Akiko Todaka

Weekly paclitaxel for heavily treated advanced or recurrent gastric cancer refractory to fluorouracil, irinotecan, and cisplatin

BackgroundAlthough triweekly administration of paclitaxel is approved for gastric cancer in Japan, currently, the drug is often delivered with a weekly schedule because of the equivalent efficacy and lesser toxicity of this dosing schedule as compared with the triweekly administration schedule. Weekly administration of paclitaxel as second-line or first-line chemotherapy for gastric cancer has been reported to yield a response rate of about 20%. Because there has been no report of the efficacy of weekly paclitaxel in the third-line setting, this retrospective study investigated the efficacy and toxicities of weekly paclitaxel used in the third-line setting for the treatment of gastric cancer refractory to all three key drugs, fluorouracil, irinotecan, and cisplatin, used in clinical practice.MethodsIn 85 patients with advanced or recurrent histologically confirmed gastric adenocarcinoma who had failed to respond to prior chemotherapy regimens containing fluorouracil, irinotecan, and cisplatin, paclitaxel (80 mg/m2) was administered weekly, three times, for 3 weeks out of 4.ResultsThe median number of courses was 3 (range, 1–38). The overall response rate was 23.2% (19/82) in the patients with measurable lesions, and ascites disappeared in 15 of 48 patients (31.3%). Progression-free survival was 105 days and the median survival time was 201 days from the initiation of paclitaxel administration. Grade 3 or 4 leukopenia, neutropenia, anemia, and thrombocytopenia were observed in 25 (29%), 25 (29%), 37 (44%), and 3 (4%) patients. Other, nonhematological, toxicities were nausea, vomiting, anorexia, sensory neuropathy, fatigue, and febrile neutropenia.ConclusionWeekly paclitaxel administration shows activity against advanced gastric cancer also in the third-line setting.

S-1 Monotherapy as Second-line Treatment for Advanced Pancreatic Cancer after Gemcitabine Failure

OBJECTIVE No standard salvage chemotherapy regimen has been established for patients with advanced pancreatic cancer after failure of gemcitabine-based treatment. Although a Phase II study of S-1 monotherapy was conducted in patients with gemcitabine-refractory advanced pancreatic cancer, the number of patients enrolled was small. METHODS We retrospectively reviewed 84 consecutive patients who received S-1 monotherapy as a second-line treatment after gemcitabine failure at the Shizuoka Cancer Center between May 2004 and April 2008. The selection criteria in this study were age 20-75 years, ECOG performance status <or=2 and preserved organ functions. S-1 was administered orally twice a day at a dose of 40 mg/m(2) for 28 days, followed by 14-day rest. RESULTS Fifty-two patients were selected for the analysis. Out of the 47/52 patients with measurable lesions, only 2 patients (4%) showed a partial response and 15 patients (32%) showed stable disease. The median progression-free survival was 2.1 months and the median overall survival was 5.8 months, with a 1-year survival rate of 12%. The common grade 3/4 toxicities were diarrhea (8%), anorexia (6%), fatigue (6%), anemia (6%) and leucopenia (4%). CONCLUSIONS S-1 monotherapy is marginally effective and well tolerated in the second-line setting in patients with gemcitabine-refractory advanced pancreatic cancer.

Regorafenib Versus Trifluridine/Tipiracil for Refractory Metastatic Colorectal Cancer: A Retrospective Comparison

Micro‐Abstract It is unclear which drug should be administered first for refractory metastatic colorectal cancer, regorafenib or trifluridine/tipiracil (TAS‐102). We retrospectively evaluated 200 patients who had received regorafenib or TAS‐102 at 2 institutions to compare these 2 drugs in terms of efficacy and safety. Our results suggest that regorafenib and TAS‐102 have similar efficacy but different toxicities, which could guide the agent choice. Background: Regorafenib and trifluridine/tipiracil (TAS‐102) both prolong survival for patients with refractory metastatic colorectal cancer. However, it is unclear which drug should be administered first. Materials and Methods: We retrospectively evaluated the data from patients who had received regorafenib or TAS‐102 at 2 institutions from May 2013 to March 2015. The inclusion criteria were disease refractory or intolerant to fluoropyrimidines, oxaliplatin, irinotecan, anti‐vascular endothelial growth factor antibodies, and anti‐epidermal growth factor receptor (EGFR) antibodies (if KRAS exon 2 wild‐type), and no previous treatment with regorafenib or TAS‐102. Results: A total of 146 and 54 patients received regorafenib and TAS‐102, respectively. The baseline characteristics were similar between the 2 groups, except for a history of irinotecan and anti‐EGFR therapy and high alkaline phosphatase levels. The median progression‐free survival and overall survival were 2.1 months and 6.7 months, respectively, with regorafenib and 2.1 months and 6.5 months, respectively, with TAS‐102 (progression‐free survival hazard ratio 1.20, P = .27; overall survival hazard ratio, 1.01, P = .97). The analysis of overall survival for patients after the approval of TAS‐102 in Japan was similar to the overall survival for the entire population. The frequency of hand–foot syndrome and increased aspartate aminotransferase, alanine aminotransferase, and bilirubin levels was higher and the frequency of neutropenia, leukopenia, anemia, nausea, and febrile neutropenia was lower with regorafenib than with TAS‐102. No remarkable differences were found in the efficacy and safety of TAS‐102 between patients with and without previous regorafenib and vice versa. Conclusion: Regorafenib and TAS‐102 had similar efficacy but resulted in different toxicities, which could guide the agent choice.

