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Background: Heterogeneous results of published studies led to conduct a randomized clinical trial to assess the efficacy of a new formulation of four probiotics as prophylaxis for complications after colorectal surgery. Methods: A double-blind, placebo-controlled randomized study was conducted enrolling patients undergoing colorectal surgery for cancer. Capsules of placebo or of a formulation containing Lactobacillus acidophilus, L. p lantarum, Bifidobacterium lactis and Saccharomyces boulardii were administered starting one day before operation and continuing for another 15 days postoperatively. Patients were followed up for 30 days with the development of postoperative complications as the primary outcome. Gene expression and serum levels of cytokines were measured on postoperative day 4 (www.clinicaltrials.gov NCT02313519). Results: The study was prematurely stopped after enrolment due to efficacy in the primary outcome. Administration of probiotics significantly decreased the rate of all postoperative major complication (28.6 vs. 48.8 % of the placebo arm, p 0.010, odds ratio 0.42). Major benefit was found in the reduction of the rate of postoperative pneumonia (2.4 vs. 11.3 %, p 0.029), of surgical site infections (7.1 vs. 20.0 %, p 0.020) and of anastomotic leakage (1.2 vs. 8.8 %, p 0.031). The time until hospital discharge was shortened as well. Gene expression of SOCS3 was positively related with gene expression of TNF and of circulating IL-6 in the probiotic group but not in the placebo group. Conclusions: The studied probiotic formulation significantly decreased the risk of postoperative complications, namely mechanical ventilation, infections and anastomotic leakage. Modulation of the gene expression of SOCS3 is one suggested mechanism (www.clinicaltrials.gov NCT02313519). © 2015 Société Internationale de Chirurgie.

Background. Although the TNM system is useful in predicting survival in resected colorectal cancer, heterogeneity within the same stages regarding prognosis exists. We are presenting a pooled analysis of prognostic factors from two randomized studies of adjuvant treatment conducted by the Hellenic Cooperative Oncology Group. Patients and Methods. Patients with stage II or III colon (n = 279) or rectal (n = 220) cancer were included in this analysis. Following surgery, patients received: 5-fluorouracil/leucovorin (5-FU/LV) (n = 135), 5-FU/LV and interferon Alfa-2a (IFNA-2a) (n = 138), 5-FU/LV and pelvic chemoradiotherapy (n = 106), and pelvic chemoradiotherapy alone (n = 108). Results. Median follow up was 92 mo. The number of involved lymph nodes (LNs), tumor differentiation, and the presence of regional implants were independent prognostic factors for both OS and TTP, while nerve invasion was only significant for TTP. Patients were stratified into three prognostic groups (low-risk: no LNs and grade 1/2; high-risk: > 3 LNs and grade 3/4; intermediate-risk: remaining patients) with distinct differences in 5-yr survival (84.7% vs 57.6% vs 32.4%) and 5-yr TTP (81.2% vs 54.5% vs 28.6%). Conclusion. The combination of clinicopathological prognostic factors can be more informative than the traditional TNM staging system. Such stratification may be necessary in randomized trials and could be useful in deciding the most appropriate adjuvant treatment strategies. © Copyright 2005 by Humana Press Inc. All rights of any nature whatsoever reserved. 36 1 29 38

