Palliative Chemotherapy Regimen Research Articles

MRI-guided stereotactic ablative body radiotherapy versus CT-guided percutaneous irreversible electroporation for locally advanced pancreatic cancer (CROSSFIRE): a single-centre, open-label, randomised phase 2 trial

Pancreatic ductal adenocarcinoma is an aggressive disease with a dismal prognosis. Stage III locally advanced pancreatic cancer is considered unresectable and current palliative chemotherapy regimens only modestly improve survival. Guidelines suggest chemoradiation or stereotactic ablative body radiotherapy (SABR) could be beneficial in certain circumstances. Other local treatments such as irreversible electroporation could enhance patient outcomes by extending survival while preserving quality of life. We aimed to compare the efficacy and safety of MRI-guided SABR versus CT-guided percutaneous irreversible electroporation following standard FOLFIRINOX chemotherapy. CROSSFIRE was an open-label, randomised phase 2 superiority trial conducted at the Amsterdam University Medical Centre (Amsterdam, Netherlands). Eligible patients were aged 18 years or older with confirmed histological and radiological stage III locally advanced pancreatic cancer. The maximum tumour diameter was 5 cm and patients had to be pretreated with three to eight cycles of FOLFIRINOX. Patients were randomly assigned (1:1) to MRI-guided SABR (five fractions of 8 Gy delivered on non-consecutive days) or CT-guided percutaneous irreversible electroporation using a computer-generated variable block randomisation model. The primary endpoint was overall survival from randomisation, assessed in the intention-to-treat population. Safety was assessed in the per-protocol population. A prespecified interim futility analysis was done after inclusion of half the original sample size, with a conditional probability of less than 0·2 resulting in halting of the study. The trial was registered at ClinicalTrials.gov, NCT02791503. Between May 1, 2016, and March 31, 2022, 68 patients were enrolled and randomly assigned to SABR (n=34) or irreversible electroporation (n=34), of whom 64 were treated according to protocol. Of the 68 participants, 36 (53%) were male and 32 (47%) were female, with a median age of 65 years (IQR 57-70). Median overall survival from randomisation was 16·1 months (95% CI 12·1-19·4) in the SABR group versus 12·5 months (10·9-17·0) in the irreversible electroporation group (hazard ratio [HR] 1·39 [95% CI 0·84-2·30]; p=0·21). The conditional probability to demonstrate superiority of either technique was 0·13; patient accrual was therefore stopped early for futility. 20 (63%) of 32 patients in the SABR group versus 19 (59%) of 32 patients in the irreversible electroporation group had adverse events (p=0·8) and five (16%) patients in the SABR group versus eight (25%) in the irreversible electroporation group had grade 3-5 adverse events (p=0·35). The most common grade 3-4 adverse events were cholangitis (two [6%] in the SABR group vs one [3%] in the irreversible electroporation group), abdominal pain (one [3%] vs two [6%]), and pancreatitis (none vs two [6%]). One (3%) patient in the SABR group and one (3%) in the irreversible electroporation group died from a treatment-related adverse event. CROSSFIRE did not identify a difference in overall survival or incidence of adverse events between MRI-guided SABR and CT-guided percutaneous irreversible electroporation after FOLFIRINOX. Future studies should further assess the added value of local ablative treatment over chemotherapy alone. Adessium Foundation, AngioDynamics.

Primary Treatment Modification and Treatment Tolerability Among Older Chemotherapy Recipients With Advanced Cancer

Older adults with advanced cancer are less likely to tolerate treatment with cytotoxic chemotherapy compared with younger patients due to their aging-related conditions. Hence, oncologists sometimes opt to employ primary treatment modifications (deviation from standard of care) during the first cycle of chemotherapy. To examine the association between primary treatment modification and treatment tolerability in older adults with advanced cancer who were starting new palliative chemotherapy regimens. This cohort study was a secondary analysis of the GAP70+ (Geriatric Assessment Intervention for Reducing Toxicity in Older Patients with Advanced Cancer) trial, which was conducted between July 2014 and March 2019. The GAP70+ trial included patients aged 70 years or older who had advanced (ie, incurable) cancer, had 1 or more geriatric assessment domain impairments, and planned to start a new palliative chemotherapy regimen. Data analysis was conducted in November 2022. Receipt of standard-of-care chemotherapy regimens vs primary treatment modification defined as any change from National Comprehensive Cancer Network guidelines or published clinical trials (eg, primary dose reduction, schedule change). Tolerability outcomes were assessed within 3 months of treatment. These outcomes included the following: (1) any grade 3 to 5 toxic effect, according to the National Cancer Institute Common Terminology Criteria for Adverse Events; (2) patient-reported functional decline, defined as the development of worse dependency in activities of daily living using scale scores; and (3) a composite adverse outcome (an end point that combined toxic effects, functional decline, and 6-month overall survival). Multivariable cluster-weighted generalized estimating equation models examined the association between primary treatment modification and outcomes adjusting for covariates. This study included 609 patients with a mean (SD) age of 77.2 (5.2) years; more than half (333 [54.7%]) were men. Race and ethnicity was available for 607 patients: 39 (6.4%) were Black, 539 (88.5%) were non-Hispanic White, and 29 (4.8%) were of other race or ethnicity. Nearly half (281 [46.1%]) received a primary modified treatment regimen. The most common cancer types were gastrointestinal cancer (228 [37.4%]) and lung cancer (174 [28.6%]). In multivariable analysis, primary treatment modification was associated with a reduced risk of grade 3 to 5 toxic effects (relative risk [RR], 0.85 [95% CI, 0.77-0.94]) and functional decline (RR, 0.80 [95% CI, 0.67-0.95]). Patients who received primary treatment modification had 32.0% lower odds of having a worse composite adverse outcome (odds ratio, 0.68 [95% CI, 0.48-0.97]). In this cohort study, primary treatment modification was associated with improved tolerability of chemotherapeutic regimens among older adults with advanced cancer and aging-related conditions. These findings may help optimize cancer treatment dosing in older adults with advanced cancer and aging-related conditions.

