Single-agent Gemcitabine Research Articles

The efficacy of gemcitabine and docetaxel chemotherapy for the treatment of relapsed and refractory osteosarcoma: A systematic review and pre-clinical study.

Osteosarcoma is the most common primary malignancy of the bone. There is a lack of effective treatments for patients who experience relapsed osteosarcoma. One treatment for relapsed patients is gemcitabine and docetaxel combination chemotherapy (GEMDOX). This systematic review aimed to establish the efficacy of this chemotherapy regimen, as well as identify the common severe toxicities that are associated with it. Resistant osteosarcoma cell lines developed from MG-63 and HOS-143B were used to represent relapsed osteosarcoma patients in a pre-clinical study. We identified 11 retrospective and Phase II studies that were suitable for inclusion in our review. 10.65% of patients had a response to gemcitabine and docetaxel combination therapy and the disease control rate was 35% (n = 197). 36%, 35.3% and 18.04% of patients experienced grade 3 or 4 neutropenia, thrombocytopenia and anaemia respectively (n = 133). Male patients (X2 = 9.14, p < 0.05) and those below the age of 18 (X 2 = 10.94, p < 0.05) responded better to GEMDOX treatment than females and patients older than 18 years. The resistant osteosarcoma cell lines remained sensitive to either single-agent gemcitabine, docetaxel, and the combination of both. Cisplatin-resistant models (MG-63/CISR8 & HOS-143B/CISR8) were the most responsive to GEMDOX treatment compared to doxorubicin, methotrexate, and triple-combination resistant models. GEMDOX treatment has potential efficacy in relapsed osteosarcoma patients especially those with cisplatin resistance. To directly compare the efficacy of GEMDOX therapy against other therapies randomised phase III clinical trials with adequate patient follow up must be performed to improve treatment options for osteosarcoma.

Treatment Response and Survival with Chemotherapy for Unresectable, Nonmetastatic Cholangiocarcinoma.

Limited studies have dwelt upon the treatment of unresectable, nonmetastatic cholangiocarcinoma as a separate entity. Hence, the management protocols are not clearly defined for this subgroup of patients. We aimed to analyze patients treated for unresectable, nonmetastatic cholangiocarcinoma. We analyzed the treatment of patients with unresectable, nonmetastatic cholangiocarcinoma retrospectively. A total of 162 cases of cholangiocarcinoma were reported to our center from 2016 to 2019, out of which 54 were unresectable and nonmetastatic. Thirty patients opted for treatment and were the subjects of this study. Of 30 patients, 24 had hyperbilirubinemia, out of which 10 received chemotherapy after biliary drainage procedure. Out of 30 patients, a total of 16 patients had received chemotherapy, while 14 did not. Gemcitabine/Cisplatin was the first-line chemotherapy administered to 9 patients, whereas 5 received Gemcitabine/Capecitabine and 2 received single-agent gemcitabine. Partial response was documented in 6 patients, and 4 patients had stable disease. The median overall survival was 12.04 months in patients who had received chemotherapy and 6.02 months in those who did not receive chemotherapy (p = 0.005). The median progression-free survival was 6.53 months for patients who had received chemotherapy. The aHR for mortality with chemotherapy compared with no chemotherapy was 0.353 (95% CI: 0.154-0.807). The study data demonstrate that gemcitabine combined with cisplatin- or capecitabine-based chemotherapy prolongs survival in patients with unresectable and nonmetastatic cholangiocarcinoma. In patients with cholangiocarcinoma associated with jaundice, biliary drainage procedure enables giving chemotherapy. Hyperbilirubinemia persisting despite drainage procedures portends poor prognosis and represents an unmet need. Gupta A, Sahai P, Prasad M, et al. Treatment Response and Survival with Chemotherapy for Unresectable, Nonmetastatic Cholangiocarcinoma. Euroasian J Hepato-Gastroenterol 2024;14(1):5-8.

Resectability rate of pancreatic cancer after neoadjuvant therapy.

