Radiotherapy for Advanced Esophageal Cancer: from Palliation to Curation.

OPINION STATEMENT: Esophageal cancer is a global health problem, which is 7th most common and 6th most deadly cancer. It has been the era of immuno-oncology for esophageal cancer management. Radiation therapy has been one of the key local therapeutic approaches for esophageal cancer treatment, while its role in advanced disease is challenging and debatable. There have been emerging clinical and translational studies of radiation therapy in recurrent or metastatic esophageal cancer. Immunotherapy has been established the standard care of 1st and 2nd line systemic therapies of advanced esophageal cancer, and the development of tumor immunity has opened a new chapter for the esophageal cancer radiation therapy. The current review will summarize the classic radiation therapy research in advanced esophageal cancer, as well as the most recent key findings. The subtitles will cover palliative radiotherapy for dysphagia, re-radiation for recurrent disease, oligo-focal disease management and stereotactic radiation therapy, and radiotherapy with immunotherapy. Radiotherapy plays vital role in multidisciplinary management of advanced EC. External or intratumoral irradiation has been used for palliation of dysphagia and improving QOL in esophageal cancer patients traditionally, while recent clinical and technical advance enables radiotherapy to be considered in recurrent or metastatic disease for curation attention. Novel clinical and translational investigation is opening a new chapter of radiotherapy with immunotherapy for benefiting advanced EC patients.

Markers of tumor inflammation as prognostic factors for overall survival in patients with advanced pancreatic cancer receiving first-line FOLFIRINOX chemotherapy.

BACKGROUND: Identifying pretreatment blood markers that distinguish prognostic groups of patients with advanced pancreatic ductal adenocarcinoma (PDAC) under first-line FOLFIRINOX chemotherapy has the potential to improve management of this condition. Aim of this study was to determine the prognostic utility of a range of pretreatment, inflammation-related, blood cell markers in this group of patients. MATERIAL AND METHODS: Data from a training cohort were analyzed to identify potential pretreatment blood markers correlating to survival outcomes. The most informative markers were further analyzed in a validation cohort comprised patients from a geographically separate cancer center undergoing the same treatment. RESULTS: A total of 138 consecutive patients receiving FOLFIRINOX chemotherapy between 2010 and 2019, constituted the training cohort. Neutrophil/lymphocyte (NLR), monocyte/lymphocyte (MLR), and platelet/lymphocyte ratio (PLR) as well as the systemic inflammatory response index (SIRI) and CA19.9 showed prognostic significance in addition to tumor stage. A pretreatment SIRI score cutoff of 2.35 differentiated between a poor prognostic group with median overall survival (mOS) 5.1 months and a better prognostic group, mOS 12.5 months. SIRI ≤/> 2.35 was predictive of mOS in patients with locally advanced and metastatic PDAC. SIRI was confirmed as a prognostic marker in a validation cohort of 67 patients with mOS of 13.4 months and 6.3 months for those with SIRI ≤ 2.35 and >2.35, respectively. Additional analysis revealed baseline SIRI as being prognostic within additional subgroups of patients in both cohorts. CONCLUSIONS: This large, retrospective, analysis of real-world patients receiving first-line FOLFIRINOX chemotherapy for advanced PDAC has identified the pretreatment blood SIRI as a strong prognostic marker for survival. This will allow better counseling of patients with regards to the benefits of treatment, improved stratification within clinical trials, and potentially identify groups of patients for novel therapy trials as first-line treatment.

Targeting the Epidermal Growth Factor Receptor in Addition to Chemotherapy in Patients with Advanced Pancreatic Cancer: A Systematic Review and Meta-Analysis.

Overexpression of epidermal growth factor receptors (EGFR) occurs in >90% of pancreatic ductal adenocarcinomas (PDACs) and is associated with a poorer prognosis. A systematic review of electronic databases identified studies exploring the addition of EGFR-targeted treatment to chemotherapy in patients with locally advanced (LA)/metastatic PDAC. Efficacy, safety and tolerability of EGFR-targeted therapy were explored using meta-analysis of randomised controlled trials (RCTs). Meta-regression was utilised to explore factors associated with improved prognosis (all studies) and benefit from EGFR-targeted therapy (RCTs). Twenty-eight studies (7 RCTs and 21 cohort studies) comprising 3718 patients were included. The addition of EGFR-targeted treatment to chemotherapy did not improve progression-free (pooled hazard ratio (HR): 0.90, p = 0.15) or overall survival (HR: 0.94, p = 0.18). EGFR-targeted therapy was associated with increased treatment-related deaths (pooled odds ratio (OR): 5.18, p = 0.007), and grade (G)3/4 rash (OR: 4.82, p = 0.03). There was a borderline significant increase in G3/4 diarrhoea (OR: 1.75, p = 0.06), but no effect on treatment discontinuation without progression (OR: 0.87, p = 0.25). Neither G3/4 rash nor diarrhoea were associated with increased survival benefit from EGFR-targeted therapy. The effect of EGFR-targeted therapy on overall survival (OS) appeared greater in studies with a greater proportion of LA rather than metastatic patients (R = -0.69, p < 0.001). Further studies in unselected patients with advanced PDAC are not warranted. The benefit from EGFR inhibitors may be limited to patient subgroups not yet clearly defined.

