A randomized, double-blind, placebo-controlled, multicenter study of a ginger extract in the management of chemotherapy-induced nausea and vomiting (CINV) in patients receiving high-dose cisplatin.

BACKGROUND: The activity of ginger in the management of chemotherapy-induced nausea and vomiting (CINV) has been suggested, but design inadequacies, heterogeneity of the population, small numbers and poor quality of tested products limit the possibility to offer generalizable results. PATIENTS AND METHODS: We conducted a randomized, double-blind, placebo-controlled, multicenter study in patients planned to receive ≥2 chemotherapy cycles with high dose (>50 mg/m2) cisplatin. Patients received ginger 160 mg/day (with standardized dose of bioactive compounds) or placebo in addition to the standard antiemetic prophylaxis for CINV, starting from the day after cisplatin administration. CINV was assessed through daily visual-analogue scale and Functional Living Index Emesis questionnaires. The main objective was protection from delayed nausea; secondary end points included intercycle nausea and nausea anticipatory symptoms. RESULTS: In total, 121 patients received ginger and 123 placebo. Lung (49%) and head and neck cancer (HNC; 35%) were the most represented tumors. No differences were reported in terms of safety profile or compliance. The incidence of delayed, intercycle and anticipatory nausea did not differ between the two arms in the first cycle and second cycle. A benefit of ginger over placebo in Functional Living Index Emesis nausea score differences (day 6-day 1) was identified for females (P = 0.048) and HNC patients (P = 0.038). CONCLUSIONS: In patients treated with high-dose cisplatin, the daily addition of ginger, even if safe, did not result in a protective effect on CINV. The favorable effect observed on nausea in subgroups at particular risk of nausea (females; HNC) deserves specific investigation.

Is it possible to encourage hope in non-advanced cancer patients? We must try.

BACKGROUND: Data are lacking on the relationship between hope and other variables in non-advanced cancer patients. The study explored the relationship between hope, symptoms, needs, and spirituality/religiosity in patients treated in a supportive care unit (SCU). PATIENTS AND METHODS: From September 2013 to March 2014, the consecutive patients who accepted to complete: (i) Needs Evaluation Questionnaire (NEQ), (ii) the Edmonton Symptom Assessment System (ESAS), (iii) Hope Herth Index (HHI), and (iv) the System of Belief Inventory (SBI) were enrolled. Moreover, clinical/demographic data were collected and the findings were analyzed. RESULTS: A total of 276 patients who completed the HHI questionnaire (participation rate 276/300 = 92%) were included; 131 reported HHI total score >37 (median value). The majority of patients had a Karnofsky performance status >80; 71% were on cancer therapies, and only 29 patients had metastases or relapse. Patients with higher HHI scores were less educated (P = 0.012), reported lower ESAS total score (15.4 versus 22.6, P < 0.001), and had less often been referred to a psychologist previously to the study (P = 0.002); patients with a higher HHI score also reported higher spirituality (P < 0.001). Some NEQ items resulted significantly associated with HHI score after adjustment for other variables: the need to have sincere clinicians (ß = -2.7), better dialogue (ß = -2.1), and more reassurance from the clinicians (ß = -2.5); better attention (ß = -4.4) and respect for intimacy (ß = -3.3) from nurses; to speak with people who have the same illness experience (ß = -2.5), to be more reassured by relatives (ß = -3.3) and to feel less abandoned (ß = -4.3). Higher SBI scores were independently associated with higher HHI scores (ß = 1.7 for 10 points increase). CONCLUSIONS: In cancer patients, hope can be encouraged by clinicians through dialogue, sincerity, and reassurance, as well as assessing and considering the patients' needs (above all the psycho-emotional), symptoms, psychological frailty, and their spiritual/religious resources.

Targeted therapy-induced diarrhea: A review of the literature.

PURPOSE OF RESEARCH: Revision of the literature on targeted therapy-induced diarrhea (TT-ID). PRINCIPAL RESULTS: TT-ID is frequent; the mechanisms are mainly secretive, followed by ischemic or autoimmune ones. The duration of TT-ID is protracted over time. Its intensity is of grade G1-G3 but may be fatal in patients with diffuse colitis or on ipilimumab. However, no specific guidelines are available on management of different grades of TT-ID. Preventive measures with antibiotics, probiotics or activated charcoal should be further investigated. Loperamide is the first choice drug followed by octreotide. The role of corticosteroids is controversial. CONCLUSION: Early assessment and management of TT-ID is essential to prevent the worsening of this side-effect, patients' hospitalization and dose reduction or oncological treatment discontinuation. Future research is needed to better understand the pathophysiological mechanisms of TT-ID and it should also be investigated whether a specific pharmacological and/or non pharmachological approach is indicated.

