FOLFOX6 and bevacizumab in non-optimally resectable liver metastases from colorectal cancer.

BACKGROUND: In patients with colorectal liver metastases (CLM) R0 resection significantly improves overall survival (OS). METHODS: In this report, we present the results of a phase II trial of FOLFOX6+bevacizumab in patients with non-optimally resectable CLM. Patients received six cycles of FOLFOX6+ five of bevacizumab. Patients not achieving resectability received six additional cycles of each. A PET-CT was performed at baseline and again within 1 month after initiating treatment. RESULTS: From September 2005 to July 2009, 21 patients were enrolled (Male/Female: 15/6; median age: 65 years). An objective response (OR) was documented in 12 cases (57.1%; complete responses (CRs): 3, partial response (PR): 9); one patient died from toxicity before surgery. Thirteen patients underwent radical surgery (61.9%). Three (23%) had a pathological CR (pCR). Six patients (46.1%) experienced minor postsurgical complications. After a median 38.8-month follow-up, the median OS was 22.5 months. Patients achieving at least 1 unit reduction in Standard uptake value (SUV)max on PET-CT had longer progression-free survival (PFS) (median PFS: 22 vs 14 months, P=0.001). CONCLUSIONS: FOLFOX6+bevacizumab does not increase postsurgical complications, yields high rates of resectability and pCR. Early changes in PET-CT seem to be predictive of longer PFS.

Prognostic role of EGFR gene copy number and KRAS mutation in patients with locally advanced rectal cancer treated with preoperative chemoradiotherapy.

BACKGROUND: Epidermal growth factor receptor (EGFR), evaluated by immunohistochemistry, has been shown to have prognostic significance in patients with colorectal cancer. Gene copy number (GCN) of EGFR and KRAS status predict response and outcome in patients treated with anti-EGFR therapy, but their prognostic significance in colorectal cancer patients is still unclear. METHODS: We have retrospectively reviewed the baseline EGFR GCN, KRAS status and clinical outcome of 146 locally advanced rectal cancer (LARC) patients treated with preoperative chemoradiotherapy. Pathological response evaluated by Dworak's tumour regression grade (TRG), disease-free survival (DFS) and overall survival (OS) were analysed. RESULTS: Tumour regression grade 4 and TRG3-4 were achieved in 14.4 and 30.8% of the patients respectively. Twenty-nine (19.9%) and 33 patients (19.2%) had an EGFR/nuclei ratio >2.9 and CEP7 polisomy >50% respectively; 28 patients (19.2%) had a KRAS mutation. Neither EGFR GCN nor KRAS status was statistically correlated to TRG. 5-year DFS and OS were 63.3 and 71.5%, respectively, and no significant relation with EGFR GCN or KRAS status was found. CONCLUSION: Our data show that EGFR GCN and KRAS status are not prognostic factors in LARC treated with preoperative chemoradiation.

Sorafenib in patients with advanced biliary tract carcinoma: a phase II trial.

BACKGROUND: Advanced biliary tract carcinoma has a very poor prognosis, with chemotherapy being the mainstay of treatment. Sorafenib, a multikinase inhibitor of VEGFR-2/-3, PDGFR-beta, B-Raf, and C-Raf, has shown to be active in preclinical models of cholangiocarcinoma. METHODS: We conducted a phase II trial of single-agent sorafenib in patients with advanced biliary tract carcinoma. Sorafenib was administered at a dose of 400 mg twice a day. The primary end point was the disease control rate at 12 weeks. RESULTS: A total of 46 patients were treated. In all, 26 (56%) had received chemotherapy earlier, and 36 patients completed at least 45 days of treatment. In intention-to-treat analysis, the objective response was 2% and the disease control rate at 12 weeks was 32.6%. Progression-free survival (PFS) was 2.3 months (range: 0-12 months), and the median overall survival was 4.4 months (range: 0-22 months). Performance status was significantly related to PFS: median PFS values for ECOG 0 and 1 were 5.7 and 2.1 months, respectively (P=0.0002). The most common toxicities were skin rash (35%) and fatigue (33%), requiring a dose reduction in 22% of patients. CONCLUSIONS: Sorafenib as a single agent has a low activity in cholangiocarcinoma. Patients having a good performance status have a better PFS. The toxicity profile is manageable.

