Sorafenib with or without everolimus in patients with advanced hepatocellular carcinoma (HCC): a randomized multicenter, multinational phase II trial (SAKK 77/08 and SASL 29).

BACKGROUND: Sorafenib (S), a multitargeted tyrosine kinase inhibitor, is the standard of care for first-line systemic treatment of advanced hepatocellular carcinoma (HCC). Everolimus (E) is a potent inhibitor of mTOR, a pathway frequently activated in HCC. Preclinical data suggest that the combination S + E has additive effects compared with single-agent S. PATIENTS AND METHODS: Patients with unresectable or metastatic HCC and Child-Pugh ≤7 liver dysfunction were randomized to receive daily S 800 mg alone or with E 5 mg until progression or unacceptable toxicity. The primary end point was progression-free survival at 12 weeks (PFS12). The secondary end points included response rate, PFS, time to progression (TTP), overall survival (OS), duration of disease stabilization (DDS), safety, and quality-of-life (QoL) assessments. RESULTS: A total of 106 patients were randomized: 46 patients received S and 60 patients received S + E. Ninety-three patients were assessable for the primary end point and 105 patients for the safety analysis. The PFS12 rate was 70% [95% confidence interval (CI) 54-83] and 68% (95% CI 53-81) in patients randomized to S and S + E, respectively. The RECIST (mRECIST) response rate was 0% (23%) in the S arm and 10% (35%) in the S + E arm. Median PFS (6.6 versus 5.7 months), TTP (7.6 versus 6.3 months), DDS (6.7 versus 6.7 months), and OS (10 versus 12 months) were similar in the S and S + E arms, respectively. Grade 3/4 adverse events occurred in 72% and 86% of patients in arm S and arm S + E, respectively. Patients had similar QoL scores over time, except for a greater worsening in physical well-being and mood in the arm S + E. CONCLUSIONS: No evidence was found that S + E improves the efficacy compared with S alone. Combining 5 mg E with full-dose S is feasible, but more toxic than S alone. Further testing of this drug combination in molecularly unselected HCCs appears unwarranted. CLINICALTRIALSGOV: NCT01005199.

Preoperative versus postoperative docetaxel-cisplatin-fluorouracil (TCF) chemotherapy in locally advanced resectable gastric carcinoma: 10-year follow-up of the SAKK 43/99 phase III trial.

BACKGROUND: Fluorouracil-based adjuvant chemotherapy in gastric cancer has been reported to be effective by several meta-analyses. Perioperative chemotherapy in locally advanced resectable gastric cancer (RGC) has been reported improving survival by two large randomized trials and recent meta-analyses but the role of neoadjuvant chemotherapy and optimal regimen remains to be determined. We compared a neoadjuvant with adjuvant docetaxel-based regimen in a prospective randomized phase III trial, of which we present the 10-year follow-up data. PATIENTS AND METHODS: Patients with cT3-4 anyN M0 or anyT cN1-3 M0 gastric carcinoma, staged with endoscopic ultrasound, computed tomography, bone scan, and laparoscopy, were assigned to receive four 21-day/cycles of docetaxel 75 mg/m(2) day 1, cisplatin 75 mg/m(2) day 1, and fluorouracil 300 mg/m(2)/day over days 1-14, either before (arm A) or after (arm B) gastrectomy. Event-free survival was the primary end point, whereas secondary end points included overall survival, toxicity, down-staging, pathological response, quality of life, and feasibility of adjuvant chemotherapy. RESULTS: This trial was activated in November 1999 and closed in November 2005 due to insufficient accrual. Of the 70 enrolled patients, 69 were randomized, 34 to arm A and 35 to arm B. No difference in EFS (2.5 years in both arms) or OS (4.3 versus 3.7 years, in arms A and B, respectively) was found. A higher dose intensity of chemotherapy was observed in arm A and more frequent chemotherapy-related serious adverse events occurred in arm B. Surgery was safe after preoperative chemotherapy. A 12% pathological complete response was observed in arm A. CONCLUSION: Docetaxel/cisplatin/fluorouracil chemotherapy is promising in preoperative setting of locally advanced RGC. The early stopping could mask the real effectiveness of neoadjuvant treatment. However, the complete pathological tumour responses, feasibility, and safe surgery warrant further investigation of a taxane-based regimen in the preoperative setting.