Prolonged Clinical Benefit with Futibatinib in a Patient with FGFR Inhibitor-Pretreated FGFR2 Fusion-Positive Intrahepatic Cholangiocarcinoma: Case Report.

Multiple FGFR inhibitors have demonstrated significant activity in pretreated advanced FGFR2 fusion-positive intrahepatic cholangiocarcinoma. The irreversible pan-FGFR inhibitor futibatinib has the potential to overcome acquired resistance to ATP-competitive FGFR inhibitors in a subset of patients. We present a case of prolonged clinical benefit using FGFR inhibitors sequentially, initially an ATP-competitive inhibitor followed by futibatinib upon progression, for a total of 36 months of FGFR-targeting therapy. This case supports sequential FGFR-targeting therapies for FGFR2 fusion-positive cholangiocarcinoma, with futibatinib acting as rescue therapy after failure of ATP-competitive inhibitors.

Targeted Therapies and Developing Precision Medicine in Gastric Cancer.

Gastric cancer is an aggressive disease with survival remaining poor in the advanced setting. More than a decade after the first targeted treatment was approved, still only HER2, MSI and PDL-1 status have reached everyday practice in terms of guiding treatment options for these patients. However, various new targets and novel treatments have recently been investigated and have shown promise in improving survival outcomes. In this review, we will summarise previous and currently ongoing studies on predictive biomarkers, possible new targeted treatments, potential reasons for conflicting trial results and hope for the future of precision medicine in gastric cancer.

Relevant Study: Patient and Clinician Perspectives on Clinically-Meaningful Outcomes in Advanced Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with a poor prognosis and significant symptom burden. This prospective observational study aimed to evaluate expectations and priorities of patients with advanced PDAC and their clinicians through a study survey and two quality of life (QoL) questionnaires (QLQ-C30 and PAN26) at three time-points: baseline (T1), before (T2) and after (T3) their 1st on-treatment CT scan. Over a 1-year period, 106 patients were approached, 71 patients and 12 clinicians were recruited. Choosing between treatment options, patients prioritised: 54% overall survival (OS), 26% balance between side-effects and OS, 15% could not choose and 5% favoured symptom control. These were significantly different from the clinician's answers (p < 0.001). Patients who prioritised OS had higher symptom burden (p = 0.03) and shorter OS compared to those who prioritised balance (p = 0.01). Most (86%) patients had personal goals they wanted to reach; clinicians knew of these in 12% of instances. Patient and clinicians' views regarding survival improvement from chemotherapy were significantly different: 81% of clinicians and 12% of patients thought 1-2 or 3-6 months extension, 58% of patients and 0% physicians thought 1-5 or >5 years (p < 0.001). At T1, patients had low QoL and worst symptoms were: 'Future worries', 'planning of activities', fatigue and pain. Patients were willing to accept significantly higher amounts of side-effects as a trade-off for extra time, than clinicians thought (p < 0.001). Overall, there are significant discrepancies between patient and clinicians' views about the aims, priorities and expected extension of life.

Career and Professional Development for Young Oncologists.

Young oncologists around the globe face many challenges when it comes to their career and professional development. Aspects such as time management, work-life balance, career progression, and educational opportunities are only some of them. Professional societies have identified these challenges in this professional group and designed programs to tackle them specifically. The importance of this strategy cannot be overstated, as young oncologists, defined by most societies as oncologists under 40 years of age, compose almost 50% of the oncology workforce. On the other hand, recent surveys have shown that many young oncologists are considering alternative career paths due to burnout issues aggravated by the COVID-19 pandemic, on top of all other challenges. The virtual setting that has been forcedly introduced into our professional life has shortened distances between professionals and might have contributed to more accessible access to information and opportunities that some young oncologists could not profit from due to their traveling constraints. On the other hand, this virtual setting has shown us the asymmetries in opportunities for these professionals. Knowledgeable of all this, we summarize in this article some of the career and professional development offers available to all young oncologists, which we consider could help them deal with current and future challenges.

