An exploration of trifluridine/tipiracil in combination with irinotecan in patients with pretreated advanced gastric cancer.

BACKGROUND: Trifluridine/tipiracil (FTD/TPI) and irinotecan are treatment options for heavily pretreated patients with advanced gastric cancer, but their efficacies are limited. We investigated the combination of FTD/TPI and irinotecan for such patients. METHODS: Patients who were refractory to fluoropyrimidine, platinum and taxane were enrolled into four cohorts (Level 1A/1B/2A/2B) and treated with irinotecan (100 [Level 1] or 125 [Level 2] mg/m2 on days 1 and 15) and FTD/TPI (35 mg/m2/dose, twice daily, on days 1-5 and 8-12 [Level A] or on days 1-5 and days 15-19 [Level B]) of a 28-day cycle. The primary endpoints were the maximum tolerated dose, dose-limiting toxicities (DLTs), and recommended phase II dose (RP2D); the secondary endpoint was the disease control rate (DCR). RESULTS: Eleven patients were enrolled: 2 at Level 1A, 3 at Level 1B, and 6 at Level 2B. DLTs occurred in 2/2 patients at Level 1A and 2/6 patients at Level 2B. Grade 3 or higher treatment-related adverse events were neutropenia (90.9%), leukopenia (54.5%), anemia (45.5%) and febrile neutropenia (18.2%). One patient at Level 2B achieved a partial response, and the DCR was 72.7% (95% CI, 39.0%-94.0%). The median progression-free survival and overall survival periods were 3.0 months (95% CI, 0.92-not reached) and 10.2 months (95% CI, 2.2-not reached), respectively. CONCLUSION: The RP2D of FTD/TPI combined with irinotecan was determined to be Level 1B; this level was associated with manageable hematologic toxicities and feasible non-hematologic toxicities. Further evaluation of the efficacy of RP2D treatment is necessary.

Nanoparticle albumin-bound paclitaxel and ramucirumab versus paclitaxel and ramucirumab as second-line chemotherapy for unresectable advanced or recurrent gastric cancer: a multicenter, propensity score-matched analysis (CROSS SELL study).

BACKGROUND: Paclitaxel plus ramucirumab (PTX + RAM) is the standard second-line chemotherapy for unresectable advanced or recurrent gastric cancer (AGC). Nanoparticle albumin-bound paclitaxel (nab-PTX) is an improved, more convenient form of PTX and is non-inferior to PTX. Although some retrospective and single-arm phase II studies regarding nab-PTX + RAM have been reported, comparative studies are lacking. Here, we compared the efficacy and toxicity of nab-PTX + RAM and PTX + RAM using propensity score matching. METHODS: Clinical data of 265 patients treated for AGC with nab-PTX + RAM or PTX + RAM were retrospectively collected. Nab-PTX was administered at dosages of 100 mg/m2, replacing PTX in the standard PTX + RAM regimen. Progression-free survival (PFS), overall survival (OS), and toxicity were compared using 1:1 propensity score matching. RESULTS: In total, 190 (72%) patients were matched. The median PFS was 5.3 [95% confidence interval (CI) 4.4-6.3] and 4.7 (95% CI 3.2-5.3) months in the nab-PTX + RAM and PTX + RAM groups, respectively [hazard ratio (HR) = 0.76, 95% CI 0.56-1.03, p = 0.07]. The median OS was 11.5 (95% CI 9.2-15.0) and 9.9 (95% CI 8.0-12.7) months, respectively (HR = 0.78, 95% CI 0.56-1.07, p = 0.12). Grade 3 and 4 neutropenia was observed more frequently in the nab-PTX + RAM group (72% vs. 56%, p = 0.03). No treatment-related deaths occurred. CONCLUSIONS: Nab-PTX + RAM exhibited more favorable trends in terms of PFS and OS but was more myelosuppressive than PTX + RAM. As neutropenia is commonly manageable toxicity, nab-PTX + RAM presents a treatment alternative for AGC. Further studies including randomized, controlled studies are warranted.

[Tolerability of Definitive Chemoradiotherapy in Elderly Patients with Esophageal Cancer].

Definitive chemoradiotherapy(CRT)for esophageal cancer is the standard treatment and alternative to surgery. However, the tolerability of CRT in elderly patients is not well known. In this study, we retrospectively analyzed 60 patients with esophageal cancer who were treated with CRT(5-FU 700 mg/m2, cisplatin 70 mg/m2, radiation 60 Gy)at our hospital between January 2015 and September 2017. The patients were divided into 2 groups: an elderly group comprising 16 patients aged >75 years and a non-elderly group comprising 44 patients aged <74 years. The relative dose intensity of cisplatin in the elderly group was significantly lower than that in the non-elderly group. Radiotherapy was successfully executed in both groups. More patients in the elderly(25%)than the non-elderly group(7%)developed pneumonitis, and all patients who developed severe pneumonitis in the elderly group died. Application of definitive CRT and irradiation methods in elderly patients with a subpleural reticular shadow should be carefully considered before initiating therapy.

