A Phase II Trial of Flouro-Gem as a First Line Treatment of Metastatic Adenocarcinoma of the Pancreas (GEFLUPAN trial)

A Phase II Trial of Flouro-Gem as a First Line Treatment of Metastatic Adenocarcinoma of the Pancreas (GEFLUPAN trial) | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article A Phase II Trial of Flouro-Gem as a First Line Treatment of Metastatic Adenocarcinoma of the Pancreas (GEFLUPAN trial) Ahmed Sohaib, Reham Abdelaziz, Faten Younis, Amira Hegazy This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3832387/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 18 Feb, 2024 Read the published version in The Egyptian Journal of Hospital Medicine → Version 1 posted You are reading this latest preprint version Abstract Background Gemcitabine and 5 FU + folinic acid both have proven activity in treatment of patients with advanced pancreatic cancer. Methods This prospective phase II study included 42 patients of metastatic cancer pancreas who met the inclusion criteria ( chemotherapy naïve, adult patients aged between 18 and 70 years, with histopathological evidence of adenocarcinoma, with radiological proof of metastatic disease, ECOG performance status (PS) ≤ 2, with adequate hematologic parameters and normal liver and kidney functions). Patients with end stage renal disease who are under regular dialysis, other histologies of pancreatic cancer, non-metastatic irresectable patients were excluded. The included patients received gemcitabine- flourouracil every 2 weeks, evaluated for response, assesed for quality of life and survival. Results The median age at diagnosis was 55 years. Males were more common (59.5%) than females. The most common site of metastasis was the liver (57.1%). Toxicity profile showed that neutropenia and thrombocytopenia were the most common forms of toxicity being high grade in 11.9% of patients. Other forms of toxicity were minimal not exceeding 5%. The ORR was 33.3% with no reported complete responses. There was a significant correlation between the change of tumor markers levels (CEA, and CA 19.9) and both response and quality of life. The changes of CEA and CA19.9 levels were found to be independent predictors of PFS. One year OS rate was 49%. The median OS was 11.3 months, while the median PFS was 8.8 months. Response was also found to be a surrogate marker for survival. Conclusions Gemcitabine- 5 FU combination is a good alternative option for treating metastatic pancreatic cancer, it had good efficacy and safety profile. pancreatic toxicity gemcitabine carcinoma 5 FU Figures Figure 1 Background - Pancreatic cancer is the fourth most common cause of cancer related death among United States men (after lung, prostate and colorectal cancer) and women (after lung, breast, and colorectal cancer) [1]. - Multiple aetiological factors have been linked to pancreatic cancer including smoking, exposure to heavy metals and chemicals as well as heavy alcohol consumption. [2,3]. About 10% of cases have familial component of the disease. ( 4 ) Gemcitabine has shown clinical efficacy when used for metastatic pancreatic adenocarcinoma. It became the standard of care for a considerable duration of time based on results from a randomized trial by Burris HA dating back to 1997( 5 ). In addition, gemcitabine offers better quality of life when compared to infusional 5-flourouracil (5FU) regimen which is also known for it’s efficacy against pancreatic cancer ( 6 ). Many studies have tested gemcitabine combinations for the treatment of pancreatic cancer. Among these studies, combination of albumin pound paclitaxel and gemcitabine has shown improvement in response rates as well as survival ( 7 ). Combination of gemcitabine plus capecitabine has been investigated in several randomized trials with proven benefit in terms of response rates and progression free survival (PFS) ( 8 ). Gemcitabine was the king of treatment for pancreatic cancer until the PRODIGE study was published showing superiority of another regimen over gemcitabine in terms of response and survival. This regimen is a four-agent protocol known as FOLFIRINOX combining oxaliplatin, irinotecan, leucovorin and 5FU. As expected, the toxicity profile of this regimen hindered it’s use in clinical practice to a great extent ( 9 ). In our study, we combined the two most active agents against pancreatic cancer; gemcitabine and 5FU; and given them every 2 weeks to gain the maximum benefit of both drugs and avoid the toxicity that occurs very frequently with FOLFIRINOX. Methodology Patients: This study is a prospective phase II clinical trial that included 42 patients with metastatic pancreatic cancer presented to Clinical Oncology Department, Menoufia University from February 2021 till July 2022 The study protocol was approved by the Research Ethics Committee of Menoufia University. Before being enrolled in the trial, all patients gave their informed consent. The trial was conducted according to Declaration Of Helsinki. It was registered in ClinicalTrials.gov under the name “A Phase II Trial of Flouro-Gem as a First Line Treatment of Metastatic Adenocarcinoma of the Pancreas (GEFLUPAN) ”, NCT04769414 Inclusion criteria chemotherapy naïve adult patients aged between 18 and 70 years with metastatic carcinoma of the pancreas with histopathological evidence of adenocarcinoma, with radiological proof of metastatic disease as defined by AJCC (8 the edition ,2017) [10], ECOG performance status (PS) ≤ 2 [11], with adequate hematologic parameters and normal liver and kidney functions. Exclusion criteria patients with end stage renal disease who are under regular dialysis, other histologies of pancreatic cancer, non metastatic irresectable pancreatic cancer. All patients underwent baseline evaluation including: thorough history taking and clinical examination, CBC, liver and kidney profiles, CEA, CA19-9, CT scan of the chest, abdomen and pelvis with contrast, or PET/CT as well as QLQ-C30 questionnaire Arabic version ( 12 ). We enrolled 48 patients but 6 of them were excluded either due to refusal of completing treatment or early death before assessment of response. Treatment : -The included patients received Gemcitabine at a dose of 1000 mg/m2 IV short infusion over 30 minutes, Leucovorin 400 mg/m2 IV short infusion over 30 minutes, Flourouracil 400 mg/m2 direct IV shot and Flourouracil 2000 mg/m2 continuous infusion over 46 hours. The whole regimen was cycled every 2 weeks. This regimen is abbreviated as Flouro-Gem. The whole protocol was given for a duration of six months for responding patients. Meanwhile, patients with progressive disease were shifted to a second line treatment as per physician’s choice. Filgrastim was not routinely used unless indicated. Toxicities of grade II or III were managed by dose reductions if occurred more than once. However, grade IV toxicity was a clear indication for permanent stopping of this protocol. Patients who presented with bilirubin level higher than 3 mg/dl were allowed to receive one or two cycles of the protocol without gemcitabine until improvement of bilirubin level. Counting of treatment cycles in these patients started with the use of gemcitabine not with the initiation of treatment. Evaluation: All patients had weekly CBC one day before chemotherapy administration and chemistry profile for liver functions (LFT) and kidney functions (KFT) every 2 weeks. Interim evaluation was done after 2–3 months of treatment with CT scan or PET/CT. We repeated the same investigation that was done in baseline assessment. CEA and CA19-9 were also repeated. Patients who had interim progression were subjected to re-assessment of quality of life. However, responding patients had quality