Chemoradiotherapy with capecitabine versus fluorouracil for locally advanced rectal cancer: a randomised, multicentre, non-inferiority, phase 3 trial.

BACKGROUND: Fluorouracil-based chemoradiotherapy is regarded as a standard perioperative treatment in locally advanced rectal cancer. We investigated the efficacy and safety of substituting fluorouracil with the oral prodrug capecitabine. METHODS: This randomised, open-label, multicentre, non-inferiority, phase 3 trial began in March, 2002, as an adjuvant trial comparing capecitabine-based chemoradiotherapy with fluorouracil-based chemoradiotherapy, in patients aged 18 years or older with pathological stage II-III locally advanced rectal cancer from 35 German institutions. Patients in the capecitabine group were scheduled to receive two cycles of capecitabine (2500 mg/m(2) days 1-14, repeated day 22), followed by chemoradiotherapy (50·4 Gy plus capecitabine 1650 mg/m(2) days 1-38), then three cycles of capecitabine. Patients in the fluorouracil group received two cycles of bolus fluorouracil (500 mg/m(2) days 1-5, repeated day 29), followed by chemoradiotherapy (50·4 Gy plus infusional fluorouracil 225 mg/m(2) daily), then two cycles of bolus fluorouracil. The protocol was amended in March, 2005, to allow a neoadjuvant cohort in which patients in the capecitabine group received chemoradiotherapy (50·4 Gy plus capecitabine 1650 mg/m(2) daily) followed by radical surgery and five cycles of capecitabine (2500 mg/m(2) per day for 14 days) and patients in the fluorouracil group received chemoradiotherapy (50·4 Gy plus infusional fluorouracil 1000 mg/m(2) days 1-5 and 29-33) followed by radical surgery and four cycles of bolus fluorouracil (500 mg/m(2) for 5 days). Patients were randomly assigned to treatment group in a 1:1 ratio using permuted blocks, with stratification by centre and tumour stage. The primary endpoint was overall survival; analyses were done based on all patients with post-randomisation data. Non-inferiority of capecitabine in terms of 5-year overall survival was tested with a 12·5% margin. This trial is registered with ClinicalTrials.gov, number NCT01500993. FINDINGS: Between March, 2002, and December, 2007, 401 patients were randomly allocated; 392 patients were evaluable (197 in the capecitabine group, 195 in the fluorouracil group), with a median follow-up of 52 months (IQR 41-72). 5-year overall survival in the capecitabine group was non-inferior to that in the fluorouracil group (76% [95% CI 67-82] vs 67% [58-74]; p=0·0004; post-hoc test for superiority p=0·05). 3-year disease-free survival was 75% (95% CI 68-81) in the capecitabine group and 67% (59-73) in the fluorouracil group (p=0·07). Similar numbers of patients had local recurrences in each group (12 [6%] in the capecitabine group vs 14 [7%] in the fluorouracil group, p=0·67), but fewer patients developed distant metastases in the capecitabine group (37 [19%] vs 54 [28%]; p=0·04). Diarrhoea was the most common adverse event in both groups (any grade: 104 [53%] patients in the capecitabine group vs 85 [44%] in the fluorouracil group; grade 3-4: 17 [9%] vs four [2%]). Patients in the capecitabine group had more hand-foot skin reactions (62 [31%] any grade, four [2%] grade 3-4 vs three [2%] any grade, no grade 3-4), fatigue (55 [28%] any grade, no grade 3-4 vs 29 [15%], two [1%] grade 3-4), and proctitis (31 [16%] any grade, one [<1%] grade 3-4 vs ten [5%], one [<1%] grade 3-4) than did those in the fluorouracil group, whereas leucopenia was more frequent with fluorouracil than with capecitabine (68 [35%] any grade, 16 [8%] grade 3-4 vs 50 [25%] any grade, three [2%] grade 3-4). INTERPRETATION: Capecitabine could replace fluorouracil in adjuvant or neoadjuvant chemoradiotherapy regimens for patients with locally advanced rectal cancer. FUNDING: Roche Pharma AG (Grenzach-Wyhlen, Germany).

High single-drug activity of nelarabine in relapsed T-lymphoblastic leukemia/lymphoma offers curative option with subsequent stem cell transplantation.

