Salvage chemotherapy for metastatic breast cancer: results of a phase II study with bendamustine.

BACKGROUND: Bendamustine, a bifunctional alkylating agent with anticipated purin-like properties is active in metastatic breast cancer (MBC) patients. This multicenter phase II trial defines the toxicity and activity of bendamustine in heavily pretreated patients. PATIENTS AND METHODS: Fifty-one patients were included. Patients had a median number of 2 prior chemotherapeutic regimens for MBC (range 0-7) consisting of anthracyclines and taxanes: 26 patients (51%); anthracyclines: nine patients (17.6%); taxanes: seven patients (13.7%); others: five patients (9.8%). Bendamustine was administered four weekly at a dose of 120 mg/m(2) on days 1 and 2. RESULTS: Fifty patients were assessable. Of total, 200 courses were administered. We observed no complete response (CR); 10 patients [20%; 95% confidence interval (CI): 10.0% to 33.7%] achieved a partial response (PR), 14 patients (28%) remained stable for at least 6 months resulting in a clinical benefit rate (CR + PR + stable disease) of 48% (95% CI: 33.7%to 52.6%). Median time to progression was 3.4 months (range 1-51.1). The median duration of remission was 6.6 months (range 1.8-48.7). The treatment was well tolerated with mainly hematologic toxic effects. CONCLUSION: Single-agent bendamustine is an active treatment in patients with MBC independent of the previous treatment. The low toxicity profile favors its use as a single agent.     

Bevacizumab combined with chemotherapy in the second-line treatment of metastatic colorectal cancer: results from the phase II BEVACOLOR study

BackgroundThis prospective phase II study assessed the efficacy and safety of bevacizumab plus chemotherapy regimens commonly used in the second-line treatment of metastatic colorectal cancer (mCRC).MethodsPatients with mCRC who progressed or relapsed after first-line oxaliplatin-based or irinotecan-based treatment received bevacizumab 2.5 mg/kg/week plus chemotherapy until disease progression. The primary endpoint was disease-control rate (DCR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and safety.ResultsFifty-three patients (66% men; median age, 62 years old) received second-line bevacizumab plus folinic acid, fluorouracil, and irinotecan (FOLFIRI; 57%), folinic acid, fluorouracil, oxaliplatin (FOLFOX; 26%), irinotecan (15%), or capecitabine plus irinotecan (XELIRI; 2%). The DCR was 87% (95% CI, 77%-97%); ORR was 32% (95% CI, 19%-46%). Median PFS was 6.5 months (95% CI, 5.8-7.8 months) and median OS 19.3 months, (95% CI, 14.2-25.1 months).The most frequent grade 3/4 adverse events included neutropenia (21%), diarrhea (15%), asthenia, and vomiting (9% each). Five patients (9%) had grade 3/4 targeted toxicities: grade 3 hypertension (n = 2), grade 3 venous thromboembolism (n = 2), and grade 4 arterial thromboembolism (n = 1). None of these events led to death during the study.ConclusionBevacizumab plus standard second-line chemotherapy is highly active in patients with mCRC and has an acceptable safety profile.     

Sequential intrahepatic and systemic fluoropyrimidine-based chemotherapy for metastatic colorectal cancer confined to the liver. A phase II study

PURPOSE: Several trials have suggested that intrahepatic chemotherapy increases the likelihood of response in advanced colon cancer patients, but has no significant impact on survival due to the development of extrahepatic metastases. We report our experience of combined hepatic intraarterial and systemic chemotherapy in advanced colorectal cancer patients. METHODS: A group of 35 patients received intrahepatic FUDR (0.3 mg/kg per day for 14 days by continuous infusion), followed, after 1 week's rest, by systemic 5-FU and L-leucovorin (370 and 100 mg/m2 per day, respectively, both for 5 consecutive days). After another week off therapy, the combined intrahepatic and systemic regimen was repeated and cycles continued until disease progression. RESULTS: Of 32 assessable patients, 17 (53.1%) had an objective response, while 8 (25%) had disease stabilization. Median time to progression (TTP) was 32 weeks (range 8-104 weeks), while the median overall survival was only 39 weeks (range 9-109 weeks). Incomplete liver perfusion was the only variable that showed a significant correlation with a poorer survival (P = 0.046, log-rank test). CONCLUSIONS: Our results are in agreement with previous data suggesting a relative efficacy of such a treatment approach for advanced colon cancer patients. More thorough investigations are warranted, especially as an adjuvant treatment for selected high-risk patients.     