of life reassessed at the end of treatment. End-of-treatment evaluation was also done by CT scan or PET/CT in addition to tumor markers assessment and quality of life. Response evaluation was done using RECIST criteria version 1.1 [13] -Toxicity was evaluated every cycle including: diarrhea, vomiting, mucositis, neutropenia, anemia, thrombocytopenia, and neuropathy. Toxicity grade was described according to CTCAE version 5[13]. -QOL was assessed for all patients using QOL-C30 at base line and at end of treatment or disease progression whichever earlier. Overall survival (OS) was calculated from the date of diagnosis to the date of death or last follow up. Progression free survival (PFS) was calculated from the date of diagnosis to the date of progression or last follow up. Statistical analysis of the data Data were tabulated and analyzed using SPSS package version 20. The primary end point was response rate and secondary end points included toxicity, quality of life and survival (PFS and OS). Chi-square test was used to examine the relation between qualitative variables. For quantitative data (change in CA19-9, CEA and QoL), comparison between three groups of response (partial, stable and progressive) was done using Kruskal Wallis test (non-parametric t-test). All tests were two-sided, with a P value of less than 0.05 considered to indicate statistical significance. Data are presented with 95% confidence intervals. Kaplan Meier method was used to calculate PFS and OS. Quality of life analysis was done according to EORTC guidelines ( 14 ). Results Over the period of one and a half years, we recruited 48 patients for the study. Only 42 patients completed the study and their data were submitted for analysis. Six patients were excluded either due to refusal of completing treatment or early death before assessment of response. The median age of diagnosis was 55 years being more common in males (59.5%) than females (40.5%). The most common site of metastasis was the liver (57.1%). The most common clinical presentations were abdominal pain (30.9%), jaundice (23.8%), vomiting (16.7%) and bony pains (16.7%). Table (1): Demographic and clinical characteristics of studied patients Parameter Studied patients (No.=42) Age (year) Mean ± SD Median (Range) 54.4 ± 7.0 55 (39–65) Gender Male Female 25 59.5% 17 40.5% Site of metastasis -Bone -Liver -Brain -LN -Lung 16 38.1% 24 57.1% 1 2.4% 8 19.0% 16 38.1% Clinical presentation -Abdominal pain -Bone pain -DVT -Vomiting -Back pain -Cord compression -Cough -Dyspnea -Jaundice 13 30.9% 7 16.7% 4 9.5% 7 16.7% 8 19.0% 1 2.4% 2 4.8% 1 2.4% 10 23.8% Baseline CEA Mean ± SD Median (Range) 143.8 ± 131.7 105.5 (5–516) Final CEA Mean ± SD Median (Range) 216.9 ± 182.5 225 (4–760) Baseline CA19-9 Mean ± SD Median (Range) 1129.4 ± 1026.9 743 (120–4500) Final CA19-9 Mean ± SD Median (Range) 1570.9 ± 1442.3 850 (40–4900) Presence of DVT Yes No 6 14.3% 36 85.7% Number of cycles 2 3 4 6 1 2.4% 4 9.5% 9 21.4% 28 66.7% Regularity Irregular Regular 3 7.1% 39 92.9% Dose density 50% 75% 80% 100% 1 2.4% 3 7.1% 1 2.4% 37 88.1% Baseline median CEA was 105.5 ng/ml that increased to 225 ng/ml at the end of treatment. Likewise, baseline median CA19-9 was 743 ng/ml that increased at end of treatment to 850 ng/ml. Deep vein thrombosis was detected in 14.3% of patients at presentation. The treatment protocol was given regularly in 92.9% of patients. The full dose regimen was given to 88.1% of patients meanwhile, 9.5% of patients had dose reductions in the range of 20–25%. One patient only had 50% dose reduction. Regarding the number of cycles, 66.7% of patients completed 6 months of treatment. Toxicity profile showed neutropenia is the most common form of toxicity being high grade in 11.9% of patients. Thrombocytopenia had a similar profile as it occurred in a high grade in 11.9% of patients. Other forms of toxicity were minimal not exceeding 5%. Low grade toxicities showed higher numbers with neutropenia being the highest occurring in 78.6% of patients and neuropathy being the least at 9.5%. Table (2): Toxicity profile of studied patients Parameter Grades of toxicity among studied patients (No.=42) Low grade (1, 2) High grade (3, 4) Diarrhea 20 (47.6%) 2 (4.8%) Vomiting 13 (31.0%) 2 (4.8%) Mucositis 14 (33.3%) 1 (2.4%) Neutropenia 33 (78.6%) 5 (11.9%) Anemia 10 (23.8%) 1 (2.4%) Thrombocytopenia 22 (52.4%) 5 (11.9%) Neuropathy 4 (9.5%) 0 (0.0%) The overall response rate was 33.3% with no patients achieving complete response. The changes in the levels of tumor markers was a significant factor for response. CA19-9 had more correlation with response than CEA. Median decrease by 70 ng/ml in the level of CA19-9 was associated with partial response while increases around 51 ng/ml was associated with disease progression. Likewise, their level had a significant relation with PFS and OS. The one-year overall survival was 49% while the one year progression free survival was 34.7%. The median overall survival was 11.3 months (95%CI = 10.17–12.45) and the median PFS was 8.8 months (95%CI = 7.3–10.4). Cox regression analysis showed that changes of CEA and CA19.9 were predictors of PFS (P. value = 0.01, 0.02 respectively). Table (3): Response of studied patients after end of treatment Parameter Studied patients (No.=42) Overall response rate (ORR) -Complete response -Partial response -Stable disease Progressive disease 14 33.3% 0 0.0% 6 14.3% 8 19.0% 28 66.7% Global health status improved for responding patients at end of treatment with a median score of 58.3 and 66.7 for partial response and stable disease respectively. Table (4) relation between changes in the levels of tumor markers and response Parameter Response after end of treatment among studied patients Test of significance P value Partial response (No.=6) Stable disease (No.=8) Progressive disease (No.=28) Change of CEA (%) Median(Range) 34 (18–159) 58 (15–318) 136 (5–516) Kruskal Wallis test = 4.85 0.09 Change of CEA (%) -Decreased -Increased 6 100% 0 0.0% 7 87.5% 1 12.5% 2 7.1% 26 92.9% χ2 test = 30.10 < 0.001* Change of CA19-9 (%) Median(Range) 70 (51.2–80.5) 6.6 (-21.9–35.7) -51.9 (-448-6.5) Kruskal Wallis test = 24.51 < 0.001* Change of CA19-9 (%) -Decreased -Increased 6 100% 0 0.0% 4 50.0% 4 50.0% 1 3.6% 27 96.4% χ2 test = 26.67 < 0.001* Table (5): Association between response and QoL Parameter Interim Response among studied patients Test of significance P value Partial response (No.=15) Stable disease (No.=13) Progressive disease (No.=14) Before treatment Global health status/QoL Median(Range) 33.3 (0–50) 16.7 (0–50) 16.7 (0–50) Kruskal Wallis test = 4.68 P = 0.09 P1 = 0.13 P2 = 0.04* P3 = 0.76 Response after the end of treatment among studied patients Partial response (No.=6) Stable disease (No.=8) Progressive disease (No.