Efficacy and tolerability of medical ozone gas insufflations in patients with osteonecrosis of the jaw treated with bisphosphonates-Preliminary data: Medical ozone gas insufflation in treating ONJ lesions.

Osteonecrosis of the Jaw (ONJ) is an adverse event reported especially in patients receiving cancer treatments regimen, bisphosphonates (BPs), and denosumab. We performed an open-label, prospective study in patients treated with zoledronic acid who developed ONJ lesions >2.5 cm, and had no benefit after the treatment with the standard therapy, to evaluate the efficacy and tolerability of medical ozone (O3) treatment delivered as gas insufflations on each ONJ lesions. Twenty-four patients (mean age 62.5, range 41-80; 12 female) with bone metastases due to breast (11), prostate (4)and lung (4)cancers, myeloma (2), or osteoporosis (3), previously treated with zoledronic acid and not underwent dental preventive measures and with ONJ lesions >2.5 cm, were observed and treated with topical O3 gas insufflation every third day for a minimum of 10 for each pathological area or till necrotic bone sequestrum or surgery. We used a special insufflation bell-shaped device adjusted to the specific characteristics of the patient, capable of eliminating any residue of O3 diffusion by degrading it and releasing O2 into the air. Azithromicin 500 mg/day was administered for 10 days in all patients before the first three gas insufflation although they had previously received various cycles of antibiotics. Ten patients required more than 10 O3 gas insufflations due to multiple lesions and/or purulent sovrainfections; one patient received two further O3 insufflations while waiting the day of surgery. Six of 24 patients interrupted the O3 gas therapy for oncological disease progression (five patients) and for fear of an experimental therapy (one patient). Six patients had the sequestrum and complete or partial (one patient) spontaneous expulsion of the necrotic bone followed by oral mucosa re-epithelization after a range of 4-27 of O3 gas insufflations. No patient reported adverse events. In 12 patients with the largest and deeper ONJ lesions, O3 gas therapy produced the sequestrum of the necrotic bone after 10 to 38 insufflations; surgery was necessary to remove it (11 patients). Of interest, removal was possible without the resection of healthy mandible edge because of the presence of bone sequestrum. All together the response rate was 75.0% (95% CI, 53.3-90.2%) in ITT analysis and 100% (95% CI, 81.5-100%) in the PP analysis. In all patients treated with O3 gas ± surgery, no ONJ relapse appeared (follow-up mean 18 months, range 1-3 years). Medical O3 gas insufflations is an effective and safe treatment for patients treated with BPs who developed ONJ lesions >2.5 cm. Short abstract: ONJ is an adverse event reported in patients receiving cancer treatments regimen, bisphosphonates and denosumab. We performed an open-label, prospective study in 24 patients with solid tumours, myeloma or osteoporosis due to hormonal therapy, treated with zoledronic acid without previuos preventive dental screening, who developed ONJ lesions >2.5 cm, and had no benefit after standard therapy, to evaluate the efficacy and tolerability of medical ozone (O3) treatment delivered as gas insufflations on each ONJ lesions. The patients were treated with O3 every third day for a minimum of 10 for each pathological area or till necrotic bone sequestrum or surgery. Eleven patients required more than ten O3 gas insufflations. Six of 24 patients interrupted the therapy for oncological disease progression. Six patients had the sequestrum and complete or partial (one patient) spontaneous expulsion of the necrotic bone followed by oral mucosa re-epithelization after a range of 4 to 27 of O3 gas insufflations. No patient reported adverse events. In 12 patients with the largest and deeper ONJ lesions, O3 gas therapy produced the sequestrum of the necrotic bone after 10 to 38 insufflations; surgery was necessary to remove it (11 patients). Of interest, removal was possible without the resection of healthy mandible edge because of the presence of bone sequestrum. All together the response rate was 75.0% (95% CI, 53.3-90.2%) in ITT analysis and 100% (95% CI, 81.5-100%) in the PP analysis. In all patients treated with O3 gas ± surgery, no ONJ relapse appeared (follow-up mean 18 months, range 1-3 years).

