Early detection of necrosis in low-enhanced pancreatic parenchyma using contrast-enhanced computed tomography was a better predictor of clinical outcomes than pancreatic inflammation: A multicentric cohort study of severe acute pancreatitis.

OBJECTIVES: We aim to assess the early use of contrast-enhanced computed tomography (CECT) of patients with severe acute pancreatitis (SAP) using the computed tomography severity index (CTSI) in prognosis prediction. The CTSI combines quantification of pancreatic and extrapancreatic inflammation with the extent of pancreatic necrosis. METHODS: Post-hoc retrospective analysis of a large, multicentric database (44 institutions) of SAP patients in Japan. The area under the curve (AUC) of the CTSI for predicting mortality and the odds ratio (OR) of the extent of pancreatic inflammation and necrosis were calculated using multivariable analysis. RESULTS: In total, 1097 patients were included. The AUC of the CTSI for mortality was 0.65 (95 % confidence interval [CI:] [0.59-0.70]; p < 0.001). In multivariable analysis, necrosis 30-50 % and >50 % in low-enhanced pancreatic parenchyma (LEPP) was independently associated with a significant increase in mortality, with OR 2.04 and 95 % CI 1.01-4.12 (P < 0.05) and OR 3.88 and 95 % CI 2.04-7.40 (P < 0.001), respectively. However, the extent of pancreatic inflammation was not associated with mortality, regardless of severity. CONCLUSIONS: The degree of necrosis in LEPP assessed using early CECT of SAP was a better predictor of mortality than the extent of pancreatic inflammation.

Bone loss over time and risk of osteoporosis in advanced pancreatic cancer.

BACKGROUND: Pancreatic cancer has a high risk of developing osteoporosis. However, the impact of osteoporosis has not been well-studied. This study aimed to evaluate bone loss over time and risk of osteoporosis in patients with advanced pancreatic cancer. METHODS: We retrospectively examined consecutive patients with unresectable pancreatic cancer who had evaluable computed tomography before treatment and at 1-year follow-up. Bone mineral density at the first lumbar vertebra was measured on computed tomography, and osteoporosis was defined as bone mineral density < 135 Hounsfield units. The prevalence and risk factors for osteoporosis, changes in bone mineral density over time and incidence of bone fractures were analyzed. RESULTS: Three hundred eighty patients were included. Osteoporosis was associated with older age, female sex, low body mass index and poor performance status at baseline. A consistent decrease in bone mineral density was observed over time regardless of age, sex or disease status, resulting in an increase in the prevalence of osteoporosis over time (47% at baseline, 79% at 1 year, 88% at 2 years, 89% at 3 years, 95% at 4 years and 100% at 5 years). Changes in bone mineral density from baseline were greater in patients with locally-advanced pancreatic cancer, in those who received modified FOLFIRINOX or S-IROX for more than 3 months, and in those who received radiation therapy. Incident fractures developed in 45 patients (12%) during follow-up. CONCLUSIONS: Osteoporosis and osteoporotic fractures were highly prevalent in patients with advanced pancreatic cancer. This study highlights the importance of screening for osteoporosis in such patients.

Clinical Efficacy of Neoadjuvant Chemotherapy with Gemcitabine plus S-1 for Resectable Pancreatic Ductal Adenocarcinoma Compared with Upfront Surgery.

BACKGROUND: The efficacy of neoadjuvant chemotherapy with gemcitabine plus S-1 (NAC-GS) in the prognosis of patients with resectable pancreatic ductal adenocarcinoma (PDAC) has been reported. NAC-GS is now assumed to be a standard regimen for resectable PDAC in Japan. However, the reason for this improvement in prognosis remains unclear. METHODS: In 2019, we introduced NAC-GS for resectable PDAC. From 2015 to 2021, 340 patients were diagnosed with resectable PDAC (anatomical and biological [carbohydrate antigen (CA) 19-9 < 500 U/mL]) and were divided according to the treatment period (upfront surgery [UPS] group, 2015-2019, n = 241; NAC-GS group, 2019-2021, n = 80). We used "intention-to-treat" analysis to compare the clinical outcomes of NAC-GS to those of UPS. RESULTS: Of the 80 patients with NAC-GS, 75 (93.8%) completed two cycles of NAC-GS, and the resection rate of the NAC-GS group was comparable to that of the UPS group (92.5 vs. 91.3%, P = 0.73). The R0 resection rate was significantly higher in the NAC-GS group than in the UPS group (91.3 vs. 82.6%, P = 0.04), even though the surgical burden was smaller. Progression-free survival tended to be better (hazard ratio [HR] = 0.70, P = 0.06), and overall survival was significantly better in the NAC-GS group than in the UPS group (HR 0.55, P = 0.02). CONCLUSIONS: NAC-GS provided improvements in microscopic invasion leading to a high R0 rate and smooth administration and completion of adjuvant therapy, which might lead to an improved prognosis in patients with resectable PDAC.