=28) After treatment Global health status/QoL Median(Range) 58.3 (58.3–83.3) 66.7 (50–83.3) 25 (0–58.3) Kruskal Wallis test = 26.99 P < 0.001* P1 = 0.73 P2 < 0.001* P3 < 0.001* Discussion In our investigation, we observed a male predominance, with males constituting 59.5% of the patient population. This is in line with the findings of Oettle et al., who reported a 65.8% male patient population, and Louvet et al., who found that 64.5% of their patient population were males. A similar trend was also reported by Oliani et al. The median age of patients in our study was 55 years, which is slightly lower than the median ages reported by Oettle et al. and Oliani et al. (60 years), and Louvet et al. (61.8 years). This variation could be due to the recruitment of a larger number of younger patients in our study, possibly due to the poorer performance status of older patients. As for the site of metastasis, our study identified the liver as the most common site in 57.1% of cases. This finding is consistent with those of Louvet et al., who reported a rate of 77.5%, and Oliani et al ( 16 , 17 ). Figuer ( 1 ) Kaplan Meier curve for overall survival and progression free survival Our study found that the most frequently reported toxicities were neutropenia and thrombocytopenia, a finding that aligns with the results of Louvet et al. However, the incidence of grade 3 and 4 toxicities in our study was lower. Specifically, we observed grade 3 neutropenia in 31.6% of patients and grade 4 neutropenia in 18.4% of patients. Thrombocytopenia of grade 3 was seen in 15.8% of patients, while grade 4 thrombocytopenia was observed in 2.6% of patients. These results were obtained with a 5-FU dosage of 2 gm/m2. In this study, Flouro-Gem regimen offered a good alternative option in treating patients with pancreatic adenocarcinoma. This regimen achieved a one-year survival of nearly half the patients (49%). The median overall survival was 11.3 months, which is better than numbers observed in similar studies by Oettle, et al (9 months), and Louvet, et al (8.4 months). Theses 2 trials used gemcitabine flurouracil, while the last one used the same protocol as our study with the same dose and schedule. This observation is consistent with and comparable to reports from other studies of gemcitabine in combination with 5-FU with or without folinic acid (FA). The median overall survivals for these studies were in the range 5.5–13 months [18,19,20]. Similarly, the median progression free survival (PFS) in this study was better (8.8 months versus 7.1 months). By far, these numbers are better than many regimens that included gemcitabine. Gemcitabine, both as a standalone treatment and in combination with other agents, has been globally studied for its effectiveness in treating pancreatic cancer. Phase III studies have demonstrated its efficacy, with a one-year overall survival rate of 18–20% and a median overall survival of approximately 6 months ( 22 ). The combination of nab-paclitaxel and gemcitabine has shown improved overall survival, extending from 6.7 months to 8.5 months. These figures reached their peak in a Swedish study, which reported a median overall survival of 10.9 months ( 23 , 24 ). The response rates were variable among trials ranging from 9 to 31%. In this study, the overall response rate was 33.3% which is very comparable to FOLFIRINOX which was 34.1%. However, the toxicity profile and safety were much better with Flouro-Gem. Neutropenia was the most frequent high grade toxicity being 11.9% versus 45% seen with FOLFIRINOX in some studies ( 9 ). Our results showed that no complete response (0%) was observed in this metastatic setting. This finding is also seen in other studies conducted on metastatic pancreatic cancer ( 15 ). Gemcitabine used in combination with cisplatin has shown evidence of increased efficacy compared to gemcitabine alone with response rates in the range of 11.5–36.4% [25], which is comparable to this study, but in all these studies the patients required hydration and treatment was associated with significant haematological toxicity, nephrotoxicity and alopecia, which is not found in this study. Also this study is more tolerable than gemcitabine- docetaxel, which was associated with significant haematological toxicity[26]. Quality of life has improved in patients responding to Flouro-Gem. The global health status scored 33.3 at interim evaluation and increased to 58 at end of treatment for patients with partial response. Interestingly, patients who had disease progression experienced numerical improvement in their QoL scores despite being non-statisctically significant. This -at least- shows that this regimen is tolerable and does not impair the QoL. This result was consistent with Oettle, et al, who showed that ≥ seventy-nine percent of patients showed a stabilization if not an improvement in their karnofosky performance status (KPS), and mild toxicity profile ( 15 ). On the contrary, FOLFIRINOX has resulted in impaired quality of life when compared with gemcitabine single agent. 31% of patients had decreased global health status scale. However, in the same study 66% of patients in the gemcitabine arm had experienced decline in the quality of life; a finding which is not observed in our study ( 9 ). Conclusion Flouro-Gem is a well-tolerated acceptable option for the first line treatment of metastatic pancreatic cancer with comparable results to other more toxic regimens and better outcomes than single agent protocols. Abbreviations 5FU: 5 flourouracil AJCC: American joint committee on cancer CA19-9: cancer antigen 19-9 CBC: complete blood count CEA: carcinoembryonic antigen CT: computed tomography CTCAE: common terminology criteria for adverse events DVT: deep vein thrombosis ECOG: Eastern co-operative oncology group EORTC: European organization for research and treatment of cancer IV: intravenous KFT: kidney function test LFT: liver function test ORR: overall response rate OS: overall survival PET/CT: positron emission tomography/computed tomography PFS: progression free survival QoL: quality of life RECIST: response evaluation criteria in solid tumors SD: standard deviation Declarations Declaration of interest: All authors declare no conflict of interest. Funding: This study was funded by Menoufia University, Egypt. Author Contribution A.S.:• Corresponding author ( [email protected] )• Recruitment of patients• Data collection• Writing the manuscript• Publishing the paperR. 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New England Journal of Medicine. 2013 Oct 31;369(18):1691-703. Kordes M, Yu J, Malgerud O, Gustafsson Liljefors M, Löhr JM. Survival benefits of chemotherapy for patients with advanced pancreatic cancer in a clinical real-world cohort. Cancers. 2019 Sep 7;11(9):1326. Heinemann V, Quietzsch D, Gieseler F, Gonnermann M, Schönekäs H, Rost A, Neuhaus H, Haag C, Clemens M, Heinrich B, Vehling-Kaiser U. Randomized phase III trial of gemcitabine plus cisplatin compared with gemcitabine alone in advanced pancreatic cancer. Journal of Clinical Oncology. 2006 Aug 20;24(24):3946-52. Jacobs AD. Gemcitabine‐based therapy in pancreas cancer: Gemcitabine‐docetaxel and other novel combinations. Cancer: Interdisciplinary International Journal of the American Cancer Society. 2002 Aug 15;95(S4):923-7. Additional Declarations No competing interests reported. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3832387","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":265205503,"identity":"695cb0a2-0e88-4848-bbe8-66b1c299d057","order_by":0,"name":"Ahmed Sohaib","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABDElEQVRIiWNgGAWjYDCCAwwMzECKsYGBgY2BweCAHFjwASlajMGCCcRrYTiQ2AASxaeF7/YBxs+FOTayDfyHjz34UXAnfX7Y4YdAW+zkdBuwa5E8l8AsPXNbmnGDRFq6YY/Bs9yNt9MMgFqSjc0OYNdicIaBQZp32+HEBgkeMwkeg8O5G2cngLQcSNyGWwvzb95t/xMb+M+YSf4xOJxuODv9AyEtbEBbQL7OMZMG2pIgL52D3xbJM4xt1rzbko3bJNLSpGUMnhlukM4pOJBggNsvfGeYD9/m3WYn2w8MMck3f+7Iy89O3/zhQ4WdHC4tkBhhgEQKxKlglQa4lGMD8g2kqB4Fo2AUjIKRAABPWWLEJgmddwAAAABJRU5ErkJggg==","orcid":"","institution":"Menoufia University","correspondingAuthor":true,"prefix":"","firstName":"Ahmed","middleName":"","lastName":"Sohaib","suffix":""},{"id":265205504,"identity":"9c3b35ef-ecdf-4287-96a8-2f7d04f9647b","order_by":1,"name":"Reham Abdelaziz","email":"","orcid":"","institution":"Menoufia University","correspondingAuthor":false,"prefix":"","firstName":"Reham","middleName":"","lastName":"Abdelaziz","suffix":""},{"id":265205505,"identity":"c6f5641e-f9fd-4685-9c3f-b5a25c02dbc4","order_by":2,"name":"Faten Younis","email":"","orcid":"","institution":"Menoufia