Background: Bevacizumab, an antibody neutralizing Vascular Endothelial Growth Factor (VEGF), is licensed for the management of patients with advanced colon cancer. However, tumor biomarkers identifying the molecular tumor subsets most amenable to angiogenesis modulation are lacking.Methods: We profiled expession of 24526 genes by means of whole genome 24 K DASL (c-DNA-mediated, Annealing, Selection and Ligation) arrays, (Illumina, CA) in 16 bevacizumab-treated patients with advanced colon cancer (Test set). Genes with correlation to 8-month Progression-free status were studied by means of qPCR in two independent colon cancer cohorts: 49 patients treated with bevacizumab + chemotherapy (Bevacizumab qPCR set) and 72 patients treated with chemotherapy only (Control qPCR set). Endpoints were best tumor response before metastasectomy (ORR) and progression-free survival (PFS).Results: Five genes were significantly correlated to 8-month progression-free status in the Test set: overexpression of KLF12 and downregulation of AGR2, ALDH6A1, MCM5, TFF2. In the two independent datasets, irinotecan- or oxaliplatin-based chemotherapy was administered as first-line treatment and metastasectomies were subsequently applied in 8-14% of patients. No prognostically significant gene classifier encompassing all five genes could be validated in the Bevacizumab or Control qPCR sets. The complex gene expression profile of all-low tumor (ALDH6A1 + TFF2 + MCM5) was strongly associated with ORR in the Bevacizumab qPCR set (ORR 85.7%, p = 0.007), but not in the Control set (ORR 36.4%, p = 0.747). The Odds Ratio for response for the all-low tumor (ALDH6A1 + TFF2 + MCM5) profile versus any other ALDH6A1 + TFF2 + MCM5 profile was 15 (p = 0.018) in the Bevacizumab qPCR set but only 0.72 (p = 0.63) in the Control set. The tumor expression profile of (KLF12-high + TFF2-low) was significantly associated with PFS only in the Bevacizumab qPCR set: bevacizumab-treated patients with (KLF12-high + TFF2-low) tumors had superior PFS (median 14 months, 95% CI 2-21) compared to patients with any other (KLF12 + TFF2) expression profile (median PFS 7 months, 95% CI 5-10, p = 0.021). The Hazard Ratio for disease progression for (KLF12-high + TFF2-low) versus any other KLF12 + TFF2 expression profile was 2.92 (p = 0.03) in the Validation and 1.29 (p = 0.39) in the Control set.Conclusions: Our «three-stage» hypothesis-generating study failed to validate the prognostic significance of a five-gene classifier in mCRC patients. Exploratory analyses suggest two gene signatures that are potentially associated with bevazicumab benefit in patients with advanced colon cancer. © 2014 Pentheroudakis et al.; licensee BioMed Central Ltd. 14 1

Surgical interventions activate a cascade of reactions that result in an aseptic inflammatory reaction. This inflammatory response initiates the organism's innate immunity. Laparoscopic surgery reduces the trauma, and patients benefit from diminished surgical trauma and maintained immune function. Cytokine levels and C-reactive protein (CRP) are related to the magnitude of surgical trauma and surgical stress. Toll-like receptors (TLRs) 2 and 4 are the first sensor-recognition receptors of the invading pathogens for the innate immune response. This study aimed to compare the inflammatory response and then the stress response during laparoscopic and open colectomy for cancer by calculating TLR-2 and TLR-4 as the first sensor-recognition receptors together with interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), and high-sensitivity CRP (hsCRP). A total 40 patients with colorectal cancer were randomized in two groups: group A (open colectomy, n = 20) and group B (laparoscopic colectomy, n = 20). An epidural catheter was placed in all patients 1 h preoperatively. Rupivocaine was administered perioperatively and 48 h postoperatively. Blood samples were taken for calculation of IL-6, TNF-alpha, hsCRP, TLR-2, and TLR-4 preoperatively and 5 min after deflation of pneumoperitoneum (group B) or 5 min after division of the colon (group A), then 6 and 24 h postoperatively. The mean operative time was 115 for group A and 142 min for group B. The mean blood loss was respectively 240 and 105 ml (P < 0.001), and the mean hospital stay was respectively 8 and 5 days (P < 0.05). The IL-6 level was significant higher in group A than in group B at 6 and 24 h postoperatively (P < 0.0001), and the hsCRP level was significant higher in group A than in group B at 24 h postoperatively (P < 0.001). The TNF-alpha values did not differ between the two groups. The TLR-2 level was significantly higher in group A than in group B at 5 min (P = 0.013) and 24 h (P = 0.007) postoperatively. The TLR-4 level was significant higher in group A than in group B at 5 min postoperatively (P = 0.03). The inflammatory response and the resultant stress response are significantly less during laparoscopic colectomy than during open colectomy for colorectal cancer. This is an obvious short-term clinical benefit for the patient, providing tinder for further study to investigate the long-term results of laparoscopic colectomy versus open colectomy for colorectal cancer (Registered clinical trial no. NCT00942461; http://www.clinicaltrials.gov). Surgical Endoscopy and Other Interventional Techniques

