Adjuvant Gemcitabine Chemotherapy Research Articles

Analysis of chemoresistance characteristics and prognostic relevance of postoperative gemcitabine adjuvant chemotherapy in pancreatic cancer.

To investigate the relationship between chemoresistance in pancreatic cancer patients receiving postoperative gemcitabine adjuvant therapy and specific clinical/pathological characteristics, as well as its impact on patient prognosis. From June 2018 to June 2021, clinical and pathological data of 148 pancreatic cancer patients were collected, and 101 patients were followed up for tumor recurrence/metastasis and survival status. The correlation between chemoresistance and specific clinical/pathological characteristics or patient prognosis was retrospectively analyzed. Of the 148 patients, 78 were in the chemoresistance group and 70 in the non-chemoresistance group. Univariate analysis showed that the development of chemoresistance may be related to patient age, combined diabetes, preoperative CA19-9 level, tumor size, AJCC stage, vascular invasion, and positive lymph node ratio. Furthermore, subsequent multivariate analysis incorporating these variables indicated that tumor size may be a key factor influencing chemoresistance (p < 0.001, OR = 1.584). Log-rank test showed patients in the chemoresistance group had worse overall survival (OS) (HR = 2.102, p = 0.018) and progression free survival (PFS) (HR = 3.208, p = 0.002) than patients in the non-chemoresistance group; and patients with smaller size tumors (diameter ≤3 cm) had significantly better OS (HR = 2.923, p < 0.001) and PFS (HR = 2.930, p = 0.003) than those with larger size tumors (diameter >3 cm). Patients with pancreatic cancer receiving postoperative gemcitabine adjuvant therapy are more likely to develop chemoresistance when their tumor sizes are larger (diameter >3 cm). Development of chemoresistance exacerbates the prognosis of patients with pancreatic cancer, and larger tumor size is also a risk factor for poor prognosis in these patients.

Adjuvant gemcitabine after resection of pancreatic cancer without significant difference in overall survival: a retrospective cohort study.

The authors retrospectively analyzed the OS of all patients who underwent pancreatic resection at their clinic because of ductal adenocarcinoma between January 2013 and December 2020 in dependence on adjuvant treatment with gemcitabine. Overall 133 pancreatic resections were performed between 2013 and 2020 due to malignant pancreatic pathology. Seventy-four patients had ductal adenocarcinoma. Forty patients received adjuvant gemcitabine chemotherapy postoperatively, 18 patients underwent only surgical resection, and 16 patients received other chemotherapy regimens. The authors compared the group receiving adjuvant gemcitabine (n=40) with the group undergoing surgery alone (n=18). The median age was 74 years (range: 45-85), and the median OS was 16.5 months [95% confidence interval (CI) 13-27]. Follow-up time was at least 23 months (range 23-99). No statistically significant difference in median OS was observed in the group who received adjuvant chemotherapy compared to the operation-only group [17.5 months (range: 5-99, 95% CI 14-27) versus 12.5 months (range: 1-94, 95% CI 5-66), P=0.75]. OS with and without adjuvant chemotherapy with gemcitabine was comparable to the results of those RCTs which serve as the basis of guideline recommendations. However, the analyzed patient cohort did not profit significantly from the adjuvant treatment.