University","correspondingAuthor":false,"prefix":"","firstName":"Faten","middleName":"","lastName":"Younis","suffix":""},{"id":265205506,"identity":"520c04aa-5f94-4754-9261-19557391981e","order_by":3,"name":"Amira Hegazy","email":"","orcid":"","institution":"Menoufia University","correspondingAuthor":false,"prefix":"","firstName":"Amira","middleName":"","lastName":"Hegazy","suffix":""}],"badges":[],"createdAt":"2024-01-03 17:14:11","currentVersionCode":1,"declarations":{"humanSubjects":false,"vertebrateSubjects":false,"conflictsOfInterestStatement":false,"humanSubjectEthicalGuidelines":false,"humanSubjectConsent":false,"humanSubjectClinicalTrial":false,"humanSubjectCaseReport":false,"vertebrateSubjectEthicalGuidelines":false},"doi":"10.21203/rs.3.rs-3832387/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3832387/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.21608/EJHM.2024.348919","type":"published","date":"2024-02-19T00:00:00+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":49324510,"identity":"d3771b4b-207e-4d20-aaaf-6ba8e3e73c7f","added_by":"auto","created_at":"2024-01-08 17:19:05","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":93718,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan Meier curve for overall survival and progression free survival\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-3832387/v1/aa44b43e3593e13f65e30863.jpeg"},{"id":54720372,"identity":"8e9ac9d6-0e00-49ba-80b7-eebd03e014f7","added_by":"auto","created_at":"2024-04-15 17:16:00","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":522422,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3832387/v1/604b5a2c-bf8f-45ed-bb5f-0f6a3ba3d36b.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"A Phase II Trial of Flouro-Gem as a First Line Treatment of Metastatic Adenocarcinoma of the Pancreas (GEFLUPAN trial)","fulltext":[{"header":"Background","content":"\u003cp\u003e \u003cb\u003e-\u003c/b\u003ePancreatic cancer is the fourth most common cause of cancer related death among United States men (after lung, prostate and colorectal cancer) and women (after lung, breast, and colorectal cancer) [1].\u003c/p\u003e \u003cp\u003e- Multiple aetiological factors have been linked to pancreatic cancer including smoking, exposure to heavy metals and chemicals as well as heavy alcohol consumption. [2,3]. About 10% of cases have familial component of the disease. (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eGemcitabine has shown clinical efficacy when used for metastatic pancreatic adenocarcinoma. It became the standard of care for a considerable duration of time based on results from a randomized trial by Burris HA dating back to 1997(\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). In addition, gemcitabine offers better quality of life when compared to infusional 5-flourouracil (5FU) regimen which is also known for it\u0026rsquo;s efficacy against pancreatic cancer (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eMany studies have tested gemcitabine combinations for the treatment of pancreatic cancer. Among these studies, combination of albumin pound paclitaxel and gemcitabine has shown improvement in response rates as well as survival (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). Combination of gemcitabine plus capecitabine has been investigated in several randomized trials with proven benefit in terms of response rates and progression free survival (PFS) (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eGemcitabine was the king of treatment for pancreatic cancer until the PRODIGE study was published showing superiority of another regimen over gemcitabine in terms of response and survival. This regimen is a four-agent protocol known as FOLFIRINOX combining oxaliplatin, irinotecan, leucovorin and 5FU. As expected, the toxicity profile of this regimen hindered it\u0026rsquo;s use in clinical practice to a great extent (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIn our study, we combined the two most active agents against pancreatic cancer; gemcitabine and 5FU; and given them every 2 weeks to gain the maximum benefit of both drugs and avoid the toxicity that occurs very frequently with FOLFIRINOX.\u003c/p\u003e"},{"header":"Methodology","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\n \u003ch2\u003ePatients:\u003c/h2\u003e\n \u003cp\u003eThis study is a prospective phase II clinical trial that included 42 patients with metastatic pancreatic cancer presented to Clinical Oncology Department, Menoufia University from February 2021 till July 2022\u003c/p\u003e\n \u003cp\u003eThe study protocol was approved by the Research Ethics Committee of Menoufia University. Before being enrolled in the trial, all patients gave their informed consent. The trial was conducted according to Declaration Of Helsinki. It was registered in ClinicalTrials.gov under the name \u0026ldquo;A Phase II Trial of Flouro-Gem as a First Line Treatment of Metastatic Adenocarcinoma of the Pancreas (GEFLUPAN)\u003cstrong\u003e\u0026rdquo;, NCT04769414\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eInclusion criteria\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003echemotherapy na\u0026iuml;ve adult patients aged between 18 and 70 years with metastatic carcinoma of the pancreas with histopathological evidence of adenocarcinoma, with radiological proof of metastatic disease as defined by AJCC (8 the edition ,2017) [10], ECOG performance status (PS)\u0026thinsp;\u0026le;\u0026thinsp;2 [11], with adequate hematologic parameters and normal liver and kidney functions.\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eExclusion criteria\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003epatients with end stage renal disease who are under regular dialysis, other histologies of pancreatic cancer, non metastatic irresectable pancreatic cancer.\u003c/p\u003e\n \u003cp\u003eAll patients underwent baseline evaluation including: thorough history taking and clinical examination, CBC, liver and kidney profiles, CEA, CA19-9, CT scan of the chest, abdomen and pelvis with contrast, or PET/CT as well as QLQ-C30 questionnaire Arabic version (\u003cspan class=\"CitationRef\"\u003e12\u003c/span\u003e).\u003c/p\u003e\n \u003cp\u003eWe enrolled 48 patients but 6 of them were excluded either due to refusal of completing treatment or early death before assessment of response.\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eTreatment\u003c/strong\u003e:\u003c/p\u003e\n \u003cp\u003e-The included patients received Gemcitabine at a dose of 1000 mg/m2 IV short infusion over 30 minutes, Leucovorin 400 mg/m2 IV short infusion over 30 minutes, Flourouracil 400 mg/m2 direct IV shot and Flourouracil 2000 mg/m2 continuous infusion over 46 hours. The whole regimen was cycled every 2 weeks. This regimen is abbreviated as Flouro-Gem.\u003c/p\u003e\n \u003cp\u003eThe whole protocol was given for a duration of six months for responding patients. Meanwhile, patients with progressive disease were shifted to a second line treatment as per physician\u0026rsquo;s choice.\u003c/p\u003e\n \u003cp\u003eFilgrastim was not routinely used unless indicated. Toxicities of grade II or III were managed by dose reductions if occurred more than once. However, grade IV toxicity was a clear indication for permanent stopping of this protocol.\u003c/p\u003e\n \u003cp\u003ePatients who presented with bilirubin level higher than 3 mg/dl were allowed to receive one or two cycles of the protocol without gemcitabine until improvement of bilirubin level. Counting of treatment cycles in these patients started with the use of gemcitabine not with the initiation of treatment.