Critical role of bevacizumab scheduling in combination with pre-surgical chemo-radiotherapy in MRI-defined high-risk locally advanced rectal cancer: Results of the BRANCH trial.

BACKGROUND: We have previously shown that an intensified preoperative regimen including oxaliplatin plus raltitrexed and 5-fluorouracil/folinic acid (OXATOM/FUFA) during preoperative pelvic radiotherapy produced promising results in locally advanced rectal cancer (LARC). Preclinical evidence suggests that the scheduling of bevacizumab may be crucial to optimize its combination with chemo-radiotherapy. PATIENTS AND METHODS: This non-randomized, non-comparative, phase II study was conducted in MRI-defined high-risk LARC. Patients received three biweekly cycles of OXATOM/FUFA during RT. Bevacizumab was given 2 weeks before the start of chemo-radiotherapy, and on the same day of chemotherapy for 3 cycles (concomitant-schedule A) or 4 days prior to the first and second cycle of chemotherapy (sequential-schedule B). Primary end point was pathological complete tumor regression (TRG1) rate. RESULTS: The accrual for the concomitant-schedule was early terminated because the number of TRG1 (2 out of 16 patients) was statistically inconsistent with the hypothesis of activity (30%) to be tested. Conversely, the endpoint was reached with the sequential-schedule and the final TRG1 rate among 46 enrolled patients was 50% (95% CI 35%-65%). Neutropenia was the most common grade ≥ 3 toxicity with both schedules, but it was less pronounced with the sequential than concomitant-schedule (30% vs. 44%). Postoperative complications occurred in 8/15 (53%) and 13/46 (28%) patients in schedule A and B, respectively. At 5 year follow-up the probability of PFS and OS was 80% (95%CI, 66%-89%) and 85% (95%CI, 69%-93%), respectively, for the sequential-schedule. CONCLUSIONS: These results highlights the relevance of bevacizumab scheduling to optimize its combination with preoperative chemo-radiotherapy in the management of LARC.

Efficacy and tolerability of biweekly bevacizumab, irinotecan, folinic acid and fluorouracil intravenous bolus (BIFF Regimen) in patients with metastatic colorectal cancer: the southern Italy cooperative oncology group experience.

BACKGROUND: We have extensively assessed a biweekly regimen of irinotecan plus folinic acid and fluorouracil bolus (IRIFAFU) in metastatic colorectal cancer (MCRC). Here, we report on the safety and activity of BIFF (bevacizumab plus IRIFAFU) regimen in 94 mCRC patients. PATIENTS AND METHODS: Bevacizumab 5 mg/kg (1 hour), and irinotecan 180 mg/m(2) (1 hour) were given intravenously on day 1, 6S-folinic acid 250 mg/m(2) (2 hours), and fluorouracil 850 mg/m(2) (bolus) were given intravenously on day 2 every 2 weeks for a median of 9 cycles per patient (range, 1-12), and maintenance bevacizumab alone was delivered in 16 cases. RESULTS: Grade ≥ 3 hematologic toxicities were neutropenia (50%) and febrile neutropenia (5%). Most common grade 3 nonhematologic side effects were diarrhea (20%), vomiting (7%), nausea (4%), and stomatitis (4%). Severe hypertension (1%) and epistaxis (1%) rarely occurred. Six complete responses and 44 partial responses were registered, giving a response rate of 53% (95% CI, 43%-64%). Median progression-free survival was 11.5 months (95% CI, 9.0-14.0 months). Forty-three (46%) patients eventually died, and the median overall survival was 24.0 months (95% CI, 20.2-27.8 months). CONCLUSION: Bevacizumab appeared to increase the activity of the IRIFAFU regimen without worsening its tolerability. Efficacy of BIFF was comparable with that reported with other bevacizumab plus irinotecan-based combinations.

Molecular analysis of Fanconi anemia and mismatch repair genes in patients with colorectal carcinoma.