Assessment of the clinicodemographic parameters and treatment outcomes of locally advanced and metastatic lung cancer cases – A retrospective study from northeast India

Background: There are many lacunae in our current understanding of the shifting epidemiological trends of lung cancer as well as lack of data among Northeast Indian patients. Aims and Objectives: This study tried to assess the clinicodemographic and treatment outcomes of advanced lung cancer cases. Materials and Methods: This was a retrospective hospital-based study. Patients with histopathologically confirmed locally advanced and metastatic lung cancer and were registered at Dr. Bhubaneswar Borooah Cancer Institute between January and December 2017 who were included in the study. A record was made of patient demographic-, clinical-, and treatment-related parameters. Kaplan–Meier survival curves were obtained. A two-tailed P<0.05 was considered statistically significant. Results: Majority of the patients were elderly males (median=60 years), with a history of smoking in three quarter of them. Non-small-cell lung carcinoma (94%) type was the most common histology. About 93% of patients presented with TNM stage IV disease. The most common palliative chemotherapy (CT) regimen used was taxanes and platinum doublet (n=24, 35%). With a median follow-up of 6 months (range 0–37), the median progression-free survival and overall survival were 8 months and 10 months, respectively. The median survival was significantly longer in patients younger than 60 years. (13 months; P=0.021) and in those with non-small-cell histology (10 months). Conclusion: In this audit of resource-limited population with advanced lung cancer, palliative CT remains the mainstay of treatment. There is a further need to improve the survival of these advanced cases in a cost-effective manner.

Cost-effective analysis of rotational intraperitoneal aerosol chemotherapy (RIPAC) in patients with platinum-resistant ovarian cancer.

e17585 Background: We developed RIPAC, which improves distribution and penetration compared to pressurized intraperitoneal aerosol chemotherapy (PIPAC). To introduce this newly developed device in the real world, we analyzed the cost-effectiveness of rotational intraperitoneal aerosol chemotherapy (RIPAC) device to improve quality of life (QoL) compared to conventional palliative chemotherapy for platinum-resistant ovarian cancer patients. Methods: A decision tree was designed to compare the quality-adjusted life year (QALY) and cost consisting of RIPAC and palliative chemotherapy regimens, such as pegylated liposomal doxorubicin (PLD), gemcitabine (GEM), and topotecan (TOP). Also, to reflect the clinician’s variable preferred regimens for palliative chemotherapy, the average direct and indirect medical costs of belotecan, docetaxel, vinorelbine, and vinblastine were also considered in addition to the three regimens (ANY). The model included quality of life which was measured by European Organization for Research and Treatment of Cancer (EORTC)-Quality of life Questionnaire 30 (QLQ-C30) data gathered from previous clinical trial reports on PIPAC and palliative chemotherapy for recurrent ovarian cancer willingness-to-pay (WTP) threshold was set at US$40,000 per quality-adjusted life year saved. Results: To complete three cycles of palliative chemotherapy using PLD, GEM, TOP, and ANY, the total medical costs were US$15,267, US$9,013, US$16,144, and US$12,631, respectively, and the corresponding QALYs for each regimen were 0.633, 0.553, 0.783, and 0.65. Since RIPAC has not yet been introduced into the medical market, when the maximum RIPAC cost is calculated from ANY considering WTP, the cost of RIPAC excluding the ward, outpatient, and anesthesia-related costs among direct medical costs was estimated to be up to US$4,391. Conclusions: The cost-effective analysis results for the palliative treatment of recurrent ovarian cancer implied that RIPAC could be a cost-effective strategy to improve the QoL of platinum-resistant recurrent ovarian cancer patients.

Impact of IDH1 mutation on clinical course of patients with intrahepatic cholangiocarcinoma: a retrospective analysis from a German tertiary center.

