Upfront FOLFOXIRI plus bevacizumab and reintroduction after progression versus mFOLFOX6 plus bevacizumab followed by FOLFIRI plus bevacizumab in the treatment of patients with metastatic colorectal cancer (TRIBE2): a multicentre, open-label, phase 3, randomised, controlled trial.

BACKGROUND: The triplet FOLFOXIRI (fluorouracil, leucovorin, oxaliplatin, and irinotecan) plus bevacizumab showed improved outcomes for patients with metastatic colorectal cancer, compared with FOLFIRI (fluorouracil, leucovorin, and irinotecan) plus bevacizumab. However, the actual benefit of the upfront exposure to the three cytotoxic drugs compared with a preplanned sequential strategy of doublets was not clear, and neither was the feasibility or efficacy of therapies after disease progression. We aimed to compare a preplanned strategy of upfront FOLFOXIRI followed by the reintroduction of the same regimen after disease progression versus a sequence of mFOLFOX6 (fluorouracil, leucovorin, and oxaliplatin) and FOLFIRI doublets, in combination with bevacizumab. METHODS: TRIBE2 was an open-label, phase 3, randomised study of patients aged 18-75 years with an Eastern Cooperative Oncology Group (ECOG) performance status of 2, with unresectable, previously untreated metastatic colorectal cancer, recruited from 58 Italian oncology units. Patients were stratified according to centre, ECOG performance status, primary tumour location, and previous adjuvant chemotherapy. A randomisation system incorporating a minimisation algorithm was used to randomly assign patients (1:1) via a masked web-based allocation procedure to two different treatment strategies. In the control group, patients received first-line mFOLFOX6 (85 mg/m2 of intravenous oxaliplatin concurrently with 200 mg/m2 of leucovorin over 120 min; 400 mg/m2 intravenous bolus of fluorouracil; 2400 mg/m2 continuous infusion of fluorouracil for 48 h) plus bevacizumab (5 mg/kg intravenously over 30 min) followed by FOLFIRI (180 mg/m2 of intravenous irinotecan over 120 min concurrently with 200 mg/m2 of leucovorin; 400 mg/m2 intravenous bolus of fluorouracil; 2400 mg/m2 continuous infusion of fluorouracil for 48 h) plus bevacizumab after disease progression. In the experimental group, patients received FOLFOXIRI (165 mg/m2 of intravenous irinotecan over 60 min; 85 mg/m2 intravenous oxaliplatin concurrently with 200 mg/m2 of leucovorin over 120 min; 3200 mg/m2 continuous infusion of fluorouracil for 48 h) plus bevacizumab followed by the reintroduction of the same regimen after disease progression. Combination treatments were repeated every 14 days for up to eight cycles followed by fluorouracil and leucovorin (at the same dose administered at the last induction cycle) plus bevacizumab maintenance until disease progression, unacceptable adverse events, or consent withdrawal. Patients and investigators were not masked. The primary endpoint was progression-free survival 2, defined as the time from randomisation to disease progression on any treatment given after first disease progression, or death, analysed by intention to treat. Safety was assessed in patients who received at least one dose of their assigned treatment. Study recruitment is complete and follow-up is ongoing. This trial is registered with Clinicaltrials.gov, NCT02339116. FINDINGS: Between Feb 26, 2015, and May 15, 2017, 679 patients were randomly assigned and received treatment (340 in the control group and 339 in the experimental group). At data cut-off (July 30, 2019) median follow-up was 35·9 months (IQR 30·1-41·4). Median progression-free survival 2 was 19·2 months (95% CI 17·3-21·4) in the experimental group and 16·4 months (15·1-17·5) in the control group (hazard ratio [HR] 0·74, 95% CI 0·63-0·88; p=0·0005). During the first-line treatment, the most frequent of all-cause grade 3-4 events were diarrhoea (57 [17%] vs 18 [5%]), neutropenia (168 [50%] vs 71 [21%]), and arterial hypertension (25 [7%] vs 35 [10%]) in the experimental group compared with the control group. Serious adverse events occurred in 84 (25%) patients in the experimental group and in 56 (17%) patients in the control group. Eight treatment-related deaths were reported in the experimental group (two intestinal occlusions, two intestinal perforations, two sepsis, one myocardial infarction, and one bleeding) and four in the control group (two occlusions, one perforation, and one pulmonary embolism). After first disease progression, no substantial differences in the incidence of grade 3 or 4 adverse events were reported between the control and experimental groups, with the exception of neurotoxicity, which was only reported in the experimental group (six [5%] of 132 patients). Serious adverse events after disease progression occurred in 20 (15%) patients in the experimental group and 25 (12%) in the control group. Three treatment-related deaths after first disease progression were reported in the experimental group (two intestinal occlusions and one sepsis) and four in the control group (one intestinal occlusion, one intestinal perforation, one cerebrovascular event, and one sepsis). INTERPRETATION: Upfront FOLFOXIRI plus bevacizumab followed by the reintroduction of the same regimen after disease progression seems to be a preferable therapeutic strategy to sequential administration of chemotherapy doublets, in combination with bevacizumab, for patients with metastatic colorectal cancer selected according to the study criteria. FUNDING: The GONO Cooperative Group, the ARCO Foundation, and F Hoffmann-La Roche.

