical outcomes and prognosis. However, a minority of patients relapse with metastatic disease, and eventually develop radioactive iodine refractory disease (RAIR). In the past there were limited and ineffective options for systemic therapy for RAIR, but over the last ten to fifteen years the emergence of tyrosine kinase inhibitors (TKIs) has provided important new avenues of treatment for these patients, that are the focus of this review. Currently, Lenvatinib and Sorafenib, multitargeted TKIs, represent the standard first-line systemic treatment options for RAIR thyroid carcinoma, while Cabozantinib is the standard second-line treatment option. Furthermore, targeted therapies for patients with specific targetable molecular abnormalities include Latrectinib or Entrectinib for patients with NTRK gene fusions and Selpercatinib or Pralsetinib for patients with RET gene fusions. Dabrafenib plus Trametinib currently only have tumor agnostic approval in the USA for patients with BRAF V600E mutations, including thyroid cancer. Redifferentiation therapy is an area of active research, with promising initial results, while immunotherapy studies with checkpoint inhibitors in combination with tyrosine kinase inhibitors are underway.

Evaluating Pain Management Practices for Cancer Patients among Health Professionals: A Global Survey.

Background: Cancer incidence in the world is predicted to increase in the next decade. While progress has been in diagnosis and treatment, much still remains to be done to improve cancer pain therapy, mainly in underserved communities in low-income countries. Objective: To determine knowledge, beliefs, and barriers regarding pain management in both high- and low-income countries (according to the WHO classification); and to learn about ways to improve the current state of affairs. Design: Descriptive survey. Setting/Subjects: Fifty-six countries worldwide; convenience sample of 1639 consisted of 36.8% physicians; 45.1% nurses, and 4.5% pharmacists employed in varied settings. Results: Improved pain management services are key elements. Top barriers include religion factors, lack of appropriate education and training at all levels, nonadherence to guidelines, patients' reluctance to report on pains, over regulation associated with prescribing and access to opioid analgesics, fear of addiction to opioids, and lack of discussions around prognosis and treatment planning. Conclusion: The majority of patients with cancer in low-income countries are undertreated for their pain. Promoting cancer pain accredited program of training and education on pain management for physicians and nurses is crucial, as well as advocating policymakers and the public at large.

Effect of Osimertinib on CTCs and ctDNA in EGFR Mutant Non-Small Cell Lung Cancer Patients: The Prognostic Relevance of Liquid Biopsy.

INTRODUCTION: Liquid biopsy is a useful tool for monitoring treatment outcome in solid tumors, including lung cancer. The relevance of monitoring CTCs and plasma ctDNA as predictors of clinical outcome was assessed in EGFR-mutant NSCLC patients treated with osimertinib. METHODS: Forty-seven EGFR-mutant NSCLC patients who had progressed on prior first- or second-generation EGFR inhibitors were enrolled in the study and treated with osimertinib, irrespective of the presence of the T790M mutation in the primary tumor or the plasma. Peripheral blood was collected at baseline (n = 47), post-Cycle 1 (n = 47), and at the end of treatment (EOT; n = 39). CTCs were evaluated in 32 patients at the same time points (n = 32, n = 27, and n = 21, respectively) and phenotypic characterization was performed using triple immunofluorescence staining (CK/VIM/CD45). RESULTS: Osimertinib resulted in an ORR of 34% (2 CR) and a DCR of 76.6%. The median PFS and OS values were 7.5 (range, 0.8-52.8) and 15.1 (range, 2.1-52.8) months, respectively. ctDNA was detected in 61.7%, 27.7%, and 61.5% of patients at baseline, post-Cycle 1, and EOT, respectively. CTCs (CK+/CD45-) were detected in 68.8%, 48.1%, and 61.9% of patients at the three time points, respectively. CTCs expressing both epithelial and mesenchymal markers (CK+/VIM+/CD45-) were detected in 56.3% and 29.6% of patients at baseline and post-Cycle 1, respectively. The detection of ctDNA at baseline and post-Cycle 1 was associated with shorter PFS and OS, whereas the ctDNA clearance post-Cycle 1 resulted in a significantly longer PFS and OS. Multivariate analysis revealed that male sex and the detection of ctDNA at baseline were independent predictors of shorter PFS (HR: 2.6, 95% C.I.: 1.2-5.5, p = 0.015 and HR: 3.0, 95% C.I.: 1.3-6.9; p = 0.009, respectively). CONCLUSIONS: The decrease in both CTCs and ctDNA occurring early during osimertinib treatment is predictive of better outcome, implying that liquid biopsy monitoring may be a valuable tool for the assessment of treatment efficacy.

