This phase II study was designed to evaluate the activity and safety of a combination of irinotecan, docetaxel and oxaliplatin in metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma. Forty patients with measurable distant metastasis received irinotecan 150 mg m−2 and docetaxel 60 mg m−2 on day 1, and oxaliplatin 85 mg m−2 on day 2. Cycles were repeated every 3 weeks. The primary end point was to demonstrate a 50% improvement in time-to-progression (TTP) over historical controls. All patients were evaluable. Median TTP was 6.5 months (95% confidence interval (CI) 5.6–7.4), the overall response rate was 50% (95% CI 35–65%) and the median overall survival was 11.5 months (95% CI 8.7–14.3). Grade 3/4 neutropaenia occurred in 47.5% of patients. There were four episodes of febrile neutropaenia in three patients. Other non-haematological grade 3 toxicities included diarrhoea in four patients (10%), vomiting in three patients (7.5%) and mucositis in two patients (5%). The irinotecan, docetaxel and oxaliplatin combination chemotherapy is an active and well-tolerated novel regimen for treating metastatic gastric or GEJ adenocarcinoma and deserves further evaluation in randomised trials and in combination with molecular targeting agents.

BACKGROUNDDocetaxel is a new agent with activity in metastatic gastric cancer. This phase II study was designed to evaluate the activity and safety of an epirubicin, cisplatin and docetaxel combination in patients with this disease.PATIENTS AND METHODSForty-six patients with gastric adenocarcinoma with measurable distant metastasis were eligible for the study. Patients received epirubicin 50 mg/m(2) and docetaxel 60 mg/m(2), on day 1, and cisplatin 60 mg/m(2) on day 2. Granulocyte colony-stimulating factor 300 mug/day subcutaneously was given on days 5 and 6. Cycles were repeated every 3 weeks for a maximum of eight courses.RESULTSAll patients were evaluable for response and toxicity. Two complete and 21 partial responses were observed, with an overall response rate of 50% [95% confidence interval (CI) 36% to 64%]. Stable disease was observed in 13 patients (28%) and progressive disease in 10 patients (22%). The median time to progression was 6 months (95% CI 5-7) and the median overall survival was 11.2 months (95% CI 8.5-13.9). Grade 3/4 neutropenia, thrombocytopenia and anemia occurred in 46%, 7% and 13% of patients, respectively. There were five episodes of febrile neutropenia in four patients. Other grade 3 toxicities included mucositis in three patients (6.5%), vomiting in four patients (8.7%) and diarrhea in one patient (2%). There were no cardiac toxicity, severe neurotoxicity or treatment-related deaths.CONCLUSIONSThe epirubicin, cisplatin and docetaxel combination is an active and well tolerated novel chemotherapy regimen for treating metastatic gastric cancer and deserves further evaluation in randomized studies.

A group of 66 patients with locally advanced T2-T4 NOMO TCC of the bladder were treated with three cycles of neo-adjuvant M-VAC chemotherapy. Of 65 evaluable patients, 18 (28%) were T2, 22 (34%) were T3a, 21 (33%) were T3b, and 4 (6%) were T4a. Patients were restaged clinically by repeat CT scan and TURB and were to undergo pathologic staging. Partial cystectomy was to be performed in patients with initial monofocal lesions who responded to therapy. As the study evolved, many patients who responded to M-VAC underwent clinical restaging only. Clinical response incorporated the results of the CT scan, cytology, and TURB. The overall clinical response rate was 82%. A cCr was attained in 28 of the 65 (43%) patients, and 25 of the 65 (38%) patients attained a cPR; 7 patients (11%) had stable disease, and 5 (8%) had progression. The median follow-up is 36(+) months (6(+)-78(+) months). The overall survival for all patients is 82% at 2 years, and 3 year survival is 73%. Of 65 patients, 44 (68%) were managed with conservative therapy (TURB or partial cystectomy). Of 44, 34 (77%) are alive, 28 (64%) with a functional bladder. Patients who had downstaging of their tumors to absence of disease (TO) or superficial disease have 2 and 3 year survival of 86 and 83%. For patients with muscle-infiltrating tumors after M-VAC, 2 and 3 year survival is 89 and 32%. Of 65 patients treated in this study, 28 (43%) have conserved normal bladder function. Response to chemotherapy may be the most important predictor of survival. Although bladder conservation is feasible in selected patients, they remain at risk for recurrence.