MicroRNA signature in metastatic colorectal cancer patients treated with anti-EGFR monoclonal antibodies.

BACKGROUND: To investigate whether microRNAs are predictive of sensitivity to anti-epidermal growth factor receptor (EGFR) monoclonal antibodies in patients with metastatic colorectal cancer (mCRC). METHODS: A total of 183 mCRC cases from 2 independent cohorts (cohort 1: 74 cases; validation cohort: 109 cases) treated with cetuximab or panitumumab were included in the study. MiRNA arrays were analyzed using Agilent's miRNA platform. RESULTS: The study identified the cluster Let-7c/miR-99a/miR-125b as a signature associated with an outcome different from that of anti-EGFR therapies. In the first cohort, patients with high-intensity signatures had a significantly longer progression-free survival (PFS) (6.1 vs. 2.3 mo; P = .02) and longer overall survival (OS) ( 29.8 vs. 7.0 mo, P = .08) than patients with low-intensity signatures. In the validation cohort, patients with high signature had significantly longer PFS and OS than individuals with low-intensity signatures (PFS 7.8 vs. 4.3 mo, P = .02; OS 12.8 vs. 7.5 mo, P = .02). In the KRAS wild-type population (n = 120), high-intensity signature patients had a significantly longer PFS (7.8 vs. 4.6 mo, P = .016) and longer OS (16.1 vs. 10.9 mo, P = .09) than low-signature individuals, with no difference in KRAS mutated patients. CONCLUSION: The MiR-99a/Let-7c/miR-125b signature may improve the selection of patients with KRAS wild-type mCRC as good candidates for anti-EGFR therapy.

[Single cardiac metastasis from colorectal cancer: an unusual localization]. / Singola metastasi cardiaca da adenocarcinoma intestinale: una rara localizzazione.

Metastasis to the heart from malignancy is a frequent but underestimated event. Tumors that are located in the mediastinum, such as pleural mesothelioma, are more frequently associated with cardiac colonization. Few reports have described metastasis from colon adenocarcinoma, which usually colonizes liver and lungs. Moreover, intracardiac localization is more common for primary cardiac neoplasms than for metastasis. We present an unusual case of a patient operated for colon adenocarcinoma who exhibited a single intracardiac secondary localization. Although the mass was huge, the patient was completely asymptomatic. Strict oncologic follow-up facilitates an early identification of the lesion, which could then be promptly resected.

Adjuvant chemotherapy in completely resected gastric cancer: a randomized phase III trial conducted by GOIRC.

