Differences in disease status between patients with progression after first-line chemotherapy versus early relapse after adjuvant chemotherapy who undergo second-line chemotherapy for gastric cancer: Exploratory analysis of the randomized phase III TRICS trial.

BACKGROUND: Second-line chemotherapy (SLC) improves survival in advanced gastric cancer (AGC). Patients receiving SLC are categorized into two disease status groups: tumour progression after first-line chemotherapy and early recurrence after adjuvant chemotherapy. Differences between these groups have not yet been clarified. PATIENTS AND METHODS: A total of 163 eligible patients registered in the randomized phase III TRICS trial evaluating SLC for patients with AGC was classified into the progressive disease (PD) group (n = 55) or the early relapse (ER) group (n = 108). We compared overall survival (OS), progression-free survival (PFS), overall response rate (ORR), and safety. Adjusted OS and adjusted PFS were estimated using inverse probability of treatment weighting (IPTW). RESULTS: The ER group had a lower median age than the PD group (66 vs. 72 years; P = 0.016), performance status (PS) 0 was more frequently seen in the ER group (87% vs. 71%; P = 0.012). The adjusted median OS was 13.7 months in the ER group and 13.6 months in the PD group (IPTW hazard ratio [HR]: 1.023; P = 0.854). The adjusted median PFS was 4.9 months in the ER group and 4.4 months in the PD group (IPTW HR: 0.707; P = 0.004). ORR was significantly better in the ER group than the PD group (21.3% vs. 4.9%; P = 0.020). No significant differences were observed in the incidence of adverse events. CONCLUSIONS: ER was associated with improved PFS and better ORR than PD, although no difference in survival was demonstrated. From the viewpoint of treatment outcome, it seems appropriate to treat patients with ER in the same way as patients with PD. CLINICAL TRIAL REGISTRATION: UMIN 000002571.

A study of second-line irinotecan plus cisplatin vs. irinotecan alone in platinum-naïve patients with early relapse of gastric cancer refractory to adjuvant S-1 monotherapy: exploratory subgroup analysis of the randomized phase III TRICS trial.

BACKGROUNDS: Many patients with gastric cancer relapse during or early after adjuvant chemotherapy. The standard treatment for early relapse patients is a second-line chemotherapy (SLC) based on irinotecan, taxanes, or a platinum-based chemotherapy. The platinum-containing biweekly irinotecan plus cisplatin (IRI/CDDP) combination was assumed to be promising in several reports of clinical trials as SLC. TRICS trial, a randomized phase III study of IRI/CDDP vs. IRI in platinum-naïve gastric cancers refractory to S-1 monotherapy, revealed that both irinotecan-based chemotherapies were effective and well tolerated. METHODS: This study analyzed 108 patients in the TRICS trial who experienced early relapse. Patients receiving IRI/CDDP (IRI, 60 mg/m2; CDDP, 30 mg/m2, q2w) versus IRI (150 mg/m2, q2w) were compared regarding overall survival (OS), progression-free survival (PFS), overall response rate (ORR), and safety. RESULTS: The OS was 14.0 (95% confidence interval [CI]: 11.0-21.2) and 14.0 (95% CI: 10.7-16.5) months for IRI/CDDP and IRI, respectively (hazard ratio [HR]: 0.782; 95% CI: 0.515-1.188, P = 0.249). No significant differences were observed for PFS (5.0 vs. 4.5 months, respectively; HR: 0.802; 95% CI: 0.543-1.185, P = 0.268) or ORR (19.6% [95% CI: 9.4-33.9%] vs. 23.3% [95% CI: 11.8-38.6%], respectively). The incidence of grade 3-4 anemia was higher for IRI/CDDP than for IRI (20% vs. 0%, respectively; P = 0.0006). CONCLUSION: Our study showed no significant survival differences between IRI/CDDP and IRI in platinum-naïve patients who relapsed during or within 6 months after S-1 adjuvant therapy; therefore, IRI may be a good option in this population. CLINICAL TRIAL INFORMATION: UMIN 000002571.

The COMET Open-label Phase II Study of Neoadjuvant FOLFOX or XELOX Treatment Combined with Molecular Targeting Monoclonal Antibodies in Patients with Resectable Liver Metastasis of Colorectal Cancer.