Prognostic impact of osteosarcopenia in patients with advanced pancreatic cancer receiving gemcitabine plus nab-paclitaxel.

BACKGROUND: Osteosarcopenia, defined as the combination of osteoporosis and sarcopenia, has recently gained attention as a novel prognostic factor for survival in patients with cancer. This study aimed to evaluate the prognostic impact of osteosarcopenia in metastatic pancreatic cancer (PC). METHODS: We retrospectively investigated consecutive metastatic PC patients receiving first-line gemcitabine plus nab-paclitaxel (GnP). Skeletal muscle index at the third lumbar vertebra and bone mineral density at the first lumbar vertebra were measured using pretreatment computed tomography. Treatment outcomes of osteosarcopenia and non-osteosarcopenia groups were compared and analyzed. Multivariate analysis was performed to identify variables associated with survival. RESULTS: Among 313 patients, osteosarcopenia was present in 59 patients (19%). The osteosarcopenia group was associated with older age, higher proportion of females, worse performance status, and higher modified Glasgow prognostic scores (mGPS). Response rates to chemotherapy, progression-free survival (3.5 months vs. 6.4 months, p < 0.001), and overall survival (5.6 months vs. 13.0 months, p < 0.001) were significantly better in the non-osteosarcopenia group. Osteosarcopenia, performance status of 1-2, mGPS score of 1-2, carcinoembryonic antigen ≥10 ng/mL, and carbohydrate antigen 19-9 ≥ 1000 IU/mL were identified as independent factors predicting shorter survival. Grade 3 or higher anemia and febrile neutropenia occurred more frequently in the osteosarcopenia group. CONCLUSIONS: Osteosarcopenia was associated with poor survival in metastatic PC treated with first-line GnP. Screening for osteosarcopenia may be helpful for better management of metastatic PC.

The impact of osteosarcopenia in patients with unresectable or recurrent biliary tract cancer receiving palliative chemotherapy.

BACKGROUND: Osteosarcopenia is a newly described syndrome that has been reported to be associated with worse outcomes in various types of cancer. However, its impact on survival in biliary tract cancer remains unclear. This study evaluated the impact of osteosarcopenia on survival in patients with unresectable or recurrent biliary tract cancer. METHODS: A total of 306 patients with unresectable or recurrent biliary tract cancer who initiated chemotherapy at our institution between 2015 and 2021 were retrospectively investigated. Skeletal muscle index and bone mineral density were measured using pretreatment cross-sectional computed tomography images. Baseline characteristics and survival outcomes were compared between patients with osteosarcopenia and those without. The Cox proportional hazards regression model was used to identify factors associated with survival. RESULTS: Osteosarcopenia was present in 66 patients (22%) and was associated with older age (74 vs. 69 years, P < 0.001) and female sex (58 vs. 37%, P = 0.003). Patients with osteosarcopenia tended to have worse performance status (P = 0.098), higher modified Glasgow prognostic score (P = 0.082), higher neutrophil to lymphocyte ratio (P = 0.058) and were significantly less likely to receive combination chemotherapy (68 vs. 80%, P = 0.044) than those without. Osteosarcopenia was associated with reduced survival (8.9 vs. 14.0 months, P < 0.001) and was identified as an independent factor predicting shorter survival in multivariate analysis. CONCLUSIONS: Osteosarcopenia was associated with poor survival in unresectable or recurrent biliary tract cancer treated with chemotherapy. This study highlights the potential importance of screening for osteosarcopenia in patients with biliary tract cancer.

