A devised method of hepatic and splenic arterial infusion chemotherapy after transcatheter peripancreatic arterial embolization for patients with advanced pancreatic cancer

We previously reported the clinical efficacy based on hepatic and splenic arterial infusion chemotherapy (HSAIC) for patients with advanced pancreatic cancer after transcatheter peripancreatic arterial embolization (TPPAE). However, this medical treatment pointed out a few problems in which the method had its complexity and a limited use of embolus micro-coil numbers. Then, we tried to improve the method in solving those problems. In order to reduce the embolus micro-coil numbers for TPPAE, we divided the micro-coil into several parts. We also devised the method of HSAIC. We used one catheter with a side hole, so that the catheter was able to supply a therapeutic drug for arterial infusion chemotherapy, both to the common hepatic artery and splenic artery. The effective rate for eleven cases was 72.7%, and there were no significant differences from the cases treated with the conventional method of TPPAE-HSAIC. Therefore, the devised treatment was considered to be an easy and useful method for TPPAE and HSAIC.     

Systemic chemotherapy and chemoradiotherapy for advanced pancreatic cancer

Currently, we are able to use S-1 with gemcitabine and erlotinib, as well as gemcitabine alone, as first-line therapy for advanced pancreatic cancer. In addition, a clinical trial of FOLFIRINOX is underway in Japan. On the other hand, chemoradiotherapy is considered to be one of the treatments of choice for locally advanced pancreatic cancer. This review summarizes current knowledge about non-surgical treatment for advanced pancreatic cancer, mainly based on the results of recent clinical trials.     

局部晚期和复发直肠癌放射治疗配合动脉灌注化疗疗效分析

目的探讨动脉灌注化疗提高局部晚期和复发直肠癌放射治疗疗效。方法62例直肠癌随机分为放射治疗配合动脉灌注化疗(综合组)31例,单纯放射治疗(单放组)31例。动脉插管化疗采取经肠系膜下动脉和髂内动脉灌注,每次氟尿嘧啶600mg/m2,顺铂70mg/m2,2～3周重复,共2～3次。放射治疗采用8～18MVX射线照射,总量达DT40～50Gy时争取手术,不能手术者加量至DT60～70Gy。结果综合组有效率为83.9%,单放组有效率为54.8%(P<0.01)。综合组1、3、5年生存率分别为90.3%、68.8%、52.0%,单放组分别为80.7%、50.6%、29.8%(P<0.05),综合组和对照组中位生存时间分别为65个月和39个月。综合组副反应大,但患者均能耐受。结论放射治疗辅以动脉灌注化疗为局部晚期和复发直肠癌有效治疗方法。     

A new regional arterial infusion chemotherapy for patients with advanced pancreatic cancer

Various arterial infusion chemotherapies have been tried for the purpose of local control of advanced pancreatic carcinoma. However, these treatments were not effective against the primary lesion because of its special anatomical position and the complex hemodynamics, although they were effective against the liver metastases. Therefore, the vascular supply distribution was altered by superselective embolization to control the primary legion in the pancreas, after transcatheter peripancreatic arterial embolization toward the primary site. Furthermore, bilateral (hepatic and splenic) arterial infusion chemotherapy was applied to both the primary site and liver metastasis. As a result, the response rate was 73.9%, with a mean survival period 18.26 +/- 10.06 months. We believe that the current chemotherapy was an effective treatment for unresectable pancreatic cancer since it was possible to treat patients with little harm to their quality of life.     