Risk factors and efficacy outcomes of early-onset severe neutropenia due to paclitaxel or nanoparticle albumin-bound paclitaxel combined with ramucirumab in advanced gastric cancer: a multicenter retrospective cohort study.

Background: Paclitaxel or nanoparticle albumin-bound paclitaxel combined with ramucirumab (PTX/nab-PTX + RAM) is widely used as second-line chemotherapy for advanced gastric cancer (AGC), but severe neutropenia often develops with this regimen. Although previous studies have reported that severe neutropenia is a favorable prognostic factor in cancer chemotherapy, it is unclear in AGC patients receiving PTX/nab-PTX + RAM. In addition, the risk factors for early-onset of severe neutropenia (EOSN) still remain unknown. Methods: Among patients with AGC treated with PTX/nab-PTX (on day 1, 8, and 15) + RAM (on day 1 and 15) every 4 weeks as second-line therapy from January 2017 to June 2020, those with grade 0 or 1 neutropenia before the treatment were retrospectively studied. Blood tests were performed on the day of treatment each time, and disease progression was primarily determined by computed tomography every 8±2 weeks. EOSN was defined as grade 4 neutropenia that occurred during the first 28 days. The risk factors for EOSN were investigated using multivariate logistic regression analysis. Progression-free survival (PFS) and overall survival (OS) in patients with and without EOSN were investigated using multivariate analysis with a Cox proportional hazards model. Results: The clinical data of 244 patients were analyzed. EOSN was observed in 51 (20.9%) patients. Multivariate analysis identified the following five risk factors for EOSN: age ≥65 years [odds ratio (OR), 2.75], presence of primary tumor (OR, 2.82), presence of peritoneal metastasis (OR, 2.52), grade 1 neutropenia (OR, 3.32), and high serum level of alkaline phosphatase (OR, 2.34). The PFS was significantly longer in patients with EOSN than in those without EOSN [adjusted hazard ratio (HR), 0.61; 95% CI, 0.41-0.92] and the OS tended to be longer in patients with EOSN than in those without EOSN (adjusted HR, 0.73; 95% CI, 0.47-1.12). HR was adjusted with patient background factors and blood test data considered important as predictive or prognostic factors. Conclusions: EOSN may be associated with favorable outcomes in patients with AGC treated with PTX/nab-PTX + RAM. We should carefully try to treat them keeping the risk factors in mind.

Clinical Outcomes of S-1 Monotherapy and Modified FOLFIRINOX Therapy after Gemcitabine plus Nab-paclitaxel Therapy in Unresectable Pancreatic Cancer.

Objective S-1 and modified FOLFIRINOX (mFFX) were often used as the second-line chemotherapies after failure of gemcitabine plus nab-paclitaxel (GnP) in unresectable pancreatic cancer (UPC) until nanoliposomal irinotecan plus 5-fluorouracil/leucovorin therapy was approved as an alternative in Japan in 2020. However, the clinical outcomes of S-1 and mFFX after GnP have scarcely been reported. Therefore, we retrospectively studied them. Methods We extracted the clinical data of 86 patients with UPC who received second-line chemotherapy after GnP between 2015 and 2020. Among the patients who had a good organ functions and no massive ascites, 41 patients treated with S-1 and 21 treated with mFFX were enrolled. Results Compared to S-1, mFFX tended to be used for younger patients with a good general condition (median age, 63 vs. 71 years, p<0.01; and performance status 0, 67% vs. 37%, p<0.05). The median progression-free and overall survival were similar between the S-1 (3.7 and 7.2 months, respectively) and mFFX (3.3 and 7.4 months, respectively) groups. The response rate in patients with measurable lesions was 4% (n=1/23) in the S-1 group and 17% (n=2/12) in the mFFX group. The incidence of grade 3 or 4 adverse events was 20% in the S-1 group and 57% (neutrophil count decreased in 43%) in the mFFX group (p<0.01). Conclusion S-1 and mFFX were both acceptable second-line chemotherapies after GnP therapy for UPC, although attention should be paid to myelosuppression during mFFX treatment. Further studies involving nanoliposomal irinotecan plus 5-fluorouracil/leucovorin therapy are necessary to facilitate the selection of the optimal regimen for each patient.

NOTCH gene alterations in metastatic colorectal cancer in the Nationwide Cancer Genome Screening Project in Japan (SCRUM-Japan GI-SCREEN).