Adjuvant therapy in biliary tract cancers: oral fluoropyrimidine as a beginning

Biliary tract cancer is a group of malignant tumours, mostly adenocarcinoma, arising from different sites of the biliary tract with diverse aetiology, molecular profiling, TNM classification, and surgical procedures and outcomes of resectable diseases. 1 Valle JW Kelley RK Nervi B Oh D-Y Zhu AX Biliary tract cancer. Lancet. 2021; 397: 428-444 Summary Full Text Full Text PDF PubMed Scopus (181) Google Scholar Radical surgical resection remains the only curative treatment, but postoperative relapse is common. 1 Valle JW Kelley RK Nervi B Oh D-Y Zhu AX Biliary tract cancer. Lancet. 2021; 397: 428-444 Summary Full Text Full Text PDF PubMed Scopus (181) Google Scholar Developing effective adjuvant therapy is mandatory. However, two modern observation-controlled phase 3 trials, the BCAT trial 2 Ebata T Hirano S Konishi M et al. Randomized clinical trial of adjuvant gemcitabine chemotherapy versus observation in resected bile duct cancer. Br J Surg. 2018; 105: 192-202 Crossref PubMed Scopus (192) Google Scholar and the PRODIGE 12-ACCORD 18 trial, 3 Edeline J Benabdelghani M Bertaut A et al. Gemcitabine and oxaliplatin chemotherapy or surveillance in resected biliary tract cancer (PRODIGE 12-ACCORD 18-UNICANCER GI): a randomized phase III study. J Clin Oncol. 2019; 37: 658-667 Crossref PubMed Scopus (230) Google Scholar did not show the benefit of adjuvant gemcitabine-based chemotherapy in resected biliary tract cancers. BILCAP 4 Primrose JN Fox RP Palmer DH et al. Capecitabine compared with observation in resected biliary tract cancer (BILCAP): a randomised, controlled, multicentre, phase 3 study. Lancet Oncol. 2019; 20: 663-673 Summary Full Text Full Text PDF PubMed Google Scholar was the first phase 3 study to support the role of adjuvant chemotherapy, with oral capecitabine, for resected biliary tract cancers. 5 Shroff RT Kennedy EB Bachini M et al. Adjuvant therapy for resected biliary tract cancer: ASCO clinical practice guideline. J Clin Oncol. 2019; 37: 1015-1027 Crossref PubMed Scopus (198) Google Scholar , 6 Yoo C Jeong H Kim KP et al. Adjuvant gemcitabine plus cisplatin (GemCis) versus capecitabine (CAP) in patients (pts) with resected lymph node (LN)-positive extrahepatic cholangiocarcinoma (CCA): a multicenter, open-label, randomized, phase 2 study (STAMP). Proc Am Soc Clin Oncol. 2022; 404019 Google Scholar , 7 Stein A Arnold D Bridgewater J et al. Adjuvant chemotherapy with gemcitabine and cisplatin compared to observation after curative intent resection of cholangiocarcinoma and muscle invasive gallbladder carcinoma (ACTICCA-1 trial)—a randomized, multidisciplinary, multinational phase III trial. BMC Cancer. 2015; 15: 564 Crossref PubMed Google Scholar The recommendation mainly relied on a significant improvement in overall survival by the prespecified sensitivity analysis (hazard ratio [HR]=0·71, 95% CI 0·55–0·92) but not on overall survival (ie, the primary endpoint; HR=0·81, 95% CI 0·63–1·04) in the primary, intention-to-treat analysis, 4 Primrose JN Fox RP Palmer DH et al. Capecitabine compared with observation in resected biliary tract cancer (BILCAP): a randomised, controlled, multicentre, phase 3 study. Lancet Oncol. 2019; 20: 663-673 Summary Full Text Full Text PDF PubMed Google Scholar and is thus debatable. The adjusted HR for overall survival increased to 0·84 (95% Cl 0·67–1·06) and the HR for recurrence-free survival was 0·81 (95% Cl 0·65–1·01) in the extension report, 8 Bridgewater J Fletcher P Palmer DH et al. Long-term outcomes and exploratory analyses of the randomized phase III BILCAP study. J Clin Oncol. 2022; 40: 2048-2057 Crossref PubMed Scopus (11) Google Scholar which further weakened the recommendation. 9 Edeline J Malka D Capecitabine: still a standard option in the adjuvant setting of biliary tract cancer?. J Clin Oncol. 2022; 40: 3667-3668 Crossref PubMed Scopus (1) Google Scholar Adjuvant S-1 compared with observation in resected biliary tract cancer (JCOG1202, ASCOT): a multicentre, open-label, randomised, controlled, phase 3 trialAlthough long-term clinical benefit would be needed for a definitive conclusion, a significant improvement in survival suggested adjuvant S-1 could be considered a standard of care for resected biliary tract cancer in Asian patients. Full-Text PDF

Colon metastasis from recurrent gallbladder cancer: a case report

Gallbladder cancer (GBC) is associated with a poor prognosis. Colonic metastases representing approximately 1% of total colorectal cancers, are very rarely reported. According to more recent data in the literature, cases of colon metastases from GBC have not been reported. We report the case of a 78-year-old woman who underwent a cholecystectomy in 2017, for a diffuse carcinoma in situ and an infiltrating adenocarcinoma pT2a G2; she completed six months of adjuvant gemcitabine chemotherapy and started a regular follow up in our institution. Three years later she came to our observation after having developed severe anemia and she was diagnosed synchronous liver and colonic metastases from GBC immunohistologically confirmed. The case was collegially evaluated by a multidisciplinary team. In consideration of the progressive deterioration of the clinical conditions, the extension of the primary GBC and the patient's age, it was decided to start in July 2020 a first-line mono-chemotherapy treatment with gemcitabine. This is probably the first reported case of colonic metastasis in a patient with a recurrent GBC with synchronous liver involvement. We conclude that though colon is a rare metastatic site of GBC, one should keep vigilance for colon metastases to prevent and detect their occurrence in symptomatic cases in order to improve the survival.