e16348 Background: Pancreatic Cancer is one of the leading causes of cancer death in Saudi Arabia. Surgery is the mainstay of treatment in resectable non-metastatic cases. Working on improving the resectability rate to achieve R0 resection is the standard of care. Methods: Unresectable cases of pancreatic adenocarcinoma seen from 2004 till 2018 in three hospitals in Saudi Arabia were reviewed to know the conversion rate from unresectable or borderline resectable to resectable after neoadjuvant chemotherapy and to explore the possible prognostic factors. The characteristics and outcomes of these patients were reviewed, with more attention on the known prognostic factors and their impact on the outcome. Notably, performance status, CA19-9, Neutrophil Lymphocyte Ration (NLR), and Platelet Lymphocyte Ratio (PLR). Overall response to neoadjuvant therapy, R0 resection, relapse free survival and overall survival were all reported. Results: Two hundred seventy-three captured cases of all types of pancreatic tumors from the tumor registry in the years between 2004 and 2018. 39 cases were unresectable or borderline resectable cases. The median age was 60 years (range:29-79), and 25 patients were males. 30 patients had an ECOG PS of 0-1and 6 had an ECOG PS of 2. The head of the pancreas was the primary tumor site in 31 patients and the body or tail was in 8 patients. 21 patients (54%) presented with weight loss ( &gt; 5kg), and 21 patients (54%) presented with obstructive jaundice. Neoadjuvant chemotherapy protocols were FOLFORINOX (13 patients, 33%), Gemcitabine/Capecitabine (10 patients), single agent Gemcitabine (10 patients), and other regimens in 6 patients. The median number of chemotherapy cycles was 6 (range: 1-14). 17 patients had dose reduction. 6 patients had preoperative radiation. Response to chemotherapy: ORR: 36%, SD: 26% and PD: 38% .Surgery was done after neoadjuvant therapy in 12 patients (31%). Only 4 out 12 had confirmed R0. Median Overall Survival (MS) and Progression-Free survival (PFS) in all patients were 30 mo (95% CI: 17.75 - 42.56) and 8 mo (95% CI: 5.65 - 11.89) respectively. MS in the surgery and the non-surgery groups was 30 and 25 mo (p- value = 0.26) respectively. The median PFS in the surgery and the non-surgery groups was 19.6 and 5.8 mo (p- value = 0.008) respectively. Multivariate regression analysis done for the following variables: ECOG PS of 2, elevated CA 199, high NLR &gt; 3, high PLR &gt; 225, weight loss and results showed numerical difference of both MS and PFS with no statistical significance (Type 2 error). Conclusions: The conversion rate from unresectable or borderline resectable to resectable after neoadjuvant therapy is 31% which is consistent with the international data. There is PFS improvement in those who underwent surgery (19.6 mo vs. 5.8 mo) with statistical significance (p:0.008), and there is numerical improvement of MS (30 mo vs. 25 mo) that did not reach statistical significance.

Patterns of chemotherapy use with primary radiotherapy for localized bladder cancer in patients 65 or older.

Bladder preservation with concurrent chemoradiotherapy after maximum transurethral resection of bladder tumor is an alternative to radical cystectomy in select patients with muscle invasive bladder cancer (MIBC). Concurrent administration of radio-sensitizing chemotherapy and radiation therapy (RT) has been shown to have superior disease control compared with RT alone and can often be administered with modest added toxicity. We sought to describe national patterns of chemotherapy use. The linked surveillance, epidemiology, and end results (SEER)-Medicare database was used to identify patients with cT2-4, N0/X, M0/X BC who received radiation between 2004 and 2018. Data on demographics, clinicopathologic factors, therapy and outcomes were extracted. Concurrent utilization of chemotherapy with RT was also identified (CRT). Multivariate logistic regression (MVA) models were used to explore factors associated with receipt of chemotherapy and overall survival (OS). 2190 patients met inclusion criteria. Of these, 850 (38.8%) received no chemotherapy. Among those receiving chemotherapy, the most frequent regimens were single agent carboplatin, cisplatin, or gemcitabine. Factors that were independently associated with decreased likelihood of chemotherapy use were increasing age (OR 0.93, CI 0.92 - 0.95), Hispanic race (compared with White, OR 0.62, CI 0.39 - 0.99), cT3 or T4 (compared with cT2, OR 0.70, CI 0.55 - 0.90), and lower National Cancer Institute comorbidity index (OR 0.60, CI 0.51 - 0.70) (p < 0.05). Variables independently associated with increased likelihood of receipt of chemotherapy were married status (OR 1.28, CI 1.06 - 1.54), higher socioeconomic status (OR 1.31, CI 1.06 - 1.64), and later year of diagnosis (OR 1.09, CI 1.06 - 1.12). Receipt of concurrent chemotherapy with RT was associated with superior OS compared with RT alone. Over a third of patients >/65 years old receiving curative-intent RT for MIBC do not receive concurrent chemotherapy. Considering the improvement in oncologic outcomes with CRT over RT alone and more options, such as low dose gemcitabine which can be administered with modest toxicity, efforts are needed to identify barriers to utilization and increase the use of radio-sensitizing chemotherapy.

Retrospective evaluation of our patients diagnosed with advanced pancreatic cancer

Aims: Pancreatic cancer attracts attention with its increasing frequency among gastrointestinal cancers. It has the worst prognosis of all cancer types. In this study, we aimed to retrospectively evaluate the clinical features and treatment results of our patients with advanced pancreatic cancer. Methods: In this study, 131 patients diagnosed with advanced pancreatic cancer and admitted to the Ankara Numune Training and Research Hospital Medical Oncology Polyclinic between November 2002 and January 2014 were retrospectively analyzed. Demographic characteristics of the patients, smoking, family history, basal CEA and basal CA 19-9 levels, treatment modalities, metastasis sites, progression-free survival, and overall survival times were evaluated. Results: The study population consisted of 131 patients, including 94 males and 37 females. Twenty of the patients were in the locally advanced stage, and 111 were in the metastatic stage. The median age of the patients was 60 years. 53.4% of the patients were smokers, and the median amount of smoking was 30 packs/year. Adenocancer was the most common histopathological subtype. The median basal CEA and Ca 19-9 levels were high at the time of diagnosis. Neoadjuvant chemotherapy was given to all locally advanced patients. The most commonly used chemotherapy regimens were single-agent gemcitabine and gemcitabine-cisplatin combination therapies. While 10 of the locally advanced patients received local treatment (chemotherapy or surgery) after neoadjuvant chemotherapy, the remaining 10 patients could not receive local treatment. The median overall and progression-free survival times were found to be significantly longer in patients with locally advanced disease who received local treatment after neoadjuvant chemotherapy [(18 months vs. 6.5 months; p=0.008), (11.3 months vs. 6.4 months; p=0.05)]. The most common site of metastasis in our patients with metastatic pancreatic cancer was the liver (80%). Cisplatin-gemcitabine was preferred as a KT regimen in 63.4% of metastatic cases. The median overall survival time of the patients in the metastatic stage was 8.1 months, and the median progression-free survival time was 5.7 months. The median progression-free survival of all patients included in the study was 6.2 months, while the median overall survival was 8.8 months. Conclusion: The median overall survival of patients with locally advanced pancreatic cancer was significantly longer compared to metastatic patients (18 months vs. 8.1 months; p=0.028). Progression-free survival and overall survival of patients with locally advanced disease who received or did not receive local treatment after neoadjuvant chemotherapy were found to be significantly longer in patients who received local treatment. (11.3 months vs. 6.4 months; p=0.05) (18 months vs. 6.5 months; p=0.008). Response rates of patients with metastatic pancreatic cancer; It was 49% in the gemcitabine-cisplatin combination arm and 30% in the single-agent gemcitabine arm.