Correction to: Human Development Index and its association with staff spiritual care provision: a Middle Eastern oncology study.

Incorrect family name of Layth Mula-Hussain.

Human Development Index and its association with staff spiritual care provision: a Middle Eastern oncology study.

BACKGROUND: Although staff spiritual care provision plays a key role in patient-centered care, there is insufficient information on international variance in attitudes toward spiritual care and its actual provision. METHODS: A cross-sectional survey of the attitudes of Middle Eastern oncology physicians and nurses toward eight examples of staff provision of spiritual care: two questionnaire items concerned prayer, while six items related to applied information gathering, such as spiritual history taking, referrals, and encouraging patients in their spirituality. In addition, respondents reported on spiritual care provision for their last three advanced cancer patients. RESULTS: Seven hundred seventy responses were received from 14 countries (25% from countries with very high Human Development Index (HDI), 41% high, 29% medium, 5% low). Over 63% of respondents positively viewed the six applied information gathering items, while significantly more, over 76%, did so among respondents from very high HDI countries (p value range, p < 0.001 to p = 0.01). Even though only 42-45% overall were positively inclined toward praying with patients, respondents in lower HDI countries expressed more positive views (p < 0.001). In interaction analysis, HDI proved to be the single strongest factor associated with five of eight spiritual care examples (p < 0.001 for all). Significantly, the Middle Eastern respondents in our study actually provided actual spiritual care to 47% of their most recent advanced cancer patients, compared to only 27% in a parallel American study, with the key difference identified being HDI. CONCLUSIONS: A country's development level is a key factor influencing attitudes toward spiritual care and its actual provision. Respondents from lower ranking HDI countries proved relatively more likely to provide spiritual care and to have positive attitudes toward praying with patients. In contrast, respondents from countries with higher HDI levels had relatively more positive attitudes toward spiritual care interventions that involved gathering information applicable to patient care.

Training for awareness of one's own spirituality: A key factor in overcoming barriers to the provision of spiritual care to advanced cancer patients by doctors and nurses.

OBJECTIVE: When patients feel spiritually supported by staff, we find increased use of hospice and reduced use of aggressive treatments at end of life, yet substantial barriers to staff spiritual care provision still exist. We aimed to study these barriers in a new cultural context and analyzed a new subgroup with "unrealized potential" for improved spiritual care provision: those who are positively inclined toward spiritual care yet do not themselves provide it. METHOD: We distributed the Religion and Spirituality in Cancer Care Study via the Middle East Cancer Consortium to physicians and nurses caring for advanced cancer patients. Survey items included how often spiritual care should be provided, how often respondents themselves provide it, and perceived barriers to spiritual care provision.ResultWe had 770 respondents (40% physicians, 60% nurses) from 14 Middle Eastern countries. The results showed that 82% of respondents think staff should provide spiritual care at least occasionally, but 44% provide spiritual care less often than they think they should. In multivariable analysis of respondents who valued spiritual care yet did not themselves provide it to their most recent patients, predictors included low personal sense of being spiritual (p < 0.001) and not having received training (p = 0.02; only 22% received training). How "developed" a country is negatively predicted spiritual care provision (p < 0.001). Self-perceived barriers were quite similar across cultures.Significance of resultsDespite relatively high levels of spiritual care provision, we see a gap between desirability and actual provision. Seeing oneself as not spiritual or only slightly spiritual is a key factor demonstrably associated with not providing spiritual care. Efforts to increase spiritual care provision should target those in favor of spiritual care provision, promoting training that helps participants consider their own spirituality and the role that it plays in their personal and professional lives.

Incidence patterns of colorectal cancers in four countries of the Middle East Cancer Consortium (Cyprus, Jordan, Israel, and Izmir, Turkey) compared with those in the United States Surveillance, Epidemiology, and End Results Program.