Advances in immunotherapy for MMR proficient colorectal cancer.

Survival in mismatch-repair proficient (MMRp) metastatic colorectal cancer (mCRC) remains poor and chemotherapy is the mainstay of treatment. Immunotherapy has demonstrated durable responses and a favourable side-effect profile in various cancer types and multiple clinical trials have been conducted in MMRp mCRC. In this review we summarise emerging trial data which demonstrate promising immunotherapy combinations in MMRp mCRC. We outline barriers to success, evaluate emerging biomarkers and discuss potential strategies to increase the effectiveness of immunotherapy in MMRp mCRC.

Current Translational and Clinical Challenges in Advanced Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is a frequent and increasing cause of cancerrelated deaths worldwide. Reversing this trend is complicated by the varied aetiological factors leading to liver cirrhosis resulting in molecular genetic and clinical heterogeneity, combined with frequent presentation at advanced stage. Large-scale genomic studies have identified alterations in key signalling pathways for HCC development and progression, but these findings have not yet directly influenced patient management in the clinical setting. Despite these translational challenges, a small number of anti-angiogenic systemic therapy agents have succeeded in recent randomized trials enriching the repertoire of available treatments for advanced HCC. In addition, the early promise of immune checkpoint inhibition is now on the cusp of delivering changes to standard systemic therapy algorithms. This review focuses on recent translational and clinical developments that have advanced. current practice and explores the challenges encountered in attempting to improve the outcomes and experience of patients diagnosed with advanced HCC.

Identification of patients with pancreatic adenocarcinoma due to inheritable mutation: Challenges of daily clinical practice.

BACKGROUND: Identification of germ-line mutations in pancreatic ductal adenocarcinoma (PDAC) could impact on patient/family. AIM: To assess the referral pathways for genetic consultations in PDAC. METHODS: Electronic records of PDAC patients were reviewed retrospectively. Patients eligible for genetic consultation referral were identified following the European Registry of Hereditary Pancreatitis and Familial Pancreatic Cancer (EUROPAC) criteria. RESULTS: Four-hundred patients were eligible. Of 113 patients (28.3%) meeting EUROPAC criteria, 8.8% were referred for genetic opinion. Germ-line mutations were identified in 0.75% of the whole population. CONCLUSION: Earlier referrals and increased awareness may be able to overcome the low rate of successful genetic appointments.

The importance of quality-of-life management in patients with advanced pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) carries a poor prognosis, and as such, a focus on quality of life is vital. This review will discuss various aspects of quality of life in patients with PDAC and their treatment. Pancreatic exocrine and endocrine insufficiency may result in issues related to nutrition, and pain and fatigue are other common symptoms, and may be managed with pharmaceutical or nonpharmaceutical methods. It has also been reported that low mood is a particular problem for patients with PDAC compared to patients with other cancers; however, the data supporting this is inconsistent. Data regarding improvements in quality of life in patients with PDAC receiving chemotherapy is also reviewed, which in some cases suggests a benefit to chemotherapy, particularly in the presence of a radiological response. Furthermore, the importance of early palliative care is discussed and the benefits reported including improved quality of life and mood, reduced aggressive interventions at the end of life and improved survival. Areas for future development may include increased use of quality of life as a trial outcome and the use of patient-reported outcomes to improve symptomatic care of patients, and particularly in those receiving active systemic treatment.

Advances in Molecular Profiling and Categorisation of Pancreatic Adenocarcinoma and the Implications for Therapy.

Pancreatic ductal adenocarcinoma (PDAC) continues to be a disease with poor outcomes and short-lived treatment responses. New information is emerging from genome sequencing identifying potential subgroups based on somatic and germline mutations. A variety of different mutations and mutational signatures have been identified; the driver mutation in around 93% of PDAC is KRAS, with other recorded alterations being SMAD4 and CDKN2A. Mutations in the deoxyribonucleic acid (DNA) damage repair pathway have also been investigated in PDAC and multiple clinical trials are ongoing with DNA-damaging agents. Rare mutations in BRAF and microsatellite instability (MSI) have been reported in about 1-3% of patients with PDAC, and agents used in other cancers to target these have also shown some promise. Immunotherapy is a developing field, but has failed to demonstrate benefits in PDAC to date. While many trials have failed to improve outcomes in this deadly disease, there is optimism that by developing a better understanding of the translational aspects of this cancer, future informed therapeutic strategies may prove more successful.