The role of adjuvant chemotherapy in colon cancer.

Surgical resection of the primary and regional lymph nodes is still, at this time, the standard treatment of colon cancer. However, the risk of recurrence is still high in many patients. Efforts of the past decades have proved the role of systemic chemotherapy in the adjuvant setting in improving the curative rates. The combination of 5-fluorouracil (5-FU)and leucovorin (LV) remains the cornestorne of colon cancer chemotherapy worldwide. The addition of Oxaliplatin to infusional 5FU/LV has been shown to prolong significantly disease-free survival and capecitabine may be considered as an alternative to 5-FU/LV in the adjuvant therapy of stage III colon cancer. Novel molecular and biological-oriented agents are being studied, with promising date.

Adjuvant treatment of colorectal cancer.

Colorectal cancer is one of the most frequent causes of cancer deaths. Survival for locoregional colorectal cancer is about 70% overall and 30-60% in stage III patients. Several randomized trials have shown that adjuvant chemotherapy can increase this survival rate. 5-Fluorouracil-based chemotherapy is strongly recommended in this context. There are still some questions about the setting in which patients should be treated as well as the optimal treatment. New data for different schedules and combinations are now available. Physicians have to choose between the different options now available to offer the best treatment to their patients. This Review analyses the current options for adjuvant therapy in colon and rectal cancer.

Raltitrexed plus oxaliplatin (TOMOX) as first-line chemotherapy for metastatic colorectal cancer. A phase II study of the Italian Group for the Study of Gastrointestinal Tract Carcinomas (GISCAD).

BACKGROUND: To evaluate the safety and efficacy of the novel raltitrexed/oxaliplatin combination (TOMOX) as first-line chemotherapy for patients with advanced colorectal cancer. MATERIALS AND METHODS: Previously untreated patients with metastatic colorectal cancer received raltitrexed 3 mg/m2 plus oxaliplatin 100 mg/m2, both intravenously, on day 1 every 3 weeks. Patients were re-evaluated after every third cycle and chemotherapy was continued up to tolerance or disease progression. RESULTS: Fifty-eight patients from 13 Italian Group for the Study of Gastrointestinal Tract Carcinomas (GISCAD) centers were accrued from September 1999 to November 2000. According to the intention-to-treat analysis from 58 patients, the overall response rate was 50% [95% confidence interval (CI) 38% to 62%], with three complete responses and 26 partial responses. The median overall survival (44 patients currently alive) was >9 months and the median time to disease progression was 6.5 months (range 1-15 months). The main hematological toxicity was grade III/IV neutropenia, which occurred in 17% of patients, while anemia and thrombocytopenia were uncommon. Grade III/IV non-hematological toxicities were transient transaminitis (17% of patients); asthenia (16% of patients); neurotoxicity (10% of patients) and diarrhea (7% of patients). No toxic death was observed, one patient with grade IV asthenia after the first cycle refused chemotherapy. CONCLUSIONS: The results of this study suggest that the TOMOX combination is an effective and well tolerated regimen for the treatment of advanced colorectal cancer. Its ease of administration and patient tolerance warrant further investigation as an alternative to fluoropyrimidine-based regimens with repeated and prolonged fluorouracil infusions.

Disease management considerations: disease management considerations.

Colorectal cancer is still a majorhealth and social problem. However, many important advances in treatment have been made in the last 4 to 5 years, and more optimism is now justified both among clinicians and patients. In surgically resectable disease, adjuvant chemotherapy has been clearly demonstrated as able to increase overall survival in patients with colon cancer Dukes' stage C, whereas the role of medical treatment in patients with Dukes' stage B colon cancer is still controversial. At present, the standard regimen is bolus fluorouracil (5-FU) modulated by folinic acid (leucovorin) for 6 months. For rectal cancer, the best adjuvant treatment seems to be represented by radiotherapy (better if administered preoperatively) combined with chemotherapy (usually based on modulated or continuously infused 5-FU). In advanced disease, many new drugs have recently emerged: the most active regimens are those combining an optimal modality of 5-FU administration (i.e. continuous infusion) and one of the most active innovative compounds (irinotecan or oxaliplatin). The role of the oral drugs (e.g. tegafur/uracil, capecitabine) is still under investigation as is the combination of agents excluding 5-FU. It is now recognised that first-line treatment must be offered to all suitable pa- tients, even though asymptomatic, and that a second-line therapy (chiefly with irinotecan) is of value in many patients with cancer that progresses during treatment with 5-FU. From a strategic point of view, the best sequence of drugs/regimens has not yet been defined, while the duration and timing of chemotherapy is still a matter for clinical research. Finally, there is an increasing interest in the role of biological prognostic factors as an aid to a patient-tailored therapy, both in the adjuvant setting and in advanced disease. To achieve further progress in knowledge in this field, we strongly recommended that more and more patients are included in clinical trials.