Prognosis of stage II and III colon cancer treated with adjuvant 5-fluorouracil or FOLFIRI in relation to microsatellite status: results of the PETACC-3 trial.

BACKGROUND: Although colon cancer (CC) with microsatellite instability (MSI) has a more favorable prognosis than microsatellite stable (MSS) CC, the impact varies according to clinicopathological parameters. We studied how MSI status affects prognosis in a trial-based cohort of stage II and III CC patients treated with 5-fluorouracil (5-FU)/leucovorin or FOLFIRI. MATERIALS AND METHODS: Tissue specimens of 1254 patients were tested for 10 different loci and were classified as MSI-high (MSI-H) when three or more loci were unstable and MSS otherwise. Study end points were overall survival (OS) and relapse-free survival (RFS). RESULTS: In stage II, RFS and OS were better for patients with MSI-H than with MSS CC [hazard ratio (HR) 0.26, 95% CI 0.10-0.65, P = 0.004 and 0.16, 95% CI 0.04-0.64, P = 0.01). In stage III, RFS was slightly better for patients with MSI-H CC (HR 0.67, 95% CI 0.46-0.99, P = 0.04), but the difference was not statistically significant for OS (HR 0.70, 95% CI 0.44-1.09, P = 0.11). Outcomes for patients with MSI-H CC were not different between the two treatment arms. RFS was better for patients with MSI-H than with MSS CC in the right and left colon, whereas for OS this was significant only in the right colon. For patients with KRAS- and BRAF-mutated CC, but not for double wild-type patients, RFS and OS were significantly better when the tumors were also MSI-H. An interaction test was statistically significant for KRAS and MSI status (P = 0.005), but not for BRAF status (P = 0.14). CONCLUSIONS: Our results confirm that for patients with stage II CC but less so for those with stage III MSI-H is strongly prognostic for RFS and OS. In the presence of 5-FU treatment, stage II patients with MSI-H tumors maintain their survival advantage in comparison with MSS patients and adding irinotecan has no added benefit. CLINICALTRIALS.GOV IDENTIFIER: NCT00026273.

Distal and proximal colon cancers differ in terms of molecular, pathological, and clinical features.

BACKGROUND: Differences exist between the proximal and distal colon in terms of developmental origin, exposure to patterning genes, environmental mutagens, and gut flora. Little is known on how these differences may affect mechanisms of tumorigenesis, side-specific therapy response or prognosis. We explored systematic differences in pathway activation and their clinical implications. MATERIALS AND METHODS: Detailed clinicopathological data for 3045 colon carcinoma patients enrolled in the PETACC3 adjuvant chemotherapy trial were available for analysis. A subset of 1404 samples had molecular data, including gene expression and DNA copy number profiles for 589 and 199 samples, respectively. In addition, 413 colon adenocarcinoma from TCGA collection were also analyzed. Tumor side-effect on anti-epidermal growth factor receptor (EGFR) therapy was assessed in a cohort of 325 metastatic patients. Outcome variables considered were relapse-free survival and survival after relapse (SAR). RESULTS: Proximal carcinomas were more often mucinous, microsatellite instable (MSI)-high, mutated in key tumorigenic pathways, expressed a B-Raf proto-oncogene, serine/threonine kinase (BRAF)-like and a serrated pathway signature, regardless of histological type. Distal carcinomas were more often chromosome instable and EGFR or human epidermal growth factor receptor 2 (HER2) amplified, and more frequently overexpressed epiregulin. While risk of relapse was not different per side, SAR was much poorer for proximal than for distal stage III carcinomas in a multivariable model including BRAF mutation status [N = 285; HR 1.95, 95% CI (1.6-2.4), P < 0.001]. Only patients with metastases from a distal carcinoma responded to anti-EGFR therapy, in line with the predictions of our pathway enrichment analysis. CONCLUSIONS: Colorectal carcinoma side is associated with differences in key molecular features, some immediately druggable, with important prognostic effects which are maintained in metastatic lesions. Although within side significant molecular heterogeneity remains, our findings justify stratification of patients by side for retrospective and prospective analyses of drug efficacy and prognosis.

[Targeted therapies in digestive oncology]. / Thérapies ciblées en oncologie digestive.

