Phase II study of capecitabine and oxaliplatin given prior to and concurrently with preoperative pelvic radiotherapy in patients with locally advanced rectal cancer

This multicentre phase II study evaluated the efficacy and safety of preoperative capecitabine plus oxaliplatin and radiotherapy (RT) in patients with locally advanced rectal cancer (T3/T4 rectal adenocarcinoma with or without nodal involvement). Treatment consisted of one cycle of XELOX (capecitabine 1000 mg m(-2) bid on days 1-14 and oxaliplatin 130 mg m(-2) on day 1), followed by RT (1.8 Gy fractions 5 days per week for 5 weeks) plus CAPOX (capecitabine 825 mg m(-2) bid on days 22-35 and 43-56, and oxaliplatin 50 mg m(-2) on days 22, 29, 43 and 50). Surgery was recommended 5 weeks after completion of chemoradiotherapy. The primary end point was pathological complete tumour response (pCR). Sixty patients were enrolled. In the intent-to-treat population, the pCR rate was 23% (95% CI: 13-36%). 58 patients underwent surgery; R0 resection was achieved in 57 (98%) patients, including all 5 patients with T4 tumours. Sphincter preservation was achieved in 49 (84%) patients. Tumour and/or nodal downstaging was observed in 39 (65%) patients. The most common grade 3/4 adverse events were diarrhoea (20%) and lymphocytopaenia (43%). Preoperative capecitabine, oxaliplatin and RT achieved encouraging rates of pCR, R0 resection, sphincter preservation and tumour downstaging in patients with locally advanced rectal cancer.     

直肠癌新辅助放化疗敏感性预测进展

直肠癌是我国最常见的恶性肿瘤之一。近年来,直肠癌的新辅助放疗或放疗联合化疗及全直肠系膜切除的根治术已逐步成为治疗中下段进展期直肠癌的标准模式。目前已经有大量研究证实新辅助治疗的优点,但尚有一部分患者无法在其中受益。在新辅助放化疗前或其早期预测其敏感性,达到肿瘤的“个体化治疗”,目前在这方面已经进行了大量研究。本文将就预测新辅助治疗敏感性的进展进行综述。     

Fourth versus eighth week surgery after neoadjuvant radiochemotherapy in T3-4/N0+ rectal cancer: Istanbul R-01 study

Background and purpose

The optimum duration between neoadjuvant radiochemotherapy and transmesorectal excision in locally advanced rectal cancer has not been defined yet. This randomized study was designed to compare the efficacy of four-week versus eight-week delay before surgery.

Methods

One-hundred and fifty-three patients with locally advanced low- or mid-rectum rectal adenocarcinoma were included in this single center prospective randomized trial. Patients were assigned to receive surgical treatment after either four weeks or eight weeks of delay after chemoradiotherapy. Patients were followed for local recurrence and survival, and surgical specimens were examined for pathological staging and circumferential margin positivity.

Results

4-week and 8-week groups did not differ with regard to lateral surgical margin positivity (9.2% vs. 5.1%, P=0.33, respectively), pathological tumor regression rate (P=0.90), overall survival (5-year, 76.5% vs. 74.2%, P=0.60) and local recurrence rate (11.8% vs. 10.3%, 0.77). Overall survival was better in patients with negative surgical margins (78.8% vs. 53.0%, P=0.04). Local recurrence rate was significantly higher among patients with positive surgical margin (28.5% vs. 9.3%, P=0.02).

Conclusions

Intentional prolongation of the chemoradiotherapy-surgery interval does not seem to improve clinical outcomes of patients with locally advanced rectal cancer. Surgical margin positivity seems to be more important with this regard.     