Neutropenia as a Predictive Factor in Metastatic Colorectal Cancer Treated With TAS-102.

Background TAS‐102 significantly improves overall survival in patients with metastatic colorectal cancer. The most common treatment‐related adverse event of TAS‐102 is bone marrow suppression, which leads to neutropenia. The potential predictive value of neutropenia caused by cytotoxic drugs has been reported in various types of cancer. Methods We retrospectively analyzed 95 consecutive patients with metastatic colorectal cancer who received TAS‐102 at 2 Japanese institutions between May 2014 and May 2015. To evaluate the association between efficacy and neutropenia, patients were divided into 4 categories according to the grade of neutropenia during the first cycle of TAS‐102: Category A (grade 0‐1), B (grade 2‐4), C (grade 0‐2), and D (grade 3‐4). Results Patient characteristics were as follows: median age, 64 years; male, 58%; Eastern Cooperative Oncology Group performance status 0 to 1, 91%; primary site colon, 49%; KRAS exon 2 wild, 57%; and number of metastatic site ≥ 3, 55%. The disease control rate was significantly different between Category A and B (29.2% vs. 52.6%; P = .045) and between Category C and D (30.9% vs. 72.2%; P = .002). In multivariate analysis, Category D remained a significant predictive factor for progression‐free survival compared with Category C (4.3 vs. 2.0 months; hazard ratio, 0.45; P = .01). Conclusion Neutropenia caused by TAS‐102 during the first cycle was associated with better efficacy. Neutropenia may be a surrogate marker for adequate antitumor doses of TAS‐102. Micro‐Abstract The most common treatment‐related adverse event of TAS‐102 monotherapy for colorectal cancer is bone marrow suppression, which leads to neutropenia. A retrospective study of 95 patients at 2 institutions was performed to evaluate the association between efficacy and neutropenia. Our findings indicate that neutropenia caused by TAS‐102 was associated with better efficacy.

Modified FOLFOX-6 Therapy for Heavily Pretreated Advanced Gastric Cancer Refractory to Fluorouracil, Irinotecan, Cisplatin and Taxanes: A Retrospective Study

OBJECTIVE Since 2007, S-1 plus cisplatin therapy has been recognized as the standard first-line treatment for advanced gastric cancer in Japan. However, no standard regimen has been established for patients refractory to first-line treatment. Furthermore, irinotecan and paclitaxel are considered key drugs for second-line treatment. Several studies have investigated the efficacy and tolerability of combination therapy with oxaliplatin, 5-fluorouracil and leucovorin (modified FOLFOX-6) for advanced gastric cancer. Here, we examined the efficacy and toxicity of modified FOLFOX-6 therapy in heavily pretreated patients with advanced gastric cancer refractory to 5-fluorouracil, irinotecan, cisplatin and taxanes. METHODS Fourteen patients with advanced gastric cancer refractory to 5-fluorouracil, irinotecan, cisplatin and taxanes were included in the study. In modified FOLFOX-6 therapy, 85 mg/m(2) oxaliplatin, 400 mg/m(2) 5-fluorouracil and 200 mg/m(2) leucovorin on Day 1 were administered biweekly by intravenous infusion, followed by the administration of 2400 mg/m(2) 5-fluorouracil by a 46-h continuous infusion. RESULTS The median age of the patients was 59 years (range, 22-74). A median of 5.5 (range, 1-13) chemotherapy cycles were administered. The overall response rate was 23.1% in patients with measurable lesions. Of the 12 patients with advanced gastric cancer refractory to cisplatin, 2 showed partial response (response rate, 18.2%). The progression-free survival was 90 days, and the median survival time from the initiation of modified FOLFOX-6 therapy was 268 days. Grade 3-4 toxicities most commonly observed included neutropenia (57%), anaemia (14%), thrombocytopenia (21%) and hyperammonaemia (7%). CONCLUSIONS Modified FOLFOX-6 therapy in patients refractory to 5-fluorouracil, irinotecan, cisplatin and taxanes may be a potential advanced gastric cancer therapeutic strategy.