Outcomes of lung oligometastasis in pancreatic cancer.

OBJECTIVE: Pancreatic cancer with lung oligometastasis may have favourable overall survival. The aim of this study was to evaluate outcomes of pancreatic cancer with lung oligometastases including both synchronous and metachronous metastases. METHODS: Consecutive pancreatic cancer patients with lung metastasis treated at our institution between February 2015 and December 2021 were identified from our prospectively maintained database. Clinical characteristics and outcomes were compared and analysed according to the extent of lung metastases. Predictors for overall survival were analysed using the Cox proportional hazards model. RESULTS: A totoal of 171 patients were included (oligometastasis/polymetastasis/multi-organ metastasis: 34/50/87). Patients with oligometastases were more likely to undergo surgical resection (41% vs. 0% vs. 2%) and showed a longer median overall survival (41.3 vs. 17.6 vs. 13.1 months) compared with those with other types of metastases. Oligometastasis (hazard ratio, 0.43; 95% confidence interval, 0.24-0.76; P = 0.004) was identified as an independent factor predicting favourable overall survival in patients with lung-only metastasis. Disease status (synchronous vs. metachronous) was not associated with survival in patients with oligometastasis (29.4 vs. 41.3 months, P = 0.527) and polymetastasis (17.9 vs. 16.7 months, P = 0.545). Selected patients who underwent surgical resection showed a median overall survival of 52.7 months. CONCLUSIONS: Patients with lung oligometastases presented a favourable prognosis. Surgical resection in selected patients was associated with a long median overall survival.

Long-term outcomes of duckbill-type anti-reflux metal stents versus conventional covered metal stents in reinterventions after covered biliary metal stent dysfunction in unresectable pancreatic cancer.

BACKGROUND: The use of duckbill-type anti-reflux metal stents (DMS) in reinterventions after covered metal stent (CMS) dysfunction has been reported in patients with distal malignant biliary obstruction (MBO). However, the superiority of DMS over conventional CMS (c-CMS) has not been established. Therefore, we conducted this retrospective study to evaluate the long-term efficacy and safety of DMS as a second stent in comparison with c-CMS. METHODS: We investigated consecutive patients with distal MBO due to unresectable pancreatic cancer who underwent reintervention after dysfunction of initial biliary CMS at our institution. We compared causes of recurrent biliary obstruction (RBO), time to RBO (TRBO), adverse events (AEs), and reintervention rates of DMS and c-CMS in this stenting. RESULTS: A total of 76 patients were included (DMS 41 and c-CMS 35). While overall RBO rates were similar between the two groups (46% vs. 63%, p = 0.172), RBO due to non-occlusion cholangitis tended to be less frequent in the DMS group than in the c-CMS group (2% vs. 14%, p = 0.089). Median TRBO was significantly longer in the DMS group (286 days vs. 112 days, p = 0.029). DMS was identified as the only significant risk factor for TRBO (hazard ratio, 0.52; p = 0.044). Overall AE rates were significantly lower in the DMS group (2% vs. 23%, p = 0.010), with non-occlusion cholangitis being the most common AE in the c-CMS group. Endoscopic reintervention was successfully performed in all patients in both groups, despite failed stent removal in 15% of patients in DMS group. CONCLUSIONS: DMS was associated with a significantly longer TRBO and lower rate of AEs compared with c-CMS in reinterventions after initial CMS dysfunction. DMS may be preferable to c-CMS as a second stent after biliary CMS dysfunction.

Outcomes after partially covered self-expandable metal stent placement for recurrent duodenal obstruction.

