Bendamustine plus rituximab versus fludarabine plus rituximab for patients with relapsed indolent and mantle-cell lymphomas: a multicentre, randomised, open-label, non-inferiority phase 3 trial.

BACKGROUND: Fludarabine-based chemoimmunotherapy with rituximab is frequently used in patients with indolent and mantle-cell lymphomas who relapse after alkylating chemotherapy. We aimed to compare the efficacy and safety of rituximab with bendamustine or fludarabine in patients with relapsed, indolent, non-Hodgkin lymphoma and mantle-cell lymphoma. METHODS: For this randomised, non-inferiority, open-label, phase 3 trial, we recruited patients from 55 centres in Germany, who were subsequently randomised centrally according to prespecified randomisation lists with permuted blocks of randomly variable block size to rituximab (375 mg/m(2), day 1) plus either bendamustine (90 mg/m(2), days 1 and 2) or fludarabine (25 mg/m(2), days 1-3) every 28 days for a maximum of six 28-day cycles. Patients were aged 18 years or older with a WHO performance status of 0-2 and had relapsed or refractory indolent or mantle-cell lymphoma; patients refractory to regimens that included rituximab, bendamustine, or purine analogue drugs were excluded. Patients were stratified by histological subtypes of lymphoma and by their latest previous therapies. Treatment allocation was not masked. The primary endpoint was progression-free survival and the final analysis was completed per protocol. Non-inferiority of bendamustine plus rituximab versus fludarabine plus rituximab was defined as a difference of less than 15% in 1-year progression-free survival. The protocol was amended in July, 2006, after approval of rituximab maintenance (375 mg/m(2) every 3 months for up to 2 years), which was then given to patients achieving a response to either trial treatment. This study is registered with ClinicalTrials.gov, number NCT01456351 (closed to enrolment, follow-up is ongoing). FINDINGS: Between Oct 8, 2003, and Aug 5, 2010, we randomly assigned 230 patients to treatment groups (116 bendamustine plus rituximab, 114 fludarabine plus rituximab). 11 patients were excluded for protocol violations and were not followed up further (two in the bendamustine plus rituximab group and nine in the fludarabine plus rituximab group). Thus, 219 patients were included in the per-protocol analysis (114 bendamustine plus rituximab, 105 fludarabine plus rituximab). 1-year progression-free survival with bendamustine plus rituximab was 0·76 (95% CI 0·68-0·84) and 0·48 (0·39-0·58) with fludarabine plus rituximab (non-inferiority p<0·0001). At a median follow-up of 96 months (IQR 73·2-112·9), median progression-free survival with bendamustine plus rituximab was 34·2 months (95% CI 23·5-52·7) and 11·7 months (8·0-16·1) with fludarabine plus rituximab (hazard ratio [HR] 0·54 [95% CI 0·38-0·72], log-rank test p<0·0001). Safety outcomes were similar in both groups, with 46 serious adverse events recorded (23 in the bendamustine plus rituximab group and 23 in the fludarabine plus rituximab group), most commonly myelosuppression and infections. INTERPRETATION: In combination with rituximab, bendamustine was more effective than fludarabine, suggesting that bendamustine plus rituximab may be the preferred treatment option for patients with relapsed indolent and mantle-cell lymphomas. FUNDING: Roche Pharma AG, Ribosepharm GmbH, Mundipharma GmbH, Studiengruppe indolente Lymphome (StiL).

Prognostic value of circulating Bcl-2/IgH levels in patients with follicular lymphoma receiving first-line immunochemotherapy.

Bcl-2/IgH rearrangements can be quantified in follicular lymphoma (FL) from peripheral blood (PB) by polymerase chain reaction (PCR). The prognostic value of Bcl-2/IgH levels in FL remains controversial. We therefore prospectively studied PB Bcl-2/IgH levels from 173 first-line FL patients who were consecutively enrolled, randomized, and treated within the multicenter phase 3 clinical trial NHL1-2003 comparing bendamustine-rituximab (B-R) with rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone. From April 2005 to August 2008, 783 pre- and posttreatment PB samples were quantified by quantitative PCR. At inclusion, 114 patients (66%) tested positive and 59 (34%) were negative for Bcl-2/IgH. High pretreatment Bcl-2/IgH levels had an adverse effect on progression-free survival (PFS) compared with intermediate or low levels (high vs intermediate: hazard [HR], 4.28; 95% confidence interval [CI], 1.70-10.77; P = .002; high vs low: HR, 3.02; 95% CI, 1.55-5.86; P = .001). No PFS difference between treatment arms was observed in Bcl-2/IgH-positive patients. A positive posttreatment Bcl-2/IgH status was associated with shorter PFS (8.7 months vs not reached; HR, 3.15; 95% CI, 1.51-6.58; P = .002). By multivariate analysis, the pretreatment Bcl-2/IgH level was the strongest predictor for PFS. Our data suggest that pre- and posttreatment Bcl-2/IgH levels from PB have significant prognostic value for PFS in FL patients receiving first-line immunochemotherapy. This trial was registered at www.clinicaltrials.gov as #NCT00991211 and at the German Federal Institute for Drugs and Medical Devices as #BfArM-4021335.

FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomised, open-label, phase 3 trial.

BACKGROUND: Cetuximab and bevacizumab have both been shown to improve outcomes in patients with metastatic colorectal cancer when added to chemotherapy regimens; however, their comparative effectiveness when partnered with first-line fluorouracil, folinic acid, and irinotecan (FOLFIRI) is unknown. We aimed to compare these agents in patients with KRAS (exon 2) codon 12/13 wild-type metastatic colorectal cancer. METHODS: In this open-label, randomised, phase 3 trial, we recruited patients aged 18-75 years with stage IV, histologically confirmed colorectal cancer, an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, an estimated life expectancy of greater than 3 months, and adequate organ function, from centres in Germany and Austria. Patients were centrally randomised by fax (1:1) to FOLFIRI plus cetuximab or FOLFIRI plus bevacizumab (using permuted blocks of randomly varying size), stratified according to ECOG performance status, number of metastatic sites, white blood cell count, and alkaline phosphatase concentration. The primary endpoint was objective response analysed by intention to treat. The study has completed recruitment, but follow-up of participants is ongoing. The trial is registered with ClinicalTrials.gov, number NCT00433927. FINDINGS: Between Jan 23, 2007, and Sept 19, 2012, 592 patients with KRAS exon 2 wild-type tumours were randomly assigned and received treatment (297 in the FOLFIRI plus cetuximab group and 295 in the FOLFIRI plus bevacizumab group). 184 (62·0%, 95% CI 56·2-67·5) patients in the cetuximab group achieved an objective response compared with 171 (58·0%, 52·1-63·7) in the bevacizumab group (odds ratio 1·18, 95% CI 0·85-1·64; p=0·18). Median progression-free survival was 10·0 months (95% CI 8·8-10·8) in the cetuximab group and 10·3 months (9·8-11·3) in the bevacizumab group (hazard ratio [HR] 1·06, 95% CI 0·88-1·26; p=0·55); however, median overall survival was 28·7 months (95% CI 24·0-36·6) in the cetuximab group compared with 25·0 months (22·7-27·6) in the bevacizumab group (HR 0·77, 95% CI 0·62-0·96; p=0·017). Safety profiles were consistent with the known side-effects of the study drugs. The most common grade 3 or worse adverse events in both treatment groups were haematotoxicity (73 [25%] of 297 patients in the cetuximab group vs 62 [21%] of 295 patients in the bevacizumab group), skin reactions (77 [26%] vs six [2%]), and diarrhoea (34 [11%] vs 40 [14%]). INTERPRETATION: Although the proportion of patients who achieved an objective response did not significantly differ between the FOLFIRI plus cetuximab and FOLFIRI plus bevacizumab groups, the association with longer overall survival suggests that FOLFIRI plus cetuximab could be the preferred first-line regimen for patients with KRAS exon 2 wild-type metastatic colorectal cancer. FUNDING: Merck KGaA.

Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: an open-label, multicentre, randomised, phase 3 non-inferiority trial.