Nelarabine, a purine analog with T-cell specific action, has been approved for relapsed/refractory T-cell acute lymphoblastic leukemia/lymphoma (ALL/LBL). This is a report of a single-arm phase 2 study conducted in adults (18-81 years of age) with relapsed/refractory T-ALL/LBL. After 1 or 2 cycles, 45 of 126 evaluable patients (36%) achieved complete remission (CR), 12 partial remission (10%), and 66 (52%) were refractory. One treatment-related death was observed, and 2 patients were withdrawn before evaluation. A total of 80% of the CR patients were transferred to stem cell transplantation (SCT). Overall survival was 24% at 1 year (11% at 6 years). After subsequent SCT in CR, survival was 31% and relapse-free survival 37% at 3 years. Transplantation-related mortality was 11%. Neurologic toxicities of grade I-IV/grade III-IV were observed in 13%/4% of the cycles and 16%/7% of the patients. This largest study so far with nelarabine in adults showed impressive single-drug activity in relapsed T-ALL/T-LBL. The drug was well tolerated, even in heavily pretreated patients. A high proportion of CR patients were transferred to SCT with low mortality but a high relapse rate. Exploration of nelarabine in earlier stages of relapse (eg, increasing minimal residual disease), in front-line therapy, and in combination is warranted.

Device for the local radiation of tumor-bearing laboratory rodents.

Since no standard method for reproducibly irradiating local tumors of laboratory rodents exists, the authors designed a device to accurately irradiate rodent tumors. Laboratory personnel can easily assemble this inexpensive device. The new device delivers highly focused treatment and avoids the need for anesthesia and sedation. It represents an improvement over former improvised procedures done at the authors' institutions, because it allows for more accurate irradiation of rodent tumors. The authors used the device to irradiate single tumors on the left hind legs of 60 mice and 10 rats with a dosage of 7 gray (Gy) ionizing radiation. At time of irradiation, the clinical condition of the animals was very poor, but all animals survived the treatment.

Severe reversible toxic encephalopathy induced by cisplatin in a patient with cervical carcinoma receiving combined radiochemotherapy.

CASE REPORT: A 45-year-old patient with cervix carcinoma received combined radiochemotherapy including cisplatin. After a cumulative dose of 240 mg/m(2) the patient suddenly became somnolent and developed a severe tetraparesis and generalized seizures. After ruling out intracranial bleeding, cerebral metastases as well as infectious and metabolic causes of this condition, a severe toxic encephalopathy was diagnosed based on the clinical findings and MRI scans. After symptomatic treatment on the intensive care unit all symptoms were completely reversible. CONCLUSION: Toxic encephalopathy is a rare but dramatic complication of various cytostatic drugs. With the widespread use of cisplatin this rare disorder should be kept in mind.

Methotrexate-albumin and aminopterin-albumin effectively prevent experimental acute graft-versus-host disease.

BACKGROUND: During the last several years, major progress has been made in developing targeted chemotherapy using cytotoxic drugs covalently bound to human serum albumin (HSA). We explored the activity of two antifolates methotrexate (MTX) and aminopterin (AMPT) bound to HSA in prophylaxis and treatment of experimental acute graft-versus-host disease (aGVHD). METHODS: In all, 113 female F1 hybrid BN/Lew-rats were irradiated with 8.2 Gy (n=103) or 9.9 Gy (n=10). One day after irradiation each rat received 4 x 10 bone marrow cells and 1.5 x 10 spleen T-cells from female Lew-rats. GVHD prophylaxis consisted of MTX-HSA 2 mg/kg (n=25), MTX-HSA 0.5 mg/kg (n=8), AMPT-HSA 0.65 mg/kg (n=8), MTX 0.5 mg/kg (n=17), or native HSA (n=39) given intraperitoneally (IP) on days 0, 4, 8, and 12. Treatment of aGVHD consisted of MTX-HSA 2 mg/kg (n=8) or AMPT-HSA 0.5 mg/kg (n=8) given intraperitoneally at the time of onset of aGVHD and subsequently every fourth day (a total of four doses). RESULTS: All animals receiving native HSA developed lethal aGVHD. Prophylactic treatment with MTX-HSA 2 mg/kg prevented aGVHD in 18 of 25 animals and in 6 of 8 receiving AMPT-HSA. In contrast, five out of nine rats receiving free MTX died due to aGVHD. The survival rates in the prophylactic MTX-HSA 2 mg/kg and AMPT-HSA groups were significantly higher compared to the MTX and control groups (P<0.05), while non hematologic toxicity of MTX-HSA was not detectable. AMPT-HSA at a dose of 0.65 mg/kg as well as MTX at a dose of 0.5 mg/kg were associated with temporary weight loss and lethargy. CONCLUSIONS: The albumin conjugates MTX-HSA and AMPT-HSA effectively prevent experimental aGVHD.