IDH1 mutation is a known biomarker for targeted therapy of intrahepatic cholangiocarcinoma (iCCA), while its prognostic relevance for current palliative chemotherapy is still unclear. Aim of this study was to analyze clinicopathological characteristics of patients with IDH1 mutations and to outline a potential impact on the outcome after state-of-the-art palliative chemotherapy regimens. All patients with iCCA receiving large panel molecular profiling and follow-up treatment at Frankfurt University Hospital until 04/2022 were retrospectively analyzed. Clinicopathological characteristics were assessed for IDH1 mutated (mut) and IDH1 wild type (wt) patients, and progression-free survival (PFS) and overall survival (OS) were determined. In total, 75 patients with iCCA received molecular profiling. Of the patients with available DNA data, pathogenic mutations in IDH1 were found in 14.5% (n = 10). IDH1 mut status was associated with lower serum CA-19/9 (p = 0.023), lower serum lactate dehydrogenase (p = 0.006), and a higher proportion of primary resectability (p = 0.028) as well as response to chemotherapy after recurrence (p = 0.009). Median PFS was 5.9months (95% CI 4.4-7.3months) for IDH1 wt in comparison to 9.8months (95% CI 7.7-12months) for patients with IDH1 mut (p = 0.031). IDH1 wt was a significant risk factor for shortened PFS in univariate (p = 0.043), but not in multivariate analysis (p = 0.061). There was no difference in OS between both groups. Patients with IDH1 mutated iCCA seem to have a favorable tumor biology including a longer PFS for palliative chemotherapy regimens compared to IDH1 wild type.

Real-world outcomes of cisplatin, capecitabine, and gemcitabine with either epirubicin (PEXG) or docetaxel (PDXG) as first-line palliative treatment in metastatic or unresectable locally advanced pancreatic adenocarcinoma.

First-line palliative chemotherapy regimens in advanced pancreatic adenocarcinoma include triplet chemotherapy with 5-fluorouracil, oxaliplatin, and irinotecan, and the doublet of nab-paclitaxel plus gemcitabine. Use of triplet chemotherapy in real-world populations is limited by tolerability and nab-paclitaxel is not universally available. Regimens using the combination of cisplatin, capecitabine, gemcitabine, and either epirubicin or docetaxel may be better tolerated, more widely available, and similarly effective, but no published real-world data exist. A retrospective cohort review of patients with metastatic or unresectable locally advanced pancreatic adenocarcinoma treated with first-line palliative cisplatin, capecitabine, gemcitabine, and either epirubicin or docetaxel chemotherapy at Auckland City Hospital between July 1, 2013 and July 30, 2020. The primary outcome was overall survival (OS). Secondary outcomes were rates of grade 3 or 4 hematological toxicity, rate of febrile neutropenia, number of cycles received, and reasons for discontinuation. Eighty-eight patients were included. Median age was 66years (range 39-79), 28.4% had unresectable, locally advanced disease and 71.6% metastatic disease. Median OS was 8.5months. Patients stopped treatment due to disease progression (53.4%), completing 12 cycles (19.3%), or toxicity (10.2%). Grade 4 neutropenia was experienced by 21.6%; 10.2% had febrile neutropenia. There were four treatment-related deaths. This retrospective study in a real-world population demonstrates that chemotherapy with cisplatin, capecitabine, and gemcitabine with epirubicin (PEXG) or docetaxel (PDXG) had similar effectiveness to more commonly used combination regimens. PDXG/PEXG are viable alternatives to nab-paclitaxel plus gemcitabine in countries that have restricted drug funding.

Identification of a new prognostic score for patients with high-grade metastatic GEP-NEN treated with palliative chemotherapy

PurposeHigh-grade gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN G3) are rare and heterogeneous malignancies with poor prognosis. Aim of this study was to develop prognosticators identifying those patients that derive the most benefit from currently available systemic therapies.MethodsThis retrospective analysis included 78 patients with metastatic GEP-NEN G3. For patients with imaging data available (n = 52), the overall response rate (ORR) and disease control rate (DCR) were evaluated according to the Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1). A Cox proportional hazard model was used to analyze the prognostic value of selected clinical and blood-based biomarkers. The impact of palliative chemotherapy regimens on time-to-treatment-failure (TTF) and overall survival (OS) was assessed.ResultsMedian OS of the study cohort was 9.0 months (95% CI 7.0–11.1). The majority of patients received first-line treatment with platinum plus etoposide (83.3%). The ORR and DCR of the RECIST-evaluable subgroup were 34.6% and 76.9%. Median TTF upon first-line treatment was 4.9 months (95% CI 3.4–6.4). Multivariate analysis identified the Eastern Cooperative Oncology Group performance status (ECOG PS), lactate dehydrogenase (LDH) and absolute lymphocyte count as independent prognostic factors. A prognostic score based on these parameters discriminated patients with favorable and unfavorable outcomes.ConclusionOutcomes of patients with GEP-NEN G3 are still limited. A new prognostic score identifying those patients benefitting from current platinum/etoposide-based chemotherapy protocols may help as stratification factor in future trial design.