Gemcitabine-based concurrent chemoradiotherapy versus chemotherapy alone in patients with locally advanced pancreatic cancer

Objective: To explore improved treatment by retrospectively comparing survival time of gemcitabine-basedconcurrent chemoradiotherapy (GemRT) versus chemotherapy (Gem) alone in patients with locally advancedpancreatic cancer (LAPC). Methods: From January 2005 to June 2010, 56 patients with LAPC from Subei People’sHospital were treated either with Gem (n=21) or GemRT (n=35). Gem consisted of 4-6 cycles gemcitabine alone(1000 mg/m2 on Days 1, 8, 15, 28-day a cycle). GemRT consisted of 50.4Gy/28F radiotherapy with concurrent 2cycles of gemcitabine (1000 mg/m2 on days of radiation 1, 8, 15, 21-day a cycle). Radiation was delivered to thegross tumor volume plus 1-1.5 cm by use of a three-dimensional conformal technique. The follow-up time wascalculated from the time of diagnosis to the date of death or last contact. Kaplan-Meier methodology wes usedto evaluate survival. Results: Patient characteristics were not significantly different between treatment groups.The disease control rate and the objective response rate of GemRT versus Gem was 97.1% vs 71.4%, 74.3%vs 38.1%. The overall survival (OS) was significantly better for GemRT compared to Gem (median 13 monthsversus 8 months; 51.4% versus 14.3% at 1 year, respectively). Conclusion: Radiation therapy at 50.4Gy with2 concurrent cycles of gemcitabine results in favorable rates of OS. Concurrent chemoradiotherapy should bethe first choice for patients with LAPC.     

Current status of chemoradiotherapy for locally advanced pancreatic cancer in Japan

Although the results of randomized controlled trials for locally advanced pancreatic cancer conducted between 1969 and 1988 demonstrated a survival advantage for concurrent radiotherapy and bolus 5-fluorouracil (FU) injection, the prognosis of patients with this disease remains very poor. In an attempt to improve patient outcome after chemoradiotherapy, various clinical trials for this disease have been conducted in Japan. These trials were designed to evaluate novel chemotherapy regimens combined with conventional radiotherapy, or intensive radiotherapy in combination with chemotherapy. After gemictabine was shown to yield a better survival outcome than 5-FU in patients with advanced disease, this drug was investigated as a chemotherapeutic agent and/or radiosensitizer for locally advanced pancreatic cancer in a number of trials. S-1, a novel oral fluoropyrimidine derivative that appears promising for the treatment of metastatic disease, is also being intensively evaluated in Japan for the treatment of locally advanced pancreatic cancer. In this review, we summarize recent treatment strategies that are being used in Japan with the goal of establishing a new standard therapy for locally advanced pancreatic cancer.     

动脉灌注新辅助化疗治疗膀胱尿路上皮癌的初步研究

背景与目的:根治性膀胱切除加盆腔区域淋巴结清扫是治疗浸润性膀胱癌的标准术式,但对于非器官局限性膀胱癌,局部复发与远处转移的风险较高。对这部分患者进行以顺铂为基础的新辅助化疗,可以降低复发率,改善手术疗效,提高生存率。本文旨在研究术前动脉灌注化疗对根治术的影响及其对肿瘤的治疗作用。方法:收集2004年至2005年间13例局部浸润性尿路上皮癌患者(T2～T4a),采用吉西他滨与顺铂(gemcitabine andcisplatin,GC)方案给予髂内动脉灌注化疗1～3次,随后8例行膀胱根治性切除术,2例由于肿瘤明显缩小放弃手术治疗,3例行经尿道膀胱肿瘤电切术。评价化疗前后白细胞、红细胞及血小板水平的变化,化疗前后肿瘤大小的变化,以及临床分期与病理分期的的比较。结果:化疗前后白细胞计数之间的差异无显著性(t=0.94,P=0.37),但红细胞及血小板计数之间的差异有显著性(t=3.41,2.38;P=0.00,0.04),但三项绝对计数值均在正常范围之内;化疗前后肿瘤大小的差异有显著性(t=2.52,P=0.04);8例根治性切除术患者中除两例临床分期与病理分期符合外,其余5例均有降期。结论:GC方案新辅助髂内动脉灌注化疗可以缩小肿瘤体积,导致肿瘤降期;化疗前后白细胞无显著降低,化疗导致红细胞及血小板降低,但未对手术造成不良影响。     

Gemcitabine in the chemoradiotherapy for locally advanced pancreatic cancer: A meta-analysis

Aims

Whether gemcitabine based chemoradiotherapy (GEM-based CRT) is superior to 5-fluorouracil based chemoradiotherapy (5-FU-based CRT) for locally advanced pancreatic cancer (LAPC) remains uncertain. The aim of the present study was to evaluate the effect of GEM-based CRT compared with 5-FU-based CRT.