Postoperative chemotherapy may not be necessary for patients with ypN0-category after neoadjuvant chemoradiotherapy of rectal cancer.

PURPOSE: After neoadjuvant radiochemotherapy and surgery, there is no general agreement about whether postoperative chemotherapy is necessary. With the help of clinical and pathohistologic data, prognostic factors were determined as a basis for the decision to spare a patient additional chemotherapy or to urgently recommend it. RESULTS: Ninety-five patients treated with neoadjuvant 5-fluorouracil-based radiochemotherapy (November 4, 1997 and June 15, 2004) without distant metastases and an R0 (microscopically complete) resection were evaluated. Adjuvant chemotherapy (5-fluorouracil or 5-fluorouracil/folinic acid) was given to 65 of 95 patients (68.4 percent). The disease-free survival rate after 36 months was chosen as the target parameter (median follow-up, 36 months). METHODS: The five-year survival rate for all patients was 80.3 +/- 5.6 percent; the five-year disease-free survival was 78.1 +/- 5.1 percent; the five-year local control rate was 94.2 +/- 5.1 percent. In the univariate and multivariate analysis of the disease-free survival, the pathohistologic lymph node status after radiochemotherapy (ypN) was the only significant prognostic parameter. Disease-free survival (36 months) for patients without lymph node metastases (ypN0) was excellent, independent of whether they had received postoperative chemotherapy (n = 43; 87.5 +/- 6.0 percent) or not (n = 29; 87.7 +/- 6.7 percent). Patients with ypN2 status have, despite chemotherapy, a poor disease-free survival at 30 +/- 17.6 percent after 36 months. CONCLUSIONS: These retrospective data suggest that, for some patients, postoperative chemotherapy can be spared. For patients with ypN2 status, an intensification of the postoperative chemotherapy should be considered. Further evaluation in prospective studies is urgently recommended.

Accidental intrathecal administration of bleomycin: favorable outcome after pneumo-encephalus and cerebrospinal fluid exchange: a case report.

Bleomycin is generally used as an antineoplastic drug for the intravenous treatment of germ cell tumors or lymphomas. Due to its toxic effect on epithelial cells bleomycin is also used for the treatment of malignant pleural or pericardial effusions. Inadvertent intrathecal administration of cytotoxic drugs may occur due to increasingly complex therapeutic protocols, even when control mechanisms are applied. We report the case of a 39-year-old man with chronic myeloid leukemia. During the treatment of a lymphoblast crisis 30 mg of bleomycin were inadvertently injected intrathecally. Prompt cerebrospinal fluid exchange, dilution with normal saline, and corticosteroid treatment resulted in a positive outcome without major side effects.

Treosulfan and fludarabine: a new toxicity-reduced conditioning regimen for allogeneic hematopoietic stem cell transplantation.

New conditioning regimens are being explored to reduce toxicity and enable allogeneic bone marrow transplantation in patients not eligible for conventional transplantation. We have investigated treosulfan, an alkylating agent, with the aim of developing an efficient and reliable but less-toxic conditioning regimen. A series of 30 patients who were not eligible for standard conditioning therapy received transplants from HLA-matched related (n = 14) or unrelated (n = 16) donors after administration of treosulfan 10 g/m2 intravenously daily for 3 days and fludarabine 30 mg/m2 intravenously daily for 5 days. Patients receiving grafts from unrelated donors also were given rabbit antithymocyte globulin 10 mg/kg intravenously daily for 3 days. All patients achieved prompt neutrophil and platelet recovery. Extramedullary toxicity was generally mild with Common Toxicity Criteria (CTC) grade 3 or 4 attributable to the conditioning seen only with transaminases. Complete donor chimerism was achieved by 90% of the patients. Acute graft-versus-host disease (GVHD) grade III or IV developed in 14% of the patients and chronic GVHD in 39%. An estimated overall survival rate of 73% and an event-free survival rate of 49% have been reached after a median of 22 months (range, 7.4-33.4 months). In summary, the combination of treosulfan and fludarabine is a safe and efficient conditioning regimen.