Betulinic acid, a major therapeutic triterpene of Celastrus orbiculatus Thunb., acts as a chemosensitizer of gemcitabine by promoting Chk1 degradation.

Celastrus orbiculatus Thunb., also called as oriental bittersweet vine or climbing spindle berry, a traditional Chinese herbal medicine has been used to treat a spectrum of painful and inflammatory diseases for centuries. Explored for their unique medicinal properties, C.orbiculatus offers additional therapeutic effects on cancerous diseases. The effect of single-agent gemcitabine on survival has not long been encouraging, combination therapies provide patients multiple chances of benefit for improved clinical response. This study aims at expounding the chemopotentiating effects and underlying mechanisms of betulinic acid, a primary therapeutic triterpene of C. orbiculatus in combination with gemcitabine chemotherapy. The preparation of betulinic acid was optimized using ultrasonic-assisted extraction method. Gemcitabine-resistant cell model was established by induction of the cytidine deaminase. MTT, colony formation, EdU incorporation and Annexin V/PI staining assays were used to evaluate cytotoxicity, cell proliferation and apoptosis in BxPC-3 pancreatic cancer cell line and H1299 non-small cell lung carcinoma cell line. Comet assay, metaphase chromosome spread and γH2AX immunostaining were applied for DNA damage assessment. Western blot and co-immunoprecipitation was used to detect the phosphorylation and ubiquitination of Chk1. Mode of action of gemcitabine in combination with betulinic acid was further captured in BxPC-3-derived mouse xenograft model. We noticed that the extraction method had an impact on the thermal stability of C. orbiculatus. Ultrasound-assisted extraction at room temperature in shorter processing time could maximize the overall yields and biological activities of C. orbiculatus. The major constituent was identified as betulinic acid, and the pentacyclic triterpene represented the prominent anticancer activity of C. orbiculatus. Forced expression of cytidine deaminase conferred acquired resistance to gemcitabine, while betulinic acid displayed equivalent cytotoxicity toward gemcitabine-resistant and sensitive cells. A combination therapy of gemcitabine with betulinic acid produced synergistic pharmacologic interaction on cell viability, apoptosis and DNA double-strand breaks. Moreover, betulinic acid abrogated gemcitabine-triggered Chk1 activation by destabilizing Chk1 loading via proteasomal degradation. The combination of gemcitabine and betulinic acid significantly retarded BxPC-3 tumor growth in vivo compared to single-agent gemcitabine treatment alone, accompanied with reduced Chk1 expression. These data provide evidence that betulinic acid is a potential candidate for chemosensitization as a naturally occurring Chk1 inhibitor and warrants further preclinical evaluation.

Ex-vivo analysis of programmed cell death on fibrolamellar carcinoma.

4103 Background: Fibrolamellar carcinoma (FLC) is a rare liver cancer with surgery as the only established treatment. Relapse is common (&gt;80%) and with 40% unresectable, there is a need for rationale systemic therapy. Empiric combinations, especially with lenvatinib (LEN) and gemcitabine (GEM), show promise, but are lacking a CLIA licensed laboratory rationale. Ex-Vivo Analysis of Programmed Cell Death (EVA-PCD), from Nagourney Cancer Institute, is an attempt to meet this need. Methods: Nagourney Institute analyzed FLC tissue (as previously described), with a panel of 34 single/26 combinations of available/promising agents from 18 drug classes. Drug concentration with 50% cell death (LC50), below, within, or above 1-standard deviation of the mean (n ≥ 15), define Highly-Sensitive/Intermediate/Resistant, respectively. Active/Moderate/Inactive are similarly defined but with n &lt; 15. Actionable defines clinically available drug(s), not resistant/inactive and ≥ 6 assays. Results: Forty-four samples from 40 patients (17M,23F, age 6-56, 23 states/4 countries) were analyzed: 80% were viable and 69% of high quality for a total of 378 assays (avg 12/patient). However, all patients had actionable agents, and 78% of the assays showed activity in at least some patients. All the universally resistant/inactive assays (22%) were single agent. 76% of assays were actionable in at least one patient (100% for combinations compared to 62% for single agents). EVA-PCD replicate FLC studies and experience, such as the failure of monotherapy and the importance of LEN. Of 11 patients who had treatment that matched testing, 72% responded as predicted, including 6 with 100% response to LEN and/or QUE as predicted. Overall LEN/QUE, LEN/EVE, TRE, REG, QUE, 5FU/INF performed the best, while single agent ALP, CAB, LAR, VOR, GEM, DAS and IBR all showed 0% activity when tested &gt; 5 times. The largest challenge is the need for an adequate amount of viable tissue to arrive within 24 hours. However our experience demonstrates that it is feasible from other countries and across the US. Conclusions: This is the first demonstration of CLIA approved human FLC tumor testing. Data are in line with literature and correlates clinically. Prospective data are needed to fully incorporate EVA-PCD testing into the clinic. [Table: see text]