吉非替尼联合XELOX方案化疗治疗转移性大肠癌的临床观察

目的:回顾性分析吉非替尼(Gefitnib,ZD1839,Iressa,易瑞沙)联合XELOX方案治疗转移性结直肠癌的临床疗效和毒副反应。方法:30例晚期转移性结直肠癌患者均经病理组织学以及影像学证实。吉非替尼给药剂量和方法为250mg,每日1次。联合化疗方案为XELOX方案(奥沙利铂+卡培他滨)。按照RECIST标准评价近期疗效,毒性反应按照WHO抗癌药物急性和亚急性毒性表现和分级标准评价。结果:30例患者部分缓解(PR)为36.7%(11/30),稳定(SD)为40.0%(12/30),疾病进展(PD)为23.3%(7/30)。临床有效率(PR+SD)为76.7%。主要毒性反应为白细胞下降(43.3%),恶心呕吐(40.0%)以及皮疹(53.3%)。结论:初步观察表明,吉非替尼联合化疗治疗转移性结直肠癌具有较好的疗效,毒副反应低,耐受性好,值得进一步研究。     

Multicentre phase II study of leucovorin plus pharmacokinetic modulating chemotherapy for metastatic colorectal cancer

The optimal administration of 5-fluorouracil (5-FU)/leucovorin (LV) for colorectal cancer (CRC) has yet to be fully defined although evidence of the combination has already been established. In a multicentre phase II study, pharmacokinetic modulating chemotherapy (PMC), which is based on the concept that continuous intravenous 5-FU infusion can be enhanced by low-dose oral uracil/tegafur, was combined with LV and administered. Thirty-seven patients were enrolled. The objective response rate was 31.4% and the tumour stabilization rate was 85.7%. The most common toxic effects were neutropenia and hand-foot skin reactions although no life-threatening grade 3-4 toxicities were noted. Grade 3 toxicities such as neutropenia, nausea, diarrhoea and oesophagitis occurred in one patient each. We identified the usefulness of a new type of infusional 5-FU combined with LV for the treatment of CRC. The combination of PMC and LV is active with an acceptable rate of toxicity as a first-line treatment of advanced CRC.     

Hepatic arterial infusion using pirarubicin combined with systemic chemotherapy: a phase II study in patients with nonresectable liver metastases from colorectal cancer.

BACKGROUND: A prospective phase II study was performed to determine the feasibility, efficacy and safety of arterial hepatic infusion (HAI) using pirarubicin combined with intravenous chemotherapy. PATIENTS AND METHODS: From December 1991 to April 1994, 75 patients with unresectable colorectal metastases confined to the liver were included in this multicenter study to receive intra-arterial hepatic pirarubicin and a systemic monthly regimen of 5-fluorouracil (5-FU) and folinic acid. Sixty-four patients were analyzed in the intention-to-treat analysis and 61 in the per-protocol analysis. RESULTS: Tolerance of this regimen was rather good; however, functional catheter problems were observed in 29 patients (45%) resulting in failure of HAI in 21 cases (33%) after a median of three cycles; vomiting grade 3 was present in 12.5% of patients, neutropenia grade 4 in 23% and alopecia grade 3 in 19%. The overall response rate was 31.9% in intention-to-treat analysis, and 39.3% in per-protocol analysis. Extrahepatic progression was reported in only 21.7% of patients. Time to hepatic progression and extra-hepatic progression was 8.3 and 15 months, respectively, in intention-to-treat analysis, and 11 and 18 months, respectively, in per-protocol analysis. Median survival was 19 and 20 months in intention-to-treat analysis and per-protocol, respectively. CONCLUSIONS: In our study, the combination of intra-arterial pirarubicin and intravenous chemotherapy demonstrated some efficacy and good tolerance in the treatment of isolated colorectal liver metastases. This treatment seems to prevent extra-hepatic spread and prolong survival time. The results of this study have to be confirmed by new trials using more active systemic chemotherapy.     

Whole-body hyperthermia in the scope of von Ardenne's systemic cancer multistep therapy (sCMT) combined with chemotherapy in patients with metastatic colorectal cancer: a phase I/II study.