BACKGROUND: Rituximab plus chemotherapy, most often CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), is the first-line standard of care for patients with advanced indolent lymphoma, and for elderly patients with mantle-cell lymphoma. Bendamustine plus rituximab is effective for relapsed or refractory disease. We compared bendamustine plus rituximab with CHOP plus rituximab (R-CHOP) as first-line treatment for patients with indolent and mantle-cell lymphomas. METHODS: We did a prospective, multicentre, randomised, open-label, non-inferiority trial at 81 centres in Germany between Sept 1, 2003, and Aug 31, 2008. Patients aged 18 years or older with a WHO performance status of 2 or less were eligible if they had newly diagnosed stage III or IV indolent or mantle-cell lymphoma. Patients were stratified by histological lymphoma subtype, then randomly assigned according to a prespecified randomisation list to receive either intravenous bendamustine (90 mg/m(2) on days 1 and 2 of a 4-week cycle) or CHOP (cycles every 3 weeks of cyclophosphamide 750 mg/m(2), doxorubicin 50 mg/m(2), and vincristine 1.4 mg/m(2) on day 1, and prednisone 100 mg/day for 5 days) for a maximum of six cycles. Patients in both groups received rituximab 375 mg/m(2) on day 1 of each cycle. Patients and treating physicians were not masked to treatment allocation. The primary endpoint was progression-free survival, with a non-inferiority margin of 10%. Analysis was per protocol. This study is registered with ClinicalTrials.gov, number NCT00991211, and the Federal Institute for Drugs and Medical Devices of Germany, BfArM 4021335. FINDINGS: 274 patients were assigned to bendamustine plus rituximab (261 assessed) and 275 to R-CHOP (253 assessed). At median follow-up of 45 months (IQR 25-57), median progression-free survival was significantly longer in the bendamustine plus rituximab group than in the R-CHOP group (69.5 months [26.1 to not yet reached] vs 31.2 months [15.2-65.7]; hazard ratio 0.58, 95% CI 0.44-0.74; p<0.0001). Bendamustine plus rituximab was better tolerated than R-CHOP, with lower rates of alopecia (0 patients vs 245 (100%) of 245 patients who recieved ≥3 cycles; p<0.0001), haematological toxicity (77 [30%] vs 173 [68%]; p<0.0001), infections (96 [37%] vs 127 [50%]); p=0.0025), peripheral neuropathy (18 [7%] vs 73 [29%]; p<0.0001), and stomatitis (16 [6%] vs 47 [19%]; p<0.0001). Erythematous skin reactions were more common in patients in the bendamustine plus rituximab group than in those in the R-CHOP group (42 [16%] vs 23 [9%]; p=0.024). INTERPRETATION: In patients with previously untreated indolent lymphoma, bendamustine plus rituximab can be considered as a preferred first-line treatment approach to R-CHOP because of increased progression-free survival and fewer toxic effects. FUNDING: Roche Pharma AG, Ribosepharm/Mundipharma GmbH.

Bendamustine compared to fludarabine as second-line treatment in chronic lymphocytic leukemia.

Bendamustine demonstrated clinical activity in pre-treated hematological malignancies due to its unique mechanism of action distinct from standard alkylating agents. This study assessed its efficacy in patients with chronic lymphocytic leukemia pre-treated with an alkylator, in comparison to fludarabine. Patients with relapsed chronic lymphocytic leukemia requiring treatment after one previous systemic regimen (usually chlorambucil-based) were randomized to either receive bendamustine 100 mg/m(2) on days 1 and 2 of a 4-week cycle or standard fludarabine treatment consisting of 25 mg/m(2) on days 1 to 5 every 4 weeks. The primary objective was to achieve non-inferior progression-free survival (PFS) with bendamustine. Out of a total of 96 patients randomized, 92 were eligible, 49 allocated to bendamustine and 43 to fludarabine. About half of the patients received six or more cycles. Overall response rates were 76 % on bendamustine and 62 % on fludarabine, with clinical complete response rates of 27 and 9 %, respectively. Median PFS was 20.1 and 14.8 months (hazard ratio, 0.87; 90 % confidence interval, 0.60-1.27), median overall survival 43.8 and 41.0 months (hazard ratio, 0.82). Thrombocytopenia and gastrointestinal toxicities were marginally more frequent on bendamustine, albeit CTC grade 3/4 event incidence was similar. These data suggest at least comparable efficacy of bendamustine vs. fludarabine, pointing to an alternative treatment option in relapsing CLL patients after chlorambucil containing initial chemotherapy.

Trastuzumab single-drug therapy after failure of cytotoxic treatment for metastatic breast cancer.

BACKGROUND: Trastuzumab is an established component of breast cancer combination regimens, but data on the safety and efficacy of single-agent therapy is sparse. PATIENTS AND METHODS: 70 Patients with HER2-overexpressing breast cancer after failure of at least one chemotherapy regimen for metastatic disease were recruited from 28 institutions. HER2 overexpression was 3+ in 96% and 2+/FISH+ in 4%. Treatment consisted of a loading dose of 4 mg/kg trastuzumab in the first week and 2 mg/kg per week thereafter, continued until progression. RESULTS: Trastuzumab treatment duration ranged from 1 to 66 weeks (median: 12). Objective responses (complete response (CR)/partial response (PR)) were seen in 12/62 fully evaluable patients (19%; 2 CR) while another 29% showed stabilization of the disease. Half of the patients had experienced progression after 13 weeks while median duration of response reached 44 weeks. Median survival was 68 weeks with nearly one-third of the patients still alive after more than 3 years. The most frequent adverse reaction was infusion-related syndrome arising during the first administration. Significant cardiovascular problems were detected in 3 cases, all with anthracycline pretreatment. CONCLUSIONS: Patients with metastatic breast cancer overexpressing HER2 may benefit from trastuzumab single-drug treatment, predominantly due to its favourable safety profile.