First-line treatment with oxaliplatin and capecitabine in patients with advanced or metastatic oesophageal cancer: a phase II study

This phase II study assessed the safety and efficacy of oxaliplatin and capecitabine in patients with advanced oesophageal cancer. Fifty-one eligible patients received oxaliplatin 130 mg m(-2) intravenously on day 1 and capecitabine 1000 mg m(-2) orally twice daily on days 1 to 14 in a 21-day treatment cycle as first-line treatment for advanced oesophageal cancer. Grade 3 neutropenia was seen in one patient and anaemia in another patient. No grade 4 haematological toxicities were observed. Grade 4 non-haematological toxicity (lethargy) occurred in one patient (2%). Grade 3 non-haematological toxicity was seen in 14 (27%) patients (vomiting and polyneuropathy (8%); nausea (6%); lethargy and hand-foot syndrome (4%); and anorexia, diarrhoea, and hyperbilirubinaemia (each in one patient)). In 22% of the patients, toxicity was the reason for stopping the treatment. The overall response rate was 39%. The median overall survival was 8 months; the 1-year survival rate was 26%. In the quality of life (QoL) analysis, the emotional well-being improved during treatment, but the physical functioning scores declined. The fatigue score on the symptom scales increased. Overall, the global QoL score did not change during treatment. In conclusion, the activity of oxaliplatin and capecitabine is comparable with other chemotherapy regimens in advanced oesophageal cancer with a low frequency of grade 3/4 toxicity. Because this treatment can be given on an outpatient basis, it is probably less toxic than cisplatin-based therapy and preserves QoL during treatment, it is a viable treatment option in patients with advanced oesophageal cancer.     

卡培他滨与氟尿嘧啶/亚叶酸钙联合奥沙利铂治疗晚期胃癌的随机对照临床研究

背景与目的：目前对进展期及转移性胃癌还没有标准的化疗方案,而且缺乏有效率高、毒副反应小、安全的化疗方案.毒副反应是晚期胃癌化疗的限制性因素,影响患者的生活质量.本研究观察及比较两种常用化疗方案卡培他滨联合奥沙利铂方案（XELOX）与氟尿嘧啶/亚叶酸钙联合奥沙利铂方案（FOLFOX4）治疗晚期胃癌的临床疗效及毒副反应,以期取得在较佳疗效保证的同时,毒副反应小,耐受性更好的效果.方法：48例晚期胃癌患者随机分成两组,XELOX组与FOLFOX4组.XELOX组25例,用卡培他滨联合奥沙利铂方案化疗,卡培他滨1000 mg/m^2,口服,2次/日,第1～14天;奥沙利铂130 mg/m^2,静脉点滴,第l天;2l d为1个周期.FOLFOX4组23例,用氟尿嘧啶/亚叶酸钙联合奥沙利铂方案化疗,奥沙利铂85 mg/m^2,静脉点滴,第1天;亚叶酸钙200 mg/m^2,静滴2 h后予氟尿嘧啶400 mg/m^2,推注,后续600 mg/m^2持续静滴22 h,第1、2天;每2周重复,4周为1周期.两组均治疗2周期以上.按wH0标准评价客观疗效和毒副反应.结果：入组48例均可评价疗效,XELOX组有效率56.0%,中位TTP 5.8个月,MST 10个月,FOLFOX4组有效率47.8%,中位TTP 5.7个月,MST 9.8个月.两组近期有效率差异无显著性.毒副反应比较,手足综合征以：XELOX组显著（P＜0.05）,Ⅲ/Ⅳ级恶心呕吐发生率以FOLFOX4.组显著（P＜0.05）,其余毒副反应除腹泻外发生率以FOIFOX4组稍高,但差异无显著性.结论：XELOX方案与FOLFOX4方案治疗晚期胃癌疗效确切,毒副反应能耐受.两组近期疗效相似,毒副反应以XELOX组更易耐受,尤其对一般情况欠佳及老年的患者耐受性好.     

Capecitabine plus oxaliplatin (CapOx) versus capecitabine plus gemcitabine (CapGem) versus gemcitabine plus oxaliplatin (mGemOx): final results of a multicenter randomized phase II trial in advanced pancreatic cancer.