Targeted therapies are relatively new molecules available for the oncologist. These drugs target a specific step of the cellular development and interfere with the intracellular signalization pathways. Amongst all others, EGF- and VEGF-pathways are currently targeted by these selective therapies. Modulating EGF and VEGF significantly improves overall survival and progression-free survival for many advanced or metastatic tumors as colorectal cancer, gastric cancer, gastrointestinal stromal tumors or hepatocellular carcinoma. Targeted therapies have a specific action site, a simple administration mode and are relatively well tolerated. In the future these molecules will probably be used "à la carte" for tumors that appear to be refractory to other drugs.

Amino Acid-Functionalized Polyelectrolyte Films as Bioactive Surfaces for Cell Adhesion.

Surfaces were prepared with polyelectrolyte derivatives of poly(styrene- alt-maleic anhydride) (PSMA) functionalized with amino acids of different hydropathy indices, with the aim of evaluating the effect of the chemical functionality of polyelectrolytes on SH-SY5Y neuroblastoma cell adhesion. Functionalizing PSMA derivatives with l-glutamine, l-methionine, and l-tyrosine yielded PSMA-Gln, PSMA-Met, and PSMA-Tyr polyelectrolytes, respectively. We first studied the adsorption behavior of PSMA functionalized with amino acids on silicon wafer surfaces modified with 3-aminopropyltriethoxysilane at pH 4.0 and 7.0 and at low and high ionic strengths. The highest rate of polyelectrolyte adsorption was at pH 4.0 and high ionic strength and was higher with the glutamine and tyrosine films. The advance contact angles (θA) of the polyelectrolyte surfaces showed a moderate effect of ionic strength and pH on polyelectrolyte film wettability, with PSMA-Tyr being slightly more hydrophobic. Atomic force microscopy images of the polyelectrolyte surfaces showed two types of morphology: the well-defined globular nanostructure of PSMA-Met and PSMA-Tyr and densely packed nanofibrous-like structure of PSMA-Gln. The highest level of ionic strength caused a slight decrease in the size of the nanostructure that formed the surface domains, which was reflected in the degree of surface roughness. Cell adhesion assays with the polyelectrolyte film showed that SH-SY5Y neuroblastoma cells cultured on PSMA-Met present a well-extended morphology characterized by a stellate shape, with five or more actin-rich thin processes, whereas SH-SY5Y cells that were seeded on PSMA-Gln and PSMA-Tyr have a round morphology, with fewer and shorter processes. These results indicate that it is possible to modulate the surface characteristics of polyelectrolyte films based on their chemical functionality and environmental parameters such as pH and ionic strength in order to evaluate their effect on cell adhesion. Thus, surfaces prepared from polyelectrolytes functionalized with amino acids are an attractive and simple platform for cell adhesion, which can be used in developing biomaterials with modulated surface properties.

Cisplatin, doxorubicin and etoposide (PAV) in advanced gastric carcinoma: the SAKK experience. Swiss Group for Clinical Cancer Research (SAKK).

EAP (etoposide, doxorubicin, cisplatin), a chemotherapeutic combination given over 8 days, proposed by German investigators in cancer of the stomach, has been considered to be too toxic by others. A positive experience with a similar regimen (PAV) developed by the SAKK given over 3 days in small cell lung cancer led us to test it in gastric adenocarcinoma. 41 patients with metastatic gastric cancer were enrolled in the study and 38 were evaluable for response and toxicity. One complete response and 12 partial responses were recorded, giving a response rate of 34% (95% confidence interval (CI) 20-51%). Median progression-free and overall survival were 3.4 and 6.3 months, respectively. Haematotoxicity was the leading toxicity with 34 (90%) and 17 (45%) grade III-IV neutropenia and thrombocytopenia, respectively. Despite this high rate of granulocytopenia, only six episodes of non-fatal febrile neutropenia were observed. Other toxicities were relatively easy to manage with infrequent grade III-IV occurrences. We conclude that PAV is active in gastric cancer and seems to be better tolerated than EAP.

Impact of clinical and therapeutic factors on major late complications after radiotherapy with or without concomitant chemotherapy for anal carcinoma.