A cohort of 206 consecutively-collected patients with colorectal carcinoma (CRC) were screened for germline mutations in the principal DNA mismatch repair (MMR) genes, MLH1 and MSH2, and in the Fanconi anemia (FA) genes involved in homologous recombination DNA repair. Mutation analysis was performed by denaturing high-performance liquid chromatography (DHPLC) and automated sequencing. Available paraffin-embedded tumor tissues were evaluated for gene expression by immunohistochemistry. Genes of the FA pathway were found to participate in CRC pathogenesis, being silenced during disease progression and metastasis formation. Conversely, MLH1 and MSH2 genes seem to be inactivated at earlier stages of the disease. Finally, very few (about 5%) cases presented a simultaneous inactivation of the MMR and FA genes. Overall, our findings indicated that: i) mismatch DNA repair remains the main mechanism to be altered at both germline and somatic levels among CRC patients; ii) functional impairments of mismatch DNA repair and FA-related repair may represent two different pathogenetic alterations which are concurring in colorectal cancer progression.

Oxaliplatin plus dual inhibition of thymidilate synthase during preoperative pelvic radiotherapy for locally advanced rectal carcinoma: long-term outcome.

PURPOSE: To assess the safety and efficacy of oxaliplatin (OXA) plus dual inhibition of thymidilate synthase during preoperative pelvic radiotherapy (RT) in patients with poor prognosis for rectal carcinoma. METHODS AND MATERIALS: Sixty-three patients with the following characteristics, a clinical (c) stage T4, cN1-2, or cT3N0 of ≤5 cm from the anal verge and/or with a circumferential resection margin (CRM) of ≤5 mm (by magnetic resonance imaging), received three biweekly courses of chemotherapy with OXA, 100 mg/m2; raltitrexed (RTX), 2.5 mg/m2 on day 1, and 5-fluorouracil (5-FU), 900 mg/m2 (31 patients) or 800 mg/m2 (32 patients); levo-folinic acid (LFA), 250 mg/m2 on day 2, during pelvic RT (45 Gy). Pathologic response was defined as complete pathological response (ypCR), major (tumor regression grade(TRG) 2 to 3, with ypCRM-ve and ypN-ve) or minor or no response (TRG4 to -5, or ypCRM+ve, or ypN+ve). Adjuvant 5-FU/LFA regimen was given in cases of cT4, ypN+ve, or ypCRM+ve. RESULTS: Overall, neutropenia (40%) and diarrhea (13%) were the most common grade≥3 toxicities, and tolerability was better with a 5-FU dose reduction. No significant difference in pathologic response was seen according 5-FU dosage: overall, a ypCR was obtained in 24 (39%) patients, and a major response in 20 (32%) patients. The 5-year probability of freedom from recurrence was 80% (95% confidence interval, 68%-92%); it was 56% for the minor/no response group, while it was around 90% for both the ypCR and the major response group. CONCLUSIONS: OXA, RTX, and 5-FU/LFA administered during pelvic RT produced promising early and long-term results in rectal carcinoma patients with poor prognosis. The postoperative treatment strategy applied in our study supports the risk-adapted approach in postoperative management.

Baseline physical functioning status of metastatic colorectal cancer patients predicts the overall survival but not the activity of a front-line oxaliplatin-fluoropyrimidine doublet.

BACKGROUND: No differences in response rate (RR), progression-free survival (PFS), overall survival (OS) and quality of life (QoL) were seen in patients randomly treated with biweekly oxaliplatin plus either fluorouracil/folinic acid or capecitabine. METHODS: We investigated the independent effect of baseline clinical characteristics and physical functioning (PF) domain on RR, PFS, and OS in 310 patients who completed the EORTC QLQ-C30 questionnaire. Multivariate analyses stratified by treatment were performed. An exploratory analysis was done by grouping patients with a PF score superior or equal to the highest quartile (n = 111), included between the highest and the lowest quartiles (n = 99), or inferior to the lowest quartile (n = 100). The relationship between these three groups and the ECOG PS was then analysed. RESULTS: At multivariate analysis, OS was negatively affected by the number of metastatic sites, the serum alkaline phosphatase, and the ECOG PS, while it was positively affected by the previous surgical resection of the primary tumour. Adding the baseline PF score, the number of disease sites (p < 0.0001), the serum alkaline phosphatase (p = 0.0057), and the PF (p = 0.0007) retained an independent significance, while the ECOG PS and the previous surgery were no longer significant. PF did not significantly affect PFS or RR. A good but not totally overlapping correlation was found between PF grouping and ECOG PS score. CONCLUSIONS: Baseline self-reported PF independently predicted the OS of patients. Assessment of QoL should be incorporated in randomised trials evaluating the management of patients with MCRC.