Opioid-induced bowel dysfunction in cancer-related pain: causes, consequences, and a novel approach for its management.

Opioids are the mainstay of management for patients with cancer-related pain. Although the analgesic efficacy of opioid therapy is well documented, the recent European Pain in Cancer survey demonstrated that the management of moderate-to-severe pain in patients with cancer is far from optimal. Bowel dysfunction, and importantly constipation, is a common side effect and has a significant impact on the patient's morbidity and quality of life. Nonpharmacological strategies and laxatives are often not effective in the management of opioid-induced constipation (OIC), making it necessary to search for new strategies for the treatment of opioid-induced bowel dysfunction. One promising strategy is the prevention of OIC with peripherally acting opioid antagonists that specifically target the underlying cause of this condition, without affecting centrally mediated analgesia. In recent studies, the novel combination of prolonged-release oral oxycodone and prolonged-release oral naloxone provided effective analgesia with improved bowel function in patients suffering from severe cancer-related and noncancer-related pain. The combination has the potential to improve the quality of pain management significantly in these patients.

Phase II trial with carboplatin and bendamustine in patients with extensive stage small-cell lung cancer.

BACKGROUND: Bendamustine is an alkylating agent with hybrid activity and proven efficacy in small-cell lung cancer associated with a favorable toxicity rate. This phase II study of carboplatin/bendamustine was conducted to evaluate the efficacy of this combination in patients with extensive disease small-cell lung cancer (ED-SCLC). METHODS: Fifty-six untreated patients with ED-SCLC were enrolled. Their median age was 63 years. Sixty-seven percent of patients were male and 18% had a World Health Organization performance status of 2. Bendamustine was administered as a 30- to 60-minute infusion at a dose of 80 mg/m2 on days 1 and 2, and carboplatin was given at an area under the curve of 5 on day 1 of a 21-day cycle. RESULTS: Fifty-five patients were assessable for response and toxicity. The overall response rate was 72.7% (95% confidence interval: 59%-84%), with one complete remission (1.8%). The median time to progression was 5.2 months (95% confidence interval: 4.2-5.6). At the time of evaluation, 71% of the patients had died. The median survival time reached 8.3 months (95% confidence interval: 6.6-9.9). The major toxicity of this regimen was myelosuppression, including grade 3 or 4 neutropenia (46%), thrombopenia (26%), anemia (15%), and infections (11%). Toxic death was recorded in two patients (3.6%). CONCLUSIONS: The carboplatin/bendamustine regimen is a well-tolerated cytostatic combination in ED-SCLC with activity comparable with that of other platinum-based regimens. Further investigations, such as a phase III trial, are currently planned.

Prospective multicenter phase II study of irinotecan as third-line therapy in metastatic colorectal cancer and progression after bolus and infusional 5-fluorouracil.

Irinotecan has proven anti-tumor activity as induction treatment in combination with 5-fluorouracil (5-FU) or as second-line treatment after 5-FU in patients with metastatic colorectal cancer. The aim of the present phase II study was to evaluate irinotecan as third-line chemotherapy in patients with colorectal cancer after sequential treatment with bolus 5-FU followed by an infusional 5-FU regimen. Patients pretreated with bolus 5-FU/folinic acid and the infusional 5-FU/folinic acid regimen were treated with 350 mg/m irinotecan i.v. once every 3 weeks in a multicenter phase II study. Tumor size was measured every cycle and treatment with irinotecan was continued until the occurrence of progressive disease or unacceptable toxicity. A total of 50 pretreated patients were included. Of the 45 evaluable patients, 13.3% [n=6, 95% confidence interval (CI) 5.1-26.8] attained a response (complete/partial response) to treatment lasting 5.6 months (95% CI 4.2-6.3) and in four patients response has been confirmed (8.9%, 95% CI 2.5-21.2). Disease stabilization was noted in 51.1% of the patients (n=23, 95% CI 35.8-66.3). The median duration of response/disease stabilization was 4.2 months (95% CI 3.2-6.0). Median overall survival was 7.9 months (95% CI 6.1-11.1), corresponding to a calculated 1-year survival of 28.3% (95% CI 15.2-41.3). Severe neutropenia occurred in 14% (n=7) and anemia grade III in 6% of the patients (n=3). The most frequent non-hematological toxicity grade III/IV related to treatment was diarrhea in 24% of the patients (n=12), followed by vomiting in 8% (n=4) and constipation as well as infection in two patients each (4%) (evaluable n=50). We conclude single-agent irinotecan is an effective and well-tolerable treatment in pretreated patients with metastatic colorectal cancer after failure of bolus and infusional 5-FU/folinic acid regimens. Elderly patients had the same probability to respond.