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\n \u003ch2\u003eEvaluation:\u003c/h2\u003e\n \u003cp\u003eAll patients had weekly CBC one day before chemotherapy administration and chemistry profile for liver functions (LFT) and kidney functions (KFT) every 2 weeks.\u003c/p\u003e\n \u003cp\u003eInterim evaluation was done after 2\u0026ndash;3 months of treatment with CT scan or PET/CT. We repeated the same investigation that was done in baseline assessment. CEA and CA19-9 were also repeated. Patients who had interim progression were subjected to re-assessment of quality of life. However, responding patients had quality of life reassessed at the end of treatment.\u003c/p\u003e\n \u003cp\u003eEnd-of-treatment evaluation was also done by CT scan or PET/CT in addition to tumor markers assessment and quality of life.\u003c/p\u003e\n \u003cp\u003eResponse evaluation was done using RECIST criteria version 1.1 [13]\u003c/p\u003e\n \u003cp\u003e-Toxicity was evaluated every cycle including: diarrhea, vomiting, mucositis, neutropenia, anemia, thrombocytopenia, and neuropathy. Toxicity grade was described according to CTCAE version 5[13].\u003c/p\u003e\n \u003cp\u003e-QOL was assessed for all patients using QOL-C30 at base line and at end of treatment or disease progression whichever earlier. Overall survival (OS) was calculated from the date of diagnosis to the date of death or last follow up. Progression free survival (PFS) was calculated from the date of diagnosis to the date of progression or last follow up.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\n \u003ch2\u003eStatistical analysis of the data\u003c/h2\u003e\n \u003cp\u003eData were tabulated and analyzed using SPSS package version 20. The primary end point was response rate and secondary end points included toxicity, quality of life and survival (PFS and OS).\u003c/p\u003e\n \u003cp\u003eChi-square test was used to examine the relation between qualitative variables. For quantitative data (change in CA19-9, CEA and QoL), comparison between three groups of response (partial, stable and progressive) was done using Kruskal Wallis test (non-parametric t-test).\u003c/p\u003e\n \u003cp\u003eAll tests were two-sided, with a P value of less than 0.05 considered to indicate statistical significance. Data are presented with 95% confidence intervals. Kaplan Meier method was used to calculate PFS and OS. Quality of life analysis was done according to EORTC guidelines (\u003cspan class=\"CitationRef\"\u003e14\u003c/span\u003e).\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eOver the period of one and a half years, we recruited 48 patients for the study. Only 42 patients completed the study and their data were submitted for analysis. Six patients were excluded either due to refusal of completing treatment or early death before assessment of response.\u003c/p\u003e \u003cp\u003eThe median age of diagnosis was 55 years being more common in males (59.5%) than females (40.5%). The most common site of metastasis was the liver (57.1%). The most common clinical presentations were abdominal pain (30.9%), jaundice (23.8%), vomiting (16.7%) and bony pains (16.7%).\u003c/p\u003e \u003cp\u003eTable\u0026nbsp;(1): Demographic and clinical characteristics of studied patients\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"No\" id=\"Taba\" border=\"1\"\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eParameter\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eStudied patients\u003c/p\u003e \u003cp\u003e(No.=42)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (year)\u003c/p\u003e \u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e \u003cp\u003eMedian (Range)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e54.4\u0026thinsp;\u0026plusmn;\u0026thinsp;7.0\u003c/p\u003e \u003cp\u003e55 (39\u0026ndash;65)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGender\u003c/p\u003e \u003cp\u003eMale\u003c/p\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e25 59.5%\u003c/p\u003e \u003cp\u003e17 40.5%\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSite of metastasis\u003c/b\u003e\u003c/p\u003e \u003cp\u003e-Bone\u003c/p\u003e \u003cp\u003e-Liver\u003c/p\u003e \u003cp\u003e-Brain\u003c/p\u003e \u003cp\u003e-LN\u003c/p\u003e \u003cp\u003e-Lung\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16 38.1%\u003c/p\u003e \u003cp\u003e24 57.1%\u003c/p\u003e \u003cp\u003e1 2.4%\u003c/p\u003e \u003cp\u003e8 19.0%\u003c/p\u003e \u003cp\u003e16 38.1%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eClinical presentation\u003c/b\u003e\u003c/p\u003e \u003cp\u003e-Abdominal pain\u003c/p\u003e \u003cp\u003e-Bone pain\u003c/p\u003e \u003cp\u003e-DVT\u003c/p\u003e \u003cp\u003e-Vomiting\u003c/p\u003e \u003cp\u003e-Back pain\u003c/p\u003e \u003cp\u003e-Cord compression\u003c/p\u003e \u003cp\u003e-Cough\u003c/p\u003e \u003cp\u003e-Dyspnea\u003c/p\u003e \u003cp\u003e-Jaundice\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13 30.9%\u003c/p\u003e \u003cp\u003e7 16.7%\u003c/p\u003e \u003cp\u003e4 9.5%\u003c/p\u003e \u003cp\u003e7 16.7%\u003c/p\u003e \u003cp\u003e8 19.0%\u003c/p\u003e \u003cp\u003e1 2.4%\u003c/p\u003e \u003cp\u003e2 4.8%\u003c/p\u003e \u003cp\u003e1 2.4%\u003c/p\u003e \u003cp\u003e10 23.8%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eBaseline CEA\u003c/b\u003e\u003c/p\u003e \u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e \u003cp\u003eMedian (Range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e143.8\u0026thinsp;\u0026plusmn;\u0026thinsp;131.7\u003c/p\u003e \u003cp\u003e105.5 (5\u0026ndash;516)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eFinal CEA\u003c/b\u003e\u003c/p\u003e \u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e \u003cp\u003eMedian (Range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e216.9\u0026thinsp;\u0026plusmn;\u0026thinsp;182.5\u003c/p\u003e \u003cp\u003e225 (4\u0026ndash;760)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eBaseline CA19-9\u003c/b\u003e\u003c/p\u003e \u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e \u003cp\u003eMedian (Range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1129.4\u0026thinsp;\u0026plusmn;\u0026thinsp;1026.9\u003c/p\u003e \u003cp\u003e743 (120\u0026ndash;4500)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eFinal CA19-9\u003c/b\u003e\u003c/p\u003e \u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e \u003cp\u003eMedian (Range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1570.9\u0026thinsp;\u0026plusmn;\u0026thinsp;1442.3\u003c/p\u003e \u003cp\u003e850 (40\u0026ndash;4900)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePresence of DVT\u003c/b\u003e\u003c/p\u003e \u003cp\u003eYes\u003c/p\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 14.3%\u003c/p\u003e \u003cp\u003e36 85.7%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eNumber of cycles\u003c/b\u003e\u003c/p\u003e \u003cp\u003e2\u003c/p\u003e \u003cp\u003e3\u003c/p\u003e \u003cp\u003e4\u003c/p\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 2.4%\u003c/p\u003e \u003cp\u003e4 9.5%\u003c/p\u003e \u003cp\u003e9 21.4%\u003c/p\u003e \u003cp\u003e28 66.7%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eRegularity\u003c/b\u003e\u003c/p\u003e \u003cp\u003eIrregular\u003c/p\u003e \u003cp\u003eRegular\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 7.1%\u003c/p\u003e \u003cp\u003e39 92.9%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eDose density\u003c/b\u003e\u003c/p\u003e \u003cp\u003e50%\u003c/p\u003e \u003cp\u003e75%\u003c/p\u003e \u003cp\u003e80%\u003c/p\u003e \u003cp\u003e100%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 2.4%\u003c/p\u003e \u003cp\u003e3 7.1%\u003c/p\u003e \u003cp\u003e1 2.4%\u003c/p\u003e \u003cp\u003e37 88.1%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eBaseline median CEA was 105.5 ng/ml that increased to 225 ng/ml at the end of treatment. Likewise, baseline median CA19-9 was 743 ng/ml that increased at end of treatment to 850 ng/ml. Deep vein thrombosis was detected in 14.3% of patients at presentation.