Gemcitabine, cisplatin, nab-paclitaxel: The effectiveness of this regimen for gall bladder cancer.

e16168 Background: Locally Advanced inoperable/metastatic Gallbladder Cancers (GBC) are treated with either GC, GO, or single-agent Gemcitabine based on physician discretion. However, based on about 50% response rates (ORR) and prolonged survival in the phase II trial of biliary tract patients, were treated with Gemcitabine - Cisplatin - Nab-Paclitaxel (GCNP). Methods: Consecutive series of patients diagnosed with locally advanced (liver infiltration &gt; 5 cm, large nodes at porta, abutting duodenum), inoperable and metastatic biliary tract patients between January 2018 to August 2022 were evaluated for first-line chemotherapy GCNP, in the Multidisciplinary Joint Clinic (MDJC). The primary endpoint was ORR and the secondary endpoints were survival and tolerance. Results: A total of 142 patients received GCNP during the specified time period. The median age of the cohort was 52 years (range: 21- 79), the majority were females (61.3%), and the majority were GB (81.7%). Response rates were available in 137 patients. CR, PR, and SD were seen in 9 (6.3%), 87 (61.3%), and 24 (16.9%) respectively, for a RR of 67.6% and CBR of 84.5%. Median EFS was 9.92 (95% CI, 7.69- 12.14) months. Of the 52 patients in whom GCNP was given with NACT intent for locally advanced GBC, 17 patients underwent surgery (34%). Conclusions: Our study indicates that GCNP leads to better response rates, better chances of unresectable disease being surgically feasible at a later date, and possibly offers better survival in the GBC cohort.

Co-delivery of gemcitabine and salinomycin in PEGylated liposomes for enhanced anticancer efficacy against colorectal cancer

Colorectal cancer remains one of the major causes of morbidity and mortality in both developed and emerging countries. Cancer stem cells (CSCs) are a subpopulation of cells within the tumor mass harboring stem cell characteristics, considered responsible for tumor initiation, growth, relapse, and treatment failure. Lately, it has become clear that both CSCs and non-CSCs have to be eliminated for the successful eradication of cancer. Drug delivery systems have been extensively employed to enhance drug efficacy. In this study, salinomycin (SAL), a selective anti-CSC drug, and gemcitabine (GEM), a conventional anticancer drug, were co-loaded in liposomes and tested for optimal therapeutic efficacy. We employed the Design of Experiments approach to develop and optimize a liposomal delivery system for GEM and SAL. The antiproliferative effect of the liposomes was evaluated in SW-620 human colorectal cancer cells. The GEM and SAL-loaded liposomes exhibited adequate size, polydispersity, zeta potential, and drug content. The in vitro release study showed a sustained release of GEM and SAL from the liposomes over 72 h. Moreover, no sign of liposome aggregation was seen over 1 month and in a biological medium (FBS). The in vitro cytotoxic effects of the co-loaded liposomes were superior to that of single GEM either in free or liposomal form. The combination therapy using GEM and SAL co-loaded in liposomes could be a promising strategy for tackling colorectal cancer.

Neoadjuvant chemotherapy and radiotherapy outcomes in borderline-resectable and locally-advanced pancreatic cancer patients.

There is no agreed upon standard of care for borderline-resectable pancreatic cancer (BRPC) or locally-advanced pancreatic cancer (LAPC) patients regarding the benefit of chemotherapy or radiation alone or in combination. We completed a retrospective cohort analysis of BRPC and LAPC patients at a cancer center with expertise in multi-disciplinary pancreatic ductal adenocarcinoma (PDAC) treatment over a 5-year period from 03/01/2014 to 03/01/2019 (cut-off date). The total evaluable newly diagnosed, treatment naïve, BRPC, and LAPC patients with adequate organ function and ability to obtain treatment after multidisciplinary review was 52 patients. After analysis, patients were evaluated for rates of resection, extent of resection (R0 or R1), median progression-free survival (mPFS), and median overall survival (mOS). Patients were treated with chemotherapy alone (gemcitabine and nab-paclitaxel=77% (20/26); FOLFIRINOX=19% (5/26); single agent gemcitabine 3.8% (1/26)), or chemotherapy followed by chemoradiation (gemcitabine +5Gy × 5 weeks), or chemoradiation alone prior to re-staging and potential resection. Of the 29% (15/52) of patients who went on to surgical resection, 73% (11/15) achieved R0 resection. An R0 resection was achieved in 35% (9/26) of patients treated with chemotherapy alone, 7.6% (1/13) in a patient treated with chemotherapy followed by radiation, and 7.6% (1/13) with concurrent chemoradiotherapy alone. Chemotherapy alone achieved a mPFS of 16.4months (p < 0.0025) and mOS of 26.2months (p < 0.0001), chemotherapy followed by chemoradiation was 13.0months and 14.9months respectively, while concurrent chemoradiotherapy was 6.9months and 7.3months. BRPC and LAPC patients capable of surgery after only receiving neoadjuvant treatment with chemotherapy had higher rates of R0 resection with prolonged median PFS and OS compared with any patient needing combination chemotherapy with radiotherapy.