Background Surgical procedures are related to the activation of the inflammatory reaction. This is called surgical stress. It is believed that diminished surgical trauma reduces surgical stress. The laparoscopic approach reduces trauma, but the systemic immune responses are still invariably activated. Cytokines and C-reactive protein (CRP) are the main markers in the study of inflammatory or stress response. alpha-Defensins play an important role in host defense, acting early in phagocytosis. alpha-Defensins, as early markers-earlier than cytokines-of the inflammatory response, have been used, together with high-sensitivity CRP (hs-CRP) and interleukin-6 (IL-6), to determine the inflammatory response in laparoscopic and open colectomy for cancer. Materials and methods A total of 40 patients with colorectal cancer were randomized to two groups: group A (n = 20), open colectomy; group B (n = 20), laparoscopic colectomy. One hour preoperatively an epidural catheter was placed in all patients and rupivacaine was administered perioperatively and again 48 h postoperatively. Blood samples were taken for calculating alpha-defensins, IL-6, and hs-CRP levels preoperatively, 5 min after division of the colon (group A), or 5 min after deflation of pneumoperitoneum (group B), 6 h and 24 h postoperatively. Results The mean operative time was 115 min for group A and 142 min for group B (p < 0.05). The mean blood loss was 240 ml and 105 ml, respectively (p < 0.001). The mean hospital stay was 8 days and 5 days, respectively (p < 0.05). alpha-Defensin levels were statistically significantly lower in group B than in group A, 5 min and 24 h postoperatively (p < 0.002 and p < 0.007, respectively). The IL-6 levels were statistically significantly lower in group B than in group A, 6 h and 24 h postoperatively (p < 0.0001 at both time intervals), whereas the levels of hs-CRP were significantly lower in group B than in group A 24 h postoperatively (p < 0.001). Conclusions The present study confirms the results of previous studies, that the inflammatory immune response and surgical stress are significantly less after laparoscopic colectomy versus open colectomy for colorectal cancer. More investigation is needed to study if surgical stress has any influence on survival of these patients. World J Surg

Background. Although the TNM system is useful in predicting survival in resected colorectal cancer, heterogeneity within the same stages regarding prognosis exists. We are presenting a pooled analysis of prognostic factors from two randomized studies of adjuvant treatment conducted by the Hellenic Cooperative Oncology Group. Patients and Methods. Patients with stage II or III colon (n = 279) or rectal (n = 220) cancer were included in this analysis. Following surgery, patients received: 5-fluorouracil/leucovorin (5-FU/LV) (n = 135), 5-FU/LV and interferon Alfa-2a (IFNA-2a) (n = 138), 5-FU/LV and pelvic chemoradiotherapy (n = 106), and pelvic chemoradiotherapy alone (n = 108). Results. Median follow up was 92 mo. The number of involved lymph nodes (LNs), tumor differentiation, and the presence of regional implants were independent prognostic factors for both OS and TTP, while nerve invasion was only significant for TTP. Patients were stratified into three prognostic groups (low-risk: no LNs and grade 1/2; high-risk: > 3 LNs and grade 3/4; intermediate-risk: remaining patients) with distinct differences in 5-yr survival (84.7% vs 57.6% vs 32.4%) and 5-yr TTP (81.2% vs 54.5% vs 28.6%). Conclusion. The combination of clinicopathological prognostic factors can be more informative than the traditional TNM staging system. Such stratification may be necessary in randomized trials and could be useful in deciding the most appropriate adjuvant treatment strategies. © Copyright 2005 by Humana Press Inc. All rights of any nature whatsoever reserved.

We conducted a phase III study in patients with advanced colorectal carcinoma (ACC). The total number of patients randomized from October 1993 until July 1998 was 192, whereas therapy was started on 179 and 158 (82.3%) have been evaluable. The treatment schedules consisted of weekly bolus administration for 6 weeks of 5-fluorouracil (5-FU), 600 mg/m2 (arm I) versus 5-FU (500 mg/m2) intravenous bolus and interferon-alpha, 5 MU subcutaneously, three times a week (arm II) versus leucovorin 200 mg/m2 in 2-hour infusion and 5-FU 500 mg/m2 intravenous bolus at the midtime of leucovorin infusion (arm III) followed by a 2-week rest period. Treatment was continued for six cycles or until progression. This study failed to show any superiority of the modulated 5-FU versus single administration of 5-FU. There were no significant differences between the three arms in the overall response rate (10.3% versus 11.3% versus 12.9%, p = 0.95), the time to tumor progression (median, 3.9 versus 3.8 versus 6.0 months, p = 0.59), or survival duration (median, 14.7 versus 12.4 versus 16.3 months, p = 0.71). The incidence of severe (grades III and IV) toxicity was significantly higher in patients in arm II and III (24.5% and 18.6%) versus arm I (6.0%) (p = 0.01). Because modulated 5-FU failed to show superiority versus 5-FU, new agents and new strategies are needed for the treatment of advanced colorectal carcinoma. Am J Clin Oncol