Optimizing the management of metastatic colorectal cancer.

The prognosis of patients with metastatic colorectal cancer has significantly improved in the last few years, with the introduction into the clinical practice of new cytotoxic treatments, the availability of non-cross resistant agents after the front-line treatment failure, and the combination of targeted agents (i.e., the inhibitors of the epidermal growth factor and vascular endothelial growth factor pathways) with conventional drugs. All these options must be incorporated into a complex strategy of management, in which a customized management according to the disease status, with an intensified induction approach followed by maintenance (and reinduction), should be investigated.

Gemcitabine combined with either pemetrexed or paclitaxel in the treatment of advanced non-small cell lung cancer: a randomized phase II SICOG trial.

PURPOSE: To estimate the safety, activity, and impact on quality of life of a combination of gemcitabine and pemetrexed in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) in the context of a randomized two-stage phase II study. PATIENTS AND METHODS: Patients in stage IIIB or IV NSCLC were randomly allocated to receive either gemcitabine 1250 mg/m(2) on day 1, and pemetrexed (Alimta) 500 mg/m(2) followed by gemcitabine 1250 mg/m(2) on day 8 of a 3-weekly cycle (GA arm), or paclitaxel 120 mg/m(2) followed by gemcitabine 1000 mg/m(2), both given on days 1 and 8 of a 3-weekly cycle (PG arm). RESULTS: 105 (GA arm, 51; PG arm, 54) eligible patients (stage IV, 32 and 30, respectively) were enrolled into this study; thereafter, accrual was stopped due to first-stage analysis. The response rate was 20% (95% confidence interval [CI], 10-33%) in the GA arm, and 32% (95% CI, 20-46%) in the PG arm. Median progression-free survival was 5.1 (95% CI, 3.7-6.5) months in the GA arm, and 8.3 (95% CI, 5.9-10.7) months in the PG arm, while median overall survival was 10.5 (95% CI 7.1-13.9), and 13.3 (95% CI 11.7-14.9) months, respectively. Severe neutropenia (36% vs 22%), and febrile neutropenia (14% vs 7%) were more common with the GA regimen, while hair loss (52% vs 16%) and any grade peripheral neuropathy (31% vs 2%) occurred more frequently with PG regimen. Other severe side effects of GA regimen were diarrhoea (10%), liver enzyme derangement (10%), and fatigue (8%). CONCLUSION: The GA regimen was tolerated and moderately active in advanced or metastatic NSCLC. However, this combination did not yield any advantage in comparison with the PG regimen, and does not deserve further evaluation.

Role of oxaliplatin in the treatment of colorectal cancer.

Oxaliplatin is a third-generation platinum compound that has shown a definite role in the management of colorectal cancer (CRC). Oxaliplatin in combination with fluorouracil and leucovorin in the FOLFOX4 regimen represents a new standard of treatment in the adjuvant setting as well as for the metastatic disease. The combination of oxaliplatin with capecitabine in the XELOX regimen has been demonstrated to be not inferior to FOLFOX4 in metastatic patients, and it is under evaluation, with or without bevacizumab, in the post-surgical management of resected patients. FOLFOX4 and XELOX regimens represent a backbone on which to add new targeted drugs. Indeed, the combination of bevacizumab with either FOLFOX4 or XELOX significantly prolonged the progression-free survival and overall survival in comparison with FOLFOX4 or XELOX combined with placebo in metastatic CRC patients, while FOLFOX4 plus cetuximab produced a significantly greater activity than FOLFOX4 alone in metastatic CRC patients with K-RAS wild type.

Emerging role of capecitabine in gastric cancer.