Efficacy and safety of neoadjuvant Folfirinox and Gemcitabine plus Nab-Paclitaxel for borderline resectable and locally advanced pancreatic cancer: a systematic review and meta-analysis.

Multi-agent regimens such as Folfirinox and gemcitabine plus nab-paclitaxel have shown significant improvements compared with single-agent gemcitabine as neoadjuvant chemotherapy for patients with borderline resectable or locally advanced pancreatic cancer. However, the efficacy and safety of Folfirinox and GNP as NAC for BRPC and LAPC is still controversial. The eligible studies including prospective, retrospective, and randomized controlled trial related to Folfirinox and GNP as NAC for patients with BRPC or LAPC up to March 2022 were searched and assessed. Pooled analysis for chemotherapy response rate, resection rate, R0 resection rate, progress free survival, overall survival, and grade 3/4 events of toxicity were performed in the study. Eight studies were included in this meta-analysis. Compared with GNP, Folfirinox had higher resection rate (HR=0.82; 95% CI 0.59-1.14) and R0 resection rate (HR=0.77; 95% CI 0.60-0.97), better PFS (HR=0.78; 95% CI 0.55-1.12) and OS (HR=0.68; 95% CI 0.46-0.99), and without increasing severe toxicity rate (HR=0.95; 95% CI 0.71-1.28). There are no differences in rate of stable disease (HR=1.06; 95% CI 0.92-1.22) and partial/complete regression (HR=0.85; 95% CI 0.59-1.23) between two groups. Higher resection and R0 resection rate and better PFS and OS results were obtained in Folfirinox group compared with GNP group for patients with BRPC and LAPC. There was no increased severe toxicity rate for Folfirinox compared with GNP.

Individual patient data meta-analysis of adjuvant gemcitabine-based chemotherapy for biliary tract cancer: combined analysis of the BCAT and PRODIGE-12 studies

BackgroundAlthough gemcitabine-based chemotherapy is the standard of care for advanced biliary tract cancers (BTCs), adjuvant phase III studies (BCAT in Japan, PRODIGE 12 in France) failed to show benefit, possibly owing to fewer patients (n = 225 and n = 194) compared with the adjuvant capecitabine BILCAP trial (n = 447). We performed a combined analysis of both gemcitabine-based chemotherapy adjuvant studies. MethodsWe performed individual patient data meta-analysis of all patients included in BCAT and PRODIGE 12. BCAT study randomised patients with extrahepatic cholangiocarcinoma to single-agent gemcitabine or observation. PRODIGE 12 randomised patients with all BTC subtypes to gemcitabine-oxaliplatin combination or observation. Combined analysis was performed using Kaplan–Meier curves and a Cox regression model stratified on the trial. ResultsTwo hundred and twelve versus 207 patients were randomised in the gemcitabine-based chemotherapy versus observation arms. Baseline characteristics were balanced between arms. The median follow-up was 5.5 years. After 258 relapse-free survival (RFS) events, there was no difference in RFS (log-rank p = 0.45; hazard ratio [HR] = 0.91 [95% confidence interval [CI] 0.71–1.16]; p = 0.46). RFS rates at five years were 40.8% (95%CI: 33.9%–47.5%) for gemcitabine-based chemotherapy versus 36.6% (95%CI: 29.8%–43.4%) for observation. After 201 deaths, there was no difference in overall survival (OS) (log-rank p = 0.83; HR = 1.03 [95%CI: 0.78–1.35]; p = 0.85). OS rates at five years were 50.5% (95%CI: 43.1%–57.4%) for gemcitabine-based chemotherapy versus 49.3% (95%CI: 41.6%–56.5%) for observation. ConclusionWith 419 patients included, this analysis did not show significant improvement in RFS and no trend in improvement in OS. Gemcitabine-based chemotherapy should not be used as an adjuvant treatment for BTC.

Pancreatic cancer treatment after FOLFIRINOX: prognostic importance of chemotherapy dose intensity and albumin/globulin ratio in second line

Aim: Pancreatic adenocarcinoma (PA) is the seventh most common cause of cancer-related mortality. Our primary endpoint of study was to determine the relationship between albumin/globulin ratio (AGR) and progression-free and overall survival (PFS and OS) in second-line treatment after FOLFIRINOX. Our secondary endpoint was to assess treatment side effects and the relationship of treatment dose intensity with treatment type and AGR.&#x0D; Material and Method: PA patients who followed-up between January 2014 and January 2021 were evaluated retrospectively. Age, gender, ECOG score and AGR recorded at the beginning of the second-line treatment. Thrombocytopenia, neutropenia, chemotherapy type, chemotherapy dose intensity, PFS and OS were recorded during the second-line treatment.&#x0D; Results: Median age 64 (44-80), 72 (70.6%) male, 102 metastatic PA patients were evaluated. 76 (74.5%) patients were ECOG 0-1, 26 (25.5%) patients were ECOG 2. Of these patients in the second step, 68 (66.7%) received single-agent gemcitabine and 34 (33.3%) received Nab-paclitaxel + gemcitabine treatment. Progression and exitus events occurred in all cases. Median PFS was 166.8 days in the AGR&gt;1.2 group, it was 80.7 days in the AGR1.2 group, it was 144 days in the AGR1.2 group, it was 71.3% in the AGR