Background: It has been shown in randomized studies that adjuvant treatment with the combination of fluorouracil (FU) and levamisole reduced the risk of recurrence and deaths of patients with stage III colon cancer. Pharmacological studies of FU led to its use in combination with a number of modulating agents including interferon-α and leucovorin (LV) that appear to enhance its activity in vitro. Furthermore, a meta-analysis suggested that the combination of FU with LV increased the response rate as compared to FU monotherapy in patients with advanced colorectal cancer. Purpose: To evaluate the impact of adjuvant treatment with the combination of FU and LV with or without interferon alfa-2a (IFN) on disease-free survival (DFS) and overall survival (OS) for patients with stage II or III colon cancer. Patients and Methods: From August 1989 to July 1997, 280 patients with stage II and III colon cancer entered the study and were randomly assigned to receive either the combination of FU (600 mg/m2/week x 6, followed by a 2-week rest) and LV (500 mg/m2/week x 6 as a 2-hour infusion, followed by a 2-week rest) for 4 cycles (group A, 139 patients), or the same chemotherapy plus recombinant IFN (3 MU subcutaneously 3 times a week) for 1 year (group B, 141 patients). Results: A total of 109 patients (78.9%) of group A and 119 (84.4%) of group B completed four cycles of chemotherapy. Also, 51.4% of patients of group A and 53.9% of group B received ≥ 80% of the planned dose of FU. One patient (group A) was found to be ineligible and was not included in the analysis. The median relative dose intensity of FU in the two groups was 0.90 and 0.85, respectively. As of August 1998, after a median follow up of 4 years, there was no significant difference in either 3-year DFS (group A, 83.1%; group B, 75.9%, p = 0.14) or OS (group A, 84.5%; group B, 80.0%, p = 0.27). In the Cox model, stage of disease, number of infiltrated nodes, tumor grade and presence of regional implants were identified as significant prognostic factors for OS. Grade 3-4 toxicities, mainly diarrhea, were observed in 26.1% of patients of group A and in 24.8% of group B. There were no treatment-related deaths. Conclusions: The addition of IFN to the combination of FU with LV postoperatively does not improve DFS and OS of patients with stage II or III colon cancer. Copyright (C) 2000 S. Karger AG, Basel. 58 3 227 236

Background: It has been shown in randomized studies that adjuvant treatment with the combination of fluorouracil (FU) and levamisole reduced the risk of recurrence and deaths of patients with stage III colon cancer. Pharmacological studies of FU led to its use in combination with a number of modulating agents including interferon-a and leucovorin (LV) that appear to enhance its activity in vitro. Furthermore, a meta-analysis suggested that the combination of FU with LV increased the response rate as compared to FU monotherapy in patients with advanced colorectal cancer. Purpose: To evaluate the impact of adjuvant treatment with the combination of FU and LV with or without interferon alfa-2a (IFN) on disease-free survival (DFS) and overall survival (OS) for patients with stage II or III colon cancer. Patients and Methods: From August 1989 to July 1997, 280 patients with stage II and III colon cancer entered the study and were randomly assigned to receive either the combination of FU (600 mg/m(2)/week x 6, followed by a 2-week rest) and LV (500 mg/m(2)/week x 6 as a 2-hour infusion, followed by a 2-week rest) for 4 cycles (group A, 139 patients), or the same chemotherapy plus recombinant IFN (3 MU subcutaneously 3 times a week) for 1 year (group B, 141 patients). Results: A total of 109 patients (78.9%) of group A and 119 (84.4%) of group B complated four cycles of chemotherapy. Also, 51.4% of patients of group A and 53.9% of group B received greater than or equal to 80% of the planned dose of FU. One patient (group A) was found to be ineligible and was not included in the analysis. The median relative dose intensity of FU in the two groups was 0.90 and 0.85, respectively. As of August 1998, after a median follow up of 4 years, there was no significant difference in either 3-year DFS (group A, 83.1%; group B, 75.9%, p = 0.14) or OS (group A, 84.5%; group B, 80.0%, p = 0.27). In the Cox model, stage of disease, number of infiltrated nodes, tumor grade and presence of regional implants were identified as significant prognostic factors for OS. Grade 3-4 toxicities, mainly diarrhea, were observed in 26.1% of patients of group A and in 24.8% of group B, There were no treatment-related deaths. Conclusions: The addition of IFN to the combination of FU with LV postoperatively does not improve DFS and OS of patients with stage II or III colon cancer. Copyright (C) 2000 S. Karger AG, Basel.