For many years, a regimen of fluorouracil and cisplatin has been the standard of care for the treatment of patients with metastatic gastric cancer. More recently, triplet regimens that incorporate fluorouracil and cisplatin with epirubicin (ECF) or docetaxel are being used in the management of patients with metastatic disease; ECF is also being used as preoperative treatment of resectable disease. Capecitabine, a prodrug of fluorouracil that can be taken orally, has been assessed as an alternative to intravenous fluorouracil and has demonstrated noninferiority to its parent compound. Several trials have demonstrated the safety and efficacy of regimens combining capecitabine with other known active drugs against gastric cancer in doublet and triplet combinations. Oral capecitabine appears to be more convenient to administer than infused fluorouracil because it may obviate the need for central venous access and its associated risk of complications. All of these findings support consideration of capecitabine among the available drug treatment options for patients with metastatic and those with operable gastric cancers.

Oxaliplatin, irinotecan, and fluorouracil/folinic acid in advanced gastric cancer: a multicenter phase II trial of the Southern Italy Cooperative Oncology Group.

PURPOSE: This phase II trial assessed the tolerability and efficacy of a triplet of oxaliplatin, irinotecan, and fluorouracil/folinic acid in advanced gastric cancer. METHODS: Patients with unresectable or metastatic gastric cancer, unexposed to palliative chemotherapy, received oxaliplatin 85 mg/m(2) iv and irinotecan 150 mg/m(2) iv on day 1, 6S-folinic acid 250 mg/m(2) iv and fluorouracil 750 mg/m(2) iv on day 2, every 2 weeks. Response rate (RR) was assessed after a minimum of four cycles, and treatment continued up to 12 cycles. RESULTS: Sixty-three patients were treated, with a median of eight (range 1-12) cycles/patient. Two complete and 19 partial responses were registered (RR 33% [95% CI, 22-46%]). Median progression-free survival was 7.5 (95% CI, 5.6-9.4) months, and median overall survival was 12.1 (95% CI, 10.8-13.4) months. Most common grade > or =3 toxicities were neutropenia (59%), febrile neutropenia (7%), vomiting (20%), and diarrhoea (10%). All-grade neurotoxicity affected 33% of patients. CONCLUSIONS: Oxaliplatin, irinotecan, and fluorouracil/folinic acid administered every 2 weeks are safe and active in advanced gastric cancer.

Randomised trial comparing biweekly oxaliplatin plus oral capecitabine versus oxaliplatin plus i.v. bolus fluorouracil/leucovorin in metastatic colorectal cancer patients: results of the Southern Italy Cooperative Oncology study 0401.

PURPOSE: Oxaliplatin combined with either fluorouracil/leucovorin (OXAFAFU) or capecitabine (OXXEL) has a demonstrated activity in metastatic colorectal cancer patients. We aimed at comparing these two regimens in terms of response rate (RR), safety, progression-free survival (PFS), and quality of life (QoL) of patients. METHODS: A total of 322 patients with metastatic colorectal cancer were randomized to receive biweekly: oxaliplatin 100 mg/m(2) i.v. on day 1, capecitabine 1,000 mg/m(2) orally twice daily from day 1 to day 11 (OXXEL); or oxaliplatin 85 mg/m(2) i.v. on day 1; 6S-leucovorin 250 mg/m(2) i.v. and fluorouracil 850 mg/m(2) i.v. on day 2 (OXAFAFU). RESULTS: Eleven complete and 42 partial responses were registered with OXXEL (RR = 34%); six complete and 48 partial responses were obtained with OXAFAFU (RR = 33%) (P = 0.999). Severe adverse events were less frequent (32 vs. 43%) with OXXEL, which also reduced the occurrence of severe neutropenia (10 vs. 27%) and febrile neutropenia (6 vs. 13%), but produced more gastric side effects (8 vs. 3%) and diarrhea (13 vs. 8%). QoL did not differ across the two arms. Median PFS was 6.6 months in the OXXEL, and 6.5 months in the OXAFAFU arm (HR = 1.12, P = 0.354). Median overall survival was 16.0 and 17.1 months (HR = 1.01, P = 0.883). CONCLUSIONS: OXXEL and OXAFAFU regimens were equally active in metastatic colorectal cancer. The choice should be based on patient preference and on pharmacoeconomic evaluations.

Capecitabine, alone and in combination, in the management of patients with colorectal cancer: a review of the evidence.