Safety of adjuvant gemcitabine plus cisplatin chemotherapy in a patient with bilateral ureteral cancer undergoing hemodialysis

An 80 year old Japanese man with bilateral ureteral cancer underwent laparoscopic bilateral nephroureterectomy and lymph-node dissection. The pathological stage of the left and right ureteral tumors was pT3pN0M0. He received two courses of adjuvant gemcitabine and cisplatin chemotherapy while undergoing hemodialysis. The standard dose of gemcitabine and 50% of the standard dose of cisplatin were administered on the same day. Hemodialysis was started 6 h after gemcitabine administration and 1 h after cisplatin administration. The side effects were evaluated according to the Common Terminology Criteria for Adverse Events v4.0. In the first course, Grade 4 side effects including leukopenia, neutropenia, and thrombocytopenia were observed. He was treated with granulocyte colony-stimulating factor and platelet transfusion. Because the second course was administered without reducing the doses, granulocyte colony-stimulating factor was administered prophylactically, and Grade 4 side effects were reduced to Grade 3. Gemcitabine plus cisplatin chemotherapy can be administered safely in a patient with advanced ureteral cancer undergoing hemodialysis by adequately managing adverse events.

FOLFIRINOX in adjuvant and metastatic settings for pancreatic cancer in the era of precision oncology

Pancreatic cancer remains an aggressive disease with an unfavorable prognosis, although progress has been made in recent years. Thirty-five percent of patients with pancreatic cancer have locally advanced unresectable disease at diagnosis. Several studies have examined the systemic chemotherapy with FOLFIRINOX (leucovorin and fluorouracil plus irinotecan and oxaliplatin) in patients with advanced local pancreatic cancer. FOLFIRINOX is now considered a standard first-line treatment because it has shown improved overall and progression-free survival in comparison with gemcitabine, proved by Conroy et al. in the ACOORD11-trial, associated with an increased toxicity profile. Currently, there are no validated biomarkers, efforts being made to identify molecular factors or biomarkers that predict the response to therapy in order to maximize the treatment efficacy and avoid unnecessary toxic effects for patients who do not respond to this combination of chemotherapy. New data indicate that molecular types of pancreatic ductal adenocarcinoma identified from immunohistochemistry (KRT81 and HNF1A) may predict the response to FOLFIRINOX or to gemcitabine-based regimen. Also, machine learning analysis of medical imaging has proven the ability to predict the response to one of the two chemotherapy regimens. Currently, FOLFIRINOX and Gem/nab-P are approved for the first line in locally advanced/metastatic pancreatic cancer, with a benefit regarding overall survival for FOLFIRINOX and a better toxicity profile for Gem/nab-P. PRODIGE 24-ACCORD demonstrates the superiority of a modified-attenuated FOLFIRINOX regimen (mFOLFIRINOX) in adjuvant settings versus gemcitabine chemotherapy. It is expected that mFOLFIRINOX may be a candidate for neoadjuvant treatment in locally advanced pancreatic cancer. Even though multiple molecular targets have been identified and the modulation of the tumor microenvironment is tried to improve the immunotherapy results, currently FOLFIRINOX regimen is the cornerstone of systemic therapy in pancreatic cancer.

Phase II Trial of Postoperative Adjuvant Gemcitabine and Cisplatin Chemotherapy Followed by Chemoradiotherapy with Gemcitabine in Patients with Resected Pancreatic Cancer

