Eisaku Sasaki

Biweekly irinotecan plus cisplatin versus irinotecan alone as second-line treatment for advanced gastric cancer: a randomised phase III trial (TCOG GI-0801/BIRIP trial).

PURPOSE We compared biweekly irinotecan plus cisplatin (BIRIP) with irinotecan alone as the second-line chemotherapy (SLC) for advanced gastric cancer (AGC). METHODS Patients with metastatic or recurrent gastric cancer refractory to S-1-based first-line chemotherapy were randomly assigned to receive BIRIP (irinotecan 60mg/m(2) plus cisplatin 30mg/m(2), every 2weeks) or irinotecan alone (irinotecan 150mg/m(2), every 2weeks). The primary end-point was to show the superiority of BIRIP to irinotecan in terms of progression free survival (PFS). RESULTS 130 patients were enrolled. PFS was significantly longer in the BIRIP group (3.8months [95% confidence interval (CI) 3.0-4.7]) than in the irinotecan group (2.8months [2.1-3.3]; hazard ratio 0.68, 95% CI 0.47-0.98; P=0.0398). Median overall survival was 10.7months in the BIRIP group and 10.1months in the irinotecan group (HR 1.00, 95% CI 0.69-1.44, P=0.9823). The objective response rate was 22% in the BIRIP group and 16% in the irinotecan group (P=0.4975). However, the disease control rate was significantly better in the BIRIP group (75%) than in the irinotecan group (54%, P=0.0162). The incidences of grade 3 or worse adverse events did not differ between the two groups. Any grade elevation of serum creatinine was more common in the BIRIP group (25% versus 8%, P=0.009), but any grade diarrhoea (17% versus 42%, P=0.002) was more common in the irinotecan group. CONCLUSION BIRIP significantly prolonged PFS as compared with irinotecan alone and was tolerated as SLC, but did not demonstrate the survival benefit in this trial.

Clinical outcomes with chemotherapy for advanced thymic carcinoma

BACKGROUND The clinical characteristics and prognostic factors of thymic carcinoma have not been investigated in detail because of its rarity. The aim of this study was to elucidate the disease profile, outcomes, and prognostic factors for survival among patients with advanced thymic carcinoma treated with palliative-intent chemotherapy. PATIENTS AND METHODS A retrospective review was conducted of the medical records of 40 patients treated with palliative-intent chemotherapy for advanced thymic carcinoma between 1991 and 2011 in our institution. Clinical demographics, histology, overall survival, and factors expected to predict survival were analyzed. Differences in survival were assessed using Kaplan-Meier analysis and univariate and multivariate Cox proportional hazards regression analyses. RESULTS The study included 22 males (55.0%) and 18 females (45.0%). The median age at diagnosis was 58.5 years. The most common metastatic sites at diagnosis were lung (45.0%), lymph nodes (20.0%), liver (15.0%), bone (15.0%), and brain (5.0%). The most common histological subtypes were squamous cell carcinoma (70.0%), followed by neuroendocrine carcinoma (17.5%), and mucoepidermoid carcinoma (7.5%). The response rate for first-line chemotherapy was 47.5%. The median survival time was 24.5 months (95% confidence interval 20.9-43.5 months). Overall survival rates at 1-, 2-, and 5-years were 72.5%, 52.5%, and 17.5%, respectively. In uni- and multivariate analyses, the only favorable prognostic factor for overall survival was response to first-line chemotherapy (p=0.01). CONCLUSION Response to first-line chemotherapy may be implicated as a potential surrogate for survival in advanced thymic carcinoma.