PURPOSE: Activated Notch receptor signaling has been implicated in tumor growth and progression in colorectal cancer (CRC). However, the pathogenic relevance of NOTCH gene alterations remains unclear. The aim of this study was to clarify mutational landscapes and assess their clinical significance in patients with metastatic CRC. METHODS: Pre-chemotherapy tumor tissues obtained from 1154 metastatic CRC patients in the Nationwide Cancer Genome Screening Project in Japan between April 2017 and March 2019 were studied using the Oncomine Comprehensive Assay. RESULTS: The frequencies of NOTCH1, NOTCH2, and NOTCH3 nonsynonymous sequence variants were 11.5%, 4.4%, and 10.4%, respectively. The majority of variants were missense of unknown significance that were distributed across all domains of all three NOTCH genes. The gain-of-function mutations in NOTCH reported in multiple malignancies were not identified. The NOTCH amplification rate was less than 1%. No NOTCH fusions were detected. In patients who were registered before, or within 1 year of, first-line chemotherapy, overall survival for 51 patients with only NOTCH3 variants was significantly longer than for 540 patients with no NOTCH variants (median, 40.2 months vs 27.7 months; P = 0.04). Multivariate analysis revealed that variant NOTCH3 was an independent prognostic factor for increased survival (hazard ratio 0.61, 95% confidence interval, 0.39-0.94; P = 0.03) besides poor prognostic factors associated with mutant TP53, KRAS, and BRAF, as well as amplified MYC. CONCLUSION: NOTCH genes are unlikely to harbor driver mutations and amplifications in patients with metastatic CRC. NOTCH3 variant should be further investigated as a favorable prognostic marker.

[A case of hepatocellular carcinoma with respiratory failure caused by widespread tumor microemboli].

A 76-year-old man with hepatocellular carcinoma (HCC) was admitted to our hospital suffering from rapidly progressing dyspnea. Chest computed tomography on admission merely showed ground-glass patterns in both lung fields without thrombi in the pulmonary trunk. On the third day, pulmonary blood flow scintigraphy was performed because of progression of his dyspnea, and showed multiple defects indicating widespread thrombi in the peripheral pulmonary arteries. He died of respiratory failure on day 13. A needle necropsy revealed the presence of multiple foci of adenocarcinoma nests in the lungs, suggesting venous thrombi from the poorly differentiated HCC. Although HCC frequently metastasizes to the lung, patients with lung metastasis rarely result in respiratory failure. It is well known that some patients with adenocarcinoma including HCC can develop respiratory failure owing to pulmonary tumor thrombotic microangiopathy (PTTM). In our case, however, pathological examination showed widespread tumor microemboli in the lung, but no stenosis or fibrocellular intimal proliferation in the small arteries and arterioles, which are essential findings of PTTM. Although we concluded that the respiratory failure in this case was mainly caused by widespread tumor microemboli, it remains unclear why such dissemination rapidly developed.

Characteristic distribution of maculopapular rash caused by gemcitabine-based chemotherapy.

Skin toxicity induced by gemcitabine, a chemotherapeutic agent, is not rare, but is usually mild. However, the occurrence of moderate to severe skin rash has been reported in patients treated with combinations of gemcitabine and other anticancer drugs. The aim of this study was to assess the characteristics of rash caused by gemcitabine-based chemotherapy. We analyzed 12 patients who developed maculopapular rash over more than 10% of their body surface following gemcitabine-based chemotherapy. Maculopapular rash appeared at 6.3 ± 1.3 days after the first administration in eight patients and the second administration in four patients. In two patients, the rash was localized on the lateral aspect of the trunk. The other 10 patients showed various degrees of rash on the chest and abdomen, in addition to the lateral aspect of the trunk. However, rash was absent on the upper and middle back in almost all patients. After the rash disappeared, gemcitabine was re-administrated in eight patients. They continued the therapy with no or only mild rash relapse. In conclusion, maculopapular rash caused by gemcitabine-based chemotherapy shows biased distribution to frontal and lateral sites of the trunk, which may be informative for consecutive chemotherapy.

A case of bleeding duodenal ulcer with pemphigus vulgaris during steroid therapy.

We report a rare case of bleeding duodenal ulceration in the different form of pemphigus vulgaris (PV). A 52-year-old female was diagnosed with acute pharyngitis and administered methylprednisolone. After several days, melena and many blisters were noted on her body. Endoscopy revealed blood oozing from the second part of a duodeneal ulcer around the major duodenal papilla. After initial endoscopic hemostasis, we observed a large regional, shallow duodenal ulcer. The blisters were suspected to represent the Nikolsky's sign. The histological findings of her skin were characterized by suprabasal acantholysis and mixed inflammatory cell infiltrates, including scattered eosinophils. There were no other significant findings on skin biopsy or by direct immunofluorescence. Enzyme-linked immunosorbent assay showed an elevated titer of anti-desmoglein 3 autoantibodies in her serum, and the patient was finally diagnosed with mucosal-dominant PV. Although we performed multiple biopsies from the esophagus, stomach and duodenum, the samples did not contain significant findings to enable us to distinguish from pemphigus vulgaris. Corticosteroids remain an essential component of PV treatment. When clinicians encounter PV development during steroid therapy, upper gastrointestinal complications should be considered and diagnostic endoscopy conducted.