The Association of Drug-Funding Reimbursement With Survival Outcomes and Use of New Systemic Therapies Among Patients With Advanced Pancreatic Cancer

Gemcitabine-nab-paclitaxel (GEMNAB) and fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) both improve survival of patients with advanced pancreatic cancer when compared with single-agent gemcitabine in clinical trials. To describe changes in the survival of patients with advanced pancreatic cancer associated with sequential drug-funding approvals and to determine if there exist distinct patient populations for whom GEMNAB and FOLFIRINOX are associated with survival benefit. This population-based, retrospective cohort study examined all incident cases of advanced pancreatic cancer treated with first-line chemotherapy in Ontario, Canada (2008-2018) that were identified from the Cancer Care Ontario (Ontario Health) New Drug Funding Program database. Statistical analysis was performed from October 2020 to January 2021. First-line chemotherapy for advanced pancreatic cancer. The main outcomes were the proportion of patients treated with each chemotherapy regimen over time and overall survival for each regimen. Cox proportional hazards regression models were used to compare overall survival between treatment regimens after adjustment for confounding variables, inverse probability of treatment weighting, and matching. From 2008 to 2018, 5465 patients with advanced pancreatic cancer were treated with first-line chemotherapy in Ontario, Canada. The median (range) age of patients was 66.9 (27.8-93.4) years; 2447 (45%) were female; 878 (16%) had prior pancreatic resection, and 328 (6%) had prior adjuvant gemcitabine. During the time period when only gemcitabine and FOLFIRINOX were funded (2011-2015), 49% (929 of 1887) received FOLFIRINOX. When GEMNAB was subsequently funded (2015-2018), 9% (206 of 2347) received gemcitabine, 44% (1034 of 2347) received FOLFIRINOX, and 47% (1107 of 2347) received GEMNAB. The median overall survival increased from 5.6 months (95% CI, 5.1-6.0 months) in 2008 to 2011 to 6.9 months (95% CI, 6.5-7.4 months) in 2011 to 2015 to 7.6 months (95% CI, 7.1-8.0 months) in 2015 to 2018. Patients receiving FOLFIRINOX were younger and healthier than patients receiving GEMNAB. After adjustment and weighting, FOLFIRINOX was associated with better overall survival than GEMNAB (hazard ratio [HR], 0.75 [95% CI, 0.69-0.81]). In analyses comparing patients treated with GEMNAB and gemcitabine, GEMNAB was associated with better overall survival (HR, 0.86 [95% CI, 0.78-0.94]). This cohort study of patients with advanced pancreatic cancer receiving first-line palliative chemotherapy within a universal health care system found that drug funding decisions were associated with increased uptake of new treatment options over time and improved survival. Both FOLFIRINOX and GEMNAB were associated with survival benefits in distinct patient populations.

Activity of single-agent gemcitabine in patients (pts) with advanced angiosarcoma: A retrospective study.

e23547 Background: Gemcitabine has shown clinical activity against angiosarcoma in single cases or small series, as a single agent or in combination with taxanes. We aimed to evaluate its activity in a larger, homogeneous series of pts with advanced angiosarcoma. Methods: We retrospectively reviewed the electronic medical records of consecutive adult pts with advanced angiosarcoma treated with gemcitabine(1000 mg/m2 IV days 1, 8 and 15 of a 28-days cycle) at our institutions from January 2010 to January 2021. All cases were confirmed by an expert pathologist from the French network of Sarcoma pathologists (RRePS). Response was evaluated according to RECIST 1.1, and survival was estimated using the Kaplan-Meier method. Results: Fourty-two pts [median age : 52 years (range : 25-90), median PS : 1 (range : 0-2), 36 women)] were identified. Ten (24%) had locally advanced disease; the median number of metastatic sites was 2 (range : 1-4) in the remaining 32 pts. Primary tumor site was breast/chest wall (12), face/scalp (9), heart (8), other viscera (7) or limbs (7). Eleven (26%) occurred in previously irradiated field. All pts but 4 had received prior anthracyclines (peri-operatively or in the metastatic setting) and weekly paclitaxel, and 9 (21%) had received pazopanib. Gemcitabine was given as second, third and fourth line in 7 (17%), 20 (47%) and 15 (36%) pts, respectively. Best tumor response by RECIST 1.1 was PR (16 pts, 38%), SD (10 pts, 24%) or PD (16 pts, 38%). All pts with cardiac angiosarcoma experienced a PR, as well as 4 of 10 pts with angiosarcoma arising in irradiated field and 3 of the 4 pts with CNS metastases. Median PFS was 5.4 months (95%CI : 3.1-6.5), and median OS was 9.9 months (95%CI : 6.6-13.4). Two febrile neutropenia occurred. No new safety signal was observed. Ongoing studies are exploring whether candidate biomarkers such as hENT1 expression could help predicting the benefit of gemcitabine in pts with angiosarcoma of the heart and large vessels. Conclusions: Single agent gemcitabine has clinically meaningful activity in advanced, heavily pre-treated angiosarcoma (including cardiac angiosarcoma). This series may serve as a benchmark for future clinical trials in angiosarcoma.