PurposeDespite curative resection, the 5-year survival for patients with resectable pancreatic cancer is less than 20%. Recurrence occurs both locally and at distant sites and effective multimodality adjuvant treatment is needed.Materials and MethodsPatients with curatively resected stage IB-IIB pancreatic adenocarcinoma were eligible. Treatment consisted of chemotherapy with gemcitabine 1,000 mg/m2 on days 1 and 8 and cisplatin 60 mg/m2 on day 1 every 3 weeks for two cycles, followed by chemoradiotherapy (50.4 Gy/28 fx) with weekly gemcitabine (300 mg/m2/wk), and then gemcitabine 1,000 mg/m2 on days 1 and 8 every 3 weeks for four cycles. The primary endpoint was 1-year disease-free survival rate. The secondary endpoints were disease-free survival, overall survival, and safety.ResultsSeventy-four patients were enrolled. One-year disease-free survival rate was 57.9%. Median disease-free and overall survival were 15.0 months (95% confidence interval [CI], 11.6 to 18.4) and 33.0 months (95% CI, 21.8 to 44.2), respectively. At the median follow-up of 32 months, 57 patients (77.0%) had recurrence including 11 patients whose recurrence was during the adjuvant treatment. Most of the recurrences were systemic (52 patients). Stage at the time of diagnosis (70.0% in IIA, 51.2% in IIB, p=0.006) were significantly related with 1-year disease-free survival rate. Toxicities were generally tolerable, with 53 events of grade 3 or 4 hematologic toxicity and four patients with febrile neutropenia.ConclusionAdjuvant gemcitabine and cisplatin chemotherapy followed by chemoradiotherapy with gemcitabine and maintenance gemcitabine showed efficacy and good tolerability in curatively resected pancreatic cancer.

"Open Sesame?": Biomarker Status of the Human Equilibrative Nucleoside Transporter-1 and Molecular Mechanisms Influencing its Expression and Activity in the Uptake and Cytotoxicity of Gemcitabine in Pancreatic Cancer.

Simple SummaryDespite the enormous advance in biomarker discovery, many potential biomarkers of drug activity are unable to satisfy the clinical need due to inadequate sensitivity and specificity. The nucleoside transporter hENT-1 has been studied as a potential biomarker to predict the effect of the widely used anticancer drug gemcitabine in pancreatic cancer. However, several studies showed controversial results regarding the predictive value of hENT-1, prompting new analyses with larger cohorts of patients and standardized methodologies. Improved insights on molecular mechanisms underlying hENT-1 expression and activity should also help in the identification of subsets of patients who are more likely to benefit from specific treatments and improve their clinical outcome. The establishment of such biomarker is especially valuable in pancreatic cancer, which is frequently characterized by complex disease biology and high mortality.Pancreatic ductal adenocarcinoma (PDAC) is an extremely aggressive tumor characterized by early invasiveness, rapid progression and resistance to treatment. For more than twenty years, gemcitabine has been the main therapy for PDAC both in the palliative and adjuvant setting. After the introduction of FOLFIRINOX as an upfront treatment for metastatic disease, gemcitabine is still commonly used in combination with nab-paclitaxel as an alternative first-line regimen, as well as a monotherapy in elderly patients unfit for combination chemotherapy. As a hydrophilic nucleoside analogue, gemcitabine requires nucleoside transporters to permeate the plasma membrane, and a major role in the uptake of this drug is played by human equilibrative nucleoside transporter 1 (hENT-1). Several studies have proposed hENT-1 as a biomarker for gemcitabine efficacy in PDAC. A recent comprehensive multimodal analysis of hENT-1 status evaluated its predictive role by both immunohistochemistry (with five different antibodies), and quantitative-PCR, supporting the use of the 10D7G2 antibody. High hENT-1 levels observed with this antibody were associated with prolonged disease-free status and overall-survival in patients receiving gemcitabine adjuvant chemotherapy. This commentary aims to critically discuss this analysis and lists molecular factors influencing hENT-1 expression. Improved knowledge on these factors should help the identification of subgroups of patients who may benefit from specific therapies and overcome the limitations of traditional biomarker studies.

Phase II Study of Adjuvant Chemotherapy of Gemcitabine with Nafamostat Mesilate for Pancreatic Cancer

Uwagawa, Tadashi MD PhD FACS; Sakamoto, Taro MD, PhD; Shirai, Yoshihiro MD, PhD; Yasuda, Jungo MD, PhD; Shiozaki, Hironori MD, FACS; Furukawa, Kenei MD, PhD; Onda, Shinji MD, PhD; Gocho, Takeshi MD, PhD, FACS; Shiba, Hiroaki MD PhD FACS; Yanaga, Katsuhiko MD PhD FACS Author Information

ESPAC-4: A multicenter, international, open-label randomized controlled phase III trial of adjuvant combination chemotherapy of gemcitabine (GEM) and capecitabine (CAP) versus monotherapy gemcitabine in patients with resected pancreatic ductal adenocarcinoma: Five year follow-up.