PURPOSE: To investigate factors potentially influencing major late morbidity after sphincter-conserving treatment for anal carcinoma. METHODS AND MATERIALS: Grade 3-4 complications were retrospectively analyzed in 144 evaluable patients (pts), 55 pts after split-course radiotherapy (RT), and 89 after concomitant chemo-RT. First sequence RT delivered a median dose of 39.6 Gy using megavoltage photon beams. Boost treatment used either 192Ir implantation or external beam RT (median dose 20 Gy). Chemotherapy started on day 1 and in 83% of pts consisted of Mitomycin-C (10 mg/m2) and a 5-day infusion of 5-fluorourcil (600-800 mg/m2/day). Uni- and multivariate analyses tested the association of following factors with complication rate: age, gender, stage, anatomic tumor extent, type of biopsy, external RT technique (dose, fraction size, field arrangement), boost type (brachytherapy vs. external), brachytherapy dose and dose rate, overall treatment time, and addition of chemotherapy. RESULTS: Five-year actuarial complication rate was 16%. Two variables were significantly associated with complication rate: anatomic tumor extent (canal or margin vs. both +/- rectum; 10 vs. 31% complications, p = 0.0004) and first sequence prescribed dose (< 39.6 Gy vs. > or = 39.6 Gy; 7 vs. 23% complications, p = 0.012), confirmed as independent factors by Cox analysis. Grade 4 anal morbidity correlated significantly with prior local excision. All six bone complications were observed in pts treated by chemo-RT using large pelvic fields, five occurring in pts older than 66. CONCLUSION: Pts with tumors involving more than one anatomic subsite or treated with the higher first sequence RT dose are at greater risk of major complications. Prior tumor excision and combined modality therapy in older pts appear to favor major anal and bone complications, respectively.

Wilms' tumor in the adult--report of a case and review of the literature.

Wilms' tumor is rare in adults. Its histology, grading and staging are identical to those in children. Investigators agree on a combined modality approach in the treatment of adult Wilms' tumor (AWT), but differ on how aggressive it should be. Some advocate adopting the current pediatric protocols which take into account tumor stage and grade. Others recommend using advanced disease regimens for all stages and grades. We report on an 18 year-old male with stage IV favorable histology Wilms' tumor. The patient underwent radical nephrectomy and received postoperative radiotherapy with intensive four-drug chemotherapy. He had one relapse after 12 months which was successfully treated with chemotherapy and radiotherapy. He remains in remission without relapses 36 months after the initial diagnosis. The genetics of Wilms' tumor has been well studied in children but is practically unknown in adults; karyotype and molecular genetic studies in this case were normal.

The use of revised habituation in the treatment of obsessive-compulsive disorders.

The effectiveness of the technique of revised habituation (Salkovskis & Westbrook, 1989) has received limited attention in the literature. This paper describes a clinical example which demonstrates both the utility and power of this intervention in complex cases of obsessive-compulsive disorder.

Treatment strategies for the management of advanced colorectal liver metastases detected synchronously with the primary tumour.

The review summarises the contributions of chemotherapy, interventional radiology and surgery to the improved survival observed in patients with colorectal liver metastases. The rationale in favour of modern neoadjuvant chemotherapy regimens, of pro-generative manoeuvres to increase the volume of the future remnant liver, and of resection techniques that preserve its function is discussed. For advanced synchronous colorectal metastases, the arguments in favour of a reversed approach with systemic chemotherapy, liver surgery and colon surgery in that order, as opposed to the traditional approach of colon surgery first, or to a simultaneous liver and large bowel resection, are presented.

Importance of histological tumor response assessment in predicting the outcome in patients with colorectal liver metastases treated with neo-adjuvant chemotherapy followed by liver surgery.