Methods

Electronic database including Medline, Embase, Cochrane controlled trials register, PubMed (update to December 2010) and manual bibliography searches were carried out. A meta-analysis of all randomized clinical trials (RCTs) or other comparative studies comparing GEM-based CRT and 5-FU-based CRT were performed.

Results

Three RCTs and one retrospective comparative study including 229 patients were assessed. Meta-analysis showed survival advantage of GEM-based CRT compared with 5-FU-based CRT for 12-month (12-mo) survival rates (SRs) (RR = 1.54, 95% CI 1.05-2.26, p = 0.03). Moreover, there were also trends of benefit for SR after 6-months (RR 1.13, 95% CI 0.98-1.30, p = 0.09) and 24-months (24-mo: RR 2.41, 95% CI 0.90-6.48, p = 0.08), though the trends did not reach statistical significance. More frequent severe acute hematologic toxicities were found in the GEM-based CRT group.

Conclusions

The meta-analysis found that GEM-based CRT was better than 5-FU-based CRT in the treatment of LAPC, especially for 12-mo SRs. However, the acute toxicity should be carefully regarded.     

Adjuvant arterial infusion chemotherapy for patients with pancreatic cancer

Although surgery is the only potentially curative treatment for pancreatic cancer, patients undergoing complete resection frequently develop liver metastasis, local recurrence, and peritoneal metastasis. Liver metastasis is a common mode for the progression of pancreatic cancer, and the prognosis of patients in whom it occurs is extremely poor. Between January 2000 and December 2002, 10 patients received adjuvant arterial infusion chemotherapy after resection of pancreatic cancer. Eight of these 10 patients underwent pancreaticoduodenectomy and 2 had distal pancreatectomy. Catheters were placed using Seldinger's technique, with the tip being advanced into the common hepatic artery via the femoral artery. Then, 1,000 mg/body of 5-FU was administered by 24-hour continuous infusion for 6 days per week (days 1-3 and 5-7). Two cycles of chemotherapy were delivered through an angiographic catheter without a reservoir port. During this treatment, no severe systemic or abdominal complications were observed. The 2 groups were well balanced with respect to prognostic factors. The survival rate at 1 year was 77.8% and 41.6% for the adjuvant chemotherapy group and non-adjuvant chemotherapy group, respectively, while the 3-year survival rates were 48.6% and 20.8% (Wilcoxon test, p = 0.0649). The median overall survival rate was superior in the adjuvant chemotherapy group, although the difference was not statistically significant. High-dose 5-FU arterial infusion chemotherapy seems to be a safe, tolerable, and effective regimen for the postoperative recurrence of pancreatic cancer.     

Optimal combination of radiofrequency ablation with chemoradiotherapy for locally advanced pancreatic cancer

Problems have been reported in the treatment of pancreatic cancer with radiofrequency ablation (RFA), such as the friability of the organ itself. This report presents possible solutions to such problems. Although our patient suffered from locally advanced unresectable pancreatic cancer, she remained well at 18 mo after RFA with no evidence of recurrence. To ameliorate the side effects of RFA, after a palliative bypass procedure, the subject was treated with combined radiotherapy and chemotherapy. After this regimen had been administered, a contrast-enhanced computed tomography scan confirmed that RFA is a viable approach to the treatment of pancreatic cancer as the chemoradiotherapy had resulted in marked tumor shrinkage and pancreatic fibrosis; i.e., sufficient tumor ablation was achieved without serious RFA-related complications, such as pancreatitis or pancreatic fistulae. The present case suggests that RFA combined with preceding chemoradiotherapy is safe and effective for the palliative treatment of locally advanced pancreatic cancer.     