BACKGROUND: Outcomes of partially covered self-expandable metal stents (SEMS) as an additional stent after recurrent duodenal obstruction (RDO) have not been elucidated. In this study, we compared outcomes of partially covered and uncovered SEMS placement after RDO in patients with malignant duodenal obstruction and explored factors affecting re-recurrent obstruction and overall survival in this population. METHODS: We conducted a retrospective study of patients undergoing SEMS placement for RDO at a cancer institute in Japan from July 2014 to June 2021. Clinical variables and outcomes of patients undergoing partially covered and uncovered SEMS placement were compared. RESULTS: Sixty-one patients underwent SEMS placement after RDO, for which the COMVI stent was used in 38 cases and uncovered stents were used in 23 cases. Stent ingrowth was the most common cause of RDO (51.4%). Stent migration only occurred after partially covered stent placement (20% vs. 0%, p = 0.018). Choice of SEMS had no impact on time to re-RDO (median 2.8 vs. 4.1 months, p = 0.776) or overall survival (median 2.6 vs. 2.4 months, p = 0.703). Median overall survival was longer in patients receiving chemotherapy after second stenting (4.6 vs. 1.8 months, p < 0.001) and shorter in those with early RDO, regardless of the SEMS used. Use of the partially covered stent had no impact on survival or time to RDO. CONCLUSIONS: While outcomes after partially covered SEMS placement for RDO were not significantly different from uncovered SEMS, migration remains a concern when they are used as a second stent. Chemotherapy after second stenting was associated with longer overall survival but not with longer time to re-RDO.

Analysis of prognostic factors for borderline resectable pancreatic cancer after neoadjuvant chemotherapy: the importance of CA19-9 decrease in patients with elevated pre-chemotherapy CA19-9 levels.

BACKGROUND: Neoadjuvant chemotherapy (NAC) is widely used to treat borderline resectable pancreatic cancer. This study aimed to evaluate the serum carbohydrate antigen (CA)19-9 response, in association with survival, after four cycles of NAC-gemcitabine plus nab-paclitaxel. METHODS: From 2015 to 2018, patients with borderline resectable pancreatic cancer were treated with NAC. Patients were stratified into two groups after excluding CA19-9 non-secretor: Group L (CA19-9 ≥2 and ≤500 U/mL) and Group H (CA19-9 >500 U/mL). The CA19-9 decrease during NAC was evaluated as a response of NAC and was assessed in association with survival concomitant with other prognosis factors. RESULTS: Eighty-seven patients were evaluated (Group L: n = 43, Group H: n = 44). In intention-to-treat-based analysis, Group L exhibited significantly better progression-free survival (PFS) than Group H (median PFS: 24 vs 14months). In resection cohort, no correlation was detected between the CA19-9 decrease and survival in Group L. In Group H, the CA19-9 decrease ≤80% was associated with unfavorable survival in multivariate analysis [Hazard ratio: 4.738 (P = 0.007)]. CONCLUSION: In patients with pre-treatment CA19-9 >500 U/mL, the CA19-9 decrease ≤80% was strongly associated with poor survival and new strategy should be reconsidered for these patients.

KRAS variant allele frequency, but not mutation positivity, associates with survival of patients with pancreatic cancer.

KRAS mutation is a major driver of pancreatic carcinogenesis and will likely be a therapeutic target. Due to lack of sensitive assays for clinical samples of pancreatic cancer with low cellularity, KRAS mutations and their prognostic association have not been fully examined in large populations. In a multi-institutional cohort of 1162 pancreatic cancer patients with formalin-fixed paraffin-embedded tumor samples, we undertook droplet digital PCR (ddPCR) for KRAS codons 12/13/61. We examined detection rates of KRAS mutations by clinicopathological parameters and survival associations of KRAS mutation status. Multivariable hazard ratios (HRs) and 95% confidence intervals (CIs) for disease-free survival (DFS) and overall survival (OS) were computed using the Cox regression model with adjustment for potential confounders. KRAS mutations were detected in 1139 (98%) patients. The detection rate did not differ by age of tissue blocks, tumor cellularity, or receipt of neoadjuvant chemotherapy. KRAS mutations were not associated with DFS or OS (multivariable HR comparing KRAS-mutant to KRAS-wild-type tumors, 1.04 [95% CI, 0.62-1.75] and 1.05 [95% CI, 0.60-1.84], respectively). Among KRAS-mutant tumors, KRAS variant allele frequency (VAF) was inversely associated with DFS and OS with HRs per 20% VAF increase of 1.27 (95% CI, 1.13-1.42; ptrend <0.001) and 1.31 (95% CI, 1.16-1.48; ptrend <0.001), respectively. In summary, ddPCR detected KRAS mutations in clinical specimens of pancreatic cancer with high sensitivity irrespective of parameters potentially affecting mutation detections. KRAS VAF, but not mutation positivity, was associated with survival of pancreatic cancer patients.