Cisplatin, epirubicin, leucovorin and 5-fluorouracil (PELF) is more active than 5-fluorouracil, doxorubicin and methotrexate (FAMTX) in advanced gastric carcinoma.

BACKGROUND: 5-Fluorouracil (5-FU), doxorubicin and methotrexate (FAMTX) and cisplatin, epirubicin, leucovorin and 5-FU (PELF) have both been reported to be superior to the combination 5-FU, doxorubicin and mitomycin C (FAM) in advanced gastric carcinoma. On the basis of the presence and dose intensity of the included agents, we hypothesised that PELF would be superior to FAMTX. PATIENTS AND METHODS: Two hundred patients with untreated advanced gastric carcinoma were randomised to receive PELF or FAMTX for a maximum of six cycles or until disease progression. RESULTS: The complete response (CR) rates to PELF and FAMTX were, respectively, 13% [95% confidence intervals (CI) 6% to 20%] and 2% (95% CI 0% to 5%; P = 0.003), and the objective response rates [CR plus partial response (PR) rates] 39% (95% CI 29% to 49%) and 22% (95% CI 13% to 30%; P = 0.009), thus significantly favouring the PELF combination. The survival rates after 12 months (30.8% versus 22.4%) and 24 months (15.7% versus 9.5%) were also higher among patients receiving PELF, but these differences were not statistically significant. The toxicities were qualitatively different but quantitatively similar. Both regimens seem to be feasible provided that careful patient monitoring is assured. CONCLUSIONS: PELF is significantly more active than FAMTX and deserves further research in the adjuvant setting.

Weight gain in women with breast cancer treated with adjuvant cyclophosphomide, methotrexate and 5-fluorouracil. Analysis of resting energy expenditure and body composition.

BACKGROUND: Weight gain is a common side effect observed in women undergoing adjuvant chemotherapy for breast cancer. Among possible causes a direct effect of chemotherapy on metabolism has been proposed. Body composition variations after adjuvant chemotherapy suggest the occurrence of sarcopenic obesity, possibly due to ovarian failure. We investigated acute and chronic effects of adjuvant chemotherapy on body weight, resting energy expenditure (REE) and plasma catecholamines in a group of menopausal women. PATIENTS AND METHODS: Thirty menopausal women with stage I-II breast cancer were recruited for the study. We measured REE and respiratory quotient (RQ) and body composition at the beginning and after 3 and 6 months of adjuvant cyclophosphomide, methotrexate, and 5-fluorouracil (CMF). REE, RQ, and plasma catecholamines were assessed before and after each chemotherapy session. At each session food intake was also assessed in all patients, by a food diary. Seven patients out of the group of 30 were also evaluated after a placebo infusion (saline). RESULTS: A significant weight gain was observed in all women (70.5 +/- 3 v.s. 67.7 +/- 3 kg, p < 0.001), with increase in both fat-free mass (FFM) (45.2 +/- 1.5 v.s. 43.6 +/- 1.3 kg, p < 0.001) and fat-mass (FM) (25.3 +/- 1.7 v.s. 24.1 +/- 1.8 kg, p < 0.005). A decrease in REE and RQ was observed both during CMF and placebo infusion (p < 0.05). During acute CMF and placebo infusion a reduction of plasma levels of noradrenaline was observed at the first and last session. REE increased progressively during the study period. CONCLUSIONS: CMF therapy apparently has no effect on REE either acutely or during a 6-month-period; the increased REE observed in the long-term is likely due to the concomitant increase in FFM. The lack of evidence of sarcopenic obesity, at variance with previous literature, is likely due to different patient selection.

Modulation of fluorouracil by methotrexate, leucovorin, and cisplatin (M-FLP) in the treatment of advanced pancreatic cancer: a phase II study of the Italian Oncology Group for Clinical Research (GOIRC).