BACKGROUND: Advantages of neoadjuvant chemotherapy combined with monoclonal antibodies for treating patients with resectable colorectal cancer liver metastasis (CLM) have not been established. The purpose of this study was to evaluate the efficacy and safety of oxaliplatin-based regimen (FOLFOX or XELOX) plus monoclonal antibodies (cetuximab or bevacizumab) treatment in patients with resectable CLM. METHODS: A single-arm, open-label, multicenter, phase II trial was conducted for patients aged ≥ 20 years with resectable and untreated CLM. Patients received preoperative FOLFOX (6 cycles) or XELOX (4 cycles). Cetuximab or bevacizumab was administered to patients with wild-type or mutated KRAS codons 12 and 13, respectively. The primary endpoint was progression-free survival (PFS). RESULTS: Between January 2010 and June 2012, 47 patients were enrolled from 12 institutions. Wild-type or mutant KRAS sequences were examined in 32 and 15 patients, respectively. Twenty-one (45 %) patients experienced Grades 3/4 adverse events, and 55 % of all patients responded to therapy. The sizes of tumors of patients in the wild-type KRAS group were significantly reduced compared with those of the mutant KRAS group. The overall rates of liver resection and postoperative morbidity were 83 and 14 %, respectively, and the median PFS was 15.6 months. The median PFS times of the KRAS wild-type and mutant groups were 22.5 months and 10.5 months, respectively. CONCLUSIONS: Neoadjuvant therapy using FOLFOX/XELOX combined with monoclonal antibodies did not improve PFS, although it was administered safely and had less adverse effects after liver resection.

Randomised phase III trial of second-line irinotecan plus cisplatin versus irinotecan alone in patients with advanced gastric cancer refractory to S-1 monotherapy: TRICS trial.

AIM: The optimal second-line regimen for treating advanced gastric cancer (AGC) remains unclear. While irinotecan (CPT-11) plus cisplatin (CDDP) combination therapy and CPT-11 monotherapy have been explored in the second-line setting, the superiority of second-line platinum-based therapies for AGC patients initially treated with S-1 monotherapy has not yet been evaluated; therefore, we aimed to examine the survival benefit of CPT-11/CDDP combination over CPT-11 monotherapy. METHODS: AGC patients showing progression after S-1 monotherapy for advanced cancer or recurrence within 6 months after completion of S-1 adjuvant therapy were randomly allocated to CPT-11/CDDP (CPT-11, 60 mg/m(2); CDDP, 30 mg/m(2), q2w) or CPT-11 (150 mg/m(2), q2w). RESULTS: Sixty-eight advanced and 95 recurrent cases were evaluated. The median overall survivals were 13.9 (95% confidence interval [CI]: 10.8-17.6) and 12.7 (95% CI: 10.3-17.2) months for CPT-11/CDDP and CPT-11, respectively (hazard ratio: 0.834; 95% CI: 0.596-1.167, P = 0.288). No significant differences were observed in the secondary end-points, including progression-free survival (4.6 [95% CI: 3.4-5.9] versus 4.1 [95% CI: 3.3-4.9]months) and response rate (16.9% [95% CI: 8.8-28.3] versus 15.4% [95% CI: 7.6-26.5]). The incidences of grade 3-4 anaemia (16% versus 4%) and elevated serum lactate dehydrogenase levels (5% versus 0%) were higher for CPT-11/CDDP than for CPT-11. Exploratory subgroup analysis revealed that CPT-11/CDDP was significantly more effective for intestinal-type AGC, compared with CPT-11 (overall survival: 15.8 versus 14.0 months; P = 0.019). CONCLUSION: No survival benefit was observed upon adding CDDP to CPT-11 after S-1 monotherapy failure.

Docosahexaenoic acid is an independent predictor of all-cause mortality in hemodialysis patients.