S-1 Monotherapy for Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck After Progression on Platinum-based Chemotherapy

OBJECTIVE Platinum compounds play pivotal roles in treatment for squamous cell carcinoma of the head and neck. The objective was to evaluate the efficacy of S-1 monotherapy in patients with recurrent or metastatic squamous cell carcinoma of the head and neck after failure of platinum-based chemotherapy. METHODS We retrospectively analyzed 39 consecutive patients with recurrent or metastatic squamous cell carcinoma of the head and neck who received S-1 monotherapy after failure of platinum-based chemotherapy or chemoradiotherapy at the Shizuoka Cancer Center between August 2003 and October 2010. S-1 was given orally twice daily (80 mg/m(2)/day) for 28 days followed by a 14-day rest. RESULTS The median follow-up period in survivors was 31.5 months. Among 38 patients with measurable lesions, 9 (24%) showed partial response and 15 (39%) showed stable disease. The median progression-free survival was 4.9 months and the median overall survival was 13.2 months. The median progression-free survival for oropharyngeal cancer (n= 7) was significantly longer than for other cancers (n = 32) (14.9 vs. 4.7 months, P= 0.035). The response rate in patients with a recurrence-free interval since the last platinum administration >6.0 months was significantly better than with a recurrence-free interval <6.0 months (40 vs. 13%, P= 0.0102). Recurrence-free interval >6.0 months also showed a significantly better progression-free survival (6.0 vs. 2.6 months, P= 0.045). The frequency of Grade 3/4 toxicities was less than 10%. CONCLUSIONS S-1 monotherapy shows promising signs of efficacy and tolerability in patients with recurrent or metastatic squamous cell carcinoma of the head and neck after failure of platinum-based chemotherapy in this retrospective cohort and warrants further investigation in this population.

Efficacy and safety of trametinib in Japanese patients with advanced biliary tract cancers refractory to gemcitabine

Gemcitabine‐based therapy remains the mainstay of treatment for patients with biliary tract cancers (BTCs) with no second‐line treatment(s) established yet. Aberrant activation of the MAPK pathway in patients with BTC indicates its importance in BTC. Trametinib is a potent, highly selective, allosteric non‐competitive inhibitor of MEK1/MEK2. In this phase IIa open‐label, single‐arm study, we investigated the efficacy and safety of trametinib in Japanese patients with advanced BTC refractory to gemcitabine‐based therapy. All patients received oral trametinib 2 mg once daily until progressive disease (PD), death, or unacceptable toxicity. The primary objective was to determine the 12‐week non‐PD rate. Secondary assessments included safety, progression‐free survival (PFS), overall survival, and overall response rate. Targeted exome sequencing was used to identify biomarkers for sensitivity or resistance to trametinib monotherapy. Twenty patients (median age, 61.5 years) with carcinoma of gall bladder (40%), intrahepatic (25%) or extrahepatic (30%) bile duct, and ampulla of Vater (5%) were enrolled. The non‐PD rate at week 12 was 10% (95% confidence interval, 1.2‐31.7); it did not reach the threshold rate of 25%. Median PFS was 10.6 weeks (95% confidence interval, 4.6‐12.1) and 1‐year overall survival was 20.0%. Stable disease and PD were observed in 13 (65%) and seven (35%) patients, respectively. No new safety signals were reported. Although the primary end‐point was not met, prolonged PFS was observed in one patient having six somatic variants including synonymous NF1 exon 12 splice variant and a loss‐of‐function variant in ARID1A. Efforts to understand responsive mutations and sensitivity to targeted therapies are warranted. This trial was registered with ClinicalTrials.gov: NCT01943864.