Capecitabine, an oral prodrug of fluorouracil (5FU), has shown efficacy in terms of progression-free and overall survival at least equivalent to standard folinic acid (leucovorin)-modulated intravenous 5FU bolus regimens in patients with metastatic colorectal cancer. Moreover, capecitabine has demonstrated a better tolerability profile, producing a significantly lower occurrence of severe stomatitis than 5FU plus folinic acid regimens, making this drug particularly attractive for treating elderly patients. In addition, capecitabine can be combined with other active drugs such as irinotecan or oxaliplatin. Indeed, the combination of capecitabine plus oxaliplatin (XELOX regimen) now represents a new standard of care for the metastatic disease and is also under evaluation in the adjuvant setting. The combination of new biological drugs, such as bevacizumab, with the XELOX regimen was shown to further prolong the time to progression of metastatic disease, and might reduce the risk of recurrence for those with resected colon cancer with poor risk factors. Cost-effectiveness analyses have demonstrated that, despite higher acquisition costs, capecitabine appears to be more cost effective than standard treatments for the management of colorectal cancer patients.

Comparison of the safety and efficacy of paclitaxel plus gemcitabine combination in young and elderly patients with locally advanced or metastatic non-small cell lung cancer. A retrospective analysis of the Southern Italy Cooperative Oncology Group trials.

We retrospectively assessed tolerability and efficacy of paclitaxel plus gemcitabine combination in 259 patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) enrolled in three randomized SICOG trials according to their age (70 years) at study entry. Apart from age, demographic and clinical characteristics were similar in the two groups. Response rate of paclitaxel plus gemcitabine was similar in younger and in elderly (36% versus 30%). Chemotherapy was well tolerated, but severe neutropenia (12% versus 7%), anaemia (6.6% versus 1.8%), and vomiting (5% versus 0) were more frequent in elderly patients. Both median progression-free survival (PFS, 5.5 months versus 4.2 months), and overall survival (OS, 11.1 months versus 9.1 months) resulted slightly prolonged for younger patients. However, only stage and performance status resulted independently affecting PFS and OS. In conclusion, paclitaxel plus gemcitabine were similarly tolerated and active in younger and elderly patients. This regimen should be considered an option for the management of fit elderly patients.

Synergistic antitumour effect of raltitrexed and 5-fluorouracil plus folinic acid combination in human cancer cells.

5-Fluorouracil, usually in combination with folinic acid, is widely used in the treatment of both colorectal and head and neck squamous cell cancer patients. Since 5-fluorouracil plus folinic acid and the antifolate thymidylate synthase inhibitor; raltitrexed have distinct mechanisms of action and toxicity profiles, we have evaluated the potential synergistic antitumor interaction between these two agents combined with a sequential schedule of administration in KB (wt-p53) and Cal27 (mut-p53) head and neck squamous cell carcinomas, and LoVo (wt-p53) and HT29 (mut-p53) colorectal cell lines. The combination between a 24-h exposure to raltitrexed followed by a 4-h exposure to 5-fluorouracil plus folinic acid was globally synergistic, as assessed by the median effect principle and combination index. A specific contribution of folinic acid to the cytotoxic effect of the raltitrexed/5-fluorouracil combination was clearly demonstrated by the evaluation of the potentiation factor. In all cell lines, a 1.5- up to 17-fold reduction in the IC50 of both raltitrexed and 5-fluorouracil plus folinic acid was observed in the combination setting compared with the concentrations of the each drug used alone. Moreover, we demonstrated that raltitrexed/5-fluorouracil plus folinic acid induced a distinct S-phase block of the cell cycle, as well as a potentiation of the apoptotic cell death, compared with 5-fluorouracil plus folinic acid or raltitrexed/5-fluorouracil combination. This preclinical work represents, at least to our knowledge, the first demonstration of a synergistic interaction between raltitrexed and 5-fluorouracil modulated by folinic acid, and could represent a rationale for further clinical investigation of raltitrexed/5-fluorouracil plus folinic acid combination.

Intra-patient alternated dose escalation of paclitaxel and gemcitabine versus paclitaxel followed by fixed dose rate infusion of gemcitabine in fit elderly non-small cell lung cancer patients. A Southern Italy Cooperative Oncology Group randomised phase II trial.