A review of evidence supporting NCCN category 2B off-label recommendations for determination of Medicare reimbursement eligibility.

6576 Background: Antineoplastic indications supported by a category 1 or 2A NCCN recommendation are reimbursed by insurance and Medicare, as are FDA-approved indications. While initial reimbursement requests for “off-label” NCCN category 2B indications may be denied, Medicare will reimburse off-label antineoplastic use supported by evidence from a peer-reviewed publication from one of 26 designated journals. Here, we evaluated the published clinical evidence supporting NCCN category 2B indications. Methods: Category 2B drug indications for the 10 most common solid tumor types were identified in the NCCN compendium (n=104). The results were then filtered to include drugs with only category 2B indications in a particular tumor type (n=14). Similarly, FDA-approved indications were excluded, resulting in a list of drugs with only a 2B indication that are not FDA approved in the specified cancer type (n=8). Published clinical studies supporting these category 2B indications were assessed for study type and journal name in PubMed, and journal names were cross-referenced with the CMS-supported list. Results: Among the 8 non-FDA-approved drug indications with only category 2B recommendations, 7 (87%) had at least one publication of a clinical trial in one of the 26 designated journals. The only 2B indication without supporting literature was single-agent gemcitabine hydrochloride in bladder cancer. For further details, see Table. Conclusions: These results suggest that clinicians should consider pursuing the appeals process and provide supporting evidence in cases of claim denial. While coverage is not guaranteed, the evidence supporting 2B indications frequently meets the criteria identified in the Medicare statute. Further studies will evaluate if these findings extrapolate to less common tumor types.[Table: see text]

Second-line chemotherapy (2L) in elderly patients with advanced biliary tract cancer (ABC): A multicenter real-world study.

322 Background: The ABC-06 trial recently established the role of 2L in ABC progressing after platinum/gemcitabine combination. However, older patients are often under-represented in clinical trials and no data are currently available regarding 2L in elderly ABC. The aim of this real-world study was to explore the treatment pattern, safety and efficacy of 2L in ABC patients aged ≥ 70 years old and to compare their outcomes with younger subjects. Methods: Institutional registries across three academic medical centers were retrospectively reviewed and data of interest retrieved to identify ABC who had received 2L from October 2002 to July 2020. Patients older than 70 years were considered as elderly individuals. The Kaplan-Meier methods was used to estimate survival and the log-rank test to make comparison. The impact of variables on survival was assessed through univariate and multivariate analysis. Results: A total of 190 ABC patients treated with 2L were identified and included in the analysis. Among them, 27.3% (n = 52) were aged ≥ 70 years (range 70-87y), of whom 25 patients had iCCA (48%), 13 GBC (25%) and 15 eCCA (27%). 56% (n = 29) were female and 38 (73%) patients had an ECOG-PS 0-1. The most frequently administered 2L regimens were capecitabine monotherapy (n = 14, 27%), single-agent gemcitabine (n = 9, 17%) and gemcitabine/capecitabine combination (n = 9, 17%). No differences in terms of prior surgery (p = 0.64) and 2L treatment intensity (p = 0.34) were observed compared to patients aged &lt; 70 years. The disease control rate of 2L was 28.8% and 29.7% in elderly and youngers, respectively. No statistically significant differences in both mOS (5.7 months in elderly vs 6.1 months in youngers, HR 0.97; p = 0.86) and mPFS (4.7 vs 4.8 months, HR 0.88; p = 0.44) were recorded. Regarding the safety profile of 2L, grade 3 or 4 treatment-related toxicities occurred more frequently in the older group (48.5% versus 8.2%; OR 6.31; p &lt; 0.001). When looking at prognostic factors, absolute lymphocyte count &lt; 1000/mmc (p &lt; 0.001) and albumin level &lt; 3 g/dL (p &lt; 0.001) were independently associated with worse prognosis. Conclusions: The results of this real-world study, limited by its retrospective nature and small sample size, suggest that for patients aged ≥ 70 years, 2L could be equally effective as for youngers, with survival outcomes aligned to those from ABC-06 trial. Notably, based on the higher incidence of grade 3-4 adverse events, the delivery of 2L should be carefully evaluated and monitored in this patient subset.

The impact of multi-agent chemotherapy in metastatic pancreatic adenocarcinoma: A population-based study utilizing the SEER database.

416 Background: Over the last decade, various landmark trials have demonstrated the impact of multi-agent chemotherapy in the treatment of PDAC. However, the impact in the ‘real world’ has been less clear. The ACCORD trial (2011) was a phase III trial comparing combination chemotherapy (FOLFIRINOX) and single agent (gemcitabine) for advanced disease. The MPACT trial introduced another beneficial regimen (nab-paclitaxel and gemcitabine) in 2013. Subsequently, multi-agent chemotherapy became standard of care for medically appropriate patients. Methods: We used the Surveillance, Epidemiology, and End Results (SEER) database to identify patients diagnosed with PDAC between 1998 and 2017. The cohort was divided into two groups: 1998-2011 (pre-ACCORD) and 2012-2017 (post-ACCORD). We analyzed all patients with metastatic PDAC for overall survival and compared results in the two groups using Kaplan Meier analysis and multivariate Cox proportional hazards models. An interrupted time series analysis was also used to compare the temporal trends in 2-year survival between 1998 and 2017. Results: A total of 47,134 patients were diagnosed with PDAC between 1998 and 2017. Nearly two-third of patients (26,438; 57%) had distant disease. On univariate survival analysis, there was a significant increased overall survival probability in the 2012-17 group compared to the 1998-2011 group (p&lt;0.05). The one- and two-year survival rates were 11% and 3% in the pre-ACCORD period compared to 14% and 4 % after the ACCORD trial respectively. This difference remained significant on multivariate analysis while adjusting for covariates (HR=0.08, 0.78-0.92, p=0.05). On interrupted time series analysis, we observed a steady rise in 2- year survival between 1998 and 2017. There was a significant jump in the two-year survival probability from 16% at 2011 to 20% at 2012 in metastatic PDAC (β=0.02, 0.009-0.03, p&lt;0.0001, Table). Conclusions: Beyond the randomized clinical trial arena, overall survival has increased over time, with a statistically significant jump around the time of the ACCORD trial. However, the absolute increase in the ‘real world’ is smaller than the gains observed in prospective clinical trials. [Table: see text]