BACKGROUND: Dietary n-3 polyunsaturated fatty acids (PUFAs), docosahexaenoic acid (DHA) and eicosapentaenoic acid have been shown to reduce cardiovascular mortality. Patients on hemodialysis (HD) have a very high mortality from cardiovascular disease. Fish consumption reduces all-cause mortality in patients on HD. Moreover, n-3 PUFAs, especially DHA levels in red blood cells (RBCs), are associated with arteriosclerosis in patients on HD. The aim of this study was to determine whether DHA levels in RBCs predict the mortality of patients on HD in a prospective cohort study. METHODS: A cohort of 176 patients (64.1 ± 12.0 (mean ± SD) years of age, 96 men and 80 women) under HD treatment was studied. The fatty acid composition of their RBCs was analyzed by gas chromatography. RESULTS: During the study period of 5 years, 54 deaths occurred. After adjustment for 10 confounding factors, the Cox hazard ratio of all-cause mortality of the patients on HD in the highest DHA tertile (>8.1%, 15 deaths) was 0.43 (95% CI 0.21-0.88) compared with those patients in the lowest DHA tertile (<7.2%, 21 deaths). CONCLUSION: The findings suggest that the level of DHA in RBCs could be an independent predictor of all-cause mortality in patients on HD.

[A case of gastric small cell carcinoma with metastatic liver tumors responding to adjuvant chemotherapy].

A 71-year-old man, whose chief complaint was a faecal occult blood, had gastrointestinal endoscopy and gastric cancer was diagnosed. CT scan and intraoperative findings revealed metastatic liver tumors. We performed total gastrectomy with D2 lymph dissection, partial hepatic resections and microwave coagulation therapy. Small cell carcinoma of the stomach was diagnosed by histopathological findings. We used combination chemotherapy consisting of carboplatin, epirubicin, etoposide and 5-FU was performed. After one course, he suffered from leucopenia and agranulocytosis of grade 3, thrombocytopenia of grade 4, so we reduced the dose and performed 6 courses in total. The patient remains alive without recurrence 48 months after operation. We conclude that adjuvant chemotherapy was effective for small cell carcinoma of the stomach, which was to be considered to have a poor prognosis.

Results of laparoscopic liver resection: retrospective study of 68 patients.

BACKGROUND: Although an increasing number of reports and publications have dealt with the laparoscopic approach to liver resection, this procedure remains uncommon, and its feasibility, safety and effectiveness are still not established. There are few reports of the advantages of this approach on postoperative recovery. METHODS: From December 1997 to March 2007, laparoscopic hepatic resection were performed in 68 patients. RESULTS: There were 52 malignant tumors (36 hepatocellular carcinomas, three intrahepatic cholangiocarcinomas, one cystadenocarcinoma, liver metastases from ten colorectal carcinomas and two other organs) and 16 benign lesions among our 68 patients. Fifteen patients with hepatocellular carcinoma had cirrhosis. The mean tumor size was 3.1 +/- 1.8 cm (range 1.0-14.0 cm), and the tumors were located in every liver segment except segment I. Liver resection was anatomical in 17 patients and consisted of a lobectomy in four patients and a lateral segmentectomy in 13 patients. Non-anatomical resections were performed in 51 patients. The operative time was 214 +/- 93 min. Mean blood loss was 393 +/- 564 g. A hand-assisted laparoscopic method or mini-laparotomy method was required in 35 patients (51.4%). Operative complications occurred mainly in our early cases and included three patients (4.4%) with operative bleeding, 2 of whom (2.9%) requiring a conversion to open surgery. Postoperative complications occurred in seven patients (10.0%), and two of then eventually required a re-operation. The mean hospital stay was 17 days. There were no complications in the more recent cases. CONCLUSIONS: The laparoscopic approach for liver tumors is feasible, if the indication is carefully selected. The safety of this procedure depends on the surgical experience of the surgeon and team and the availability of the necessary technology.

Hand-assisted laparoscopic hepatectomy for tumors located in posterior segment.

BACKGROUND/AIMS: In spite of recent advances in laparoscopic surgery, laparoscopic approach is still not a standard option for the tumors located in the posterior segment of the right hepatic lobe mainly due to its technical difficulties and the risk for injuring major adjacent vessels. METHODOLOGY: In order to evaluate the feasibility of laparoscopic posterior segment hepatectomy (LPSH) compared to open posterior segment hepatectomy (OPSH), we retrospectively reviewed a total of 46 laparoscopic hepatectomies and 169 open hepatectomies. Among them, three patients underwent LPSH and seven patients underwent OPSH for tumors located in the posterior segment of the right hepatic lobe. RESULTS: Although duration of operation showed a trend toward being longer in LPSH, LPSH was not accompanied by significant increase of blood loss. Furthermore, LPSH had a trend to result in earlier recovery of the patients, including shorter hospital stay and earlier start of walking or meal. CONCLUSIONS: In conclusion, our data suggested that LPSH could be as safe and feasible as OPSH for tumors located in the posterior segment.