Gastrojejunostomy versus duodenal stent placement for gastric outlet obstruction in patients with unresectable pancreatic cancer

BACKGROUND/OBJECTIVE Whether gastrojejunostomy (GJJ) or duodenal stent (DS) placement is preferable for treatment of gastric outlet obstruction (GOO) in patients with unresectable pancreatic cancer is unclear. We compared the usefulness of GJJ with that of DS placement in these patients. METHODS We retrospectively reviewed 66 consecutive patients with unresectable pancreatic cancer who underwent GJJ or DS placement for symptomatic GOO. RESULTS We analyzed 30 patients who underwent GJJ and 23 who underwent DS placement. Peritoneal metastasis was more common in the DS group. Median survival after the first intervention was similar in both groups. Although clinical success (maintaining a GOO Scoring System score ≥2 for more than 7 days) rate was significantly higher in the GJJ group (100% vs. 81%), clinical benefit (maintaining a score ≥2 for more than half of their survival after the first intervention) rate was similar between the GJJ and DS groups (66.7% vs. 69.7%), even among patients who survived for ≥90 days (73.3% vs. 75.0%). Further, the proportion of patients who could receive planned chemotherapy after the first intervention was higher and the time to administration of chemotherapy was significantly shorter in the DS group (9 vs. 32 days). Major complication rate was similar in both groups. CONCLUSIONS These findings suggest that DS placement is as effective as GJJ for the treatment of GOO in patients with unresectable pancreatic cancer, even in those with a long life expectancy. DS placement might be more beneficial than GJJ in patients for whom chemotherapy is planned.

Metabolic profiling of gemcitabine- and paclitaxel-treated immortalized human pancreatic cell lines with K-RAS G12D

The mechanisms of action of gemcitabine (GEM) and paclitaxel (PTX) have been well investigated, and shown to be the inhibition of DNA polymerase and polymerization of tubulin, respectively. Meanwhile, genomic research has revealed that mutations in the K-RAS oncogene occur in over 90% of pancreatic cancer. Oncogenic alteration rewires alternative metabolic pathways to satisfy the demands of growth. The K-RAS oncogene also has been shown to upregulate glycolysis and glutaminolysis. However, it is still unclear whether K-RAS independently plays a central role in controlling tumor metabolism. Here, we conducted a metabolomic analysis of a simple oncogenic K-RAS cell line model constructed using human telomerase catalytic subunit-immortalized human pancreatic epithelial nestin-expressing cell lines with and without K-RASG12D. We also investigated the effect of GEM and PTX on these cells. As a result, it was shown in the cell with K-RASG12D that the level of lactate was increased and glutamic acid, glutamine, and aspartic acid levels were decreased. In the nucleotide metabolism, GEM-treated cells showed metabolic changes, whereas these phenomena were not observed in PTX-treated cells. In conclusion, it was suggested that K-RASG12D independently modified tumor metabolism and the difference between GEM and PTX in the nucleotide metabolism was revealed.

Clinicopathological features and outcomes of gastric cancer patients with pulmonary lymphangitis carcinomatosa.

OBJECTIVE Breast, gastric and lung cancers are the most common cancers that cause pulmonary lymphangitis carcinomatosa. However, little is known about the clinical features of pulmonary lymphangitis carcinomatosa in advanced gastric cancer. METHODS We retrospectively reviewed the data throughout the clinical courses of 33 patients with gastric cancer who developed pulmonary lymphangitis carcinomatosa. Pulmonary lymphangitis carcinomatosa was confirmed by both a pulmonologist and a diagnostic radiologist on the basis of computed tomography findings of interstitial patterns such as thickening or irregularity of interlobular septa and bronchovascular bundles. RESULTS The median age of the 33 patients was 55 years old (range, 25-73 years). The percentages of female patients, those with performance status 3 or 4, and those with respiratory symptoms at diagnosis were 70, 36 and 76%, respectively. The histologically diffuse type of gastric cancer accounted for 85% of cases. Mediastinal lymph node, peritoneal and bone metastases were found in 64, 61 and 39% of patients, respectively. Disseminated intravascular coagulation was noted in 21% of patients. The median survival time of the 18 chemotherapy-naïve patients treated with chemotherapy was 5.7 months (range, 0.4-37.0 months). Two patients obtained symptomatic relief, and one patient treated with S-1 + cisplatin + sunitinib survived >3 years. CONCLUSIONS Pulmonary lymphangitis carcinomatosa caused by gastric cancer has some specific clinicopathological features. While the prognosis of gastric cancer patients with pulmonary lymphangitis carcinomatosa is extremely poor, some patients may have survival benefit from chemotherapy.