BACKGROUND:Based on the excellent results with combination chemotherapy such as M-VAC (methotrexate, vinblastine, doxorubicin, and cisplatin) in patients with advanced disease, neoadjuvant chemotherapy has been advocated to improve survival and in some cases to permit bladder conservation. METHODS:A Phase II study of neoadjuvant M-VAC chemotherapy was performed in patients with T2-T4N0M0 bladder tumors. After clinical staging, three cycles of M-VAC were given. After patients underwent postchemotherapy clinical restaging, pathologic restaging (partial or radical cystectomy) was planned. RESULTS:Forty-six patients are evaluable. A clinical response was attained in 78%. Six patients (13%) had stable disease, and four (9%) had progression. After chemotherapy, 17 patients underwent radical cystectomy, none of whom were pTO. In this group, 10 of the 17 (59%) are alive at a median follow-up of 37+ months (range, 8-62+ months). Eleven patients had a partial cystectomy; 7 of the 11 (64%) are alive, 6 (55%) with a preserved bladder. Eighteen patients had clinical restaging only, and did not have pathologic staging. Median follow-up for this group is 36+ months (11-65+ months). Twenty-one of the 29 (72%) patients managed with conservative surgery or transurethral resection of the bladder alone are alive with a functional bladder. Median survival for all patients has not yet been reached. Two-year survival is 82%, and 3-year survival is 70%. CONCLUSIONS:The current study is of interest in terms of bladder conservation. Assessment of the true success of any bladder-preserving treatment will require longer follow-up.

BACKGROUND:In view of the difficulties in administering aggressive treatment to elderly patients, frequently with concomitant medical problems, a treatment program with the combination of carboplatin and 5-FU for advanced urothelial tumors was designed. The aim was to maintain an efficacious therapeutic schedule while minimizing toxicity.PATIENTS AND METHODS:Twenty-three patients with advanced bidimensionally measurable urothelial carcinoma were given carboplatin 100 mg/m2 and 5-fluorouracil 500 mg/m2 days 1-3 which was escalated to carboplatin 125 mg/m2 and 5-fluorouracil 625 mg/m2. 5 patients were > 70 years, the ECOG performance status was 2-3 in 10 patients (43%), and the creatinine was > 2.0 mg/dl in 3 patients (13%). Five patients (22%) had pre-existing cardiac disease, and 1 had hepatopathy. Nine patients (39%) had prior cisplatin.RESULTS:Ten patients remained at level 1, and 12 others had the dosage escalated to level 2. Twenty-one patients are evaluable for response. Response was observed in 5 of 21 (24%) evaluable patients (95% confidence limits 15%-33%), only at dose level 2. There was 1 CR (5%) and 4 PR (19%). There were no responses in patients who had prior DDP versus 5 of 13 (38%) responses in patients who had not had prior DDP. The median time to response was 2 months. The median duration of response was 8 months. At level 2 myelotoxicity was significant, and led to a return to level 1 in 2 patients. Nine of 12 patients (75%) treated at level 2 had grade 3 leukopenia, and 1 patient had nadir sepsis. 4 patients (33%) had grade 4 thrombocytopenia.CONCLUSIONS:Moderate activity was shown with this regimen in untreated patients at level 2. This regimen presents a feasible outpatient alternative for patients who are unable to undergo more aggressive chemotherapy.