Adding weekly irinotecan to high-dose 5-fluorouracil and folinic acid (HD-5-FU/FA) after failure for first-line HD-5-FU/FA in advanced colorectal cancer--a phase II study.

UNLABELLED: Irinotecan (CPT-11) has been shown to prolong survival and improve quality of life in comparison to best supportive care in colorectal cancer patients with pretreatment of bolus 5-fluorouracil (5-FU). After first-line 24-h high-dose (HD) 5-FU/folinic acid (FA) an objective response rate of 11% with 3-weekly CPT-11 350 mg/m was reported. In the present study we investigated weekly CPT-11 in combination with 24-h HD-5-FU/FA as second-line treatment after prior exposure to 24-h HD-5-FU. Synergy between 5-FU and CPT-11 is the rationale to combine both substances for second-line therapy in order to overcome resistance to 5-FU. Thirty-five patients were recruited in a single institution to receive 6 x weekly CPT-11 80 mg/m(2), FA 200 mg/m(2) and 24-h HD-5-FU 2000 mg/m(2). Treatment was repeated on day 57. PATIENT CHARACTERISTICS: M/F=20/15, median WHO performance status 1, range (0-2). Thirty-four patients were evaluable for response: partial response 17% and no change 40%. Median time to progression and overall survival were 3.3 and 8.4 months, respectively. All patients were evaluable for toxicity analysis (National Cancer Institute Common Toxicity Criteria grade 3): leukocytopenia 3%, diarrhea 12% and vomiting/nausea 6%. Of the assigned doses, a median 100% of 5-FU and 92% of CPT-11 were administered during the first cycle of chemotherapy. We conclude that weekly CPT-11 and HD-5-FU/FA is an active and safe combination chemotherapy resulting in response rates in the upper range of other CPT-11-based second-line regimen. The toxicity profile in our series compared to 3-weekly CPT-11 seems favorable.

Efficacy and tolerability of an aminopterin-albumin conjugate in tumor-bearing rats.

The antifolate aminopterin (AMPT) was developed before methotrexate (MTX), but was not clinically established or generally used due its increased toxicity compared to MTX. Recently, we reported on the increased metabolism of albumin conjugates such as methotrexate-albumin (MTX-SA) in malignant tumors and the feasibility of using albumin as a carrier for drug targeting. Consequently, AMPT was covalently bound to serum albumin (AMPT-SA) at a 1:1 molar ratio. Biodistribution, tolerability and efficacy of this novel conjugate were studied in Walker-256 (W-256) carcinoma-bearing rats. As compared to native albumin, the same biodistribution and plasma clearance were found for AMPT-SA, which achieved 20.1% tumor uptake (estimated uptake per g tumor 6.4%) within 24 h after i.v. administration in rats. In a randomized study, AMPT-SA, repeatedly i.v. injected, was compared with low-molecular-weight AMPT. Depending on the molar concentration, the maximum tolerated dose (MTD) of AMPT covalently bound to SA was twice that of unbound AMPT (three repeated injections of 1.0 mg AMPT-SA/kg body weight versus three repeated injections of 0.5 mg AMPT/kg body weight; p=0.0006). Efficacy was studied at the level of the MTD and MTD/2, and demonstrated that AMPT-SA was significantly more active. At the MTD/2 in W-256 carcinoma-bearing rats, AMPT-SA achieved a 100% volume reduction and an optimal volume reduction during treatment/control (T/C) of 8.3% compared to a 53% volume reduction of AMPT and a T/C of 16.5% (p=0.032). Tumor relapses were reduced and occurred later in the AMPT-SA group (two tumor recurrences for AMPT-SA versus seven for AMPT; p=0.05). In this comparative study, the AMPT-SA conjugate showed high antitumor activity in vivo and a favorable toxicity compared to low-molecular-weight AMPT. These effects are attributed to the albumin carrier which seems to be an effective tool for selective tumor drug targeting.