BACKGROUND: To compare the efficacy and safety of three different chemotherapy doublets in the treatment of advanced pancreatic cancer (PC). PATIENTS AND METHODS: At total of 190 patients were randomly assigned to receive capecitabine 1000 mg/m(2) twice daily on days 1-14 plus oxaliplatin 130 mg/m(2) on day 1 (CapOx), capecitabine 825 mg/m(2) twice daily on days 1-14 plus gemcitabine 1000 mg/m(2) on days 1 and 8 (CapGem) or gemcitabine 1000 mg/m(2) on days 1 and 8 plus oxaliplatin 130 mg/m(2) on day 8 (mGemOx). Treatment cycles were repeated every three weeks. The primary end point was progression-free survival (PFS) rate at 3 months; secondary end points included objective response rate, carbohydrate antigen 19-9 response, clinical benefit response, overall survival and toxicity. RESULTS: The PFS rate after 3 months was 51% in the CapOx arm, 64% in the CapGem arm and 60% in the mGemOx arm. Median PFS was estimated with 4.2 months, 5.7 months and 3.9 months, respectively (P = 0.67). Corresponding median survival times were: 8.1 months (CapOx), 9.0 months (CapGem) and 6.9 months (mGemOx) (P = 0.56). Grade 3/4 hematological toxicities were more frequent in the two Gem-containing arms; grade 3/4 non-hematological toxicity rates did not exceed 15% in any arm. CONCLUSION: CapOx, CapGem and mGemOx have similar clinical efficacy in advanced PC. Each regimen has a distinct but manageable tolerability profile.     

奥沙利铂联合卡培他滨治疗晚期胃癌的临床分析

目的:研究奥沙利铂(LOHP)联合卡培他滨(CAPE)治疗进展及转移性胃癌的疗效和毒性作用。方法:LOHP85mg/m2,静滴2小时,第1、8天,CAPE2500mg/m2,第1～14天,每3周重复,行2周期后判断疗效。结果:19例病人中完全有效3例(15.8%),部分有效7例(36.8%),稳定5例(26.3%),进展4例(21.1%),总有效率52.6%,中位生存期11月,毒性反应以手足综合症、神经毒性反应、骨髓抑制为主,无化疗相关死亡。结论:奥沙利铂联合卡培他滨治疗晚期胃癌疗效肯定,毒性反应可耐受。     

Conservative treatment with transurethral resection, neoadjuvant chemotherapy followed by radiochemotherapy in stage T2-3 transitional bladder cancer

Purpose Organ preservation has been investigated in patients (p) with infiltrating transitional cell carcinoma (TCC) of the bladder over the past decade as an alternative to radical cystectomy. This is a trimodal schedule study, including transurethral resection of bladder tumor (TURB), neoadjuvant chemotherapy and concomitant radiochemotherapy (RTC). Patients and methods From April 1996 until August 2005, 29 evaluable patients (p) with T2-T3NXM0 bladder cancer were enrolled. After a transurethral resection of bladder tumor (TURB), we administered 2 cycles of induction chemotherapy with CMV (15 p) or Gemcitabine-Cisplatin (14 p) followed by radiotherapy 45 Gy 1.8 Gy/fraction and two cycles of concomitant cisplatin 70 mg/m². 2–3 weeks later, a cystoscopy with tumor-site biopsy was performed. If complete histological response, p were treated with consolidation radiotherapy until 64.8 Gy. For p with residual or recurrent tumor, cystectomy was performed. Results We included 28 men and 1 women (median age 63, range 39–72 years) with PS (ECOG) 0–1. The stage was: 21 p T2; 6 p T3a; and 2 p T3b. Toxicity was higher in CMV compared with Gem-Cis: grade 3/4 neutropenia 4/15 (26%) vs 1/14 (7%); febrile neutropenia 3/15 (20%) vs 1/14 (7%); grade 3/4 trombocytopenia 2/15 (13%) vs 1/14 (7%). Toxicities with concomitant RCT were low-moderate: urocystitis (26%) and enteritis (18%). Response: microscopically complete TURB was obtained in 20 p (69%), but not in 9 p (31%) (7 microscopic, and 2 macroscopic residual tumor). We found a complete histologic response after induction RCT in 25 p (86%). After a median follow-up of 69.4 months (m) (range: 8–97.7), there were 8 deaths, with a overall survival of 72%. Furthermore 14 of 29 p (48%) were alive with intact bladder, and median survival time with intact bladder was 63.6 m (50.1–77.2); were predictive of best outcome T2 stage vs T3 (p<0.0001), and complete histologic resection in initial TURB vs residual tumor (p=0.0004). Conclusions Combined treatment provide high response rates and can be offered as an alternative option to radical cystectomy in selected patients with TCC. Patients with T2 stage and complete histologic resection in initial TURB had the best outcome. Radiotherapy Oncology Unit . CROASA, S.A.     

Capecitabine (Xeloda) in combination with oxaliplatin: a phase I, dose-escalation study in patients with advanced or metastatic solid tumors.