BACKGROUND: The purpose of the study was to characterize histological response to chemotherapy of hepatic colorectal metastases (HCRM), evaluate efficacy of different chemotherapies on histological response, and determine whether tumor regression grading (TRG) of HCRM predicts clinical outcome. PATIENTS AND METHODS: TRG was evaluated on 525 HCRM surgically resected from 181 patients, 112 pretreated with chemotherapy. Disease-free survival (DFS) and overall survival (OS) were correlated to TRG. RESULTS: Tumor regression was characterized by fibrosis overgrowing on tumor cells, decreased necrosis, and tumor glands (if present) at the periphery of HCRM. With irinotecan/5-fluorouracil (5-FU), major (MjHR), partial (PHR), and no (NHR) histological tumor regression were observed in 17%, 13%, and 70% of patients, respectively. With oxaliplatin/5-FU, MjHR, PHR, and NHR were observed in 37%, 45%, and 18% of patients, respectively. Five patients, treated with oxaliplatin, had complete response in all their metastases. MjHR was associated with an improved 3-year DFS compared with PHR or NHR. MjHR and PHR were associated with an improved 5-year OS compared with NHR. CONCLUSION: Histological tumor regression of HCRM to chemotherapy corresponds to fibrosis overgrowth and not to increase of necrosis. TRG should be considered when evaluating efficacy of chemotherapy for HCRM. Histological tumor regression was most common among oxaliplatin-treated patients and associated with better clinical outcome.

Multicenter trial of neo-adjuvant chemotherapy followed by extrapleural pneumonectomy in malignant pleural mesothelioma.

BACKGROUND: The aim of this multicenter trial was to prospectively evaluate neo-adjuvant chemotherapy followed by extrapleural pneumonectomy (EPP) and radiotherapy, including quality of life as outcome. PATIENTS AND METHODS: Eligible patients had malignant pleural mesothelioma of all histological types, World Health Organization performance status of zero to two and clinical stage T1-T3, N0-2, M0 disease considered completely resectable. Neo-adjuvant chemotherapy consisted of three cycles of cisplatin and gemcitabine followed by EPP. Postoperative radiotherapy was considered for all patients. RESULTS: In all, 58 of 61 patients completed three cycles of neo-adjuvant chemotherapy. Forty-five patients (74%) underwent EPP and in 37 patients (61%) the resection was complete. Postoperative radiotherapy was initiated in 36 patients. The median survival of all patients was 19.8 months [95% confidence interval (CI) 14.6-24.5]. For the 45 patients undergoing EPP, the median survival was 23 months (95% CI 16.6-32.9). Psychological distress showed minor variations over time with distress above the cut-off score indicating no morbidity with 82% (N = 36) at baseline and 76% (N = 26) at 3 months after surgery (P = 0.5). CONCLUSIONS: The observed rate of operability is promising. A median survival of 23 months for patients undergoing EPP compares favourably with the survival reported from single center studies of upfront surgery. This approach was not associated with an increase in psychological distress.

Complete closure of cancer-related anovaginal and anoperineal fistulas in locally advanced anal canal carcinomas by upfront intra-arterial chemotherapy followed by combined radiochemotherapy: report of two cases.

PURPOSE: Cancer-related fistulas are a major problem in locally advanced anal canal carcinoma, because conservative radiochemotherapy may not be recommended in this setting. Therefore, it is usually recommended to proceed to an abdominoperineal resection with definitive colostomy in the presence of such lesions. METHODS: Because chemotherapy can lead to closure of cancer-related fistulas and local intra-arterial chemotherapy is effective in locally advanced anal canal cancer, we treated two anal canal carcinoma patients presenting with cancer-related fistulas with upfront intra-arterial chemotherapy followed by radiochemotherapy, leading to complete closure of fistulas. RESULTS: Both patients are free of colostomy and in complete remission after more than four years of follow-up. CONCLUSIONS: This conservative approach combining local intra-arterial chemotherapy and standard radiochemotherapy is feasible and should be considered in the management of such locally advanced anal canal carcinoma.

Neoadjuvant chemotherapy and resection of advanced synchronous liver metastases before treatment of the colorectal primary.

BACKGROUND: In many patients with advanced synchronous liver metastases from colorectal tumours, the metastases progress during treatment of the primary, precluding curative treatment. The authors have investigated a management strategy that involves high-impact chemotherapy first, resection of liver metastases second and finally removal of the primary tumour in patients with adverse prognostic factors. METHODS: Twenty consecutive patients with non-obstructive colonic (nine patients) or rectal (11 patients) cancer and advanced synchronous liver metastases were treated according to this strategy. Median age was 56 years. Patients received between two and six cycles of 5-fluorouracil, oxaliplatin and irinotecan-based chemotherapy. Data were collected prospectively. RESULTS: Overall survival rates at 1, 2, 3 and 4 years after the start of treatment were 85, 79, 71 and 56 per cent respectively, with a median survival of 46 months. Sixteen of the 20 patients had complete removal of liver metastases and colorectal tumours (resectability rate 80 per cent). CONCLUSION: This new strategy produced resectability and survival rates better than those expected from the published data on patients with disease of similar severity. It allows initial control and downstaging of liver metastases, and delivery of preoperative radiotherapy for rectal cancer without the fear that liver metastases will meanwhile progress beyond the possibility of cure.