BACKGROUND: Complete surgical resection of gastric cancer is potentially curative, but long-term survival is poor. METHODS: Patients with histologically proven adenocarcinoma of the stomach of stages IB, II, IIIA and B, or IV (T4N2M0) and treated with potentially curative surgery were randomly assigned to follow-up alone or to intravenous treatment with four cycles (repeated every 21 days) of PELF (cisplatin [40 mg/m(2), on days 1 and 5], epirubicin [30 mg/m(2), days 1 and 5], L-leucovorin [100 mg/m(2), days 1-4], and 5-fluorouracil [300 mg/m(2), days 1-4] in a hospital setting. Frequencies and severity of adverse events were determined. Overall survival (OS) and disease-free survival (DFS) were compared between the treatment arms using Kaplan-Meier analysis and a Cox proportional hazards regression model. All statistical tests were two-sided. RESULTS: From January 1995 through September 2000, 258 patients were randomly assigned to chemotherapy (n = 130) or surgery alone (n = 128). Patient characteristics were well balanced between the two arms. Among those who received chemotherapy, grade 3 or 4 toxic effects including vomiting, mucositis, and diarrhea were experienced by 21.1%, 8.4%, and 11.8% of patients, respectively. Leucopenia, anemia, and thrombocytopenia of grade 3 or 4 were experienced by 20.3%, 3.3%, and 4.2% of patients, respectively. After a median follow-up of 72.8 months, 128 patients (49.6%) experienced recurrence and 139 (53.9%) deaths were observed, one toxicity-related. Relative to treatment with surgery alone, adjuvant chemotherapy did not increase disease-free survival (hazard ratio [HR] of recurrence = 0.92; 95% confidence interval [CI] = 0.66 to 1.27) or overall survival (HR of death = 0.90; 95% CI = 0.64 to 1.26). CONCLUSIONS: Our results failed to provide proof of an effect of adjuvant chemotherapy with PELF on overall survival or disease-free survival. The estimated effect of chemotherapy (10% reduction in the hazard of death or relapse) is modest and consistent with the results of meta-analyses of adjuvant chemotherapy without platinum agents.

Renal cancer.

In Europe, renal cancer (that is neoplasia of the kidney, renal pelvis or ureter (ICD-9 189 and ICD-10 C64-C66)) ranks as the seventh most common malignancy in men amongst whom there are 29,600 new cases each year (3.5% of all cancers). Tobacco, obesity and a diet poor in vegetables are all acknowledged risk factors, along with specific occupational and environmental factors. A familial history of renal carcinoma is also likely to increase the risk. Renal carcinoma may remain clinically occult for most of its course. The classic presentation of pain, haematuria, and flank mass occurs in only 9% of patients and is often indicative of advanced disease. Approximately 30% of patients with renal carcinoma present with metastatic disease, 25% with locally advanced renal carcinoma and 45% with localized disease. Metastases are typically found in the lung, soft tissue, bone, liver, cutaneous sites, and central nervous system. The most important staging technique is a computed tomography (CT) scan of the whole abdomen. Survival rates are more favourable for patients with tumours confined to the kidney. Five-year survival for patients with metastatic renal carcinoma is comprised between 0 and 20%. Radical nephrectomy is the standard intervention for renal cancer. Intrinsic resistance to chemotherapy has long been a hallmark of renal carcinoma. Limited options are available for the systemic therapy, and no chemotherapeutic regimen is accepted as a standard of care. Biologic agents represent the major effective therapies for widespread metastatic renal cancer. An antiangiogenic strategy, the neutralization of VEGF, can slow the growth rate of advanced cancer.

Oxaliplatin with raltitrexed and preoperative radiotherapy in T3-T4 extraperitoneal rectal cancer. A dose finding study.