New drugs and combinations in the palliative treatment of colon and rectal cancer.

Colorectal cancer (CRC) is a common disease. The overall survival has improved only marginally in recent decades despite advances in surgery and early detection. Potentially curative resection at disease presentation can be performed only in 70-80% of the patients, and overall survival at 5 years is less than 60%. Advanced disease is associated with a poor prognosis. Treatment for advanced colorectal cancer has nevertheless made progress in the last few years. Systemic chemotherapy doubles the survival of these patients compared to untreated controls. Chemotherapy has demonstrated effective palliation, improvement of quality of life (QoL) and symptom improvement in such patients. For nearly four decades, fluorouracil (5FU) has been the mainstay of treatment. New compounds active against colorectal cancer are now available. Several studies on this topic are ongoing.

5-fluorouracil modulated by leucovorin, methotrexate and mitomycin: highly effective, low-cost chemotherapy for advanced colorectal cancer.

We have reported that an alternating regimen of bolus and continuous infusion 5-fluorouracil (FU) was superior to bolus FU in terms of response rate and progression-free survival in advanced colorectal cancer. Biochemical modulation was an essential part of this regimen and it was selective for the schedule of FU administration: bolus FU was in fact modulated by methotrexate (MTX) while continuous infusion FU was potentiated by 6-s-leucovorin (LV). Considering the low cost and the favourable report on the activity of mitomycin C (mito) added to CI FU, we have incorporated this agent in the infusional part of our treatment programme. 105 patients with untreated, advanced, measurable colorectal cancer were accrued from 13 Italian centres and treated with the following regimen. 2 biweekly cycles of FU bolus (600 mg/m(2)), modulated by MTX (24 h earlier, 200 mg/m(2)) were alternated with a 3-week continuous infusion of FU (200 mg/m(2)daily), modulated by LV (20 mg/m(2)weekly bolus). Mito, 7 mg/m(2), was given on the first day of the infusional period. After a 1 week rest, the whole cycle (8 weeks) was repeated, if indicated. 5 complete and 34 partial responses were obtained (response rate, 37% on the intention to treat basis; 95% confidence limits, 28-46%). After a median follow-up time of 26 months, 37 patients are still alive. The median progression-free survival is 7.7 months with an overall survival of 18.8 months and a 2-year survival rate of 30%. The regimen was very well tolerated with fewer than 13% of patients experiencing WHO grade III-IV toxicity. These results are consistent with those obtained by our group in 3 previous trials of schedule specific biochemical modulation of FU. They also indicate a highly active, little toxic, inexpensive regimen of old drugs to be used (a) as an alternative to the more expensive combinations including CPT-11 or oxaliplatin or (b) as the basis for combination programmes with these agents.

A combination of a fixed dose rate infusion of gemcitabine associated to a bolus 5-fluorouracil in advanced pancreatic cancer, a report from the Italian Group for the Study of Digestive Tract Cancer (GISCAD).

BACKGROUND: Laboratory evidences suggest the possibility that an infusion rate of 10 mg/m2/min may be more effective than the standard 30-min infusion of Gemcitabine (GEM). PATIENTS AND METHODS: Thirty-four patients with histologically verified locally unresectable and/or metastatic pancreatic carcinoma received GEM at the dose of 1,500 mg/m2 with an infusion rate of 10 mg/m2/min, associated to 5-fluorouracil (5-FU) at the dose of 600 mg/m2. Both drugs were administered weekly for two consecutive weeks out of every three weeks. RESULTS: One complete and five partial responses have been observed for an overall response rate of 17% (95% CI: 3%-27%). The time to progression was 3.7 months with a median survival of 5.7 months. A clinical benefit was obtained in 5 of 29 patients (17%). Grade 3-4 WHO toxicities included neutropenia (35%) and thrombocytopenia (10%). CONCLUSION: It is unlikely that a fixed dose rate infusion of GEM, at least with this dose, can improve palliation in comparison with the standard 30-min infusion schedule in advanced pancreatic cancer.