Prognostic factors affecting long-term outcomes in patients with resected stage IIIA pN2 non-small-cell lung cancer: 5-year follow-up of a phase II study.

The aim was to investigate the efficacy of neoadjuvant docetaxel-cisplatin and identify prognostic factors for outcome in locally advanced stage IIIA (pN2 by mediastinoscopy) non-small-cell lung cancer (NSCLC) patients. In all, 75 patients (from 90 enrolled) underwent tumour resection after three 3-week cycles of docetaxel 85 mg m-2 (day 1) plus cisplatin 40 or 50 mg m-2 (days 1 and 2). Therapy was well tolerated (overall grade 3 toxicity occurred in 48% patients; no grade 4 nonhaematological toxicity was reported), with no observed late toxicities. Median overall survival (OS) and event-free survival (EFS) times were 35 and 15 months, respectively, in the 75 patients who underwent surgery; corresponding figures for all 90 patients enrolled were 28 and 12 months. At 3 years after initiating trial therapy, 27 out of 75 patients (36%) were alive and tumour free. At 5-year follow-up, 60 and 65% of patients had local relapse and distant metastases, respectively. The most common sites of distant metastases were the lung (24%) and brain (17%). Factors associated with OS, EFS and risk of local relapse and distant metastases were complete tumour resection and chemotherapy activity (clinical response, pathologic response, mediastinal downstaging). Neoadjuvant docetaxel-cisplatin was effective and tolerable in stage IIIA pN2 NSCLC, with chemotherapy contributing significantly to outcomes.

Oxaliplatin combined with irinotecan and 5-fluorouracil/leucovorin (OCFL) in metastatic colorectal cancer: a phase I-II study.

BACKGROUND: A phase I-II multicenter trial was conducted to define the maximal tolerated dose and describe the activity of an OCFL combination using oxaliplatin (OHP), irinotecan (CPT-11) and 5-fluorouracil (FU)/leucovorin (LV) in metastatic colorectal cancer (CRC). PATIENTS AND METHODS: CRC patients not pretreated with palliative chemotherapy, with performance status < or =1 and adequate haematological, kidney and liver function, were eligible. Treatment consisted in weekly 24-h infusion 5-FU (2300 mg/m(2))/LV (30 mg) and alternating OHP (70-85 mg/m(2), days 1 and 15) and CPT-11 (80-140 mg/m(2), days 8 and 22) repeated every 5 weeks. OHP and CPT-11 were escalated in cohorts of three to six patients. RESULTS: Thirty patients received a median of five cycles. Dose-limiting toxicity occurred at dose level 3, and the recommended dose was OHP 70 mg/m(2), CPT-11 100 mg/m(2), LV 30 mg and 5-FU 2300 mg/m(2)/24 h. Grade > or =3 toxicities were diarrhea 23%, neutropenia 20%, fatigue 7%, and neurologic 7%. Two febrile neutropenia episodes (one fatal) were recorded. Among 28 patients with measurable disease (90%), we observed two complete and 20 partial responses; overall RR was 78% (95% CI, 59% to 92%). Median time to progression and overall survival were 9.5 and 25.4 months, respectively. Seven patients underwent liver metastases resection. CONCLUSION: OCFL is an overall well tolerated regimen with very high efficacy, which makes it most suitable for tumour control before surgery of metastatic disease.

A randomized phase II trial of capecitabine and two different schedules of irinotecan in first-line treatment of metastatic colorectal cancer: efficacy, quality-of-life and toxicity.