Sorafenib as first-line therapy in patients with advanced Child-Pugh B hepatocellular carcinoma-a meta-analysis.

BACKGROUND: Sorafenib has demonstrated survival benefit in first-line treatment of advanced hepatocellular carcinoma (HCC); utility of sorafenib in patients with advanced HCC and Child-Pugh B (CP-B) liver function remains a subject of debate. METHODS: A systematic review identified studies using first-line sorafenib in patients with advanced HCC and CP-A/B liver function. Meta-regression analysis comprising linear regression was conducted to explore the association between the baseline factors and overall survival (OS). Differences between efficacy/safety and tolerability parameters were explored using meta-analysis. RESULTS: Thirty studies (12 Asian) comprising 8678 patients (August 2002 - September 2012) were included (four randomised controlled trials, 26 cohort studies). Median age was 61 years and 83% were men. Hepatitis B/C status was positive in 35%/22%, respectively. The CP status was available for 8577 patients (99%); CP-A, 79% and CP-B, 19%. Median OS on sorafenib for entire cohort was 7.2 months; 8.8 months in CP-A and 4.6 months in CP-B. Multivariable meta-regression analysis showed significant negative association between OS and proportion of patients with the Eastern Cooperative Oncology Group performance status 2 (P = 0.04) and CP-B liver function (P = 0.001). Among four studies reporting multivariable comparison of the CP status, CP-B was associated with significantly worse OS (P < 0.001). There were no differences in the response rate to sorafenib between patients with CP-A (4.6%) and CP-B (4.2%) liver function. Safety and tolerability were similar; 35% of patients with CP-A/B liver function developed grade III/IV adverse events (P = 0.7). Meta-regression analysis showed similar rates of treatment discontinuation without progression (P = 0.31) and treatment-related death (P = 0.94) in patients with CP-B liver function. CONCLUSION: CP-B liver function (versus CP-A) is associated with worse OS (but the similar response rate, safety and tolerability of first-line sorafenib, is unlikely to be clinically meaningful).

Irreversible Electroporation in pancreatic ductal adenocarcinoma: Is there a role in conjunction with conventional treatment?

BACKGROUND: The incidence of pancreatic ductal adenocarcinoma (PDAC) is rapidly increasing. Up to 30% of patients present with locally advanced disease and therefore are not candidates for surgery. Locally advanced pancreatic cancer (LAPC) is an emerging entity lacking in level III evidence-based recommendations for its treatment. Currently, systemic chemotherapy is the main treatment for LAPC. However, due to lack of response or disease progression, downsizing of the tumour, making it resectable is successful in only a small proportion of patients. Radiotherapy is often advocated to improve local disease control if there is stability following chemotherapy. Recently, Irreversible Electroporation (IRE), a novel non-thermal ablation technique, has been proposed for the treatment of LAPC. AIMS AND METHODS: This narrative review aims to explore the potential role and timing for the use of IRE in patients with LAPC. RESULTS: To date, there is limited and inconsistent level I and II evidence available in the literature regarding the use of IRE for the treatment of PDAC. DISCUSSION: Although some of the preliminary experience of the use of IRE in patients with LAPC is encouraging, it should only be used after conventional evidence-based treatments and/or within the research context.

Germline mutations in pancreatic cancer and potential new therapeutic options.

Due to short-lived treatment responses in unresectable disease, pancreatic ductal adenocarcinoma (PDAC) continues to be one of the deadliest cancers. There is availability of new information about germline and sporadic mutations in the deoxyribonucleic acid (DNA) damage repair pathway in PDAC in recent decades and the expectation is that novel targeted therapies will thus be developed. A variety of germline mutations (BRCA2, BRCA1, PALB2, CDKN2A, ATM, TP53 and mismatch repair genes MLH1, MSH2, MSH6) have been reported in these patients with the highest prevalence being BRCA1/2. Positive results have been reported with the use of targeted therapies, particularly poly (ADP-ribose) polymerase inhibitors in BRCA-mutated ovarian and breast cancers, and their use is currently being investigated in germline-mutated pancreatic cancer. The aim of this review is to provide an outline of germline DNA damage repair mutations in pancreatic cancer and their effect on the incidence, outcomes and responses to different therapeutic options.