4516 Background: The ESPAC-4 trial demonstrated that adjuvant GEM/CAP for pancreatic cancer significantly improved survival compared to GEM monotherapy. The aim of this study is to evaluate the long-term outcomes in the ESPAC-4 trial. Methods: Patients with pancreatic ductal adenocarcinoma were randomized within 12 weeks of surgery (stratified for R0/R1 resection margin status and country) to have either six 4-week cycles of IV GEM alone or GEM with oral CAP. The primary endpoint was five-year survival; secondary endpoints were toxicity and relapse free survival. 722 patients (480 expected events), 361 in each arm, were needed to detect a 10% difference in 2-year survival rates with 90% power (log-rank test with 5% two-sided alpha). Results: Between Nov 10 2008 and Sep 11 2014, 732 patients were randomized with 730 included in the full analysis set (366 GEM, 364 GEM/CAP). Median age was 65 years, 57% were men. WHO performance status was 0, 1 or 2 in 42% 55% and 3% respectively. Postoperative median CA19-9 was 19 kU/L. Median maximum tumor size was 30 mm, 61% were R1 resections, 80% were node positive and 40% were poorly differentiated. The data freeze was on 24 February 2020; median follow up was 60 months with 531 overall deaths, 280 in GEM, and 251 in GEM/CAP. Median (95% CI) survival (months) for patients treated with GEM/CAP was 27.7 23.3 – 31.2) and 26.0 (22.7 – 28.4) for GEM. Five-year (95% CI) survival rates were 20 (16 – 25) % for GEM and 28 (23 – 33) % for GEM/CAP. Stratified log-rank analysis revealed an HR=0.84 [95% CI, 0.70 – 0.99]; χ2 (1) = 3.87, P=0.049. 70 out of 366 GEM patients in the safety set reported 101 grade 3/4 serious adverse events, while 65 out of 359 GEM/CAP patients reported 97 grade 3/4 serious adverse events ( P=0.724). Conclusions: Adjuvant GEM/CAP for pancreatic cancer had a statistically significant improvement in survival compared to GEM monotherapy. Clinical trial information: 96397434 .

Carcinosarcoma of the Pancreas with Longer Survival: A Case Report and Literature Review

BackgroundCarcinosarcoma is a rare type of malignant tumor that can occur at various organs, such as the digestive tract, lung, and mammary glands (1-4). Carcinosarcoma of the pancreas is an extremely rare and complicated malignant neoplasm, with the characteristics of high invasiveness and rapid progression, early metastasis, and poor prognosis (4).Case PresentationWe reported a 75-year-old male patient who was admitted with the chief complaint of intermittent pain in the right upper abdomen for more than one month. Computed tomography scans revealed a space-occupying lesion located in the tail of the pancreas considering pancreatic carcinoma. The patient underwent surgical resection of the tumor. Macroscopic observations showed a mass of approximately 6 cm × 5 cm with grayish-white cut surface. Histological analysis showed a large amount of abnormal differentiated epithelial cells and spindle cells. The immunohistochemistry results demonstrated biphasic neoplasm with both malignant epithelial and mesenchymal components. Then, the patient was diagnosed with carcinosarcoma of the pancreas. Although pancreatic carcinosarcoma was considered to have a poor outcome as previously reported, the patient was free of recurrence for 15 months after the surgery, a longer tumor-free survival recorded for this type of cancer, maybe because the patient received gemcitabine adjuvant chemotherapy after the surgery. The current literature shows that the longest postoperative survival time is 26 months (5).ConclusionsCarcinosarcoma of the pancreas is a rare tumor. Surgery is the main way of treatment, and chemotherapy can delay tumor development to some extent.

Are ENT1/ENT1, NOTCH3, and miR-21 Reliable Prognostic Biomarkers in Patients with Resected Pancreatic Adenocarcinoma Treated with Adjuvant Gemcitabine Monotherapy?