BACKGROUND: To determine the efficacy, impact on quality-of-life (QoL) and tolerability of two different irinotecan administration schedules in combination with capecitabine as first-line treatment of metastatic colorectal cancer. PATIENTS AND METHODS: We carried out a randomized phase II trial to select one of the following treatment regimens for further investigation: weekly irinotecan at a dose of 70 mg/m(2) days 1, 8, 15, 22, 29 (arm A) or 3-weekly irinotecan at a dose of 300/240 mg/m(2) day 1 and days 22 (arm B) in combination with capecitabine 1000 mg/m(2) twice daily days 1-14 and days 22-35 every 6 weeks. RESULTS: Seventy-five patients with good performance status entered the trial. The two arms were well balanced for relevant patient and disease characteristics. The most frequent toxic effects were grade 3/4 diarrhea (arm A: 34%, B: 19%), grade 3/4 neutropenia (A: 5%, B: 19%) and grade 2/3 alopecia (A: 26%, B: 65%). Other grade 3/4 toxic effects were rare (<5%). Response rates were 34% [95% confidence interval (CI) 20% to 51%] in arm A and 35% (95% CI: 20% to 53%) in arm B. Median time to progression was 6.9 (4.6-10.1) and 9.2 (7.9-11.5) months and median overall survival was 17.4 (12.6-23.0+) and 24.7 (16.3-26.4+) months. Patients with an objective tumor response reported better physical well-being (P < 0.01), mood (P < 0.05), functional performance (P < 0.05) and less effort to cope (P < 0.05) compared with the non-responders and stable disease patients. CONCLUSIONS: The primary end point of this study was the objective response rate and based on the statistical design of the trial, the 3-weekly irinotecan schedule was selected over weekly irinotecan administration. The 3-weekly irinotecan schedule also seemed advantageous in terms of grade 3/4 diarrhea, time to progression, overall survival and patient convenience, but the study was not designed to detect differences in these parameters. In addition, tumor response was shown to have a beneficial effect on QoL indicators.

Docetaxel-based chemotherapy in the treatment of gastric cancer.

Docetaxel-based chemotherapy appears to have considerable promise in advanced gastric cancer. In phase II studies of single agent docetaxel, response rates (RRs) of 17% to 24% have been achieved in previously untreated patients. Importantly, RRs of 20% to 22% are seen in second-line treatment. Work by a Swiss and Italian collaborative group has shown that the combination of docetaxel 85 mg/m(2) with cisplatin 75 mg/m(2) every 3 weeks is quite active, achieving an RR of 55% and median survival of 9 months. Hematotoxicity was the main adverse event but was manageable. In other respects the docetaxel/cisplatin doublet (TC) was relatively well tolerated. The same group demonstrated that continuous infusion of 5-fluorouracil (5-FU) 300 mg/m(2) can be given on 2 weeks out of 3 to patients receiving TC. The addition of 5-FU, by this schedule, to TC (TCF) does not increase hematological toxicity, and does not compromise the tolerability of TC. An overall RR of 55% has been reported with TCF. A randomized phase II comparison of TC or TCF versus an ECF (epirubicin/cisplatin/5-FU) control arm is ongoing and should lead to a randomized phase III trial comparing TC or TCF with ECF. In an already completed international randomized phase II comparison of TC versus TCF (TAX-325), the three-drug combination proved significantly more active (RR 54% versus 32% with TC, among patients treated per protocol). Time to progression was also longer for TCF. Gastrointestinal (but not hematological) toxicity was less with TC. TCF was chosen for ongoing phase III comparison against a control 5-FU/cisplatin arm. It is possible that data from these randomized studies will confirm the value of docetaxel-based chemotherapy in advanced gastric cancer and that docetaxel combinations will also be effective in the multidisciplinary efforts to cure earlier stage cancer.

New clinical trials with interleukin-2: rationale for regional administration.

The recent availability of recombinant interleukin-2 (IL-2) has led to its rapid introduction as systemic agent against solid tumors. Much less has been undertaken so far in the exploration of the potential advantages of regional applications of IL-2. The potential advantages of regional administration of IL-2 include an ability to achieve higher levels of IL-2 at the site of the tumor, to abrogate local and systemic immunosuppression and to activate specific and nonspecific cytotoxic effectors, with avoidance or reduction of major organ toxicity of high-dose systemic IL-2 therapy. This article reviews that data which support the regional application of IL-2 and other lymphokines for superficial bladder tumors, stage III ovarian carcinoma, melanoma and head and neck cancers. The rationale for regional administration of cytokines like IL-2 in an adjuvant setting, and as a first step in the systemic immunotherapy of solid tumors, is developed.