Arterial infusion chemotherapy for patients with advanced pancreatic cancer

Although various therapies have been tried to improve advanced nonresectable pancreatic cancer, a sufficient consensus has not yet been obtained about the treatment. We have performed arterial infusion chemotherapy for pancreatic cancer in order to maintain QOL. The response rate was 17.3%, the mean survival time 282.1+/-204.7 days, median survival time 243.0+/-84.7 days, and many patients were continuously treated on an outpatient basis. It is thus expected that survival time and maintenance of QOL can be extended by self-sustaining arterial infusion chemotherapy.     

替吉奥与吉西他滨同步放化疗治疗局部晚期胰腺癌的临床研究

目的探讨替吉奥联合吉西他滨同步放化疗治疗局部晚期胰腺癌的疗效和安全性。方法选择26例不可手术切除的局部晚期胰腺癌患者,随机分为替吉奥联合吉西他滨同步放化疗组(观察组,13例)和5氟尿嘧啶(5-FU)联合吉西他滨同步放化疗组(对照组,13例)。观察组给予替吉奥40mg/m2,bid,第1～18天;同时给予吉西他滨1000mg/m2第1天、第5天、第29天,应用6 MV直线加速器,接受总放疗剂量54 Gy、27次。对照组给予5-Fu 750mg/m2,第1～4天、第25～28天;吉西他滨的用法及放疗方法均同观察组。结果观察组总有效率为38.5%,1年生存率为53.8%,与对照组比较有生存优势。观察组不良反应较轻,患者耐受性更好,生活质量明显改善。结论替吉奥联合吉西他滨同步放疗治疗局部晚期胰腺癌患者临床疗效好,不良反应明显轻,患者耐受性良好。     

动脉灌注健择治疗中晚期胰腺癌

目的 评价经动脉灌注健择治疗中晚期胰腺癌的疗效。方法 36例患者共行65次经动脉内灌注健择，药量按800～1200mg／m^2，间隔2～4周给药一次。结果 以疾病相关症状改善(DRSI)作为评价近期疗效依据，其中以疼痛改善最为显著。结论 经动脉内灌注健择是治疗中晚期胰腺癌的有效方法，可改善临床症状，提高生存质量。     

Novel implications of combined arterial resection for locally advanced pancreatic cancer in the era of newer chemo-regimens

IntroductionIn this study, we assessed the prognostic efficacy and feasibility of combined arterial resection (AR) for locally advanced pancreatic cancer (LAPC), and aimed to identify significant prognostic factors for patients who underwent combined AR.MethodsBetween 1981 and 2018, 733 consecutive patients who underwent pancreatic surgery for PC were identified. The 730 cases with detailed information were enrolled in the analysis.ResultsAmong 730 resected PC patients, 44 (6%) underwent AR including 21 hepatic (48%), 12 celiac (27%), five splenic (12%), four superior mesenteric (9%), and two other arteries (4%). The combined AR surgery showed significantly longer operative time (median, 608 vs 451 min, P < 0.0001), and the incidence of intraoperative blood transfusion was significantly higher in AR than surgery without AR (P = 0.0002), whereas there was no significant difference in the intraoperative blood loss (970 vs 1200 mL, P = 0.2) and occurrence of major complications (P = 0.5). In prognostic analysis of AR cases, multivariate Cox proportional hazard models revealed preoperative and postoperative therapy were the independent factors for both recurrence-free survival (RFS) and overall survival (OS) (preoperative therapy: RFS, HR = 0.21, P = 0.007; OS, HR = 0.18, P = 0.01; postoperative therapy: RFS, HR = 0.31, P = 0.003; OS, HR = 0.19, P = 0.002).ConclusionThis study showed the feasibility of combined AR for LAPC and robust association of pre- and postoperative therapy and survival after AR surgery. Preoperative therapy following combined AR surgery is potentially powerful strategy for LAPC.     