Impact of first-line FOLFIRINOX versus Gemcitabine/Nab-Paclitaxel chemotherapy on survival in advanced pancreatic cancer: Evidence from the prospective international multicentre PURPLE pancreatic cancer registry

BackgroundFirst-line palliative chemotherapy regimens in advanced pancreatic ductal adenocarcinoma (PDAC) have not been compared in head-to-head phase III randomised controlled trials (RCT). Data on optimum first-line treatment and subsequent sequencing is lacking. ObjectiveTo compare overall survival (OS) between first-line treatment regimens in a real-world population to determine if an optimal therapeutic sequence is associated with survival benefit. MethodsA retrospective analysis of prospectively collated data from the Australasian PURPLE pancreatic cancer registry was undertaken. FindingsFrom 2016 to 2020, of 1551 pancreatic cancer patients, 615 received palliative-intent chemotherapy. Patients with early-stage resected disease without recurrence (n = 369), radiotherapy alone (n = 43), received supportive care alone (n = 458) or had less than 3 months follow-up (n = 66) were excluded. Median OS was comparable between patients receiving first-line Gemcitabine/Nab-Paclitaxel (n = 376) and those receiving FOLFIRINOX (n = 73) (11.3 versus 12.3 months, P = 0.37), with 38% proceeding to second-line chemotherapy which was associated with longer mOS compared to first-line treatment alone (17.4 versus 8.2 months, P < 0.001). With second-line treatment following prior FOLFIRINOX (n = 29) or Gemcitabine/Nab-Paclitaxel (n = 101), mOS did not differ significantly (17.3 versus 15.9 months, P = 0.92), respectively, whilst median progression-free survival was longer with prior FOLFIRINOX (5.2 versus 2.9 months, P = 0.03). ConclusionThere was no significant difference in overall survival between either first-line chemotherapy choice, despite patients receiving FOLFIRINOX being younger, fitter, and more likely to have localised disease. However, FOLFIRINOX was associated with delayed progression. In the absence of phase III RCT data, clinicians should be comfortable using either Gemcitabine/Nab-Paclitaxel or FOLFIRINOX as first-line therapy in advanced PDAC.

All-Oral Low-Dose Chemotherapy TEPIP is Effective and Well-Tolerated in Relapsed/Refractory Patients With Aggressive B-Cell Lymphoma.

PurposeTreatment options in patients (pts.) with advanced relapsed and refractory aggressive B-cell lymphoma are limited. Palliative all-oral chemotherapy regimens reduce in-patient visits and contribute to quality of life. The all-oral low-dose chemotherapy regimen TEPIP comprises the conventional chemotherapy agents trofosfamide, etoposide, procarbazine, idarubicin and prednisolone.MethodsSafety and efficacy of TEPIP was evaluated in an observational retrospective, single-center study at the University Medical Center Regensburg between 2010 and 2020. Treatment with TEPIP was applied for 7 or 10 days during a 28-days period. In a subgroup of fit and therapy-motivated pts. rituximab was added. End points were overall survival (OS) and progression free survival (PFS). Adverse events ≥ CTCAE grade III were reported.Results35 highly pre-treated pts. with aggressive B-cell lymphoma were enrolled. Median age at TEPIP start was 67 years and 85% of pts. received TEPIP as ≥ third treatment line. Overall response rate (ORR) was 23% (CR 17%). Pts. benefited from additional rituximab administration (ORR 67%) and a lower number of pre-treatments (ORR 41%). The OS was 3.3 months (m) with a 1y-OS of 25.7% and the PFS amounted to 1.3 m with a 1y-PFS of 8.8%. OS and PFS were significantly prolonged in pts. that responded to treatment or additionally received rituximab. Adverse events were mainly hematological and occurred in 49% of pts.ConclusionTEPIP was well-tolerated and induced respectable response in a difficult-to-treat patient cohort. In particular, the all-oral administration enables out-patient use with palliative intent.

A comparative study of gemcitabine and cisplatin versus oral capecitabine alone in metastatic gallbladder cancer.

There is no consensus for palliative chemotherapy regimen in metastatic gallbladder cancer. We did a retrospective study to compare the treatment outcome in patients of metastatic gallbladder cancer treated with either gemcitabine + cisplatin (regimen A) or oral capecitabine (regimen B) alone. A total of 67 patients between January 2015 and September 15 treated with either regimen A or regimen B were retrospectively evaluated. Statistical analysis was done in June 2019. Kaplan-Meir and Log rank test were used to compare survival between two arms. Out of 67 patients, 31/67 (46%) received regimen A, and 36/67 (54%) received regimen B. Male to female ratio was 1:3. About 42% patients in regimen A and 20% in regimen B required palliative stenting. Median number of chemotherapy cycles was 4 in both regimen A (range 1->6) and regimen B (range 1->6). Patients receiving 3 cycles and 6 cycles of chemotherapy in regimen A and regimen B was 68% and 31% versus 70% and 63%, respectively (P = 0.86). Response assessment as any response (complete response + partial response + disease was stable) after 3 cycles and 6 cycles was 71% and 57% (P = 0.20), 44% and 39% (P = 0.29), in regimen A and B, respectively. Median survival was 23 weeks (range 2-106 weeks) in regimen A and 15 weeks (range 4-83 weeks) in regimen B (P = 0.40). The present study shows gemcitabine and cisplatin has nonsignificant better survival compared to oral capecitabine. However, oral capecitabine is more convenient and easy to administer. Studies with larger sample size are needed to further establish the standard chemotherapy guidelines.