BACKGROUND/AIMS: There are wide variations in colorectal cancer (CRC) incidence across the world. Historically, the highest incidence rates have been reported historically in more developed countries; however, increasing trends have been seen in developing countries. Here, we present the CRC incidence pattern in Cyprus, Israel, Jordan, and Izmir, Turkey, which are countries of the Middle East Cancer Consortium (MECC). MATERIALS AND METHODS: We analyzed 2005-2010 CRC data from population-based registries and calculated crude and age standardized rates for CRC, colon and rectum subsites, and annual percent changes (APCs) for trends. RESULTS: The age-adjusted incidence rates (AAIRs) for CRC were the highest in Israeli Jews (IJ) (46.7 for males and 35.5 for females), which exceeded those of the USA Surveillance, Epidemiology, and End Result (SEER) program registries. In both sexes, AAIRs in Cyprus and Israeli Arabs (IA) were close to those in SEER registries. For both sexes, AAIRs in Izmir and Jordan were substantially lower than those in other registries. Statistically significant decreasing trends over time were observed in AAIRs for both sexes in the SEER program (APCs: males, -3.24% and females, -2.54%), whereas the trends varied within the MECC registries. There were decreasing AAIR trends for males in IJ and IA and for females in Cyprus and IJ; APC for females in IJ (-4.29%) was significant. Conversely, increasing trends with the significant APCs were observed in males in Izmir (2.43%) and Jordan (7.57%). CONCLUSION: MECC countries comprise both high- and low-risk populations for CRCs. However, increasing trends in low-risk populations have been alarming. Thus, the need for implementing tailored primary and secondary prevention programs in the region is essential.

The impact of specialized palliative care on cancer patients' health-related quality of life: a systematic review and meta-analysis.

PURPOSE: Specialized palliative care (SPC) is currently underutilized or provided late in cancer care. The aim of this systematic review and meta-analysis is to critically evaluate the impact of SPC on patients' health-related quality of life (HRQoL). METHODS: Five databases were searched through June 2016. Randomized controlled trials (RCTs) and prospective studies using a pre- and post- assessment of HRQoL were included. The PRISMA reporting statement was followed. Criteria from available checklists were used to evaluate the studies' quality. A meta-analysis followed using random-effect models separately for RCTs and non-RCTs. RESULTS: Eleven studies including five RCTs and 2939 cancer patients published between 2001 and 2014 were identified. There was improved HRQoL in patients with cancer following SPC especially in symptoms like pain, nausea, and fatigue as well as improvement of physical and psychological functioning. Less or no improvements were observed in social and spiritual domains. In general, studies of inpatients showed a larger benefit from SPC than studies of outpatients whereas patients' age and treatment duration did not moderate the impact of SPC. Methodological shortcomings of included studies include high attrition rates, low precision, and power and poor reporting of control procedures. CONCLUSIONS: The methodological problems and publication bias call for higher-quality studies to be designed, funded, and published. However, there is a clear message that SPC is multi-disciplinary and aims at palliation of symptoms and burden in line with current recommendations.

Cancer burden in four countries of the Middle East Cancer Consortium (Cyprus; Jordan; Israel; Izmir (Turkey)) with comparison to the United States surveillance; epidemiology and end results program.

It is important that population-based cancer registries provide accurate and reliable data for public health purposes. These data are essential data for planning of cancer control and prevention. In this study, we examined cancer incidence rates (year 2005-2010) in four MECC registries (Cyprus, Jordan, Israel, Izmir (Turkey)) and compared with the rates in the US. The overall age-standardized incidence rates for males were highest in the US followed by Israeli Jews, Izmir (Turkey), Cyprus, Israeli Arabs, and lowest in Jordan. In women the rates of cancer of all sites were also highest in US women followed by Israeli Jews, Cyprus, Israeli Arabs, Izmir (Turkey), and lowest in Jordan. It is of interest that although site-specific cancer rates differ between the countries studied, prostate, lung and colorectal cancers are within the five most common cancers males in all countries studied. In females, breast colorectal and endometrium cancers are three of the five most common cancers in females in all countries studied. The results presented in this paper can have implications for opportunities in cancer control and prevention in these countries. Future studies on individual cancer sites with highest rates in these Countries are currently underway.

Communication and integration: a qualitative analysis of perspectives among Middle Eastern oncology healthcare professionals on the integration of complementary medicine in supportive cancer care.

CONTEXT AND OBJECTIVES: The use of complementary and traditional medicine (CTM ) in Middle Eastern countries is widespread, including among patients with cancer. Perspectives of oncology healthcare professionals (HCPs) in this region regarding the integration of CTM within conventional supportive cancer care were explored. METHODS: An 11-item questionnaire with an open-ended question asking respondents to comment about the integration of CTM within supportive cancer care was sent to Middle Eastern oncology HCPs, using snowball sampling methodology. The narratives provided were examined using thematic analysis. RESULTS: A total of 339 oncology HCPs completed and returned the study tool (80.3 % response rate ), of which 178 from 15 Middle Eastern countries responded to the open-ended question. The majority of respondents are in favor of the integration of CTM within supportive cancer care, though ideas on how this should be implemented varied. Thematic analysis identified multifactorial barriers to integration, which focused on HCPs' perspectives (e.g., a lack of knowledge and training; a skeptical approach to CTM), attitudes of patients and caregivers (e.g., unrealistic expectations regarding the outcomes of CTM treatments) and HCP-patient communication. In order to overcome these barriers, respondents suggested education and training programs for oncology HCPs which would focus on improving patients' quality-of-life-related outcomes. CONCLUSIONS: Middle Eastern oncology HCPs support the integration of CTM within supportive cancer care, while recognizing the need for education and training in this field. A better understanding of CTM would provide the knowledge and skills which would promote a non-judgmental, evidence-based approach, fostering better communication with patients.