Assessment of efficacy of arterial infusion chemotherapy with gemcitabine for four cases of advanced pancreatic cancer

We treated 4 cases of advanced pancreatic cancer: 2 cases were nonresectable and the other 2 cases did not choose an operation but arterial infusion chemotherapy with gemcitabine after the transcatheter peripancreatic arterial embolizaiton. One case resulted in a tumor decrease but the other 3 cases observed a tumor progress. Although we confirmed cancer pain suppression in all cases and a disappearance of tumor fever in one case, the survival period was 7 months in spite of the treatment. As for the complication of arterial infusion chemotherapy with gemcitabine, we recognized bone marrow suppression (grade 1) in 3 cases. This therapy seemed to be effective for suppression of pain and tumor fever caused from the advanced pancreatic cancer. However, we need to improve in survival period from this therapy.     

Clinical benefit response of concurrent chemoradiotherapy with protracted 5-fluorouracil infusion in patients with locally advanced pancreatic cancer

Background Pancreatic cancer is a highly virulent disease with a poor prognosis. Although objective tumor response to chemotherapy and/or radiotherapy is low, some patients show an improvement in their symptoms after treatments, without obvious tumor regression. Methods We assessed the clinical benefit of concurrent chemoradiotherapy with protracted 5-fluorouracil infusion in patients with locally advanced pancreatic cancer. Sixteen patients were enrolled in this study. The clinical benefit response to the chemoradiotherapy was evaluated by 2 indicators, including pain (intensity of pain and consumption of morphine) and performance status. A patient was defined to be a clinical benefit responder if 1 of these 2 variables was positive, and the other variable was positive or stable. Results Seven patients (44%) responded. Six patients (38%) were classified as stable, and 3 (19%) as nonresponders. The survival period in responders was significantly longer than that in nonresponders and stable patients. Conclusion Concurrent external-beam radiation therapy, with protracted 5-fluorouracil infusion, may be a meaningful treatment for locally advanced pancreatic cancer.     

Usefulness of CT arteriography for transcatheter peripancreatic arterial embolization to patients with advanced pancreatic cancer

We reported previously the clinical benefit of hepatic and splenic arterial infusion chemotherapy (HSAIC) for patients with advanced pancreatic cancer alter transcatheter peripancreatic arterial embolization (TPPAE). TPPAE has two therapeutic purposes: (1) preparation for effective arterial infusion chemotherapy, and (2) transcatheter arterial embolization (TAE) against pancreas head cancer. The present paper describes the advantage of CT arteriography in performing TPPAE for advanced pancreatic cancer. CTA was useful in identifying the arterial blood supply in pancreatic cancer, especially blood vessels branched off from the supramesenteric artery (SMA). Since the anti-tumor effect of TPPAE against pancreas head cancer is dependent mainly on whether the blood supply from SMA could be shut off, it is suggested that CTA is useful to evaluate the embolization effect of TPPAE.     

Tailored-dose chemotherapy using gemcitabine for advanced pancreatic cancer

Eighteen patients with metastatic or post-surgery recurrent pancreatic cancer were given weekly gemcitabine therapy. Almost all of these patients were aged or had other complications. We determined the individualized maximum repeatable dose (iMRD)as follows. We started at 500 mg/m(2) gemcitabine and repeated the treatment with an increase or a decrease of 100mg/m(2) each week, if the hematological toxicity was 0 or more than grade 1. If toxicity was grade 1, the same dose was given. And the third-week dose was an iMRD. Dose intensity was 286 mg/m(2)/week. The median survival time was 262 days. Of these 18 patients, 2 (11.1%), 11(61.1%) and 5 (27.8%) patients showed partial response, stable disease, and progressive disease, respectively. The therapeutic effects of iMRD equaled those of standard administration of gemcitabine.     