This phase I/II study evaluated the feasibility, toxicity and response rates of von Ardenne's systemic cancer multistep therapy (sCMT) when applied as an adjunct to cytostatic therapy in patients with metastatic colorectal cancer. sCMT consists of whole-body hyperthermia (WBH) at 41.8-42.1 degrees C, hyperglycaemia and hyperoxaemia. All patients who entered the trial first received three monthly courses of chemotherapy (folinic acid, 50 mg, days 1-5; 5-fluorouracil, 425 mg/m2, days 1-5; mitomycin 8 mg/m2, day 1), followed by response evaluation according World Health Organization (WHO) criteria. Responders (partial/complete remission) were assigned to three further courses of chemotherapy, whereas non-responders (stable/progressive disease) were allocated to additional sCMT on day 1 of every subsequent chemotherapy course. The WBH procedure was administered under general anaesthesia employing the Iratherm-2000 radiant heat device. Of 28 patients enrolled, 19 received more than three treatment courses. Eight of these 19 patients had responded to chemotherapy (PR) and thus obtained three further courses of chemotherapy alone. In 10 of 19 patients who had not responded (SD, PD), three additional courses of chemotherapy were combined with sCMT (with 25 sCMT applications). One patient who did not respond to initial treatment declined sCMT and was continued with chemotherapy alone. It was found that sCMT was feasible, but associated with a specific spectrum of grade III/IV toxicity (skin 20%, pain 16%, peripheral nerves 8% of treatment courses). The fact that three patients who did not respond to initial chemotherapy achieved a PR after additional sCMT suggests that sCMT may enhance the effect of chemotherapy in patients with colorectal cancer.     

Whole-body hyperthermia in the scope of von Ardenne's systemic cancer multistep therapy (sCMT) combined with chemotherapy in patients with metastatic colorectal cancer: a phase I/II study

This phase I/II study evaluated the feasibility, toxicity and response rates of von Ardenne's systemic cancer multistep therapy (sCMT) when applied as an adjunct to cytostatic therapy in patients with metastatic colorectal cancer. sCMT consists of whole-body hyperthermia (WBH) at 41.8–42.1°C, hyperglycaemia and hyperoxaemia. All patients who entered the trial first received three monthly courses of chemotherapy (folinic acid, 50?mg, days 1–5; 5-fluorouracil, 425?mg/m2, days 1–5; mitomycin 8?mg/m2, day 1), followed by response evaluation according World Health Organization (WHO) criteria. Responders (partial/complete remission) were assigned to three further courses of chemotherapy, whereas non-responders (stable/progressive disease) were allocated to additional sCMT on day 1 of every subsequent chemotherapy course. The WBH procedure was administered under general anaesthesia employing the Iratherm-2000 radiant heat device. Of 28 patients enrolled, 19 received more than three treatment courses. Eight of these 19 patients had responded to chemotherapy (PR) and thus obtained three further courses of chemotherapy alone. In 10 of 19 patients who had not responded (SD, PD), three additional courses of chemotherapy were combined with sCMT (with 25?sCMT applications). One patient who did not respond to initial treatment declined sCMT and was continued with chemotherapy alone. It was found that sCMT was feasible, but associated with a specific spectrum of grade III/IV toxicity (skin 20%, pain 16%, peripheral nerves 8% of treatment courses). The fact that three patients who did not respond to initial chemotherapy achieved a PR after additional sCMT suggests that sCMT may enhance the effect of chemotherapy in patients with colorectal cancer.     