Long-term complete remission in a patient with intravascular large B-cell lymphoma with central nervous system involvement

This report describes a patient with intravascular large B-cell lymphoma (IVLBCL) with central nervous system involvement at the time of diagnosis who achieved complete remission for over 5 years in response to therapy. The patient, a 71 year-old woman, was previously healthy with the exception of taking verapamil for paroxysmal supraventricular tachycardia. She had presented with pyrexia and gradually progressive anemia. Brain magnetic resonance imaging revealed an infarct-like lesion in the pons, although no paralysis was observed. She was diagnosed with IVLBCL on the basis of random skin biopsy. After eight cycles of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone therapy, abnormal laboratory data had normalized, and no pontine lesion was evident on magnetic resonance imaging without receiving any intrathecal chemotherapy. IVLBCL is associated with poor prognosis, particularly in patients with central nervous system involvement. Early initiation of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone therapy and drug interactions between anticancer agents and verapamil as a p-glycoprotein inhibitor were considered the possible reasons for favorable outcome in the present case.

Second allogeneic peripheral blood stem cell transplantation with fludarabine-based low-intensity conditioning regimen for relapsed myelodysplastic syndrome after allogeneic bone marrow transplantation.

We describe the case of a 51-year-old patient with relapsed myelodysplastic syndrome after allogeneic bone marrow transplantation (BMT), who underwent allogeneic peripheral blood stem cell transplantation (PBSCT) after conditioning with a novel regimen consisting of fludarabine, busulfan, and antithymocyte globulin. The second PBSCT was performed early, at 3 months after the initial allogeneic BMT, but it was well tolerated and complete hematologic remission was documented.The patient did not experience any early transplantation-related organ toxicity but died from opportunistic infection 6 months after the second transplantation. Our experience suggests that this novel regimen may induce remission and could be offered to patients relapsing after the first transplantation; however, the fludarabine-containing regimen might be accompanied by profound immunosuppression.

Abstract 2979: Effects of VEGF inhibition on skin ulcer induced by administration of cytotoxic anticancer drugs

Introduction: An accidental extravasation of vesicant drugs-containing chemotherapy leads to skin ulcer, necrosis and severe tissue destruction. The clinical evidences that VEGF inhibition suppresses tumorigenesis via inhibiting angiogenesis and causes delaying wound repair have been accumulated. We observed the cases that simultaneous administration of anti-human VEGF antibody, Bevacizumab, avoided critical skin ulcer which should be caused by extravasation of cytotoxic drug in the colorectal cancer combination chemotherapy. Therefore, we examined effects of VEGF or anti-VEGF-antibody and angiogenesis inhibitor on skin ulcer caused by administration of anticancer drug in a mouse model. Methods: Experiments were performed in accordance with the United Kingdom Coordinating Committee on Cancer Research Guidelines for the welfare of animals in experimental neoplasia. Subcutaneous injections of doxorubicin (0.2mg/0.2ml of saline) in mice induced dose-dependent ulcerations under general anesthesia. The ulcers reached maximal size at 2-3 weeks following doxorubicin administration and were completely healed by 9 weeks. Effects of co-administration of test drugs on the area of the skin ulcer caused by administration of Adriamycin, were compared with control. Bevacizumab is anti-human VEGF antibody, it has no reactivity with mouse VEGF. An anti-mouse VEGF antibody was used alternatively. Results: VEGF (5μg) increased the skin ulcer size up to 150%, and the healing time was increased to 11 weeks. Anti-VEGF antibody (50μg) and suramin reduced the maximum ulcer size (50%), and the healing time was reduced to 6 weeks. Hydrocortisone (100μg) slightly reduced the skin ulcer size and the healing time (8 week). Conclusion: VEGF aggravated skin ulcer caused by the administration of the Adriamycin. Anti-VEGF antibody and angiogenesis inhibitor, suramin, reduced skin ulcer caused by the administration of the Adriamycin. Discussion: Inhibition of VEGF signaling and/or anti-angiogenesis were suggested to reduce skin ulcer caused by the Adriamycin. Anti-human VEGF antibody, Bevacizumab was suggested to be an effective antidote for skin ulcer and necrosis by extravasation of anticancer drugs and had potential for clinical use. Citation Format: Tatsu Shimoyama, Kiyoshi Ogura, Yuusuke Kanemasa, Shigeo Yamaguti, Eisaku Sasaki, Yasushi Omuro, Takeshi Sawada, Fumiaki Koizumi, Yoshiharu Maeda. Effects of VEGF inhibition on skin ulcer induced by administration of cytotoxic anticancer drugs. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2979. doi:10.1158/1538-7445.AM2014-2979