871 Liver Transplant for Colorectal Liver Metastases: A Systematic Review and Meta-Analysis of Proportions

Abstract Introduction Colorectal liver metastases were historically considered a contraindication to liver transplantation, but dismal outcomes for those with metastatic colorectal cancer and advancements in liver transplantation (LT) have led to a renewed interest in the topic. We aim to compare the current evidence for liver transplantation for non-resectable colorectal liver metastases (NRCLM) with the current standard treatment of palliative chemotherapy reported in literature – 5-year survival rate &amp;lt;10%. Method A systematic review and meta-analysis of proportions was conducted following screening of MEDLINE, EMBASE, SCOPUS and CENTRAL for studies reporting liver transplantation for colorectal liver metastases. Post-operative outcomes measured included 1-, 3- and 5-year survival, overall survival, disease-free survival, and complication rates. Results Three non-randomised studies met the inclusion criteria, reporting a total of 48 patients receiving LT for NRCLM. Survival at 1-, 3- and 5-years was 83.3-100%, 58.3-80% and 50-80% respectively with no significant difference detected (p = 0.22, p = 0.48, p = 0.26). Disease free survival was 35-56% with the most common site of recurrence being lung. Thirteen out of fourteen deaths were due to disease recurrence. Conclusions Although current evidence suggests a survival benefit conferred by LT in NRCLM compared to palliative chemotherapy, the ethical implications of organ availability and allocation demand rigorous justification. Eight registered clinical trials will report on 300 more patients undergoing LT for NRCLM over the next 10 years: concomitant improvements in the management of patients following liver resection and of palliative chemotherapy regimens is paramount.

First-Line Palliative Chemotherapy for Esophageal and Gastric Cancer: Practice Patterns and Outcomes in the General Population.

Clinical trials have shown that palliative chemotherapy (PC) improves survival in patients with incurable esophageal and gastric cancer; however, outcomes achieved in routine practice are unknown. We describe treatment patterns and outcomes among patients treated in the general population of Ontario, Canada. The Ontario Cancer Registry was used to identify patients with esophageal or gastric cancer from 2007 to 2016, and data were linked to other health administrative databases. Patients who received curative-intent surgery or radiotherapy were excluded. Factors associated with the receipt of PC were determined using logistic regression. First-line PC regimens were categorized, and trends over time were reported. Survival was determined using the Kaplan-Meier method. The cohort included 9,848 patients; 22% (2,207 of 9,848) received PC. Patients receiving PC were younger (mean age, 63 v 74 years; P < .0001) and more likely male (71% v 65%; P < .0001). Thirty-seven percent of non-PC patients saw a medical oncologist in consultation. Over the study period, utilization of PC increased (from 11% in 2007 to 19% in 2016; P < .0001), whereas the proportion of patients receiving triplet regimens decreased (65% in 2007 to 56% in 2016; P = .04). In the PC group, the median overall and cancer-specific survival from treatment initiation was 7.2 months. One fifth of patients with incurable esophageal and gastric cancer in the general population receive PC. Median survival of patients treated in routine practice is inferior to that in clinical trials. Only one third of patients not treated with PC had consultation with a medical oncologist. Further work is necessary to understand low utilization of PC and medical oncology consultation in this patient population.

Irreversible Electroporation and Nivolumab Combined with Intratumoral Administration of a Toll-Like Receptor Ligand, as a Means of In Vivo Vaccination for Metastatic Pancreatic Ductal Adenocarcinoma (PANFIRE-III). A Phase-I Study Protocol.

Simple SummaryMetastatic pancreatic ductal adenocarcinoma has a dismal prognosis, and to date no curative treatment options exist. The image guided tumor ablation technique irreversible electroporation (IRE) employs high-voltage electrical pulses through the application of several needle electrodes in and around the tumor in order to induce cell death. IRE ablation of the primary tumor has the ability to reduce pancreatic tumor induced immune suppression while allowing the expansion of tumor specific effector T cells, hereby possibly shifting the pancreatic tumor microenvironment into a more immune permissive state. The addition of immune enhancing therapies to IRE might work synergistically and could potentially induce a clinically significant treatment effect. This study protocol describes the rationale and design of the PANFIRE-III trial that aims to assess the safety of the combination of IRE with IMO-2125 (toll-like receptor 9 ligand) and/or nivolumab in patients with metastatic pancreatic ductal adenocarcinoma.Irreversible electroporation (IRE) is a novel image-guided tumor ablation technique with the ability to generate a window for the establishment of systemic antitumor immunity. IRE transiently alters the tumor’s immunosuppressive microenvironment while simultaneously generating antigen release, thereby instigating an adaptive immune response. Combining IRE with immunotherapeutic drugs, i.e., electroimmunotherapy, has synergistic potential and might induce a durable antitumor response. The primary objective of this study is to assess the safety of the combination of IRE with IMO-2125 (a toll-like receptor 9 ligand) and/or nivolumab in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC). In this randomized controlled phase I clinical trial, 18 patients with mPDAC pretreated with chemotherapy will be enrolled in one of three study arms: A (control): nivolumab monotherapy; B: percutaneous IRE of the primary tumor followed by nivolumab; or C: intratumoral injection of IMO-2125 followed by percutaneous IRE of the primary tumor and nivolumab. Assessments include contrast enhanced computed tomography (ceCT), 18F-FDG and 18F-BMS-986192 (PD-L1) positron emission tomography (PET)-CT, biopsies of the primary tumor and metastases, peripheral blood samples, and quality of life and pain questionnaires. There is no curative treatment option for patients with mPDAC, and palliative chemotherapy regimens only moderately improve survival. Consequently, there is an urgent need for innovative and radically different treatment approaches. Should electroimmunotherapy establish an effective and durable anti-tumor response, it may ultimately improve PDAC’s dismal prognosis.