重组人血管内皮抑制素联合化疗治疗转移性结直肠癌的临床观察

目的 观察重组人血管内皮抑制素（恩度）与化疗联合治疗晚期结直肠癌的有效性和安全性。方法 自2006年8月至2009年5 月,5 例初治转移性结直肠癌患者和18 例复治转移性结直肠癌患者接受恩度联合细胞毒药物治疗。恩度15mg/d,加人生理盐水500ml 静脉滴注,连用14 天。同时8 例患者采用FOLFIRI 方案化疗,2 例患者采用CAPIRI 方案化疗,9 例患者采用GLF 方案化疗,4 例患者采用FOLFOX4 或XELOX 方案化疗。分别按照RECIST 1.0 和NCI-CTC 3.0 评价疗效和毒性。结果23 例可评价毒性,21 例可评价疗效。在4 例初治患者中,2 例SD, 2 例PD。在17 例复治患者中,8 例SD, 9 例PD,疾病控制率（DCR）为47.1％。全组中位肿瘤进展时间（mTTP）为5 个月（95 % CI: 2.2～7.8 个月）,中位总生存时间(mOS）为12 个月（95% CI: 10.5～13.5 个月）。复治患者的mTTP 和mOS 分别为4 个月（95% CI: 1.7～6.3 个月）和11.5 个月(95 %CI: 8.5～14.5 个月）。主要不良反应为血液学毒性、恶心呕吐,考虑主要与化疗相关。轻度心血管系统毒性考虑与恩度相关。结论恩度联合细胞毒药物治疗转移性结直肠癌安全性好,恩度未增加化疗药物的毒性。对复治患者有延长疾病控制时间的趋势,值得进一步研究。     

First-line treatment with irinotecan and raltitrexed in metastatic colorectal cancer. Mature results of a multicenter phase II study

OBJECTIVES: The combination of irinotecan and raltitrexed is safe and active in 5-fluorouracil-refractory, metastatic colorectal cancer (CRC), with the advantage of its convenient three-weekly schedule. The aim of this multicenter phase II study was to assess its efficacy and toxicity in first-line treatment. METHODS: Between May 2000 and March 2001, 62 previously untreated patients received irinotecan (350 mg/m(2)) plus raltitrexed (3 mg/m(2)), with courses repeated every 21 days. Objective response was assessed every three courses, and treatment maintained until tumor progression or unacceptable toxicity. RESULTS: A total of 331 cycles were administered, with a median of five cycles per patient (range, 1-16). Seventeen patients achieved a partial response and 2 a complete response, for an overall intention-to-treat response rate of 30% (95% confidence interval, 18-44%). The incidence of grade 3-4 toxicity per patient was diarrhea (27%), emesis (13%), anemia (12%), neutropenia (9%), and asthenia (7%). Three patients (5%) died from treatment-related adverse events (diarrhea plus neutropenia). The median potential follow-up is now 37 months. Median survival was 12.2 months, and median time to progression was 6.3 months. CONCLUSIONS: The combination of irinotecan plus raltitrexed is an easy comfortable schedule for patients with metastatic CRC, but both efficacy and toxicity results seem suboptimal for first-line treatment.     

Efficacy of chemotherapy combined with bevacizumab for metastatic colorectal cancer

Bevacizumab (BV) is widely used for patients with metastatic colorectal cancer. We investigated the efficacy and safety of chemotherapy combined with BV for metastatic colorectal cancer. From July 2007 to October 2008, 59 patients were treated by chemotherapy with BV in our hospital. Of the 47 patients who received BV in first-line therapy, 3 cases (6%) with complete response (CR), 25 cases(53%) with partial response (PR), and 17 cases (36%) with stable disease (SD) were observed. The overall response rate and tumor control rate were 60% and 96%, respectively. The median progression-free survival (PFS) was 11. 9 months, and median overall survival (OS) was 23. 6 months. There were 12 patients treated first with BV in second-line therapy. Of the 12 patients, 1 case (8%) with CR, 3 cases (25%) with PR, and 4 (33%) with SD were observed. The overall response rate and tumor control rate were 33% and 67%, respectively. The median PFS was 6.0 months and median OS was not reached. With regard to the grade 3 to 4 adverse events by NCI-CTCAE ver3.0, neutropenia was observed in more than half of the patients (56%), but a few of patients had gastrointestinal toxicities, peripheral neuropathy and infections in non-hematologic toxicities. BV-associated adverse events were hypertension, proteinuria, venous thrombosis, wound healing complication, gastrointestinal perforation and bleeding, each of which were few and not serious. Six of the patients experienced PD after first-line therapy treated with BV continuously in second-line therapy. Four of six were surviving without disease progression at the last follow-up, which suggests the effectiveness of continuation of BV. Our study showed the efficacy and safety of BV for metastatic colorectal cancer.     

Capecitabine and irinotecan as first-line chemotherapy in patients with metastatic colorectal cancer: results of an extended phase I study.