OBJECTIVES: This phase I, dose-escalation study was conducted to determine the recommended dose of intermittent oral capecitabine in combination with a fixed dose of i.v. oxaliplatin. Secondary objectives included evaluation of the safety profile and antitumor activity. PATIENTS AND METHODS: Twenty-three patients with advanced or metastatic solid tumors received a 21-day regimen of oral capecitabine (500, 825, 1000 or 1250 mg/m2 twice daily, days 1-14) in combination with oxaliplatin (130 mg/m2, 2-h i.v. infusion, day 1). Dose-limiting toxicities were determined during the first treatment cycle, and safety and efficacy were evaluated throughout treatment. RESULTS: The recommended dosing schedule is oral capecitabine 1000 mg/m2 twice daily (days 1-14) with i.v. oxaliplatin 130 mg/m2 (day 1) in a 21-day treatment cycle. The principal dose-limiting toxicity was diarrhea. The most frequent treatment-related adverse events occurring during the study were gastrointestinal (nausea/vomiting, diarrhea) and neurological (dysesthesia, paresthesia). The majority of treatment-related adverse events were mild to moderate in intensity, and no grade 4 adverse events occurred in the 15 patients treated at or below the recommended dose. The most common grade 3/4 laboratory abnormalities were lymphocytopenia (52% of patients), thrombocytopenia (22%; grade 3 only), neutropenia (17%) and hyperbilirubinemia (17%). Among patients treated at or below the recommended dose level (n = 15), only two patients experienced grade 3 neutropenia and no patients experienced grade 4 neutropenia. Partial tumor responses occurred in six patients (26%), including five of nine patients (55%) with colorectal cancer. All responding patients were pretreated with 5-fluorouracil and four responders had received prior irinotecan. CONCLUSIONS: Oral capecitabine with i.v. oxaliplatin is a feasible combination regimen that shows promising antitumor activity in patients with colorectal cancer. There is an ongoing, phase II study to further characterize the safety and efficacy of this combination as first-line therapy for metastatic colorectal cancer, using the recommended dose identified in this study.     

奥沙利铂联合卡培他滨或替吉奥对晚期结肠癌患者疗效对比

目的 探究奥沙利铂联合卡培他滨或替吉奥对晚期结肠癌患者的治疗效果.方法 选取晚期结肠癌患者112例,依据抽签法将患者分为卡培他滨组和替吉奥组,每组各56例;给予卡培他滨组患者奥沙利铂联合卡培他滨进行化疗,给予替吉奥组患者奥沙利铂联合替吉奥进行化疗.观察比较两组患者治疗前后的白细胞计数(WBC)、血小板计数(PLT)、miRNA(miR-21)水平及恶心呕吐、手足综合征(HFS)、口腔黏膜炎、肝功能异常发生率,并比较两组疗效.结果 治疗前两组患者的WBC、PLT及miR-21水平比较,差异无统计学意义(P﹥0.05);治疗后两组患者WBC、PLT及miR-21水平较本组治疗前均降低,组间比较卡培他滨组患者的PLT高于替吉奥组,差异有统计学意义(P﹤0.05);治疗过程中卡培他滨组患者HFS及恶心呕吐发生率高于替吉奥组,差异有统计学意义(P﹤0.05);两组患者的总有效率比较,差异无统计学意义(P﹥0.05).结论 奥沙利铂联合卡培他滨或替吉奥均可对晚期结肠癌患者起到明显治疗效果,两者均可作为结肠癌的临床治疗方案.     

Phase I/II trial of capecitabine and oxaliplatin in combination with bevacizumab and imatinib in patients with metastatic colorectal cancer: AIO KRK 0205

Background:

Combined inhibition of platelet-derived growth factor receptor beta signalling and vascular endothelial growth factor promotes vascular normalisation in preclinical models and may lead to increased delivery of chemotherapy to tumour tissue. This phase I/II trial assessed the safety and efficacy of capecitabine plus oxaliplatin (XELOX) plus bevacizumab and imatinib in the first-line treatment of patients with metastatic colorectal cancer.