PURPOSE: This study was undertaken to select the best schedule of administration for the paclitaxel plus gemcitabine combination in fit elderly patients affected by locally advanced or metastatic non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Ninety-eight patients in stage III or IV NSCLC, aged 70 years or more and in ECOG performance status (PS)

A review of the role of capecitabine in the treatment of colorectal cancer.

5-fluorouracil/leucovorin, with or without oxaliplatin or irinotecan, is the most widely used treatment for the metastatic as well for the adjuvant setting of colorectal cancer. These agents are administered intravenously (by bolus or infusion), thereby causing significant inconvenience to patients. Capecitabine, an oral fluoropyrimidine, has been demonstrated to be at least as effective as bolus 5-fluorouracil/leucovorin in terms of time to disease progression, time to treatment failure, and overall survival, but achieves significantly higher response rates and has the advantage of oral administration. In addition, capecitabine has improved tolerability with a significantly lower incidence of stomatitis, nausea, and alopecia than 5-fluorouracil/leucovorin. Clinical trials have shown that combination therapy with capecitabine and either irinotecan or oxaliplatin is effective and well tolerated. The combination of capecitabine plus oxaliplatin, with or without bevacizumab, could represent the new standard of care for metastatic as well as surgically resected high-risk stage II and III colon cancer patients. Some pharmacoeconomic analyses have highlighted that capecitabine plus oxaliplatin results in cost savings compared with 5-fluorouracil/leucovorin plus oxaliplatin.

18F-FDG PET is an early predictor of pathologic tumor response to preoperative radiochemotherapy in locally advanced rectal cancer.

UNLABELLED: 18F-FDG PET is a useful tool for assessing the effects of chemo- or radiotherapy. The aim of this study was to correlate the change in tumor 18F-FDG standardized uptake value (SUV) during and after preoperative radiochemotherapy, with the pathologic response achieved in locally advanced rectal cancer (LARC) patients. METHODS: Thirty-three patients with LARC underwent total mesorectal excision after preoperative treatment, including 3 cycles of oxaliplatin, raltitrexed, 5-fluorouracil, and folinic acid during pelvic radiotherapy (45 Gy). Staging procedures included endoscopic ultrasound, MRI, and CT. 18F-FDG PET scans were performed at baseline and 12 d after starting radiochemotherapy (intermediate) in all patients. Seventeen patients also had a presurgical scan. For each scan, mean and maximum SUVs were measured. The percentages of SUV decrease from baseline to intermediate (early change) and to presurgical scan (overall change) were assessed and correlated with pathologic response classified as tumor regression grade (TRG). RESULTS: Eighteen tumors (55%) showed complete (TRG1) or subtotal regression (TRG2) and were classified as responders, whereas 15 cases (45%; TRG3 or TRG4) were considered nonresponders. The early median decrease of tumor SUV significantly differed between responders (-62%; range, -44% to -100%) and nonresponders (-22%; range, -2% to -48%). A significant correlation was also found between TRGs and early SUV changes (P < 0.0001). Responders were identified correctly by an early decrease of the mean SUV of > or =52%. CONCLUSION: This study shows that early 18F-FDG PET can predict pathologic response to preoperative treatment. These findings support the usefulness of (18)F-FDG PET during the management with radiochemotherapy of LARC patients.

Biweekly oxaliplatin plus irinotecan and folinic acid-modulated 5-fluorouracil: a phase II study in pretreated patients with metastatic colorectal cancer.