Real-World Treatment Patterns and Outcomes in Patients with Head and Neck Cancer: Point-in-Time Survey of Oncologists in Italy and Spain.

Squamous cell carcinomas of the head and neck (SCCHN) account for approximately 4% of all malignancies and are associated with high morbidity and poor prognosis. For patients who are not eligible for surgery or radiotherapy, treatment options are limited, especially for those with recurrent or metastatic (R/M) disease. Current European guidelines recommend first-line (1L) treatment with palliative chemotherapy, using biologic or platinum-based regimens. In the absence of new clinical trials in SCCHN, the use of real-world data has facilitated the assessment of treatment patterns and outcomes in different healthcare systems. This study reports on the 1L treatment of platinum-eligible patients with R/M SCCHN in Italy and Spain. A point-in-time survey of the management of patients with R/M SCCHN was completed by clinical oncologists in Italy and Spain between October 2018 and February 2019. Patient demographics and clinical characteristics were obtained by retrospective chart review, whilst participating patients self-reported the impact of their disease on their quality of life (QoL) and well-being. A total of 436 patients were recruited from Italy (216) and Spain (220). Patient demographics for both countries comprised mostly male patients, aged 65years in Italy and 63 in Spain on average. The primary site for the SCCHN was the pharynx and 36% of patients had metastatic disease overall. EXTREME or cetuximab-based regimens were the most common treatments administered at 1L (52% in Italy and 78% in Spain). Scores on the FACT-G in both countries were substantially lower than those of the general and other advanced cancer populations, while scores on the EQ-5D were clinically meaningfully lower than local population norms. Despite 1L treatment of platinum-eligible patients with R/M SCCHN in Italy and Spain following current European guidelines, patients' QoL remains poor, which highlights the need for alternative treatments that could improve clinical outcomes.

HYAL4-V1/Chondroitinase (Chase) Drives Gemcitabine Resistance and Predicts Chemotherapy Failure in Patients with Bladder Cancer.

Gemcitabine-based chemotherapy regimens are first-line for several advanced cancers. Because of better tolerability, gemcitabine + cisplatin is a preferred neoadjuvant, adjuvant, and/or palliative chemotherapy regimen for advanced bladder cancer. Nevertheless, predicting treatment failure and overcoming resistance remain unmet clinical needs. We discovered that splice variant (V1) of HYAL-4 is a first-in-class eukaryotic chondroitinase (Chase), and CD44 is its major substrate. V1 is upregulated in bladder cancer and drives a malignant phenotype. In this study, we investigated whether V1 drives chemotherapy resistance. V1 expression was measured in muscle-invasive bladder cancer (MIBC) specimens by qRT-PCR and IHC. HYAL-4 wild-type (Wt) and V1 were stably expressed or silenced in normal urothelial and three bladder cancer cell lines. Transfectants were analyzed for chemoresistance and associated mechanism in preclinical models. V1 levels in MIBC specimens of patients who developed metastasis, predicted response to gemcitabine + cisplatin adjuvant/salvage treatment and disease-specific mortality. V1-expressing bladder cells were resistant to gemcitabine but not to cisplatin. V1 expression neither affected gemcitabine influx nor the drug-efflux transporters. Instead, V1 increased gemcitabine metabolism and subsequent efflux of difluorodeoxyuridine, by upregulating cytidine deaminase (CDA) expression through increased CD44-JAK2/STAT3 signaling. CDA inhibitor tetrahydrouridine resensitized V1-expressing cells to gemcitabine. While gemcitabine (25-50 mg/kg) inhibited bladder cancer xenograft growth, V1-expressing tumors were resistant. Low-dose combination of gemcitabine and tetrahydrouridine abrogated the growth of V1 tumors with minimal toxicity. V1/Chase drives gemcitabine resistance and potentially predicts gemcitabine + cisplatin failure. CDA inhibition resensitizes V1-expressing tumors to gemcitabine. Because several chemotherapy regimens include gemcitabine, our study could have broad significance.

A cost-utility analysis of avelumab for metastatic Merkel cell carcinoma in Taiwan.