Early-onset pancreatic cancer: Clinical characteristics and survival outcomes.

BACKGROUND: Early-onset pancreatic cancer (≤50 years, EOPC) is uncommon. This study aims to characterize the clinical and survival characteristics of EOPC in comparison to late-onset pancreatic cancer (>50 years, LOPC). METHODS: We retrospectively investigated consecutive PC patients treated at our institution between 2010 and 2019. We analyzed and compared clinicopathological characteristics, treatments, and outcomes of EOPC and LOPC. RESULTS: Of 1646 PC patients identified (768 resectable/borderline resectable; 248 locally advanced; 630 metastatic), 127 (8%) had EOPC. Current smoking and heavy drinking were associated with EOPC. EOPC presented at a more advanced stage and had higher neutrophil-to-lymphocyte ratios than LOPC. Survival outcomes were similar between the two groups, both in the entire cohort and in each resectability group. In patients undergoing resection, EOPC tended to have a higher N stage (p = 0.099) and had a higher pathological stage (stage IV, 20% vs. 7%, p = 0.005) and a lower rate of macroscopically curative resection (80% vs. 93%, p = 0.006). Liver recurrence was more commonly observed in EOPC (42% vs. 23%, p = 0.015). In the metastatic cohort, combination chemotherapy regimens were more frequently administered in EOPC as first-line treatment (79% vs. 64%, p = 0.028). Both median PFS (4.4 vs. 5.3 months, p = 0.647) and OS (11.5 vs. 9.5 months, p = 0.183) were not significantly different between the two groups. CONCLUSIONS: EOPC presented with a more aggressive tumor biology. Survival outcomes were similar to LOPC due to more intensive treatment.

Treatment outcomes of nanoliposomal irinotecan as second-line chemotherapy after gemcitabine and nab-paclitaxel in metastatic and recurrent pancreatic cancer.

BACKGROUND: To compare the treatment outcomes of nanoliposomal-irinotecan (nal-IRI) plus fluorouracil and leucovorin (5-FU/LV) and modified FOLFIRINOX (mFFX) as second-line treatment after gemcitabine with nab-paclitaxel (GnP) for metastatic and recurrent pancreatic cancer. METHODS: We retrospectively analyzed consecutive patients with metastatic or recurrent pancreatic cancer treated with nal-IRI plus 5-FU/LV or mFFX after first-line GnP treatment between March 2014 and October 2021 in our hospital. Patient characteristics, treatment outcomes and adverse events were extracted for comparison. RESULTS: Two hundred sixteen patients were included (nal-IRI plus 5-FU/LV/mFFX: 50/166). Patients in the nal-IRI plus 5-FU/LV group were older, had poorer ECOG PS, and a higher rate of peritoneal metastasis than those in the mFFX group. Median overall survival was 9.5 and 9.8 months (P = 0.97), respectively, and the median progression-free survival was 4.5 vs 4.8 months (P = 0.61), respectively. Anorexia, fatigue and peripheral neuropathy were more common in the mFFX group, but there was no difference in grade 3/4 adverse events between the two groups. CONCLUSIONS: There was no significant difference in efficacy between nal-IRI plus 5-FU/LV and mFFX after GnP. Nal-IRI plus 5-FU/LV appears to be a viable alternative to mFFX as second-line treatment after GnP.

Molecular Features and Clinical Management of Hereditary Pancreatic Cancer Syndromes and Familial Pancreatic Cancer.

Hereditary pancreatic cancers are caused by several inherited genes. Familial pancreatic cancer is defined as pancreatic cancer arising in a patient with at least two first-degree relatives with pancreatic cancer in the absence of an identified genetic cause. Hereditary pancreatic cancer syndromes and familial pancreatic cancers account for about 10% of pancreatic cancer cases. Germline mutations in BRCA1, BRCA2, ATM, PALB2, CDKN2A, STK11, and TP53 and mismatch repair genes (MLH1, MSH2, MSH6, PMS2, and EPCAM) are among the well-known inherited susceptibility genes. Currently available targeted medications include poly (ADP-ribose) polymerase inhibitors (PARP) for cases with mutant BRCA and immune checkpoint inhibitors for cases with mismatch repair deficiency. Loss of heterozygosity of hereditary pancreatic cancer susceptibility genes such as BRCA1/2 plays a key role in carcinogenesis and sensitivity to PARP inhibitors. Signature 3 identified by whole genome sequencing is also associated with homologous recombination deficiency and sensitivity to targeted therapies. In this review, we summarize molecular features and treatments of hereditary pancreatic cancer syndromes and surveillance procedures for unaffected high-risk cases. We also review transgenic murine models to gain a better understanding of carcinogenesis in hereditary pancreatic cancer.