Evidence on equilibrative nucleoside transporter 1 (ENT1) and microRNA-21 (miR‑21) is not yet sufficiently convincing to consider them as prognostic biomarkers for patients with pancreatic ductal adenocarcinoma (PDAC). Here, we investigated the prognostic value of ENT1/ENT1, miR-21, and neurogenic locus homolog protein 3 gene (NOTCH3) in a well-defined cohort of resected patients treated with adjuvant gemcitabine chemotherapy (n = 69). Using a combination of gene expression quantification in microdissected tissue, immunohistochemistry, and univariate/multivariate statistical analyses we did not confirm association of ENT1/ENT1 and NOTCH3 with improved disease-specific survival (DSS). Low miR-21 was associated with longer DSS in patients with negative regional lymph nodes or primary tumor at stage 1 and 2. In addition, downregulation of ENT1 was observed in PDAC of patients with high ENT1 expression in normal pancreas, whereas NOTCH3 was upregulated in PDAC of patients with low NOTCH3 levels in normal pancreas. Tumor miR‑21 was upregulated irrespective of its expression in normal pancreas. Our data confirmed that patient stratification based on expression of ENT1/ENT1 or miR‑21 is not ready to be implemented into clinical decision-making processes. We also conclude that occurrence of ENT1 and NOTCH3 deregulation in PDAC is dependent on their expression in normal pancreas.

Impact of adjuvant chemotherapy using gemcitabine plus S-1 after surgical resection for advanced biliary cancer.

132 Background: The impact of adjuvant chemotherapy for advanced biliary cancer remains controversial. We previously failed to show survival benefit of adjuvant gemcitabine chemotherapy (UMIN000014018). The aim of this study was to evaluate the safety and efficacy of adjuvant gemcitabine plus S-1 chemotherapy after surgical resection for advanced biliary cancer. Methods: Between January 2006 and May 2019, a total of 110 patients who underwent surgical resection for biliary cancer (UICC Stage II or more) were enrolled in this study. Of these, 33 patients subsequently received 12 cycles of adjuvant chemotherapy (GS group), and 77 patients underwent surgery alone (S group). A cycle of chemotherapy consisted of oral S-1 70mg/m2 for 7 consecutive days and intravenous gemcitabine 1000mg/m2 on day 7, followed by a 1-week break from chemotherapy. Clinicopathological factors and patient survival were compared between the two groups. Results: GS group had significantly younger patients ( P = 0.036) and higher UICC T factor ( P = 0.001). Surgical procedure was significantly different in the two groups (P = 0.010). Other patient demographics and tumor characteristics were similar between the two groups. The completion rate of adjuvant chemotherapy was 57.6%, and there was no treatment-related deaths. All grades and grade 3/4 adverse event were seen in 60.6% and 33.3%, respectively. Three-year recurrence-free and overall survival rates were significantly higher in GS group than S group (61.9% vs. 34.4%, P = 0.016; 77.6% vs. 39.7%, P &lt; 0.001, respectively). Conclusions: Adjuvant chemotherapy using gemcitabine plus S-1 was well tolerated and it would be an effective treatment strategy for the patients with resected advanced biliary cancer. Based on these results, randomized controlled study should be warranted.

Hybrid Laparoscopic and Robotic Hepatopancreaticoduodenectomy for Cholangiocarcinoma

IntroductionCombined hepatic resection and pancreaticoduodenectomy is the treatment of choice for patient with extensive horizontal-spreading cholangiocarcinoma involving both the perihilar bile duct and the intrapancreatic distal bile duct.1-3 This surgical procedure is extremely complex, and incurs a high risk of postoperative morbidity and mortality.4 However, in recent years, this complicated high-risk operation can be safely performed in well-selected patients.5 However, as we know, none of these operations have been reported as minimally invasive surgery. Patient and MethodsA 73-year-old female presented with jaundice and was diagnosed with cholangiocarcinoma. The preoperative image studies revealed a 4.3-cm-long diffuse, infiltrative cholangiocarcinoma from the hilar bile duct to the intrapancreatic bile duct without major vascular invasion. The patient was scheduled to undergo left hepatectomy with caudate lobectomy and pancreaticoduodenectomy to obtain a free resection margin. In order to maximize the efficiency of each surgical modality, we designed a hybrid method of laparoscopic resection and robotic reconstruction for this complicated surgery with a long operation time. A 12-mm port was placed at the subxiphoid area, which was utilized for laparoscopic CUSA during the liver resection. Three 12-mm ports around the umbilicus and an 8-mm robotic port at the right flank were placed. In the resection phase, pancreaticoduodenectomy was performed first, followed by hilar dissection and liver resection in en bloc manner. Here, a hanging maneuver was helpful for the complete resection of the caudate lobe in environment with the large specimen attached. In reconstruction phase, the right flank 8-mm port and the left side 12-mm port (using the double docking technique) were used for docking of two robotic working arms. ResultsThe total operation time was 510 min, and the estimated blood loss was 350 mL without transfusion. The patient’s postoperative recovery was smooth, except for a mild fever due to cystitis, and she was discharged on the 16th postoperative day. Permanent pathologic examination revealed a disease-free proximal bile duct margin, but a metastasis was discovered in one regional lymph node metastasis from 18 retrieved lymph nodes. The patient is receiving adjuvant gemcitabine chemotherapy and regular surveillance. We performed two consecutive cases and the perioperative outcomes were summarized in the attached video. ConclusionHepatopancreaticoduodenectomy has a long operative time, involves complicated anatomical structures and difficulty of R0 resection, and it is a remaining frontier of minimally invasive surgery. However, we expect that highly selected patients can carefully undergo minimally invasive surgery if the advantages of the currently available surgical methods are well utilized.