BACKGROUND: It has been shown in randomized studies that adjuvant treatment with the combination of fluorouracil (FU) and levamisole reduced the risk of recurrence and deaths of patients with stage III colon cancer. Pharmacological studies of FU led to its use in combination with a number of modulating agents including interferon-alpha and leucovorin (LV) that appear to enhance its activity in vitro. Furthermore, a meta-analysis suggested that the combination of FU with LV increased the response rate as compared to FU monotherapy in patients with advanced colorectal cancer. PURPOSE: To evaluate the impact of adjuvant treatment with the combination of FU and LV with or without interferon alfa-2a (IFN) on disease-free survival (DFS) and overall survival (OS) for patients with stage II or III colon cancer. PATIENTS AND METHODS: From August 1989 to July 1997, 280 patients with stage II and III colon cancer entered the study and were randomly assigned to receive either the combination of FU (600 mg/m(2)/week x 6, followed by a 2-week rest) and LV (500 mg/m(2)/week x 6 as a 2-hour infusion, followed by a 2-week rest) for 4 cycles (group A, 139 patients), or the same chemotherapy plus recombinant IFN (3 MU subcutaneously 3 times a week) for 1 year (group B, 141 patients). RESULTS: A total of 109 patients (78.9%) of group A and 119 (84.4%) of group B completed four cycles of chemotherapy. Also, 51.4% of patients of group A and 53.9% of group B received > or =80% of the planned dose of FU. One patient (group A) was found to be ineligible and was not included in the analysis. The median relative dose intensity of FU in the two groups was 0.90 and 0.85, respectively. As of August 1998, after a median follow up of 4 years, there was no significant difference in either 3-year DFS (group A, 83.1%; group B, 75.9%, p = 0.14) or OS (group A, 84.5%; group B, 80.0%, p = 0.27). In the Cox model, stage of disease, number of infiltrated nodes, tumor grade and presence of regional implants were identified as significant prognostic factors for OS. Grade 3-4 toxicities, mainly diarrhea, were observed in 26.1% of patients of group A and in 24.8% of group B. There were no treatment-related deaths. CONCLUSIONS: The addition of IFN to the combination of FU with LV postoperatively does not improve DFS and OS of patients with stage II or III colon cancer. Oncology

Summary Background Randomized studies have shown that postoperative chemotherapy with or without radiation therapy (RT) improved local control and survival of patients with stages II or III rectal cancer. However, the optimal sequence of treatments and the optimal chemotherapeutic regimen have not been defined. Modulation of fluorouracil (FU) by leucovorin (LV) has yielded a highly significant difference in response rate from that of FU monotherapy, as suggested by an overview of randomized trials in patients with advanced colorectal cancer. However, this difference in response rate did not translate into a survival benefit. Purpose To evaluate the impact on the disease-free survival (DFS) and overall survival (OS) of patients with stages II or III rectal cancer of postoperative RT and concomitant bolus FU administration alone or with additional chemotherapy using FU and high-dose LV. Patients and methods From October 1989 until February 1997, 220 patients were randomized postoperatively to receive either one cycle of chemotherapy with FU (600 mg/m2/week × 6 followed by a two-week rest) and leucovorin (LV, 500 mg/m2/week × 6 as a two-hour infusion) followed by pelvic RT with concomitant FU (400 mg/m2) as a rapid intravenous injection during the first three and last three days of RT, and three more cycles of the same chemotherapy with FU and LV (standard, group A, 111 patients) or pelvic RT with concomitant FU only (experimental, group B, 109 patients). Results As of August 1998, after a median follow-up of 4.9 years, there was no significant difference in either three-year DFS (Group A, 70.3%; group B, 68.2%, P = 0.53) or OS (group A, 77%; group B, 73.3%, P = 0.75). Cox multivariate analysis revealed stage of disease, number of infiltrated nodes, tumor grade, presence of regional implants and perforation to be significant prognostic factors. The incidence of severe side effects was significantly higher in the patients in group A than in those in group B (32.4% vs. 4.6%, P > 0.0001). Conclusions The incorporation of additional chemotherapy with FU and LV into postoperative concomitant RT and bolus infusion of FU does not offer a ≥ 10% three-year survival benefit over that of concomitant RT and bolus infusion of FU, and significantly increases toxicity in patients with stages II or III rectal cancer.