P2-2-4TREATMENT OUTCOME OF ADVANCED GASTRIC CANCER WITH DOUBLE PRIMARY CANCER

Abstract Purpose: An aging population and advances in diagnostic technology have led to an increase in the incidence of double or multiple primary cancers (DMPC) in patients with inoperable gastric cancer. We thus performed a retrospective analysis to clarify whether we should treat only gastric cancer as therauptic target and ignore other primary cancer in patients with DPMC. Patients and methods: We use Chart Review to identify 454 advanced or metastatic gastric cancer patients who were diagnosed between December 2000 and April 2013. Results: Of 454 patients, 43 patients had DMPC. All of the 43 patients were treated by fluorouracil agent and cisplatin combination therapy. Among these 43 patients, 20 had synchronous primary cancers, and 23 patients were diagnosed gastric cancer over 6 months after diagnosed second primary cancer. Nine of the 20 synchronous DMPC patients were treated regarding only gastric cancer as therapeutic targets, and 11 patients were treated second primary cancers as therapeutic targets in addition to gastric cancer. Six of the 20 patients had DMPC which were applied for fluorouracil agent and cisplatin combination therapy, and the other 14 patients had DPMC that were not adaptive this combination therapy. With a median follow-up of 12 months, no difference in OS was observed between DMPC patients and simple gastric cancer patients (P = 0.49). Likewise, there was no difference in OS between patients treated only gastric cancer and both cancers (P = 0.64). Moreover, no difference in OS was observed between fluorouracil agent and cisplatin combination therapy sensitive DMPC patients and non-sensitive DMPC patients (P = 0.83). All except one of DMPC patients were dead of progression of gastric cancer. Conclusion: We could treat gastric cancer patients with DMPC with fluorouracil drug and cisplatin combination chemotherapy regarding advanced gastric cancer as first therapeutic target

O2-1-6VALIDATION OF AN ENHANCED INTERNATIONAL PROGNOSTIC INDEX(NCCN-IPI)FOR RISK STRATIFICATION OF DLBCL PATIENTS

Abstract Background: The U.S. National Comprehensive Cancer Network Prognostic Index (NCCN-IPI) was recently developed for risk stratification of diffuse large B-cell lymphoma (DLBCL) cases in the rituximab era (Zhou, Blood 2013). It provided better discrimination of risk groups of DLBCL patients than the conventional IPI. We report the validation of NCCN-IPI compared with IPI by using our institution dataset. Methods: We retrospectively analyzed patients with de novo DLBCL referred to our department from September 2004 to March 2013. NCCN-IPI used a maximum of 8 scoring points for categorized age >40-60 (1 pt.), >60-75 (2 pts.) and >75 yrs. (3 pts.), and LDH ratio >1-3 (1 pt.) and ≥3 (2pts.) upper limit of normal, in addition to extranodal disease in major organs (either bone marrow, CNS, liver/GI tract or lung), Ann Arbor stage III/IV and ECOG performance status (≥2), each having a score of 1. Four risk groups were defined: low (L, 0-1 pt.), low-intermediate (L-I, 2-3 pts.), intermediate-high (HI, 4-5 pts.) and high risk (H, ≥6 pts.). Results: A total of 315 patients were identified. Patients characteristics were the following: age (>40-60/ > 60-75/ >75 yes: 24/44/29%); stage III/IV (53%); extranodal disease (47%); LDH (1-3/ > 3 times: 45/14%); and PS ≥2, (31%). On univariate analysis, all characteristics were significant for OS, and were the same on multivariate analysis except for extranodal disease. The 5-year OS estimates between the NCCN-IPI and IPI differed in each risk groups, 100% (95% CI: 100-100%) vs. 91% (82-96%), 84% (74-90%) vs. 78% (63-87%), 59% (46-69%) vs. 46% (29-60%), 25% (12-40%) vs. 24% (11-39%), in L, L-I, H-I, and H risk groups, respectively. Compared to IPI, the 95% CI did not overlap among NCCN-IPI risk group. Conclusions: NCCN-IPI demonstrated improved risk stratification compared to IPI. NCCN-IPI is a valuable prognostic index for DLBCL patients in the rituximab era.