Safety and efficacy of docetaxel combined with cisplatin as induction chemotherapy followed by cisplatin concurrent chemoradiotherapy plus gemcitabine as adjuvant chemotherapy in locally advanced nasopharyngeal carcinoma: A prospective and multicenter phase II trial.

6064 Background: Radiation therapy is the only curative treatment modality for nonmetastatic nasopharyngeal cancer (NPC). Concurrent chemoradiation (CCRT) is the standard treatment strategy for NPC in locally advanced stages. However, the results after such treatment are suboptimal. Clearly, novel treatment strategies are needed to further improve patients’ survival rates. This trial aimed to determine the safety and efficacy of a new treatment strategy. Methods: Patients with stage III – IVa-b NPC received TP (docetaxel 75 mg/m2, cisplatin 75 mg/m2 every 3 weeks for 2-3 cycles) followed by cisplatin chemotherapy concurrently with either 3-dimentional conformal radiation therapy or intensity-modulated radiation therapy plus gemcitabine (1000mg/m2 every 2 weeks for 2 cycles) as adjuvant chemotherapy. Objective response rates and acute toxicity were assessed based on RECIST (1.1) and CTCAE v.4.0, respectively. Kaplan-Meier analysis was used to calculate survival rates. This trial is registered with the Chinese Clinical Trials Registry, number ChiCTR-OIC-17011464. Results: From July 2010 to July 2017, 20 eligible patients with nonmetastatic stage III-IVb NPC were enrolled. The objective response rates were 90% (3 complete responses [CRs] and 15 partial responses [PRs]) after two or three cycles of induction chemotherapy (ICT) and 100% (17 CRs and three PRs) after CCRT plus gemcitabine adjuvant chemotherapy, respectively. With a median follow-up time of 41 months, the 3-year overall survival rates were 90% (18/20,95% confidence interval [CI], 76.9%-100%).The 3-year progression-free survival, distant metastasis-free survival, and local progression-free survival rates were 80% (16/20,95% CI, 62.5%-97.5%), 85% (17/20,95% CI, 69.4%-100%),95% (19/20,95% CI, 85,4%-100%), respectively. The most frequent grade 3–4 toxicities were neutropenia (3/20,15%) and nausea (2/20,10%) after ICT and thrombocytopenia (6/20,30%) and leukopenia (6/20,30%) after CCRT plus gemcitabine adjuvant chemotherapy. Conclusions: Neoadjuvant TP followed by concurrent chemoradiation plus gemcitabine as adjuvant chemotherapy was well tolerated and produced promising outcomes in patients with LA-NPC in this hypothesis-generating study. The authors concluded that randomized controlled trials are warranted to definitively confirm this aggressive and potentially efficacious strategy. Clinical trial information: ChiCTR-OIC-17011464.

Adjuvant Capecitabine After Biliary Cancer Resection

A recent phase III trial showed that adding adjuvant gemcitabine and oxaliplatin chemotherapy to surgical resection did not improve survival in

A phase II study of intraoperative radiotherapy using a low-energy x-ray source for resectable pancreatic cancer: a study protocol

BackgroundThe current standard treatment for resectable pancreatic cancer is surgical resection followed by adjuvant chemotherapy. Local recurrence rates are high even after curative resection; thus, the long-term outcome of locally advanced pancreatic cancer remains poor. Intraoperative radiotherapy (IORT) uses a low-energy x-ray source to deliver a single fraction of high-dose radiation to the tumor bed during a surgical procedure, while effectively sparing the surrounding normal tissues. IORT has the potential to improve the efficacy of radiation therapy for pancreatic cancer.Methods/designThis prospective, one-armed, phase II study will investigate the role of IORT in improving local control in patients with resectable pancreatic adenocarcinoma. The patients will receive surgery and IORT of 10 Gy prescribed at a 5-mm depth of the tumor bed, followed by adjuvant gemcitabine chemotherapy according to the current standard of care. The aim is to enroll 42 patients.DiscussionThe primary endpoint of this trial is to evaluate the feasibility of IORT and the local recurrence rate after one year. The secondary endpoints include the acute and late toxicities, and disease-free survival and overall survival rates.Trial registrationThe trial was prospectively registered at Clinicaltrials.gov NCT03273374 on September 6, 2017.