AIMS AND BACKGROUND: The availability of new drugs offers the opportunity to improve the outcome of locally advanced rectal cancer. Raltitrexed and oxaliplatin are effective in advanced colorectal cancer with acceptable toxicity and can act as radiation enhancers as shown in phase I-II studies. The aim of the study was thus to determine the recommended dose of oxaliplatin concomitantly administered with raltitrexed and concurrent preoperative radiotherapy in patients with stage II-III extraperitoneal rectal cancer. METHODS: From September 2001 to September 2002, 18 consecutive patients with T3/T4 rectal cancer were treated at our Institution with preoperative chemoradiation followed by surgery after 6-8 weeks. Pelvic radiotherapy was delivered at a dose of 45 Gy in 25 fractions in 5 weeks followed by a 5.4 Gy boost at 1.8 Gy daily. Concomitant chemotherapy consisted of 3 mg/m2/i.v. of raltitrexed on days 1, 19, 38 of radiotherapy treatment with incremental doses of oxaliplatin according to dose finding rules (4 dose levels: 65, 85, 110, 130 mg/m2). Dose-limiting toxicity for oxaliplatin was defined as either grade 3-4 hematological or grade 3-4 gastrointestinal or neurological toxicity. We studied a minimum of 3 patients at each dose level. RESULTS: Three patients were treated at 65, 85, and 110 mg/m2/i.v., respectively, while 9 patients were recruited at the last dose level. Neither grade 3-4 gastrointestinal nor neurological toxicity were documented. Dose-limiting toxicity was documented in 2/9 subjects at the 130 mg/m2 level consisting of grade 3 transient asymptomatic leukopenia. Thirteen patients developed transient increase of one or more liver enzymes (grade 3-4) and 2 patients developed grade 3 perineal dermatitis. All patients received the programmed dose of radiotherapy. The chemotherapy regimen was not completed in 4 cases due to grade 2 protracted leukopenia. CONCLUSIONS: The maximum tolerated dose of oxaliplatin was not reached at the maximum dose level (i.v.); 130 mg/m2 can therefore be defined as the recommended dose. The combination of oxaliplatin with raltitrexed and radiotherapy can be considered feasible and well tolerated.

Raltitrexed and radiotherapy as adjuvant treatment for stage II-III rectal cancer: a feasibility study.

AIMS AND BACKGROUND: Adjuvant 5-FU chemotherapy plus radiotherapy represents the standard treatment for radically resected rectal cancer at high risk of relapse according to the NIH Consensus Conference. The therapeutic gain was obtained with a high rate of severe treatment-related toxicity and a suboptimal patient compliance with this regimen. Raltitrexed is a specific thymidylate synthase inhibitor with a convenient administration schedule, acceptable toxicity and radiosensitizing properties, as the published phase I trials in combination with radiotherapy have shown. The aim of this prospective multicenter phase II study was to evaluate the feasibility, gastrointestinal and hematological acute toxicity of raltitrexed in combination with radiotherapy in rectal cancer patients. METHODS: From September 2000 to June 2004, 50 patients with radically resected stage II-III rectal adenocarcinoma were treated. All patients were evaluable for compliance and acute toxicity. Within 45-60 days of surgery, each patient underwent concomitant adjuvant radiochemotherapy. Radiotherapy was administered to the pelvis (plus perineum after abdominoperineal resection) with photon beam energy exceeding 5 MV, 3-4 fields, 45 Gy/25 fractions/5 weeks plus a boost delivered to the site of resected disease with 3-4 fields, 9 Gy/5 fractions/1 week to a total dose of 54 Gy. The boost dose was administered after complete exclusion of the small bowel from the treatment volumes; if this was not possible a total dose of 50.4 Gy was given. Raltitrexed was administered intravenously at a dose of 3 mg/m2 as a bolus injection on days 1 and 22 of radiotherapy one hour before treatment, for a total of two cycles. Each patient underwent weekly clinical evaluation and laboratory tests. Toxicity was assessed by the WHO scale. RESULTS: Forty-five (90%) patients completed the established treatment. Acute severe toxicity included grade III proctitis in 4/50 (8%), grade III-IV diarrhea in 4/50 (8%), grade III perineal dermatitis in 4/50 (8%) and grade III leukopenia in 2/50 (4%) patients; five patients (10%) experienced a transient grade Ill increase in their liver biochemistry values. CONCLUSIONS: Our data related to acute toxicity and patient compliance proved the feasibility of this adjuvant radiochemotherapy treatment. A longer follow-up is necessary to evaluate the effectiveness of this new regimen in terms of disease-free and overall survival.