[A case of giant hepatocellular carcinoma treatable with radio frequent ablation therapy after effective UFT administration].

A 71-year-old man was diagnosed with giant hepatocellular carcinoma (HCC) and hepatitis C cirrhosis at a nearby hospital. Image diagnosis showed no other metastasis, but the tumor was very huge with daughter nodules in the bilateral lobe of the liver. He was thus treated by oral administration of UFT (300 mg/day). Two months later, the giant liver tumor had shrunk remarkably, and the daughter tumors had disappeared. Eight months later, the levels of serum AFP and PIVKA-II had also reduced remarkably. Twelve months following the first treatment, the levels of both serum AFP and PIVKA-II began increasing again, and he was referred to our hospital. CT showed 2 liver tumors, 1 of which showed viability with moderately differentiated hepatocellular carcinoma and the other evidencing necrosis histologically. Radio frequency ablation therapy was performed for 2 tumors by open laparotomy. It was considered that administration of UFT is a useful and safe therapy for far advanced HCC.

[A case report of unresectable gastric cancer that responded to 5-FU plus paclitaxel (FT) therapy].

We report a case of a 63-year-old man who has been treated by FT therapy (5-fluorouracil (5-FU) plus paclitaxel therapy). The regimen includes 600 mg/m2/day of 5-FU by continuous i.v. administration from day 1 to 5 and consequent administration of paclitaxel (90 mg/m2/day) on days 8, 15, and 22 for 28 days repetitively. Before the therapy was started, that occurred were obstructive jaundice, ascites, and poor performance status due to gastric cancer were observed. After percutaneous transhepatic drainage was performed, the patient was started on the above-mentioned regimen even before full recovery from the hepatic dysfunction. As the treatment proceeded, he showed good response (ascites disappeared and the size of swollen perigastric lymph node was reduced, which were confirmed as a partial response by sequential CT examination) to the therapy and his QOL and PS also improved. He has continued to receive this regimen for over 1 year and 4 months without any sign of progressive disease by CT examination. No adverse event greater than grade 1 by the NCI-CTC criteria was seen, except for alopecia (grade 2). Considering the favorable response and mild toxicity, this regimen is useful even for the patients with poor performance status and severe hepatic dysfunction.

[Effective use of combination chemotherapy with paclitaxel and 5-fluorouracil in a case of non-resectable advanced gastric cancer].

The patient was a 67-year-old man who had gastric cancer located in the posterior wall of the stomach and who underwent surgery on June 27, 2001. The operative finding was carcinomatous peritonitis in which the primary lesion was considered to be surgically unresectable. Therefore, only a probe laparotomy was performed. Under full informed consent, we performed combination chemotherapy with paclitaxel and 5-fluorouracil, 5-fluorouracil (600 mg/m2/day) was infused continuously for 120-hours (day 1-5) on administration and paclitaxel (60 mg/m2) was infused for 1.5 hours after premedication at day 8, 15 and 22 on an outpatient basis. After 2 courses of the chemotherapy, the tumor markers were reduced remarkably, ascites had completely disappeared, and abdominal lymph nodes had decreased. No serious adverse event was observed and the patient maintained good QOL throughout the treatment.

Hand-assisted laparoscopic left lateral segmentectomy of the liver for hepatocellular carcinoma with cirrhosis.

BACKGROUND/PURPOSE: Despite recent progress in trials with laparoscopic hepatectomy, it is still necessary to develop safe and stable techniques. We have performed laparoscopic hepatic resection for 30 patients with liver tumors to date. We have recently been applying a hand-assisted laparoscopic surgical technique for greater safety. METHODS: In the present study, we report techniques using a hand-assisted laparoscopic anatomical left-lateral segmentectomy for hepatocellular carcinoma with liver cirrhosis. RESULTS: Direct feeling with the surgeon's hand makes possible a procedure that is almost identical to open surgery in which there is better visualization of the surgical field and transected margin, and immediate hemostasis is also achieved by manually depressing the bleeding point. CONCLUSIONS: With this method, laparoscopic anatomical hepatectomy can be performed more safely for patients with cirrhosis than by the fully laparoscopic method, although a larger incision is necessary.