Schedule specific biochemical modulation of 5-fluorouracil in advanced colorectal cancer: a randomized study. GISCAD, IOR and collaborating centers.

BACKGROUND: We have recently suggested that bolus 5-fluorouracil (5-FU) may work via a RNA directed mechanism while continuous infusion 5-FU may kill cells via a thymidylate synthase related pathway. It may thus be possible to selectively modulate each schedule biochemically. We have compared an alternating regimen of bolus and continuous infusion 5-FU, selectively modulated for the schedule of administration, with modulated bolus 5-FU in advanced colorectal cancer patients. PATIENTS AND METHODS: Two hundred fourteen patients from nineteen Italian centers were randomized to the control arm consisting of biweekly cycles of MTX, 200 mg/m2 on day 1, followed by bolus 5-FU 600 mg/m2 on day 2 and 6-S-leucovorin rescue, or to the experimental arm consisting of two biweekly cycles of the same regimen as in the control arm alternated to three weeks of continuous infusion 5-FU (200 mg/m2 day) + weekly bolus 6-S-leucovorin, 20 mg/m2. RESULTS: Nine CR and twenty-seven PR were obtained on one hundred eleven evaluable patients treated in experimental arm (RR = 32%, 95% confidence interval (95% CI): 24%-42%), while two CR and eleven PR were observed among one hundred three evaluable patients in control arm (RR = 13%, 95% CI: 7%-21%). WHO grade 3-4 toxicity occurred in 13% of cycles of experimental arm and in 8% of cycles in control arm. The PFS was significantly longer in experimental arm (6.2 vs. 4.3 months, odds ratio 0.66, P = 0.003), while the overall survival was similar in both arms (14.8 months in experimental arm vs. 14.1 months in control arm); quality of life was similar as well. Eighty percent of patients receiving second-line chemotherapy in control arm were treated with continuous infusion 5-FU. CONCLUSIONS: Alternating, schedule-specific biochemical modulation of FU is more active than MTX --> 5-FU as first-line treatment of advanced colorectal cancer. However, the overall survival was similar suggesting that alternating bolus and infusional 5-FU upfront may be as effective as giving them in sequence as first- and second-line treatment.

A combination of gemcitabine and 5-fluorouracil in advanced pancreatic cancer, a report from the Italian Group for the Study of Digestive Tract Cancer (GISCAD).

In a randomized clinical trial, gemcitabine (GEM) was more effective than 5-fluorouracil (5-FU) in advanced pancreatic cancer patients. GEM and 5-FU have different mechanisms of action and their combination, from a theoretical point of view, could result in a higher activity. To test activity and feasibility of such a combination, a multi-institutional phase II study was initiated in November 1996 by the Italian Group for the study of Digestive Tract Cancer (GISCAD). Primary objectives of this study were to determine the activity in terms of response rate and clinical benefit, while the secondary objective was toxicity. According to the optimal two-stage phase II design, 54 patients were enrolled. Schedule was: GEM 1000 mg m(-2) intravenous (i.v.), and 5-FU 600 mg m(-2) bolus i.v. weekly for 3 weeks out of every 4. All the 54 patients were symptomatic (pain, weight loss, dyspepsia). A clinical benefit was obtained in 28 patients (51%) (95% confidence interval (CI) 38-64%). Two patients achieved a partial response and 34 a stable disease. Median survival for all the patients was 7 months. Side-effects were mild: no gastrointestinal or haematological grade 3-4 toxicity (WHO) were recorded. We observed only six episodes of grade 2 (WHO) leukopenia and seven episodes of thrombocytopenia. Although the non-randomized design of this study suggests caution in the interpretation of these data, in consideration of the low incidence of toxicity and the favourable results obtained in terms of clinical benefit, it may be worthwhile to test more active schedules of 5-FU (continuous infusion) in combination with gemcitabine.

Evaluation of factors influencing 5-fluorouracil-induced diarrhea in colorectal cancer patients. An Italian Group for the Study of Digestive Tract Cancer (GISCAD) study.