Potential risks associated with traditional herbal medicine use in cancer care: A study of Middle Eastern oncology health care professionals.

BACKGROUND: The authors assessed the use of herbal medicine by Middle Eastern patients with cancer, as reported by their oncology health care professionals (HCPs). Herbal products identified by the study HCPs were evaluated for potential negative effects. METHODS: Oncology HCPs from 16 Middle Eastern countries received a 17-item questionnaire asking them to list 5 herbal products in use by their patients with cancer. A literature search (PubMed, Micromedex, AltMedDex, and the Natural Medicine Comprehensive Database) was conducted to identify safety-related concerns associated with the products listed. RESULTS: A total of 339 HCPs completed the study questionnaire (response rate of 80.3%), identifying 44 herbal and 3 nonherbal nutritional supplements. Safety-related concerns were associated with 29 products, including herb-drug interactions with altered pharmacodynamics (15 herbs), direct toxic effects (18 herbs), and increased in vitro response of cancer cells to chemotherapy (7 herbs). CONCLUSIONS: Herbal medicine use, which is prevalent in Middle Eastern countries, has several potentially negative effects that include direct toxic effects, negative interactions with anticancer drugs, and increased chemosensitivity of cancer cells, requiring a reduction in dose-density. Oncology HCPs working in countries in which herbal medicine use is prevalent need to better understand the implications of this practice. The presence of integrative physicians with training in complementary and traditional medicine can help patients and their HCPs reach an informed decision regarding the safety and effective use of these products.

International palliative care: Middle East experience as a model for global palliative care.

Care for elderly people with life-limiting illness cannot be delivered primarily by geriatricians or palliative care practitioners. The role of these clinicians is to help carers become adept in palliative care medicine. In a culture in which family ties run deep, the offer of palliative care from an outsider may be met with suspicion. The family bond in the Middle East is strong, but the emotional response to terminal illness may push families to request futile treatments, and physicians to comply. When palliative care is well developed and well understood, it provides a viable alternative to such extreme terminal measures.

Integration of complementary medicine in supportive cancer care: survey of health-care providers' perspectives from 16 countries in the Middle East.

INTRODUCTION: In this multinational Middle-Eastern study, we assessed health-care providers' (HCPs) perspectives on their patients' use of complementary and traditional medicine (CTM) and identified the leading barriers to CTM integration in supportive cancer care. METHODS: A 17-item questionnaire was developed and administered to HCPs attending palliative medicine workshops conducted across the Middle East by the Middle East Cancer Consortium. RESULTS: 339 HCPs from 16 countries across the Middle East completed the questionnaire (80.3 % response rate). Respondents perceived their patients' reasons for CTM use primarily in the context of cancer cure (63 %) and quality of life (QOL) improvement (57 %). Expectation regarding CTM's role in cancer cure/survival was more pronounced in Turkey, Jordan, the Palestinian Authority, and the Persian Gulf area. In contrast, the expectation that CTM would improve QOL was more emphasized in Israel. A mid-position between the cure/survival and QOL poles was observed in Cyprus, Lebanon, and the North African countries. Leading barriers to CTM integration in supportive cancer care included oncologists' skepticism and a gap between patients' expectations and HCP's objectives. Respondents' leading recommendation to HCPs was to communicate integrative care emphasizing well-being and improved functioning in accordance with their patients' health beliefs. CONCLUSION: CTM integration in supportive cancer care can be facilitated by implementing a platform for Middle Eastern clinical collaborations. HCPs' expectations and experiences with CTM have been positive in the oncology setting. These data need to be corroborated with information of patients' expectations on the provision of CTM over all phases of the oncology treatment.

Evaluating palliative care needs in Middle Eastern countries.