Methods:

Two dose levels (I/II) were defined: capecitabine 850/1000 mg m⁻² twice daily on days 1–14; oxaliplatin 100/130 mg m⁻² on day 1; bevacizumab 7.5 mg kg⁻¹ on day 1; imatinib 300 mg day⁻¹ on days 1–21 every 21 days. The primary study endpoint was safety. The phase II secondary endpoint was 6-month progression-free survival (PFS).

Results:

Dose level I was chosen for phase II testing because, even though further dose escalation was permitted by the protocol, gastrointestinal toxicities were considered to be clinically significant. A total of 49 patients were evaluated. The 6-month PFS rate was 76%, median PFS was 10.6 months and median overall survival was 23.2 months. Haematological toxicities were generally mild. Sensory neuropathy and diarrhoea were the most common grade 3 toxicities.

Conclusion:

The combination of XELOX with bevacizumab and imatinib is tolerable and has promising efficacy.     

中低位进展期直肠癌患者全直肠系膜切除术前应用同步新辅助放化疗效果分析

目的：分析中低位进展期直肠癌患者全直肠系膜切除术前同步新辅助放化疗应用疗效。方法选取45例中低位进展期直肠癌患者为研究对象,将其随机分为联合组（23例）与对照组（22例）,对照组患者行单纯全直肠系膜切除术,联合组患者在行全直肠系膜切除术前同步新辅助放化疗,比较联合组新辅助放化疗前后肿瘤分期（TNM）情况,两组患者治疗前后肿瘤标志物水平变化情况及术后3个月保肛率、复发率、转移率、术后并发症发生情况。结果新辅助治疗后联合组TNM分期较治疗前降低,差异具有统计学意义（P﹤0.05）;治疗前两组患者癌胚抗原（CEA）、糖链抗原19-9（CA19-9）、糖链抗原242（CA242）水平差异无统计学意义（P﹥0.05）,治疗后均降低（P﹤0.05）,且联合组低于对照组（P﹤0.05）;两组患者术后3个月转移率及并发症发生率差异无统计学意义（P﹥0.05）,联合组保肛率高于对照组,复发率低于对照组（P﹤0.05）。结论采用全直肠系膜切除术前同步新辅助放化疗,可以有效提高中低位进展期直肠癌患者保肛率,降低复发率,改善肿瘤TNM分期,降低CEA、CA19-9、CA242水平,具有良好的应用前景。     

Intermediate neoadjuvant radiotherapy for T3 low/middle rectal cancer: postoperative outcomes of a non-controlled clinical trial

Background

The benefits of adjuvant radiotherapy in rectal carcinoma are well known. However, there is still considerable uncertainty about the optimal radiation treatment. There is an ongoing debate about the choice between very short treatments immediately followed by surgical resection and prolonged treatments with delayed surgery. In this paper, we describe an interim analysis of a non-controlled clinical trial in which radiotherapy delivered with intermediate dose/duration was followed by surgery after about 2 weeks to improve local control and survival after curative radiosurgery for cT3 low/middle rectal cancer.

Methods

Preoperative radiotherapy (36 Gy in 3 weeks) was delivered in 248 consecutive patients with cT3NxM0 rectal adenocarcinoma within 10 cm from the anal verge, followed by surgery within the third week after treatment completion.

Results

166 patients (66.94%) underwent anterior resection, 80 patients (32.26%) the Miles'' procedure and 2 patients (0.8%) the Hartmann''s procedure. Local resectability rate was 99.6%, with 226 curative-intent resections. The overall rate of complications was 27.4%. 5-year oncologic outcomes were evaluated on 223 patients. The median follow-up time was 8.9 years (range 5-17.4 years); local recurrence (LR) rate and distal recurrence (DR) rate after 5 years were 6.28% and 21.97%, respectively. Overall survival was 74.2%; disease free survival was 73.5%; local control was 93.4 % and metastasis-free survival was 82.1%.

Conclusions

preoperative radiotherapy with intermediate dose/duration and interval between radiotherapy and surgery achieves high local control in patients with cT3NxM0 rectal cancer, and high DR rate seems to be the major limitation to improved survival.     

A phase Ib dose-escalation study of erlotinib, capecitabine and oxaliplatin in metastatic colorectal cancer patients.