The objective of this trial was to evaluate the activity and tolerability of biomodulation of 5-fluorouracil by leucovorin, methotrexate, and platinum in patients with advanced measurable disease. Thirty-five patients with histologically or cytologically proven adenocarcinoma of the pancreas were treated with methotrexate (100 mg/m2 in 500 ml 5% dextrose in a 2-hour infusion, day 1), 5-fluorouracil (800 mg/m2/day, i.v. in continuous infusion from days 2 to 5) plus 1-leucovorin (7.5 mg/m2 given per os every 6 hours, from days 2 to 5) and platinum (60 mg/m2 i.v., day 2), every 28 days. Four partial responses (12%; exact 95% confidence interval: 1-23%) were obtained in 34 evaluable patients with a median survival time of 49 weeks (range, 20-77 weeks). Ten (29%) of 34 patients had stable disease. Median time to treatment failure from the beginning of therapy was 11 weeks (range, 4-59 weeks) and median survival time was 20 weeks (range, 4-77 weeks). The most common grade III-IV toxicities were diarrhea (15%), stomatitis (41%), and vomiting (17%). Hematologic toxicity was mild. There were no therapy-related deaths. In conclusion, this trial did not report an increase or improvement in response rate and survival rates, and this regimen cannot be recommended as effective therapy for advanced pancreatic cancer.

High-dose folinic acid and 5-fluorouracil alone or combined with hydroxyurea in advanced colorectal cancer: a randomized trial of the Italian Oncology Group for Clinical Research.

Patients with histologically confirmed advanced colorectal cancer were randomized to receive folinic acid (FA; 500 mg/mq in 2-hour intravenous infusion) and 5-fluorouracil (5FU; 600 mg/mq given as an intravenous bolus 1 hour after FA), beginning every week for 6 weeks, followed by a 2-week rest period, either without hydroxyurea (HU, arm A) or with HU (35 mg/kg per day) given orally in three administrations (every 8 hours) starting 6 hours after 5FU administration (arm B). Six weekly doses were considered one course. One hundred eighty-two patients were randomized in this trial and 162 (89%) were evaluable for response: 81 patients in arm A and 81 patients in arm B. Objective response was observed in 18 (one complete response and 17 partial responses) of 81 evaluable patients (22%; 95% confidence interval, 13-31%) in arm A, and 24 (nine complete responses and 15 partial responses) of 81 patients (30%; 95% confidence interval, 20-40%) in arm B. There was no difference in terms of median time to progression and median survival. Gastrointestinal toxicity was the most frequently observed toxicity in both arms. The double modulation of 5FU, FA plus HU does not appear to be better than the classic 5FU plus FA schedule. This trial confirms that 5FU and FA reached a plateau of 20% to 30%.

High-dose folinic acid and fluorouracil with or without ifosfamide is an inactive combination in advanced pancreatic cancer. A randomized phase II study of the Italian Oncology Group for Clinical Research (G.O.I.R.C.).

The Italian Oncology Group for Clinical Research (GOIRC) randomized 55 naive patients with advanced pancreatic cancer (APC) between intravenous fluorouracil (5FU) 400 mg/m2, days 1-5 and folinic acid (FA) 200 mg/m2, days 1-5 alone, using Machover's schedule, or with FU, FA, and ifosfamide (IFO) 5 g/m2, day 1 and Mesna. In both arms, treatment was repeated every 28 days. Fifty-one patients were evaluable for response. The overall response rate was 6% (3 out of 51), 1 out of 29 (3%) complete response (CR) in the arm with FU plus FA, and 2 out of 22 (9%) partial responses (PR) in the arm with IFO. The duration of response rate was 39, 55, and 74 weeks, respectively. Median survival time was 21 weeks (range, 4-83 weeks) for 5FU/FA and 16 weeks (range, 3-106 weeks) for the FU/FA/IFO arm. Diarrhea, mucositis, and vomiting occurred in the majority of patients. One patient died due to toxicity. The combination of 5FU plus FA failed to demonstrate therapeutic activity in patients with APC and was associated with moderate to severe toxicity that could lower the quality of life of these patients. Ifosfamide did not potentiate the activity of this combination. Neither of these combinations should be considered for treatment of patients with APC.

Fluorouracil, doxorubicin, and mitomycin combination versus PELF chemotherapy in advanced gastric cancer: a prospective randomized trial of the Italian Oncology Group for Clinical Research.