Real-world outcomes in recurrent versus de novo metastatic pancreatic adenocarcinoma.

387 Background: Optimal management of patients with recurrent pancreatic ductal adenocarcinoma (PDAC) is unknown. In the clinical trials that established a survival benefit with combination chemotherapy compared to single agent gemcitabine, patients with recurrent PDAC were either excluded (PRODIGE-4) or severely underrepresented (MPACT). In this study, we evaluated clinical outcomes of recurrent PDAC patients who receive systemic therapy and compared outcomes to patients with de novo advanced PDAC. Methods: Patients diagnosed with advanced PDAC between 2014 and October of 2019 were included using the nationwide Flatiron Health EHR-derived de-identified database. Patients without a clinic visit or initiation of treatment within 90 days of diagnosis were excluded. Patients were characterized as either de novo or recurrent PDAC based on stage at diagnosis and history of surgery. Patients with recurrent PDAC were further stratified based on time to recurrent disease. Overall survival (OS) was summarized within groups via Kaplan-Meier survival estimates, and compared between groups in the context of univariable and multivariable Cox proportional hazards models. The covariates adjusted for were gender, age, race, ECOG, smoking status, primary site, CA199, albumin, lymphocytes, neutrophils and monocytes. Results: We included 5170 patients with advanced PDAC, of which 1101 (21.3%) met criteria for recurrent disease. Patients with recurrent PDAC were more likely to have tumors in the head of the pancreas (71% vs 40%, p &lt; 0.001) and had lower median CA19-9 (92.8 vs 617, p &lt; 0.001), compared to the de novo PDAC patients. Median OS for the recurrent group was 10.8 m (95% CI = 9.9-11.7) vs. 7.3 m (95% CI = 7.0-7.7) in the de novo group (p &lt; 0.001, both univariate and multivariable adjusted analyses). The most common first line palliative chemotherapy in patients with recurrent disease was Nab-paclitaxel plus gemcitabine (41%) or FOLFIRINOX (21%). Patients who recurred within six months of surgery (28%) had an OS of 10.0 m (95% CI = 8.7 -11) vs. 11.6 m (95% CI 10-12, p = 0.256) in those who recurred greater than six months from surgery. Conclusions: Our data suggest that patients with recurrent disease have significantly better survival outcomes compared to patients with de novo metastatic disease. We did not observe a significant difference in survival of patients who recurred within 6 months of resection compared to those who recurred greater than six months after surgery. These data support the inclusion of patients with recurrent PDAC in clinical trials, including those who develop recurrent disease within 6 months of surgery, with appropriate stratification for these variables.

A Population-Based Retrospective Study of Biliary Tract Cancers in Alberta, Canada.

Background: Biliary tract cancers (BTC) are uncommon malignancies and are underrepresented in the literature. Methods: We performed a retrospective population-based review of adult patients with biopsy-confirmed BTC in Alberta from 2000 to 2015. Demographic data, risk factors, symptoms, treatment, and staging data were collected and analyzed. Survival analyses were completed. Results: A total of 1604 patients were included in our study, of which 766 (47.8%) were male. The median age at diagnosis was 68 (range 19–99). There were 374 (23.3%) patients with resectable tumors at diagnosis versus 597 (37.2%) with unresectable tumors. Of the patients, 380 (21.5%) received chemotherapy (CT) and 81 (5.0%) underwent radiation therapy. There was a clear trend with worsening stage and performance status associated with shorter median overall survival (OS). Ampulla of Vater tumors had the best median OS (25.69 months), while intrahepatic bile duct cancers had the worst (5.78 months). First-line palliative CT regimens included gemcitabine+cisplatin (OS 14.98 months (mo), n = 212), single agent gemcitabine (OS 12.42 mo, n = 22), capecitabine (OS 8.12 mo, n = 8), and capecitabine+gemcitabine (OS 6.93 mo, n = 13). Patients with advanced or metastatic disease who received first-line gemcitabine+cisplatin had a median OS of 11.8 months (n = 119). Conclusion: BTCs have poor survival. Worse outcomes occur in higher stage and poorer Eastern Cooperative Oncology Group (ECOG) performance status patients across all tumor subtypes. Tumor resectability at diagnosis was associated with better OS. Our study supports the use of gemcitabine+cisplatin as a combination first-line palliative CT, as patients treated in Alberta have a comparable OS to that reported in the ABC-02 phase III study.