BACKGROUND: Dysregulation of the epidermal growth factor receptor (HER1/EGFR) has been reported in colorectal cancer (CRC). Erlotinib is a potent inhibitor of HER1/EGFR-mediated signaling. This trial of patients with metastatic CRC (MCRC) examined the safety, maximum tolerated dose (MTD) and pharmacokinetics (PK) of erlotinib in combination with capecitabine and oxaliplatin (XELOX), a regimen with established efficacy. PATIENTS AND METHODS: Patients previously untreated or treated with one line of 5-fluorouracil and/or irinotecan received escalating oral doses of erlotinib (daily), capecitabine (days 1-14) and i.v. oxaliplatin (day 1 of a 21-day cycle). RESULTS: The first six patients in cohort 1 (erlotinib 100 mg/day, capecitabine 825 mg/m(2) twice daily, oxaliplatin 130 mg/m(2)) had no dose-limiting toxicities (DLTs). In cohort 2 (capecitabine increased to 1000 mg/m(2) twice daily), two of six patients had DLTs. When cohort 2 was expanded to 11 patients two further DLTs occurred, exceeding the definition of MTD. Cohort 1 was expanded to 12 patients, and no DLTs occurred. The most common adverse events (AEs) were diarrhea and rash. There was a trend for reduced capecitabine concentrations in the presence of erlotinib. While this was not statistically significant, the possibility of an interaction affecting capecitabine PK cannot be excluded. Antitumor activity was observed in both cohorts (one complete and four partial responses, and stable disease in 11 patients). CONCLUSION: The MTD for this combination in MCRC is capecitabine 825 mg/m(2) twice daily days 1-14, oxaliplatin 130 mg/m(2) day 1 and erlotinib 100 mg/day of a 21-day cycle. The combination was well tolerated at the MTD, with no unexpected AEs. The use of this combination in MCRC warrants further investigation.     

伊立替康和奥沙利铂联合氟尿嘧啶类药物一线治疗晚期结直肠癌的临床观察

目的 观察伊立替康(IRI)和奥沙利铂(OXA)联合氟尿嘧啶类药物(5-FU/替吉奥胶囊/卡培他滨)一线治疗晚期结直肠癌的疗效和不良反应.方法 选取有可测量指标的晚期结直肠癌患者35例,第1天应用IRI 130~l60 mg/m2静脉滴注,同时予亚叶酸钙(CF)200 mg/m2静脉滴注后5-FU 400 mg/m2静脉推注,之后5-FU 2400 mg/m2持续泵注44 h;或替吉奥胶囊每次40~60 mg(根据体表面积确定),卡培他滨每次1000 mg/m2,早晚饭后各1次,连续服用10 d,停药4 d;第2天奥沙利铂85~100 mg/m2静脉滴注;14 d为1个周期.每3个周期评价疗效及相关毒性反应.结果 全组35例可评价疗效,中位化疗为4个周期(3~11).客观有效率(ORR)为54.3%(19/35),其中完全缓解(CR)1例,部分缓解(PR)18例.化疗后接受手术的25例患者中,20例患者达到R0切除(57.1%),其中18例患者系初始局部晚期,2例患者初始伴肝转移.所有35例患者在治疗期间,未出现治疗相关性死亡,3级不良反应发生率为54.3%(19/35),其中粒细胞下降发生率为20.0%(7/35),恶心发生率为17.1%(6/35),呕吐发生率为14.3%(5/35),腹泻发生率40.0%(14/35).4级不良反应主要为粒细胞下降发生率,发生率为17.1%(6/35).结论 三药联合方案一线治疗晚期结直肠癌近期疗效高,毒性反应可以耐受.     

多西他赛联合奥沙利铂治疗晚期胃癌的临床观察

目的:观察多西他赛、奥沙利铂联合方案治疗晚期胃癌的疗效和安全性。方法:经病理证实的晚期胃癌患者26例,采用多西他赛联合奥沙利铂,治疗2-4个周期。按照RECIST标准和WHO毒性反应分级标准,分别评价疗效和毒性。结果:26例晚期胃癌患者中,获得CR 0例,PR 8例,SD 12例,PD 6例,总有效率30.8%,疾病控制率76.9%;中位TTP 6.3个月,中位总生存10.7个月,毒性反应主要为血液学毒性、消化道反应和神经毒性等。结论:多西他赛、奥沙利铂联合方案治疗晚期胃癌的客观疗效高,安全性好。