BackgroundMetastatic Merkel cell carcinoma (mMCC) has traditionally been managed with palliative chemotherapy regimens or best supportive care (BSC). Avelumab, a novel anti‐programmed death‐ligand 1 (PD‐L1) human monoclonal antibody for mMCC treatment, is being studied in the pivotal JAVELIN Merkel 200 trial.AimIncorporating trial results, this analysis aimed to evaluate the cost‐utility of avelumab in Taiwan.Methods and resultsA de novo partitioned‐survival model with three key health states related to survival (progression‐free disease, progressed disease, and death) was applied in this study. The data of clinical efficacy, safety, and patient utilities were obtained from the JAVELIN Merkel 200 trial, literature review, and Taiwanese clinical expert opinion. Cost‐utility analysis was performed, and results were presented as cost per quality‐adjusted life year (QALY) gained. For treatment‐naïve patients, the incremental cost‐effectiveness ratios (ICERs) for avelumab vs BSC and avelumab vs chemotherapy were US$44885.06 and US$42993.06 per QALY gained, respectively. As to treatment‐experienced mMCC patients, avelumab was associated with ICERs of US$27243.06 (vs BSC)/US$26557.43 (vs chemotherapy) per QALY gained. All ICERs remained consistently within the willingness‐to‐pay (WTP) threshold of US$53,333.33 per QALY gained.ConclusionThis study demonstrated avelumab to be a cost‐effective treatment option for both treatment‐experienced and treatment‐naïve mMCC patients with very poor prognosis in Taiwan.

Investigating real-world treatment sequencing outcomes in advanced pancreatic cancer: A purple translational registry analysis.

386 Background: Current standard combination first line palliative chemotherapy regimens in advanced pancreatic ductal adenocarcinoma (PDAC) have not been compared in head-to-head trials. Data on optimum treatment sequencing is also lacking. Methods: To assess whether first line (1L) treatment with gemcitabine/nab-paclitaxel (Gem/Nab-P)(SEQ1) or FOLFIRINOX (SEQ2) in the palliative treatment setting impacts survival outcomes, data for patients receiving palliative intent combination chemotherapy between 2016 and May 2020 was extracted from PURPLE, a prospective pancreatic cancer registry enrolling consecutive patients across multiple institutions. Results: Of 637 patients, 180 (28%) who received 1L single agent therapy and/or palliative radiotherapy were excluded. Of the remaining 449 patients, 132 (29%) had locally advanced disease (LA PDAC), 67 had local recurrence (15%), and 250 (56%) had de novo metastatic disease (mPDAC). Patients receiving 1L Gem/Nab-P (n=376, 84%) were older (median 67 vs 59 years, P&lt;0.001), had a higher Charlson Comorbidity Index (CCI) (CCI ≥2: 18% vs 3%, Odds Ratio [OR] 8.0, P=0.002), and poorer performance status (ECOG≥2: 10% vs 1%, OR 8.4, P=0.01) compared to the 1L FOLFIRINOX group (n=73, 16%). 140 (37%) patients receiving 1L Gem/Nab-P (SEQ1) and 32 (44%) patients receiving 1L FOLFIRINOX (SEQ2) received second line (2L) chemotherapy. SEQ1 2L regimens included FOLFIRINOX (n=14), FOLFIRI (n=49), FOLFOX (n=35) and 5FU alone (n=3). SEQ2 2L regimens included Gem/Nab-P (n=19), Gem/5FU (n=4), Gem/Cisplatin (n=1) and gemcitabine alone (n=5). Median progression free survival (mPFS) did not differ between patients receiving 1L Gem/Nab-P vs 1L FOLFIRINOX (5.7 vs 5.1 months, P=0.54); nor did median overall survival (mOS; 11.3 vs 12.3 months, P=0.37). In the subset of patients who went on to receive 2L chemotherapy, mPFS in 2L was shorter for SEQ1 compared to SEQ2 (2.9 vs 5.2 months, Hazard Ratio [HR] 1.3, P=0.03) but mOS did not differ (15.9 vs 17.3 months P=0.91). In the subset with LA PDAC, mPFS in 2L was comparable (2.9 vs 3.3 months, P=0.55) but mOS was significantly longer with SEQ1 (22.5 vs 13.8 months, HR 0.50, P=0.01). In mPDAC, mPFS in 2L was shorter with SEQ1 (2.3 vs 5.6 months, HR 1.64, P=0.03), but mOS did not differ by sequence (13 vs 17 months, P=0.23). Conclusions: There were no significant differences in survival outcomes between 1L choices of chemotherapy, despite patients offered 1L FOLFIRINOX (SEQ2) being younger and fitter. Survival differences observed for LA PDAC versus mPDAC will be further explored. Given the multiple potential confounders, randomised clinical trials are needed to make firmer conclusions regarding the optimal initial treatment for each patient subset.

Comparison of Gemcitabine Plus Cisplatin vs. Docetaxel Plus Fluorouracil Plus Cisplatin Palliative Chemotherapy for Metastatic Nasopharyngeal Carcinoma.