\u003c/p\u003e \u003cp\u003eThe treatment protocol was given regularly in 92.9% of patients. The full dose regimen was given to 88.1% of patients meanwhile, 9.5% of patients had dose reductions in the range of 20\u0026ndash;25%. One patient only had 50% dose reduction. Regarding the number of cycles, 66.7% of patients completed 6 months of treatment.\u003c/p\u003e \u003cp\u003eToxicity profile showed neutropenia is the most common form of toxicity being high grade in 11.9% of patients. Thrombocytopenia had a similar profile as it occurred in a high grade in 11.9% of patients. Other forms of toxicity were minimal not exceeding 5%. Low grade toxicities showed higher numbers with neutropenia being the highest occurring in 78.6% of patients and neuropathy being the least at 9.5%.\u003c/p\u003e \u003cp\u003eTable\u0026nbsp;(2): Toxicity profile of studied patients\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"No\" id=\"Tabb\" border=\"1\"\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eParameter\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eGrades of toxicity among studied patients\u003c/p\u003e \u003cp\u003e(No.=42)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLow grade (1, 2)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eHigh grade (3, 4)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eDiarrhea\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e20 (47.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2 (4.8%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eVomiting\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e13 (31.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2 (4.8%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMucositis\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e14 (33.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1 (2.4%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eNeutropenia\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e33 (78.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e5 (11.9%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAnemia\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e10 (23.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1 (2.4%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eThrombocytopenia\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e22 (52.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e5 (11.9%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eNeuropathy\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e4 (9.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0 (0.0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThe overall response rate was 33.3% with no patients achieving complete response. The changes in the levels of tumor markers was a significant factor for response. CA19-9 had more correlation with response than CEA. Median decrease by 70 ng/ml in the level of CA19-9 was associated with partial response while increases around 51 ng/ml was associated with disease progression. Likewise, their level had a significant relation with PFS and OS. The one-year overall survival was 49% while the one year progression free survival was 34.7%. The median overall survival was 11.3 months (95%CI\u0026thinsp;=\u0026thinsp;10.17\u0026ndash;12.45) and the median PFS was 8.8 months (95%CI\u0026thinsp;=\u0026thinsp;7.3\u0026ndash;10.4). Cox regression analysis showed that changes of CEA and CA19.9 were predictors of PFS (P. value\u0026thinsp;=\u0026thinsp;0.01, 0.02 respectively).\u003c/p\u003e \u003cp\u003eTable\u0026nbsp;(3): Response of studied patients after end of treatment\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"No\" id=\"Tabc\" border=\"1\"\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eParameter\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eStudied patients\u003c/p\u003e \u003cp\u003e(No.=42)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eOverall response rate (ORR)\u003c/b\u003e\u003c/p\u003e \u003cp\u003e-Complete response\u003c/p\u003e \u003cp\u003e-Partial response\u003c/p\u003e \u003cp\u003e-Stable disease\u003c/p\u003e \u003cp\u003e\u003cb\u003eProgressive disease\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e14 33.3%\u003c/b\u003e\u003c/p\u003e \u003cp\u003e0 0.0%\u003c/p\u003e \u003cp\u003e6 14.3%\u003c/p\u003e \u003cp\u003e8 19.0%\u003c/p\u003e \u003cp\u003e\u003cb\u003e28 66.7%\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eGlobal health status improved for responding patients at end of treatment with a median score of 58.3 and 66.7 for partial response and stable disease respectively.\u003c/p\u003e \u003cp\u003eTable\u0026nbsp;(4) relation between changes in the levels of tumor markers and response\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"No\" id=\"Tabd\" border=\"1\"\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eParameter\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e \u003cp\u003eResponse after end of treatment among studied patients\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eTest of significance\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePartial response\u003c/p\u003e \u003cp\u003e(No.=6)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eStable\u003c/p\u003e \u003cp\u003edisease\u003c/p\u003e \u003cp\u003e(No.=8)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eProgressive disease\u003c/p\u003e \u003cp\u003e(No.=28)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eChange of CEA (%)\u003c/b\u003e\u003c/p\u003e \u003cp\u003eMedian(Range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e34 (18\u0026ndash;159)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e58 (15\u0026ndash;318)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e136 (5\u0026ndash;516)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eKruskal Wallis test\u0026thinsp;=\u0026thinsp;4.85\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.09\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eChange of CEA (%)\u003c/b\u003e\u003c/p\u003e \u003cp\u003e-Decreased\u003c/p\u003e \u003cp\u003e-Increased\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 100%\u003c/p\u003e \u003cp\u003e0 0.0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7 87.5%\u003c/p\u003e \u003cp\u003e1 12.5%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2 7.1%\u003c/p\u003e \u003cp\u003e26 92.9%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eχ2 test\u0026thinsp;=\u0026thinsp;30.10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eChange of CA19-9 (%)\u003c/b\u003e\u003c/p\u003e \u003cp\u003eMedian(Range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e70 (51.2\u0026ndash;80.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6.6 (-21.9\u0026ndash;35.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-51.9 (-448-6.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eKruskal Wallis test\u0026thinsp;=\u0026thinsp;24.51\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eChange of CA19-9 (%)\u003c/b\u003e\u003c/p\u003e \u003cp\u003e-Decreased\u003c/p\u003e \u003cp\u003e-Increased\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 100%\u003c/p\u003e \u003cp\u003e0 0.0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 50.0%\u003c/p\u003e \u003cp\u003e4 50.0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 3.6%\u003c/p\u003e \u003cp\u003e27 96.4%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eχ2 test\u0026thinsp;=\u0026thinsp;26.67\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eTable\u0026nbsp;(5): Association between response and QoL\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"No\" id=\"Tabe\" border=\"1\"\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eParameter\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e \u003cp\u003eInterim Response among studied patients\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eTest of significance\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003ePartial response\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003e(No.