Randomized phase III trial of irinotecan plus cisplatin versus irinotecan alone after S-1 based chemotherapy failure for patients with advanced and recurrent gastric cancer (AGC) (TCOG GI-0801).

61 Background: S-1based chemotherapy is the standard first-line chemotherapy for AGC in Japan. Currently, there is no high level evidence established for second-line treatment. Irinotecan (CPT-11) plus cisplatin (CDDP) are active in AGC. The combination of these 2 agents is synergistic effect in preclinical and clinical studies. We conducted a phase III study of CPT-11 plus CDDP (CP) compared with CPT-11 alone (C) in patients with AGC refractory to S-1 based chemotherapy. Methods: Patients with previously treated with S-1-based chemotherapy for AGC, an ECOG PS of 0-1 and adequate organ functions were randomly assigned to receive either CPT-11 60 mg/m2 plus CDDP 30 mg/m2 on day 1 every 2 weeks or CPT-11 150mg/m2on day 1 every 2 weeks. The primary endpoint is progression free survival (PFS). The statistical design is based on superiority hypothesis; PFS is 110days in CP, 65days in C; two-sided α=0.05, 1-β=0.8; and planed accrual is 130 pts. Secondary endpoints include Overall Survival (OS), Time to Treatmen...

Interim analysis of a single-arm, phase II study of bevacizumab (BV) with modified OPTIMOX1 as first-line treatment of patients with metastatic colorectal cancer (mCRC): TCOG-GI0802.

578 Background: BV is widely used for treatment of metastatic colorectal cancer (mCRC) patients. Although BV was often administrated to mCRC patients in combination with oxaliplatin, optimal schedule remains unclear. Many mCRC patients cannot continue to use oxalipatin because of cumulative neurotoxity, which decreases patients QOL and motivation.We postulated that modification of oxaliplatin schedule would improve TTF in intermittent oxaliplatin usage. Therefore, we planned to use BV with original OPTIMOX1 adiministration schedule; modified oxaliplatin dose (85 mg/m3). METHODS Patients were enrolled with the criteria excluding neuropathy, PS ≥ 1, or no previous usage of oxaliplatin and BV, and then were received modified FOLFOX6 regimen (L-OHP 85 mg/m2, l-LV 200 mg/m2, 5-FU 400 mg/m2 bolus, 5-FU 2,400 mg/m2 46h continuous infusion) plus BV (5 mg/kg) q2wks x 6 cycles, followed sLV5FU2 (omit L-OHP) plus BV x 12 cycles regimen. After that, oxaliplatin reintroduction was done and mFOLFOX6 plus BV regimen was continued until PD. The evaluation of antitumor effect was done according to RECIST Criteria. RESULTS 40 patients accrued this trial. Median age was 65 years old. PS0: 89.5%, male: 75%, female: 25%, colon: 65.8%, rectal: 31.6%,colon + rectal: 2.6%. During initial 6 cycles of chemotherapy, 90% patients could continue chemotherapy. Response rate was 50%, and clinical benefit (including SD) was 92.1%. During Intial 6 cycles, G3 neuropathy occurred 2.6%, and G2 were 5%. Most frequent toxicity (≥G3) was neutropenia (30.8%) and anorexia (5.3%). One patient could complete the scheduled regimen. This patient continued mFOLFOX6+BV for 12 cycles after reintroduction keeping with PS 0, and was received FOLFIRI+BV regimen as second-line chemotherapy. Further information are under examination. CONCLUSIONS This administration schedule was well tolerated and could continue chemotherapy longer than usual method. sLV5FU2+BV regimen was not affected reintroduction rate and progression free survival. BV with mOPTIMOX1 regimen can be expected to become a good treatment options for mCRC patients. No significant financial relationships to disclose.