Improved prognosis of pancreatic cancer patients with peritoneal metastasis.

BACKGROUND: Peritoneal metastasis is one of the most important poor prognostic factors in advanced pancreatic cancer (PC). Whether the prognosis of PC with peritoneal metastasis has improved with the advent of gemcitabine plus nab-paclitaxel (GnP) and modified FOLFIRINOX (mFFX) is uncertain. The aim of this study was to evaluate the improvements in treatment outcomes of PC with peritoneal metastasis. METHODS: We retrospectively investigated consecutive PC patients with peritoneal metastasis treated with chemotherapy at our institution between 2010 and 2019. We compared the clinical characteristics and survival outcomes according to the period of diagnosis (group A, 2010-2014; group B, 2015-2019) and chemotherapy regimen. We also examined the prognostic factors for overall survival (OS). RESULTS: Among 180 patients included (GnP 88; mFFX 14; other regimens 78), distant metastasis was confined to the peritoneum in 89 patients. Although group B had a worse performance status compared to group A, median OS was significantly longer in group B. GnP and mFFX showed a significantly higher objective response rate and disease control rate in addition to longer progression free survival and OS compared to other regimens. The administration of GnP or mFFX, performance status, and neutrophil to lymphocyte ratio ≥5 were identified as independent prognostic factors for OS. Furthermore, the amount of ascites and extent of peritoneal metastasis were significantly associated with OS in patients with distant metastasis confined to the peritoneum. CONCLUSIONS: The prognosis of PC with peritoneal metastasis has significantly improved over time with the advent of GnP and mFFX.

The safety and efficacy of self-expandable metallic stent placement for malignant biliary obstruction with surgically altered anatomy.

BACKGROUND: Single-balloon enteroscopy-assisted endoscopic retrograde cholangiopancreatography (SBE-ERCP) has been increasingly performed for the treatment of malignant biliary obstruction (MBO) in patients with surgically altered anatomy (SAA), however evidence is scarce. Therefore, we conducted this study to evaluate the efficacy and safety of self-expandable metallic stent (SEMS) placement using a short type SBE. METHODS: We retrospectively examined consecutive patients with SAA who received initial SEMS for MBO at our institution between February 2016 and February 2019. We evaluated patient characteristics, technical and functional success rates, time to recurrent biliary obstruction (TRBO) and complications according to the location of the biliary stricture. RESULTS: A total of 26 patients were included in this study. The primary tumor was gastric cancer in 12, pancreatic cancer in 6, cholangiocarcinoma in 6 and gallbladder cancer in 2. The biliary stricture site was distal bile duct in 14, hilar bile duct in 3 and hepaticojejunostomy (HJ) anastomosis in 9. Technical and functional success rates were 92 and 88%, respectively. TRBO, median survival time, overall rate of RBO and early complications were not different according to the stricture site (p=.36, .67, .67 and .12, respectively), whereas late complications were significantly different among the three groups (Distal vs. Hilar vs. HJ anastomosis; 0 vs. 67 vs. 22%, p<.05). Furthermore, stent patency was not different between fully covered and uncovered SEMS in distal MBO. CONCLUSIONS: SEMS placement via SBE-ERCP was safe and effective for the management of MBO in patients with SAA, especially in distal MBO.

The impact of body composition on short-term outcomes of neoadjuvant chemotherapy with gemcitabine plus S-1 in patients with resectable pancreatic cancer.