PURPOSE: The combination of cisplatin, epirubicin, and leucovorin preceding fluorouracil (PELF) includes three novel agents compared with the standard combination of fluorouracil, doxorubicin, and mitomycin (FAM) in the treatment of advanced gastric carcinoma. We report the results of a prospective randomized comparison of the two combinations in previously untreated patients. PATIENTS AND METHODS: One hundred thirty assessable patients were entered onto the trial; 52 received FAM and 85 PELF. A 1:2 unbalanced randomization in favor of the experimental treatment was chosen. Approximately 90% of patients had measurable tumor masses. RESULTS: The overall response rates (complete responses [CRs] and partial responses [PRs]) were 15% and 43% for the FAM and the PELF regimens, respectively, with a statistically significant advantage for the experimental treatment (P = .001). Time to progression (median, 2.6 and 4.7 months), duration of response (median, 10.7 and 10.2 months), and survival durations (median, 5.6 and 8.1 months) were not significantly different between the FAM and PELF regimens, respectively. The PELF combination was more toxic compared with FAM, but generally tolerable. CONCLUSION: This study showed that the PELF combination is about three times more effective than the FAM combination in inducing objective responses. Due to tolerability, it is not recommended for routine clinical use. However, it should be considered, among other second-generation chemotherapy combinations, in future randomized studies aimed to improve the therapeutic outcome in gastric carcinoma.

Soluble interleukin-2 receptor and urinary neopterin concentrations in malignant lymphoma.

The serum concentrations of soluble interleukin-2 receptors and urine neopterin were studied in 82 patients with malignant lymphomas (25 patients with Hodgkin's disease and 57 patients with non-Hodgkin's lymphoma. Increases in soluble interleukin-2 receptors and in urinary neopterin were significantly correlated with the clinical phase of the disease. The average values in both Hodgkin's disease and non-Hodgkin's lymphoma patients suffering from the disease in its active phase were significantly higher than those of patients in complete remission. Neopterin concentrations (but not soluble interleukin-2 receptor concentrations) were also elevated in clinical stages III-IV of each disease. Urinary neopterin correlated directly and significantly with the erythrocyte sedimentation rate and inversely with haemoglobin. Finally, a longitudinal analysis showed a general tendency for the markers to return to normal values, in accordance with the favourable outcome of therapy; this was more evident for urinary neopterin than for soluble interleukin-2 receptors. These findings seem to confirm that soluble interleukin-2 receptors and especially urinary neopterin can be useful markers for monitoring and prognosis of malignant lymphomas.

Urinary neopterin in malignant lymphoma.

Urinary neopterin levels were studied in 96 patients with malignant lymphomas. Twenty-eight had Hodgkin's disease and 68 non-Hodgkin's lymphoma. Neopterin excretion was significantly related to the clinical stage of the disease. Mean neopterin excretion in patients with active disease (634 +/- 527 mumol neopterin/mol creatinine) was significantly higher (p = 0.000) than in patients in complete remission (198 +/- 105 mumol neopterin/mol creatinine). Mean neopterin levels of patients in stage III-IV were higher than for patients in stage I-II. These findings were the same in patients with Hodgkin's disease and those with non-Hodgkin's lymphoma (659 +/- 593-425 +/- 316 mumol neopterin/mol creatinine), regardless of the histological subtype. A significant correlation was found between neopterin excretion, ESR (r = 0.31; p = 0.003) and hemoglobin (r = -0.40; p = 0.000). Longitudinal analysis showed a trend towards a correlation between response to therapy and neopterin excretion. These findings suggest that neopterin may be a useful prognostic marker in non-Hodgkin's lymphoma.

Prevention of cisplatin-induced vomiting in patients with cancer. A pilot study with a multiagent protocol.

Forty patients receiving a total of 102 courses of cisplatin (CDDP)-based treatment were observed in the present study. The patients received an antiemetic prophylaxis with metoclopramide (6 mg/kg), dexamethasone (12 mg/m2), lorazepam (2.5 mg), promethazine (50 mg), and diazepam (10 mg). Complete protection from acute vomiting was obtained in 77.5% of patients during the first course, and partial protection (1 to 3 episodes of vomiting) was observed in 10.1% additional cases. Complete protection was achieved in 84.6% of males vs 57.1% of females. Patients at their first course of chemotherapy had 80% complete protection compared to 66.7% in those who received prior chemotherapy. No differences in the response rate between patients treated with high versus patients receiving low doses of CDDP were noted. The same pattern of response was observed in subsequent courses of therapy. Side effects were minimal (mild sedation in almost all the cases and hiccups in a few cases). No major extrapyramidal reaction was observed. The regimen used in the study showed good efficacy in preventing acute CDDP-induced nausea and vomiting. Moreover, the very low incidence of major side effects makes this protocol safe and recommendable in patients undergoing CDDP chemotherapy.