Objective: Our study aimed to compare the efficacy and toxicity of two chemotherapy regimens, gemcitabine plus cisplatin (GP) vs. docetaxel plus, fluorouracil plus cisplatin (TPF), in metastatic nasopharyngeal carcinoma (NPC) patients.Methods: We retrospectively enrolled metastatic NPC patients between July 2006 and December 2016 who were treated with TPF or GP palliative chemotherapy (PCT). The association between the PCT regimens and survival conditions was evaluated by log-rank tests and the Cox proportional hazards model. A cohort was created using propensity score matching with the ratio of 1:1 to clarify the results of the multivariable Cox regression analyses. Overall survival (OS) was the primary endpoint.Results: Of 266 eligible patients, 186 and 80 patients, respectively, received TPF and GP regimen. No significant difference was demonstrated in the survival rate between the GP and TPF groups (3-year OS: 52.6 vs. 50.3%; P = 0.929). However, multivariable analysis suggested receiving GP as an independent protective factor (hazard ratio, 0.864; 95% confidence interval, 0.753–0.992; P = 0.042). In the matched cohort, treatment with GP was also associated with a significantly higher OS (3-year OS: 52.6 vs. 35.6%, P = 0.042). Subgroup analysis indicated that the superiority of GP reflected in patients with secondary metastases rather than primary metastases. The incidence of grade 3 to 4 treatment-related toxicity was more common in the TPF group than in the GP group.Conclusion: Our study suggested that GP might be superior to TPF for metastatic NPC patients, especially those with secondary distant metastases. Further studies are necessary to validate our results.

Perbaikan Kualitas Hidup pada Pasien Solitary Fibrous Tumor Mediastinum: Perspektif Kemoterapi Paliatif

Background: Mediastinal solitary fibrous tumor (SFT) is a rare spindle cell neoplasm. Approximately 1 to 8% of these intrathoracic tumors have been reported to occur in the mediastinum. The chief complaints of mediastinal SFT are cough, shortness of breath or chest pain, or may occur as asymptomatic incidental mass. The treatment of choice for SFT is extensive surgical resection. However, when the tumor cannot be removed surgically or when metastases occur, chemotherapy and or radiotherapy can be proposed as palliative treatments. Case: A 19-year-old man with chief complaint of left chest pain and referred to his left back. The complaint is accompanied by cough without sputum and hoarseness. In thoracic CT scan with contrast, we found giant cystic mass suspect malignancy around 17x12x18 cm in left hemithorax, a minimal pericardial effusion, and left pleural effusion. There were positive tumor cell cytoplasm results in vimentin, negative tumor cell cytoplasm in CK, positive tumor cell membrane in CD99, cytoplasm of focal positive tumor cells in EMA, and negative tumor cells in CD34 which supported a solitary fibrous tumor in the immunohistochemical staining analysis. Doxorubicin-Ifosfamide regimen was the choice of chemotherapy palliative treatment in the case report. In the CT scan evaluation of thorax with contrast, we found stable disease (RECIST criteria) with improve quality of life (QOL) according to EQ-5D-3L, 11111 indicated no problems in 5 dimensions, such as mobility, self-care, usual activities, pain or discomfort, and anxiety or depression. Conclusion: Mediastinal SFT is a rare spindle cell neoplasm, and the diagnosis requires pathological and immunohistochemical staining analysis. Doxorubicin-Ifosfamide regimen can be proposed as a palliative chemotherapy regimen, which has been shown to improve QOL patients in Mediastinal SFT. EQ-5D is a simple tool that can be used to measure QOL such as mobility, self-care, usual activities, pain or discomfort, and anxiety or depression.

Survival of esophageal and gastric cancer patients with adjuvant and palliative chemotherapy\u2014a retrospective analysis of a register-based patient cohort

PurposeThe survival of esophageal and gastric cancer patients treated with chemotherapy is rarely assessed outside of clinical trials. Therefore, we compared the effectiveness of various curative or palliative chemotherapy regimens on the survival of esophageal and gastric cancer patients in a “real world” clinical setting.MethodsWe identified a cohort of 966 incident esophageal and gastric cancer patients in Stockholm/Gotland County (a low-risk Western population) during 2008–2013. Patients who received chemotherapy with curative intention (n = 279) and palliative intention (n = 182) were analyzed separately. Using Cox proportional hazards regression models, we estimated hazard ratios (HRs) with 95% confidence intervals (CIs) and adjusted for the potential confounding factors: age, sex, TNM stage, radiotherapy, comorbidity, marital status, education, income, and country of birth.ResultsIn esophageal cancer patients with curative treatment intention, we observed a higher hazard for death among patients who received carboplatin-fluorouracil compared to patients who received cisplatin-fluorouracil, corresponding to a HR of 2.18 (95% CI 1.09–4.37). Conversely, in patients with cancer in the gastroesophageal junction who had a curative treatment intention at diagnosis, we observed a reduced hazard for death among those who received fluorouracil-oxaliplatin, compared to patients who received cisplatin-fluorouracil (HR 0.28; 95% CI 0.08–0.96).ConclusionAmong patients with esophageal cancer who received treatment with curative intention, cisplatin-fluorouracil was associated with better survival compared to carboplatin-fluorouracil, while patients with gastroesophageal junction cancer who were treated with cisplatin-fluorouracil had worse survival compared to fluorouracil-oxaliplatin.