Orotate phosphoribosyltransferase as a predictor of benefit from S‐1 adjuvant chemotherapy for cholangiocarcinoma patients

To improve the prognosis of cholangiocarcinoma, we investigated potential biomarkers that may enable the selection of patients for whom postoperative adjuvant chemotherapy is likely effective. The cohort of this retrospective study included 170 surgically resected cholangiocarcinoma patients, 26 with gemcitabine adjuvant chemotherapy (GEM group), 36 with S-1 adjuvant chemotherapy (S-1 group), and 103 receiving no adjuvant chemotherapy (NC group). Propensity score matching was performed to adjust patient backgrounds; 36 patients from the NC group then were selected. Immunohistochemistry of orotate phosphoribosyltransferase (OPRT) and human equilibrative nucleoside transporter 1 (hENT1) was performed to determine the correlation between their expression and disease-free survival (DFS). After matching, the backgrounds of these three groups were unbiased. No significant improvement of DFS by adjuvant chemotherapy was observed in the whole cohort. However, among the high-OPRT-expression patients, DFS of GEM, S-1, and NC groups at 5years was 28.8%, 53.8%, and 25.5%, respectively. The DFS of the S-1 group was significantly longer than that of the NC group (P=0.034). On the other hand, no significant differences in DFS were observed among the low OPRT expression patients. hENT1 expression was shown to have no predictive value. Multivariate analysis of the high-OPRT-expression patients demonstrated that S-1 adjuvant chemotherapy can reduce tumor recurrence (HR, 0.303; P=0.013). Cholangiocarcinoma patients with high OPRT expression would benefit from postoperative adjuvant S-1 therapy, which increases the DFS. Assessment of OPRT expression may contribute to the optimization of adjuvant chemotherapy for cholangiocarcinoma.

Adjuvant gemcitabine chemotherapy versus observation in resected bile duct cancer: a multicenter randomized clinical trial in Japan

Adjuvant gemcitabine chemotherapy versus observation in resected bile duct cancer: a multicenter randomized clinical trial in Japan

Long-term results of a phase II study of gemcitabine and cisplatin chemotherapy combined with intensity-modulated radiotherapy in locoregionally advanced nasopharyngeal carcinoma

To evaluate long-term results of a phase II study of induction and adjuvant gemcitabine and cisplatin (GP) chemotherapy with intensity-modulated radiotherapy (IMRT) in locoregionally advanced nasopharyngeal carcinoma (NPC). One hundred and twelve patients (Stage III: 65, IVA-B: 47) with locoregionally advanced NPC were enrolled in this study. All patients received induction chemotherapy consisting of 1000 mg/m2 gemcitabine on day 1 and 8, and cisplatin 25 mg/m2 on day 1–3, every 3 weeks for 2 cycles. Adjuvant chemotherapy for 2 cycles of the same regime was given 28 days after the end of IMRT. The IMRT technique was utilized for all patients. In total, 97.3% patients completed 2 cycles of induction chemotherapy. The overall response rate (RR) of cervical lymph nodes was 89.0%. Acute toxicities were mainly grade 1–2 myleosuppression and vomiting. And 83.9% patients completed 2 cycles of adjuvant chemotherapy. All patients finished IMRT with RR at the end of IMRT for nasopharynx, lymph nodes of neck and retropharyngeal area being 99.1%, 97.9% and 97.7%, respectively. The 5-year local control, regional control, distant metastasis-free and overall survival rates were 93.2%, 92.3%, 89.0% and 82.1%, respectively. The 5-year overall survival of stage III and IVA-B were 87.0%, and 75.5%, respectively. The incidence of grade 3–4 acute radiotherapy-related mucositis was 28.6%. Severe late toxicities were uncommon. IMRT combined with GP for locoregionally advanced NPC is well tolerated, effective, and convenient, and warrants further studies.