BACKGROUND: Cancer incidence in Middle Eastern countries, most categorized as low- and middle-income, is predicted to double in the next 10 years, greater than in any other part of the world. While progress has been made in cancer diagnosis/treatment, much remains to be done to improve palliative care for the majority of patients with cancer who present with advanced disease. OBJECTIVE: To determine knowledge, beliefs, barriers, and resources regarding palliative care services in Middle Eastern countries and use findings to inform future educational and training activities. DESIGN: Descriptive survey. SETTING/SUBJECTS: Fifteen Middle Eastern countries; convenience sample of 776 nurses (44.3%), physicians (38.3%) and psychosocial, academic, and other health care professionals (17.4%) employed in varied settings. MEASUREMENTS: Palliative care needs assessment. RESULTS: Improved pain management services are key facilitators. Top barriers include lack of designated palliative care beds/services, community awareness, staff training, access to hospice services, and personnel/time. The nonexistence of functioning home-based and hospice services leaves families/providers unable to honor patient wishes. Respondents were least satisfied with discussions around advance directives and wish to learn more about palliative care focusing on communication techniques. Populations requiring special consideration comprise: patients with ethnic diversity, language barriers, and low literacy; pediatric and young adults; and the elderly. CONCLUSIONS: The majority of Middle Eastern patients with cancer are treated in outlying regions; the community is pivotal and must be incorporated into future plans for developing palliative care services. Promoting palliative care education and certification for physicians and nurses is crucial; home-based and hospice services must be sustained.

Attitudes and referral patterns of lung cancer specialists in Europe to Specialized Palliative Care (SPC) and the practice of Early Palliative Care (EPC).

PURPOSE: To examine availability of Palliative Care (PC) services and referral patterns of European Lung cancer specialists to PC. METHODS: All members of the EORTC Lung Cancer Group (LCG) were asked via email to participate in an on-line survey. RESULTS: 50 out of 170 (29.4%) replied: 24 medical oncologists, 14 radiation/clinical oncologists, 11 pulmonologists and 1 thoracic surgeon. All but two of respondents (96%) had access to at least one component of PC services. In terms of referral of patients to PC almost 75% of respondents would refer most of their patients when there were no treatment options or at the end of life, while only 22% would refer patients at earlier stages of disease. Barriers for referral to PC were negative attitudes of patients to PC (26%), lack of availability of PC services (20%), lack of expertise of PC physicians(18%), the belief that referral to PC signifies abandoning patients (8%), and that PC specialists discourage active oncological therapy (8%). Whilst most of the respondents expressed positive attitudes, 12-22% had overtly negative attitudes towards PC. Seventy-eight (78%) of respondents expressed an interest to participate in a trial of early PC (EPC). CONCLUSION: Despite good availability of SPC services at institutions of members of the EORTC LCG, and most respondents expressing positive attitudes towards PC, their practice involved referral of patients to PC late in the disease trajectory, hence Lung Cancer specialists in Europe have not adopted the practice of EPC concurrent with active oncological care.

Docetaxel and irinotecan as second-line therapy for advanced oesophagogastric cancer.

INTRODUCTION: Systemic chemotherapy improves survival in oesophagogastric cancer however no standard second-line regimen exists due to a paucity of randomised data. Docetaxel combined with irinotecan (DI) provides a suitable option due to the lack of cross-reactivity with first-line therapeutics and a tolerable toxicity profile. METHODS: We retrospectively reviewed a cohort of patients with advanced oesophagogastric cancer in two institutions treated with the combination of docetaxel 35 mg/m(2) plus irinotecan 60 mg/m(2) day 1 and day 8 every 21 days, following progression with first-line platinum-based therapy. RESULTS: Between January 2000 and September 2009, 41 eligible patients were identified. Median age was 58 years, male:female 25:16, adenocarcinoma:squamous cell carcinoma 37:4, oesophageal:oesophagogastric junction:gastric 7:10:24. Locally advanced:metastatic disease 6:35. Previous radical surgery:radiotherapy:both 6:4:7. 27/41 had progressed within 90 days of receiving platinum-based therapy. Median number of chemotherapy cycles: 3 (range 1-12). Eight patients required dose reductions due to DI toxicity. 10/28 evaluable patients had a response, median progression-free survival (PFS) was 11 weeks (95% confidence intervals (CI): 9-13 weeks) with median overall survival 24 weeks (95%CI: 12-35 weeks). No significant prognostic factors were identified. CONCLUSION: Weekly docetaxel combined with irinotecan has acceptable safety and modest efficacy in the second-line treatment of advanced oesophagogastric cancer. Further prospective evaluation of this regimen is warranted.