Oxaliplatin (OXA) and irinotecan (IRI) are active drugs for metastatic colorectal cancer, their toxicity profiles are not overlapping, and both drugs have shown at least additivity with folinic acid-modulated 5-fluorouracil (5FU). We carried out this phase II study to assess the activity and toxicity of a biweekly regimen including OXA plus IRI on day 1, and levo-folinic acid (LFA) plus 5FU on day 2 (OXIRIFAFU) in pretreated patients with metastatic colorectal cancer. Forty-one patients, all previously treated with adjuvant and/or palliative 5FU-based chemotherapy (16 of them already exposed to IRI, OXA or both), were enrolled into this trial. On the basis of sensitivity to previous treatment, 19 patients were considered as chemo-resistant and 14 patients as chemo-refractory. OXA 110 mg/m (over 2 h) and IRI 175 mg/m (over 1 h) were delivered on day 1, followed by LFA 250 mg/m (2-h infusion) plus 5FU 800 mg/m as intravenous bolus on day 2. Cycles were repeated every 2 weeks. A total of 348 cycles were delivered, with a median of nine cycles per patient (range, 1-12 cycles per patient). Five complete and 13 partial responses were reported on 40 assessable patients, giving a response rate of 45% [95% confidence interval (CI), 29-62%]; eight of 19 (42%) resistant patients and five of 14 (36%) refractory patients achieved a major response, which was also obtained in four of eight (50%) patients pretreated with IRI and in three of eight (38%) patients pretreated with OXA. Grade 3 or higher neutropenia occurred in 68% of patients, but febrile neutropenia or infections affected only seven (17%) patients. No episodes of grade 3 or higher thrombocytopenia or anemia were recorded. Occurrence of severe non-hematologic toxicities by patients were: diarrhea, 34%; vomiting, 17%; peripheral cumulative neuropathy, 15%; stomatitis, 10%; acute cholinergic syndrome, 7%. Actually delivered dose intensities of all three drugs resulted in about two-thirds of the planned ones. After a follow-up of 39 months, median progression-free survival was 7.5 months. Median overall survival was 14.4 (95% CI, 10.4-18.4) months from the start of OXIRIFAFU and 25.3 (95% CI, 18.1-32.5) months from the diagnosis of metastatic disease. This OXIRIFAFU triplet regimen was highly effective in resistant/refractory colorectal cancer patients. A slight dose reduction of all cytotoxic drugs could be advisable in order to improve the tolerability of this regimen without jeopardizing its activity.

Real-time contrast-enhanced specific ultrasound in staging and follow-up of splenic lymphomas.

From January 2003 to April 2005 we studied 25 lymphoma patients (10 with HD, 4 with low-grade NHL, 6 with high-grade NHL and 5 with chronic lymphatic leukaemia; 14 men, 11 women, age range 28-79 years). After a baseline US study we rapidly injected 4.8 mL of the second-generation microbubble contrast agent SonoVue (Bracco, Italy). Contrast enhanced studies were carried out with the contrast-specific software named Contrast Tuned Imaging (Esaote, Italy) using a continuous, harmonic acquisition and a low acoustic pressure. The CS-US findings were correlated with results of standard tools, including CT, MRI, US follow up. CS-US revealed correctly 47 out of the 52 lesions identified by CT scan, in the absence of false positive findings (sensitivity = 90%; Specificity = 100%, in comparison to CT scan). Complete concordance in evaluating the lesion extension of the CS-US in respect to CT was 88%, while underestimate occurred in 9% and overestimate in 3% of cases. On the contrary, basic sonography defined correctly the dimensional alteration in 52% of the cases, underestimated in 35% and overestimated in 13%, thus showing significantly lower accuracy (chi-square = 30.0, p < 0.001). In our experience, CS-US was superior to conventional sonography even from a qualitative point of view.

Phase I study of temozolomide and lomustine in the treatment of high grade malignant glioma.

Systematic reviews and meta-analysis have demonstrated an improved prognosis by chemotherapy of malignant glioma patients. The effects of clinical research therefore have the aim to find more active drugs or new combination therapies. The combination of Temozolomide (TMZ) and nitrosoureas was evaluated preclinically with an evidence of therapeutic synergy. Based on these findings, we have carried out a phase I study with TMZ administered in low, prolonged doses of 75 mg/m2 per day, once a day for 21 days, escalated in cohorts of 3 patients, in combination with a fixed dose of Lomustine (CCNU) 100 mg/m2 orally on day 1. MTD was evident. The treatment was generally well tolerated. We did not observe bleeding or severe infections, as described for several combination chemotherapies with TMZ and other agents. In this study, for the first time in high grade malignant glioma, two orally administrated drugs were associated .TMZ 75 mg/m2 for 28 consecutive days and CCNU 100 mg/m2 on day 1 of every 6 weeks could be recommended as a safe treatment dosage. One of the ten patients evaluated for clinical response showed a partial response, while nine showed stability of disease, with a median duration of from 5 to 6 months.