Diarrhea is one of the dose-limiting toxicities for administration of fluorouracil (5FU) in patients with colorectal cancer and can result in severe morbidity and mortality. No well-defined prognostic factors influencing 5FU-associated diarrhea have been identified, which means its occurrence is unforeseeable. The aim of this study was to check whether any characteristics related to patients or chemotherapy could allow the identification of subsets of patients at higher risk of developing diarrhea while receiving a regimen containing 5FU. A logistic regression analysis was performed with age, sex, site of primary tumor, presence of primary tumor, presence of colostomy, time since surgery, number of courses of chemotherapy, diarrhea in previous courses, season of treatment, and chemotherapeutic regimens used as model parameters to predict occurrence of diarrhea in 258 colorectal cancer patients receiving a 5FU-containing regimen. Presence of primary tumor (P = 0.004), previous episodes of chemotherapy-related diarrhea (P = 0.00005) and summer season (P = 0.014) were found to be significant risk factors for developing diarrhea. The other variables examined, such as age, sex, chemotherapeutic regimen, site of primary tumor, presence of colostomy, and time since surgery, were not significantly correlated to diarrhea. Chemotherapeutic regimen was the only parameter that allowed prediction of the severity of diarrhea: 5FU/6S-leucovorin/interferon caused more severe diarrhea, followed by 5FU/leucovorin weekly. Although the analysis of these clinical features does not seem to allow the definition of a well-defined subset of colorectal cancer patients at higher risk of 5FU-induced diarrhea, it can be recommended that patients with primary tumor, or who have experienced diarrhea in earlier courses of chemotherapy or are receiving treatment in summer should be carefully monitored, especially in the first cycles.

Treatment of colorectal cancer. Current guidelines and future prospects for drug therapy.

Colorectal carcinoma is one of the most common cancers in Western countries (yearly incidence rate of 1:3000), and represents, after lung cancer, the second leading cause of deaths due to cancer. During the past decades, knowledge about this carcinoma has considerably increased, but little progress has been made in improvement in patient survival. At least 40% of patients with colorectal cancer will have metastases sometime during the course of their illness. In colon cancer, the first therapeutic approach is surgery, but the important role of adjuvant chemotherapy in these patients, in terms of disease-free survival and overall survival benefit, is now well established. Until today, standard therapy was represented by fluorouracil plus levamisole and/or calcium folinate (folinic acid). Other strategies are represented by monoclonal antibodies (mAb), which improve survival, (with a decrease in mortality by 32%), and by portal vein fluorouracil, alone or in combination with systemic therapy. In rectal cancer, the best results have been obtained with a combination of radiotherapy and chemotherapy. In advanced colorectal cancer, a standard treatment has not yet been established. This disease is usually considered as poorly chemosensitive and for more than 30 years fluorouracil has been the standard drug. Tumour response rates (partial+complete) for patients treated with bolus intravenous fluorouracil are 10 to 15%, with a median survival about 1 year. Many attempts have been made to improve these results. Biochemical modulation of fluorouracil is one of the most interesting strategies developed in the last few years in an attempt to increase the therapeutic index of this compound. Another way has been to administer fluorouracil by continuous infusion. Further innovative compounds such as irinotecan and raltitrexed are now being evaluated in clinical trials. Preliminary data from phase II and III studies have provided encouraging results on the use of these new drugs. In metastatic disease confined to the liver, the possibility of locoregional therapy through implantable pumps should be taken into consideration.

[Locoregional chemotherapy of liver metastasis from colorectal carcinoma]. / Chemioterapia locoregionale delle metastasi epatiche da carcinoma del colon-retto.

Hepatic metastases are a major cause of death in patients with colorectal carcinoma. Traditional intravenous chemotherapy produces responses in 10% to 30% of patients and surgical resection is feasible in approximately 20% of patients. Infusion of cytotoxic agents into the hepatic artery is the most promising form of therapy for unresectable hepatic metastases. The recent development of a totally implantable pump has allowed prolonged infusion of chemotherapeutic agents with a good compliance and quality of life of the patients. The rationale for hepatic arterial infusion (HAI) present an anatomical and pharmacological basis with the use of agents with high hepatic extraction resulting in minimal systemic toxicity. The results of eight randomized trial assessing the value of HAI Floxuridine shows that such regional chemotherapy increases the likelihood of hepatic response compared with systemic treatment (52% vs 15%). Survival information is difficult to evaluate because some of the studies are small, some had a crossover design and some others had bias factors. Extrahepatic disease develops in 40-70% of patients undergoing HAI; the use of systemic therapy plus HAI may produce a decrease in extrahepatic disease. Further studies of combined systemic/arterial regiment are necessary.