BACKGROUND: Although the efficacy of neoadjuvant chemotherapy with gemcitabine plus S-1 (NAC GS) has recently been reported in resectable pancreatic cancer, severe adverse events were frequently observed. Sarcopenia has been reported to be associated with reduced antitumor response and chemotherapy toxicity in several malignancies. The aim of this study is to evaluate the impact of body composition on short-term outcomes of NAC GS in resectable pancreatic cancer patients. METHODS: Clinicopathological data of consecutive patients treated with NAC GS at our institution from February 2019 to April 2020 were retrospectively reviewed. Anthropometric variables were calculated at the third lumbar vertebra using pretreatment computed tomography images. We investigated the association between body composition variables, and antitumor response and chemotherapy toxicity. RESULTS: Among 62 patients included in this study, 25 patients (40%) were sarcopenic at diagnosis. Sixty-one patients received surgery at our institution and 57 patients received pancreatic resection (R0/R1 resection 56/1). Fifty-six patients completed two cycles of NAC GS and severe adverse events (≥grade 3) occurred in 42 patients (hematologic toxicity 41 patients [66%]; non-hematologic toxicity 3 patients). Body mass index and total adipose tissue index were significantly lower in sarcopenic patients compared to non-sarcopenic patients. Completion rate of NAC, rate of treatment delay/interruption, relative dose intensity of gemcitabine and S-1, radiological and pathological tumor response after NAC were not different between sarcopenic and non-sarcopenic patients. Furthermore, there was no significant association between body composition, and severe adverse events and intolerance. CONCLUSIONS: In our experience, NAC GS was similarly tolerable and effective in resectable pancreatic cancer patients regardless of the presence of sarcopenia.

The prognostic impact of tumour location and first-line chemotherapy regimen in locally advanced pancreatic cancer.

BACKGROUND: The prognostic impact of tumour location (pancreatic head vs. pancreatic body/tail) and first-line chemotherapy regimen (gemcitabine plus nab-paclitaxel vs. modified FOLFIRINOX) has not been fully elucidated in locally advanced pancreatic cancer. Therefore, we conducted this study to examine the prognostic impact of tumour location and first-line chemotherapy regimen. METHODS: We retrospectively investigated locally advanced pancreatic cancer patients who initiated first-line chemotherapy (gemcitabine plus nab-paclitaxel or modified FOLFIRINOX) between March 2014 and December 2019. We compared clinical characteristics and survival outcomes according to chemotherapy regimen and tumour location. Furthermore, we examined the prognostic factors associated with overall survival using cox proportional hazards model. Distant metastasis pattern was also compared according to tumour location. RESULTS: A total of 128 patients were included (GnP 95, mFFX 33; Ph 66, Pbt 62). Distribution of chemotherapy regimen was balanced between pancreatic head and pancreatic body/tail cancers. Eight patients underwent conversion surgery and 81 patients (63%) developed distant metastasis. Although patients receiving modified FOLFIRINOX were significantly younger and tended to have better performance status compared to patients receiving gemcitabine plus nab-paclitaxel, radiological tumour response, progression-free survival, overall survival and chemotherapy-related adverse events were similar between the two groups except for grades 3-4 anorexia (9% vs. 1%, P = 0.05). Furthermore, overall survival was similar between pancreatic head and pancreatic body/tail cancers. Conversion surgery and radiation therapy were identified as independent prognostic factors for overall survival. The most common site of distant metastasis was liver metastasis in both groups and pattern of distant metastasis was not different between the two groups. CONCLUSIONS: In our experience, tumour location and first-line chemotherapy regimen were not a prognostic factor for overall survival in locally advanced pancreatic cancer.

Treatment outcomes of erlotinib plus gemcitabine as late-line chemotherapy in unresectable pancreatic cancer.