Twenty patients with histologically documented superficial bladder cancer (Ta, T1, Tis) were treated with intravesical administration of TNF 400-1800 micrograms. Of 18 patients with a marker lesion, 2 obtained a complete response for 8+ and 18 months. Two had a partial response and were given other intravesical therapies after 5 and 7 months. No or minimal systemic absorption of TNF was observed and documented in 4 of 20 patients by pharmacokinetic studies, and no patients developed antibodies to intravesically administered TNF. TNF was well tolerated in doses up to 1800 micrograms. No systemic or local side effects were observed. Modest activity was attained with intravesical TNF, even in pretreated patients.

The 3924A Morris hepatoma was surgically implanted into the liver of 85 ACI/T rats to evaluate the percentage of take, the possibility of inducing a single primary lesion in the liver and the time, growth and vascular characterization of the tumor.After death or planned sacrifice, a three diameter measurement of the explanted tumor and a Gompertzian growth curve were made. A successful implant was obtained in 89.4% of the operated rats, with a minimum appearance time of three days.No metastases were observed before the 21st day after the implant. In the subgroup of deceased rats with no metastases, the liver tumor volume was significantly smaller than in the subgroup with single (p = .03) or multiple (p = 0.4) metastases. By translumbar aortography, a predominant arterial supply of the neoplastic area was documented. Median survival was 31 days.This experimental model is useful for future studies to define the pharmacokinetic characteristics and the effectiveness of loco-regionally administered drugs.

As early as 10-15 min after the start of a 30 min interleukin-2 (IL-2) infusion, a rapid, virtually complete disappearance of all natural killer (NK) lymphocyte subpopulations (including both CD3- CD56+ and CD3+ CD56+ cells with either alpha/beta or gamma/delta T-cell receptor) was observed from peripheral blood. In contrast, the number of T lymphocytes (CD3+ CD56-) was unmodified for at least 2 h after IL-2 injection. The IL-2-induced, rapid disappearance from peripheral blood of NK and NK-like lymphocytes may be related to their massive adherence to the activated endothelium. In this regard, IL-2 infusion caused a very rapid rise of tumour necrosis factor-alpha (TNF-alpha) plasma concentration, whereas other cytokines, such as interferon-gamma (IFN-gamma), were induced only at later times. In vitro experiments indicated that IL-2, either alone or better combined with TNF-alpha, exerts a rapid and selective stimulatory effect on NK adhesion to endothelial cells. On the basis of these findings, we suggest that the activation of NK lymphocytes induced by IL-2, alone or combined with TNF-alpha, plays a key role in mediating the massive and selective adherence of NK and NK-like cells following IL-2 bolus infusion.

Adoptive cancer immunotherapy consists of in vitro activation of natural killer (NK) cells and non-major histocompatibility complex (MHC)-restricted cytotoxic T cells by recombinant interleukin-2 (IL-2) and subsequent administration of the lymphokine-activated killer (LAK) cells to a tumor-bearing host [1]. LAK cells are routinely generated in short-term cultures of peripheral blood mononuclear cells (PBMC) in the presence of IL-2 [1]. They are distinguished from NK cells and MHC-restriced cytotoxic T cells by their ability to lyse not only NK-sensitive target cells, but also NK-resistant lines and fresh tumor cells in a non-MHC-restricted fashion [1]. Due to their ability to lyse fresh tumor cells, LAK effectors have been used in adoptive immunotherapy of advanced cancer; indeed, Rosenberg et al. have recently reported that infusion of LAK cells with high-dose rIL-2 induced a marked or complete reduction of the tumor mass in a minority of patients with otherwise refractory metastatic malignancies (particularly melanomas and renal carcinomas) [2–4]. These findings were recently extended using in vitro expanded tumor infiltrating lymphocytes (TIL) instead of IL-2-stimulated PBMC [5].

We report the serum levels of soluble interleukin2 receptor (siL2R), β-microglobulin (β-M) and interferon-γ (IFN-γ) in patients undergoing adoptive immunotherapy with rIL2 and lymphocyte-activated killer (LAK) cells. Our results indicate that rIL 2 induced a marked increase of the serum concentration of these markers, although this increase varied considerably for different individuals.