=15)\u003c/b\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003eStable\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003edisease\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003e(No.=13)\u003c/b\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003eProgressive disease\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003e(No.=14)\u003c/b\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBefore treatment Global health status/QoL Median(Range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e33.3 (0\u0026ndash;50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e16.7 (0\u0026ndash;50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e16.7 (0\u0026ndash;50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eKruskal Wallis test\u0026thinsp;=\u0026thinsp;4.68\u003c/p\u003e \u003cp\u003eP\u0026thinsp;=\u0026thinsp;0.09\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eP1\u0026thinsp;=\u0026thinsp;0.13\u003c/p\u003e \u003cp\u003eP2\u0026thinsp;=\u0026thinsp;0.04*\u003c/p\u003e \u003cp\u003eP3\u0026thinsp;=\u0026thinsp;0.76\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e \u003cp\u003e\u003cb\u003eResponse after the end of treatment among studied patients\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\" morerows=\"1\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003ePartial response\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003e(No.=6)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003eStable\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003edisease\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003e(No.=8)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003eProgressive disease\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003e(No.=28)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAfter treatment\u003c/p\u003e \u003cp\u003eGlobal health status/QoL Median(Range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e58.3 (58.3\u0026ndash;83.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e66.7 (50\u0026ndash;83.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e25 (0\u0026ndash;58.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eKruskal Wallis test\u0026thinsp;=\u0026thinsp;26.99\u003c/p\u003e \u003cp\u003eP\u0026thinsp;\u0026lt;\u0026thinsp;0.001*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eP1\u0026thinsp;=\u0026thinsp;0.73\u003c/p\u003e \u003cp\u003eP2\u0026thinsp;\u0026lt;\u0026thinsp;0.001*\u003c/p\u003e \u003cp\u003eP3\u0026thinsp;\u0026lt;\u0026thinsp;0.001*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn our investigation, we observed a male predominance, with males constituting 59.5% of the patient population. This is in line with the findings of Oettle et al., who reported a 65.8% male patient population, and Louvet et al., who found that 64.5% of their patient population were males. A similar trend was also reported by Oliani et al. The median age of patients in our study was 55 years, which is slightly lower than the median ages reported by Oettle et al. and Oliani et al. (60 years), and Louvet et al. (61.8 years). This variation could be due to the recruitment of a larger number of younger patients in our study, possibly due to the poorer performance status of older patients. As for the site of metastasis, our study identified the liver as the most common site in 57.1% of cases. This finding is consistent with those of Louvet et al., who reported a rate of 77.5%, and Oliani et al (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eFiguer (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) Kaplan Meier curve for overall survival and progression free survival\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eOur study found that the most frequently reported toxicities were neutropenia and thrombocytopenia, a finding that aligns with the results of Louvet et al. However, the incidence of grade 3 and 4 toxicities in our study was lower. Specifically, we observed grade 3 neutropenia in 31.6% of patients and grade 4 neutropenia in 18.4% of patients. Thrombocytopenia of grade 3 was seen in 15.8% of patients, while grade 4 thrombocytopenia was observed in 2.6% of patients. These results were obtained with a 5-FU dosage of 2 gm/m2.\u003c/p\u003e \u003cp\u003eIn this study, Flouro-Gem regimen offered a good alternative option in treating patients with pancreatic adenocarcinoma. This regimen achieved a one-year survival of nearly half the patients (49%). The median overall survival was 11.3 months, which is better than numbers observed in similar studies by \u003cb\u003eOettle, et al\u003c/b\u003e (9 months), and \u003cb\u003eLouvet, et al\u003c/b\u003e (8.4 months). Theses 2 trials used gemcitabine flurouracil, while the last one used the same protocol as our study with the same dose and schedule. This observation is consistent with and comparable to reports from other studies of gemcitabine in combination with 5-FU with or without folinic acid (FA). The median overall survivals for these studies were in the range 5.5\u0026ndash;13 months [18,19,20]. Similarly, the median progression free survival (PFS) in this study was better (8.8 months versus 7.1 months). By far, these numbers are better than many regimens that included gemcitabine.\u003c/p\u003e \u003cp\u003eGemcitabine, both as a standalone treatment and in combination with other agents, has been globally studied for its effectiveness in treating pancreatic cancer. Phase III studies have demonstrated its efficacy, with a one-year overall survival rate of 18\u0026ndash;20% and a median overall survival of approximately 6 months (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e). The combination of nab-paclitaxel and gemcitabine has shown improved overall survival, extending from 6.7 months to 8.5 months. These figures reached their peak in a Swedish study, which reported a median overall survival of 10.9 months (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe response rates were variable among trials ranging from 9 to 31%. In this study, the overall response rate was 33.3% which is very comparable to FOLFIRINOX which was 34.1%. However, the toxicity profile and safety were much better with Flouro-Gem. Neutropenia was the most frequent high grade toxicity being 11.9% versus 45% seen with FOLFIRINOX in some studies (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eOur results showed that no complete response (0%) was observed in this metastatic setting. This finding is also seen in other studies conducted on metastatic pancreatic cancer (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eGemcitabine used in combination with cisplatin has shown evidence of increased efficacy compared to gemcitabine alone with response rates in the range of 11.5\u0026ndash;36.4% [25], which is comparable to this study, but in all these studies the patients required hydration and treatment was associated with significant haematological toxicity, nephrotoxicity and alopecia, which is not found in this study. Also this study is more tolerable than gemcitabine- docetaxel, which was associated with significant haematological toxicity[26].