BACKGROUND: To define the maximum-tolerated dose (MTD) and to evaluate the dose-limiting toxicities (DLTs) of the combination of capecitabine and irinotecan in patients with metastatic colorectal cancer. PATIENTS AND METHODS: Thirty-seven patients with measurable metastatic colorectal cancer with no prior chemotherapy for metastatic disease were treated at three dose levels (DLs). For the first two dose levels, irinotecan (70 mg/m(2)) was administered once a week for 6 weeks in combination with 2 weeks of capecitabine at 1000 mg/m(2) (DL1) or 1250 mg/m(2) (DL2) twice daily, starting on days 1 and 22. In the last dose escalation step, the dose of irinotecan was increased to 80 mg/m(2) (DL3). One cycle lasted 7 weeks. RESULTS: In the subsequent phase I trial, 96 cycles of capecitabine and irinotecan were administered. At DL3, three out of six patients experienced DLTs (diarrhea, neutropenia, asthenia). In order to confirm the safety of the recommended dose, DL2 was extended to 15 patients. Five patients (33%) showed DLTs at this dose level, which was considered too high to embark on further clinical studies. Subsequently, the starting dose (DL1) was extended to a total of 16 patients, with diarrhea being the main toxicity. The overall response rate was 38% [95% confidence interval (CI) 21% to 58%], with a median response duration of 8.7 months (95% CI 6.4-11.5 months). CONCLUSIONS: The recommended doses for further studies are irinotecan 70 mg/m(2) and capecitabine 1000 mg/m(2). The combination of capecitabine and irinotecan appears to have significant therapeutic efficacy with manageable toxicity.     

Short-course preoperative radiotherapy combined with chemotherapy,delayed surgery and local hyperthermia for rectal cancer: a phase II study

Purpose: The aim of this study was to investigate the feasibility of short-course radiotherapy with oral capecitabine, hyperthermia and delayed surgery for neoadjuvant treatment of rectal cancer.

Methods: Patients with clinically staged T2-3N0-2M0 primary rectal cancer were included. All patients received short-course 25?Gy in 5?Gy fractions radiotherapy with capecitabine, local hyperthermia and metronidazole. Capecitabine 1000?mg/m² twice a day was given on days 1–14. Local hyperthermia, 41–45?°C for 60?min, was performed on days 3–5. Metronidazole 10?g/m² was administered per rectum on days 3 and 5. The time interval to surgery was not less than four weeks after neoadjuvant treatment. The primary end-point was pathological complete response (pCR). Secondary end-points included neoadjuvant treatment toxicity, tumour regression, surgical and oncological outcomes.

Results: A total of 81 patients were included in the analysis. Ten (12.3%) patients had grade 3 toxicity and one (1.2%) patient had grade 4 toxicity. Sphincter-sparing surgery was performed for 78 (96.3%) patients. There was no postoperative mortality. Postoperative complications occurred in 11 (13.8%) patients. Sixteen (20%) patients had a pCR. The median follow-up was 40.9 months. There were no local recurrences. Nine (11.1%) patients developed distant metastases. Three-year overall survival was 97% and the three-year disease-free survival was 85%.

Conclusions: Short-course radiotherapy with chemotherapy, radiosensitizers and delayed surgery is a feasible treatment for rectal cancer and may lead to tumour regression rate comparable with long-course chemoradiation.     

A phase II study of radiofrequency ablation of unresectable metastatic colorectal cancer with hepatic arterial infusion pump chemotherapy

BACKGROUND: Adjuvant hepatic arterial infusion (HAI) chemotherapy has been demonstrated to improve disease-free survival for colorectal cancer liver metastases. It is unclear if this improvement can be extrapolated to unresectable liver metastases that undergo RFA. The aim of this study was to evaluate the combination of RFA and HAI chemotherapy for unresectable liver metastases. METHODS: Phase II study was conducted from November 2000 to July 2003 evaluating the use of complete extirpation by RFA, or resection/ablation with adjuvant HAI consisting of FUDR for 6 months. RESULTS: Twenty-one patients had successful resection and/or RFA with HAI pump, which included treatment for 100 liver metastases (22 resected, 78 ablated; mean 4.8 tumors/patient). Four of 21 patients completed the full 6-month course of HAI. Six of these patients had 12 adverse events related to HAIP, most commonly elevated liver enzymes. After a median follow-up of 24 months, the median liver specific disease-free and overall survival rates for the entire group were 17 and 30 months, respectively. CONCLUSIONS: Given the complications and toxicity associated with HAI pump chemotherapy, adjuvant HAI chemotherapy after RFA of liver metastases may not be warranted as a first line treatment option.     