Background: Randomized studies have shown that postoperative chemotherapy with or without radiation therapy (RT) improved local control and survival of patients with stages II or III rectal cancer. However, the optimal sequence of treatments and the optimal chemotherapeutic regimen have not been defined. Modulation of fluorouracil (FU) by leucovorin (LV) has yielded a highly significant difference in response rate from that of FU monotherapy, as suggested by an overview of randomized trials in patients with advanced colorectal cancer. However, this difference in response rate did not translate into a survival benefit. Purpose: To evaluate the impact on the disease-free survival (DFS) and overall survival (OS) of patients with stages II or III rectal cancer of postoperative RT and concomitant bolus FU administration alone or with additional chemotherapy using FU and high-dose LV. Patients and methods: From October 1989 until February 1997, 220 patients were randomized postoperatively to receive either one cycle of chemotherapy with FU (600 mg/m(2)/week x 6 followed by a two-week rest) and leucovorin (LV, 500 mg/m(2)/week x 6 as a two-hour infusion) followed by pelvic RT with concomitant FU (400 mg/m(2)) as a rapid intravenous injection during the first three and last three days of RT, and three more cycles of the same chemotherapy with FU and LV (standard, group A, 111 patients) or pelvic RT with concomitant FU only (experimental, group B, 109 patients). Results: As of August 1998, after a median follow-up of 4.9 years, there was no significant difference in either three-year DFS (Group A, 70.3%; group B, 68.2%, P = 0.53) or OS (group A, 77%; group B, 73.3%, P = 0.75). Cox multivariate analysis revealed stage of disease, number of infiltrated nodes, tumor grade, presence of regional implants and perforation to be significant prognostic factors. The incidence of severe side effects was significantly higher in the patients in group A than in those in group B (32.4% vs. 4.6%, P < 0.0001). Conclusions: The incorporation of additional chemotherapy with FU and LV into postoperative concomitant RT and bolus infusion of FU does not offer a greater than or equal to 10% three-year survival benefit over that of concomitant RT and bolus infusion of FU, and significantly increases toxicity in patients with stages II or III rectal cancer.

One hundred and seven previously untreated patients with measurable metastatic colorectal cancer who were treated with 5-fluorouracil (5FU) and leucovorin (LV) in two different maximum doses and schedules were retrospectively analyzed. Group A, 52 pts, was treated with LV 200 mg/m(2)/D IV push, followed by 5FU 700 mg/m(2)/D IV 1 h infusion for 5 D. Cycle was repeated every 21 D. Group B, 55 pts, was treated with LV 500 mg/m(2)/D in a 2 h infusion and 5FU 600 mg/m(2)/D IV bolus at mid-time of LV infusion, repeated every week for 6 wk followed by 2-wk rest period. There was no difference in response (A 8%, B 11%). Median survival for A was 37 (2-131) wk, B was 59 (1-112) wk (P = 0.021), time to progression for A was 20 (0-131) wk, B 30 (0-102) wk (P = 0.021). Administered mean dose intensity of LV was 350.8 mg/m(2)/wk in group A and 405.0 mg/m(2)/wk in group B without any significant difference; that of 5FU was significantly higher in group A as compared to group B (1205.3 vs 468.9 mg/m(2)/wk, respectively) (p < 0.0001). This difference was a consequence of the planned dose intensity for this drug in the two treatment regimens. Toxicity was more frequent and intense in group A for mucositis (P < 0.001), fatigue (P < 0.01), and neurotoxicity (P < 0.05), and in group B for neutropenia (P < 0.001) and nausea-vomiting (P < 0.001). There were one and four iatrogenic deaths in group A and B patients, respectively (NS). Although this study was not prospective and randomized, we can conclude that toxicity was significantly different in the two groups, with a prevalence of mucositis in group A and neutropenia in group B and a higher number of iatrogenic deaths in the latter group. Response rates were the same for the two groups although survival and time to progression were significantly increased for group B patients.