OBJECTIVE: With the introduction of modified FOLFIRINOX and gemcitabine plus nab-paclitaxel therapy for unresectable pancreatic cancer, erlotinib plus gemcitabine therapy is now occasionally used as late-line therapy. This study investigates outcomes of treatment with erlotinib plus gemcitabine for unresectable pancreatic cancer. METHODS: We retrospectively analysed consecutive patients with unresectable pancreatic cancer treated with erlotinib plus gemcitabine as the third or later-line chemotherapy between March 2014 and December 2020 in our hospital. RESULTS: A total of 56 patients were included (third line/fourth or later line = 42/14). All patients were previously treated with gemcitabine plus nab-paclitaxel and 45 patients were previously treated with modified FOLFIRINOX. The median progression-free survival (PFS) and overall survival (OS) were 1.6 and 4.6 months, respectively. The disease control rate was 21.4%. Performance status, modified Glasgow prognostic score and carcinoembryonic antigen level were independently associated with survival. Our prognostic model using these parameters could classify patients into good (n = 32) and poor (n = 24) prognostic groups. The median PFS and OS were longer in good than in poor prognostic group, but the difference in PFS was very small (PFS: 2.1 vs. 1.4 months, P = 0.01. OS: 6.8 vs. 2.4 months, P < 0.01). Interstitial pneumonia occurred in one patient (1.8%). CONCLUSIONS: Benefits of erlotinib plus gemcitabine as late-line chemotherapy were limited, particularly with respect to PFS. Development of more effective third-line treatment options is desirable in the future.

The impact of cachexia and sarcopenia in elderly pancreatic cancer patients receiving palliative chemotherapy.

BACKGROUND: Elderly pancreatic cancer (PC) patients are often considered vulnerable to treatment and standard treatment strategy for this subpopulation is uncertain. Cachexia and sarcopenia are reported to be associated with reduced physical performance, reduced anti-tumor response, increased chemotherapy toxicity, and poor prognosis in several malignancies. The aim of this study was to evaluate the impact of cachexia and sarcopenia on the clinical course of elderly PC patients receiving chemotherapy. METHODS: We retrospectively investigated consecutive elderly metastatic PC patients (≥ 75 years) treated with chemotherapy at our institution between January 2015 and April 2020. Skeletal muscle index was calculated at the third lumbar vertebra using pretreatment computed tomography. We evaluated time to treatment failure (TTF), progression-free survival (PFS), overall survival (OS), early treatment discontinuation, relative dose intensity (RDI), and severe adverse events (AEs). RESULTS: Among 80 patients included (gemcitabine plus nab-paclitaxel [GnP] 52; gemcitabine 21; S1 6; modified FOLFIRINOX 1), cachexia and sarcopenia were present in 48 (60%) and 61 (76%) patients, respectively. Cachexia was associated with older age, worse performance status, higher level of neutrophil to lymphocyte ratio, worse nutritional status, and shorter TTF and PFS. Furthermore, it was also associated with early treatment discontinuation, reduced RDI of nab-paclitaxel, and increased incidence of grade 4 neutropenia in patients receiving GnP. On the other hand, sarcopenia had less impact on the clinical course of elderly PC patients. CONCLUSIONS: In our experience, cachexia was considered an effective tool in the management of elderly PC patients receiving palliative chemotherapy.

Risk factors for gemcitabine plus nab-paclitaxel-induced interstitial lung disease in pancreatic cancer patients.

BACKGROUND: Drug-induced interstitial lung disease (ILD) is one of the most serious adverse events with a high mortality rate and represents a serious clinical problem. However, gemcitabine plus nab-paclitaxel (GnP)-induced ILD in pancreatic cancer (PC) patients has not been thoroughly investigated. Therefore, we conducted this study to examine the clinical characteristics of GnP-induced ILD and identify risk factors for developing ILD. METHODS: We retrospectively investigated consecutive patients with PC who received GnP between January 2015 and April 2020. We compared the clinical characteristics and overall survival (OS) according to ILD occurrence and explored risk factors including ABO blood type for developing ILD. RESULTS: Of the 910 patients included in this study, ILD occurred in 20 patients (2.2%). PC patients who developed ILD had a significantly higher frequency of blood type B compared to those without ILD (42% vs. 22%, p ˂ 0.05). Other baseline characteristics including smoking history and current/previous lung disease were not different between the two groups. Median time from initiation of GnP to onset of ILD was 80 days. All patients recovered from ILD and OS was not significantly different according to ILD occurrence. Multivariate analysis revealed that blood type B was an independent risk factor for developing ILD. CONCLUSIONS: We demonstrated that GnP-induced ILD occurred in 2.2% of PC patients with no mortality and OS did not differ according to ILD occurrence. Furthermore, we clarified that ABO blood type B was an independent risk factor for developing ILD in PC patients receiving GnP.