Irinotecan combined with docetaxel in pre-treated metastatic breast cancer patients: a phase II study

Purpose: This is a phase II study where a novel chemotherapy combination was tested in pre-treated breast cancer patients: docetaxel and irinotecan have already been established as agents for breast and colorectal cancer, respectively. Methods: Forty-eight (median age 54 years, range 26–77 year) patients, all evaluable, were enrolled. All patients had been pre-treated with anthracycline-combined chemotherapy, 30 of whom were also treated with paclitaxel and 2 with docetaxel. World Health Organization (WHO) performance status was 0–2. The dominant metastasis was in the liver (54.17%), in the lungs (27.08%), in soft tissues (12.50%) and in the skeleton (6.25%). Treatment involved irinotecan infusion 200 mg/m² for 90 min and docetaxel infusion 80 mg/m² for 90 min, repeated once every 3 weeks. Results: Twenty-five (52.08%, 95% confidence interval [CI] 37.95–66.21) patients showed responses: 3 complete (6.25%, 95% CI 0–13.05) and 22 (45.83%, 95% CI 31.74–59.92) partial; the most responsive metastases were observed at the liver site (53.85%). Grade 3 and 4 neutropenia was observed in 18 patients (37.50%); 14 (29.17%) patients developed anaemia and three (6.25%), thrombocytopenia. Concerning non-haematologic toxicity, alopecia and fatigue were common; grade 3 diarrhea was observed in only one (2.08%) patient. Conclusion: The irinotecan-docetaxel combination produces quite a high response rate in pre-treated advanced breast cancer patients.     

Cediranib in combination with mFOLFOX6 in Japanese patients with metastatic colorectal cancer: results from the randomised phase II part of a phase I/II study

BackgroundColorectal cancer (CRC) is the second most common malignancy in Japan. Treatment with inhibitors of the vascular endothelial growth factor (VEGF) signalling pathway has proven benefit in metastatic CRC. Cediranib is an oral highly potent VEGF signalling inhibitor that inhibits all three VEGF receptors.Patients and methodsIn this phase II, double-blind, placebo-controlled study, 172 patients with metastatic CRC were randomised to receive once-daily cediranib (20 or 30 mg) or placebo, each combined with modified FOLFOX6 (mFOLFOX6). The primary objective was comparison of progression-free survival (PFS).ResultsThe comparison of cediranib 20 mg versus placebo met the primary objective of PFS prolongation [hazard ratio = 0.70 (95% confidence interval 0.44–1.11), P = 0.167], which met the protocol-defined criterion of P < 0.2. Median PFS was 10.2 versus 8.3 months, respectively. The PFS comparison for cediranib 30 mg versus placebo did not meet the criterion. The most common adverse events (AEs) in the cediranib-containing groups were diarrhoea and hypertension.ConclusionsCediranib 20 mg plus mFOLFOX6 met the predefined criteria in terms of improved PFS compared with placebo plus mFOLFOX6. Cediranib 20 mg was generally well tolerated and the AE profile was consistent with previous studies.     

A phase II pharmacodynamic study of pyrazoloacridine in patients with metastatic colorectal cancer

Purpose: To perform a phase II trial of pyrazoloacridine (PZA), a novel DNA intercalator, in patients with metastatic colorectal carcinoma and no previous therapy. Methods: PZA was administered at a dose of 750 mg/m² intravenously over 3 h every 21 days. Pharmacokinetic studies to determine PZA plasma concentrations were performed. Results: No responses were seen in 14 response-evaluable patients. Patients received a median of two cycles of PZA (range 1–6). Toxicity included neutropenia and neurologic side-effects, which were ≥ grade III in 73% and 14%, respectively. High plasma concentrations of PZA (C_max) correlated with low neutrophil counts (P=0.04). Conclusions: PZA is inactive at this dose and schedule in colorectal cancer, and produces moderately severe toxicity. Received: 18 October 1999 / Accepted: 16 March 2000