\u003c/p\u003e \u003cp\u003eQuality of life has improved in patients responding to Flouro-Gem. The global health status scored 33.3 at interim evaluation and increased to 58 at end of treatment for patients with partial response. Interestingly, patients who had disease progression experienced numerical improvement in their QoL scores despite being non-statisctically significant. This -at least- shows that this regimen is tolerable and does not impair the QoL. This result was consistent with Oettle, et al, who showed that \u0026ge;\u0026thinsp;seventy-nine percent of patients showed a stabilization if not an improvement in their karnofosky performance status (KPS), and mild toxicity profile (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eOn the contrary, FOLFIRINOX has resulted in impaired quality of life when compared with gemcitabine single agent. 31% of patients had decreased global health status scale. However, in the same study 66% of patients in the gemcitabine arm had experienced decline in the quality of life; a finding which is not observed in our study (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e).\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eFlouro-Gem is a well-tolerated acceptable option for the first line treatment of metastatic pancreatic cancer with comparable results to other more toxic regimens and better outcomes than single agent protocols.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003e5FU: 5 flourouracil\u003c/p\u003e\n\u003cp\u003eAJCC: American joint committee on cancer\u003c/p\u003e\n\u003cp\u003eCA19-9: cancer antigen 19-9\u003c/p\u003e\n\u003cp\u003eCBC: complete blood count\u003c/p\u003e\n\u003cp\u003eCEA: carcinoembryonic antigen\u003c/p\u003e\n\u003cp\u003eCT: computed tomography\u003c/p\u003e\n\u003cp\u003eCTCAE: common terminology criteria for adverse events\u003c/p\u003e\n\u003cp\u003eDVT: deep vein thrombosis\u003c/p\u003e\n\u003cp\u003eECOG: Eastern co-operative oncology group\u003c/p\u003e\n\u003cp\u003eEORTC: European organization for research and treatment of cancer\u003c/p\u003e\n\u003cp\u003eIV: intravenous\u003c/p\u003e\n\u003cp\u003eKFT: kidney function test\u003c/p\u003e\n\u003cp\u003eLFT: liver function test\u003c/p\u003e\n\u003cp\u003eORR: overall response rate\u003c/p\u003e\n\u003cp\u003eOS: overall survival\u003c/p\u003e\n\u003cp\u003ePET/CT: positron emission tomography/computed tomography\u003c/p\u003e\n\u003cp\u003ePFS: progression free survival\u003c/p\u003e\n\u003cp\u003eQoL: quality of life\u003c/p\u003e\n\u003cp\u003eRECIST: response evaluation criteria in solid tumors\u003c/p\u003e\n\u003cp\u003eSD: standard deviation\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eDeclaration of interest:\u003c/h2\u003e \u003cp\u003eAll authors declare no conflict of interest.\u003c/p\u003e \u003ch2\u003eFunding:\u003c/h2\u003e \u003cp\u003eThis study was funded by Menoufia University, Egypt.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eA.S.:\u0026bull; Corresponding author ([email protected])\u0026bull; Recruitment of patients\u0026bull; Data collection\u0026bull; Writing the manuscript\u0026bull; Publishing the paperR. 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Journal of Clinical Oncology. 2007 Jun 20;25(18):2607-15.\u003c/li\u003e\n\u003cli\u003eVon Hoff DD, Ervin T, Arena FP, Chiorean EG, Infante J, Moore M, Seay T, Tjulandin SA, Ma WW, Saleh MN, Harris M. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. New England Journal of Medicine. 2013 Oct 31;369(18):1691-703.\u003c/li\u003e\n\u003cli\u003eKordes M, Yu J, Malgerud O, Gustafsson Liljefors M, L\u0026ouml;hr JM. Survival benefits of chemotherapy for patients with advanced pancreatic cancer in a clinical real-world cohort. Cancers. 2019 Sep 7;11(9):1326.\u003c/li\u003e\n\u003cli\u003eHeinemann V, Quietzsch D, Gieseler F, Gonnermann M, Schönekäs H, Rost A, Neuhaus H, Haag C, Clemens M, Heinrich B, Vehling-Kaiser U. Randomized phase III trial of gemcitabine plus cisplatin compared with gemcitabine alone in advanced pancreatic cancer. Journal of Clinical Oncology. 2006 Aug 20;24(24):3946-52.\u003c/li\u003e\n\u003cli\u003eJacobs AD. Gemcitabine‐based therapy in pancreas cancer: Gemcitabine‐docetaxel and other novel combinations. Cancer: Interdisciplinary International Journal of the American Cancer Society. 2002 Aug 15;95(S4):923-7.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"pancreatic, toxicity, gemcitabine, carcinoma, 5 FU","lastPublishedDoi":"10.21203/rs.3.rs-3832387/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3832387/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eGemcitabine and 5 FU\u0026thinsp;+\u0026thinsp;folinic acid both have proven activity in treatment of patients with advanced pancreatic cancer.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eThis prospective phase II study included 42 patients of metastatic cancer pancreas who met the inclusion criteria \u003cb\u003e(\u003c/b\u003echemotherapy na\u0026iuml;ve, adult patients aged between 18 and 70 years, with histopathological evidence of adenocarcinoma, with radiological proof of metastatic disease, ECOG performance status (PS)\u0026thinsp;\u0026le;\u0026thinsp;2, with adequate hematologic parameters and normal liver and kidney functions). Patients with end stage renal disease who are under regular dialysis, other histologies of pancreatic cancer, non-metastatic irresectable patients were excluded. The included patients received gemcitabine- flourouracil every 2 weeks, evaluated for response, assesed for quality of life and survival.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eThe median age at diagnosis was 55 years. Males were more common (59.5%) than females. The most common site of metastasis was the liver (57.1%). Toxicity profile showed that neutropenia and thrombocytopenia were the most common forms of toxicity being high grade in 11.9% of patients. Other forms of toxicity were minimal not exceeding 5%. The ORR was 33.3% with no reported complete responses. There was a significant correlation between the change of tumor markers levels (CEA, and CA 19.9) and both response and quality of life. The changes of CEA and CA19.9 levels were found to be independent predictors of PFS. One year OS rate was 49%. The median OS was 11.3 months, while the median PFS was 8.8 months. Response was also found to be a surrogate marker for survival.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eGemcitabine- 5 FU combination is a good alternative option for treating metastatic pancreatic cancer, it had good efficacy and safety profile.\u003c/p\u003e","manuscriptTitle":"A Phase II Trial of Flouro-Gem as a First Line Treatment of Metastatic Adenocarcinoma of the Pancreas (GEFLUPAN trial)","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-01-08 17:19:00","doi":"10.21203/rs.3.rs-3832387/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"0374639d-253b-4ea1-919d-e2f4db047f60","owner":[],"postedDate":"January 8th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-04-15T17:15:55+00:00","versionOfRecord":{"articleIdentity":"rs-3832387","link":"https://doi.org/10.21608/EJHM.2024.348919","journal":{"identity":"the-egyptian-journal-of-hospital-medicine","isVorOnly":true,"title":"The Egyptian Journal of Hospital Medicine"},"publishedOn":"2024-02-19 00:00:00","publishedOnDateReadable":"February 19th, 2024"},"versionCreatedAt":"2024-01-08 17:19:00","video":"","vorDoi":"10.21608/EJHM.2024.348919","vorDoiUrl":"https://doi.org/10.21608/EJHM.2024.348919","workflowStages":[]},"version":"v1","identity":"rs-3832387","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3832387","identity":"rs-3832387","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}