局部晚期鼻咽癌诱导化疗联合同期放化疗的临床观察

目的:研究TP和PF方案诱导化疗联合同期放化治疗局部晚期鼻咽癌的疗效及毒副作用。方法:经组织病理学确诊的局部晚期鼻咽癌患者80例,随机平分为TP组(多西他赛联合顺铂)和PF组(顺铂联合5-FU)。TP组先行2个周期多西他赛联合顺铂诱导化疗,PF组先行2个周期顺铂联合5-FU诱导化疗,3周重复。第7周开始放疗,放疗同期行顺铂单药化疗,3周重复。放疗采用调强适形放射治疗(IMRT)。处方剂量:PTVnx68～72Gy,PTVnd66～70Gy,PTV160～64Gy,PTV250～54Gy,5次/周,共30次。结果:TP组GTVnx体积缩小(15.32±4.18)cm3,PF组缩小(14.11±3.98)cm3,P>0.05;TP组GTVnd体积缩小(10.67±2.02)cm3,PF组缩小(8.95±2.44)cm3,P>0.05。治疗结束3个月后两组近期疗效对比差异均无统计学意义,P>0.05。TP和PF组的Ⅲ～Ⅳ度白细胞减少的发生率分别为37.5%和10.0%,P=0.003 8;Ⅲ～Ⅳ级口腔黏膜反应的发生率分别为7.5%和27.5%,P=0.001 9;Ⅲ～Ⅳ度恶心、呕吐/食欲减退发生率两组比较差异均无统计学意义,P>0.05。两组1、2年总生存率分别为100.0%、87.5%和100.0%、82.5%,差异均无统计学意义,P>0.05。结论:TP诱导化疗联合同期放化疗是治疗局部晚期鼻咽癌的有效方案,近期疗效较好,毒副作用轻,尤其是口腔黏膜反应较PF组轻,患者耐受性好。     

A phase II study of induction chemotherapy with gemcitabine plus S-1 followed by chemoradiotherapy for locally advanced pancreatic cancer

Purpose

The aim of this study was to investigate the feasibility and efficacy of induction chemotherapy with gemcitabine and S-1 followed by chemoradiotherapy for locally advanced pancreatic cancer.

Methods

Patients with locally advanced unresectable pancreatic cancer received four cycles of induction chemotherapy consisting of 30-min intravenous infusions of gemcitabine 1,000 mg/m² on days 1 and 8 and oral S-1 40 mg/m² twice daily on days 1–14 of a 21-day cycle. Those without disease progression received chemoradiotherapy of 30 Gy in ten fractions with 250 mg/m² of gemcitabine on days 1 and 8.

Results

A total of 20 patients were treated. Median follow-up time was 431 days (range 133–1,014 days). Four cycles of induction chemotherapy were completed in 18 patients, and 16 patients received chemoradiotherapy, which was completed without delay in all. Grade 3–4 toxicities associated with induction chemotherapy were neutropenia (50%); anemia (20%); thrombocytopenia (10%); febrile neutropenia (5%); nausea (10%); anorexia (10%); and vomiting, fatigue, dehydration, stomatitis, and rash (5%). Grade 3–4 toxicities among those receiving chemoradiotherapy were neutropenia (13%) and anemia (6%). Median progression-free survival was 8.1 months. Median overall survival was 14.4 months, with a 1-year survival rate of 54.2%.

Conclusions

The regimen of induction chemotherapy with gemcitabine and S-1 followed by chemoradiotherapy used in the present study demonstrated promising activity in locally advanced pancreatic cancer. Further consideration of radiation schedule and duration of induction chemotherapy is required to enhance the efficacy of this strategy.