Phase II trial of recombinant IFN-alpha2a with etoposide/cisplatin induction and interferon/megestrol acetate maintenance in extensive small cell lung cancer.

Previous data suggested interaction of cisplatin with interferon (IFN) in non-small cell lung cancer and a possible effect of IFN in maintaining remission in small cell lung cancer (SCLC). This study was designed to further examine the effect of IFN in the treatment of extensive disease (ED) SCLC. Forty previously untreated patients with performance status (PS) of 0-2 (Zubrod scale) were treated with etoposide (100 mg/m2 for 3 days), cisplatin (25 mg/m2 for 3 days) (EP), and recombinant IFN-alpha2a (rIFN-alpha2a) (5 x 10(6) U/m2 for 3 days) for six cycles (induction), followed by rIFN-alpha2a (5 x 10(6) U/m2) thrice weekly and megestrol acetate (40 mg q.i.d.) as maintenance therapy for 6 months or until progressive disease or intolerable toxicity was documented. Patients were 25 men (62%) and 15 women (38%), median age 58 (28-76), median Zubrod performance status 1 (0-2). Major sites of metastasis include liver (55%), bone (42%), bone marrow (25%), and adrenal gland (18%). Of 40 eligible patients accrued to this trial, 35 were evaluable for response, and 37 were evaluable for toxicity. There were 3 complete and 28 partial responses, for an overall response rate of 89%. With 39 of 40 patients followed until death, median survival (Kaplan-Meier) is estimated at 46 weeks (95% CI range 35-55). Twenty patients completed six cycles of induction, and 16 received maintenance therapy, median 2 cycles (range 1-3). Major toxicity during induction included grade 4 granulocytopenia in 24%, grade 2-3 nausea or vomiting or both in 41%, grade 2 fatigue in 24%, grade 2 anorexia in 22%, and grade 2-3 renal insufficiency in 9% of 175 total courses of chemotherapy administered. Toxicity during the maintenance phase was notable for grade 2-3 fatigue in 43%, grade 2-3 anorexia in 24%, grade 2-3 weight loss in 10%, and grade 3-4 anemia in 17% of 30 courses. There were no treatment-related deaths. The addition of rIFN-alpha2a to EP in induction chemotherapy of ED SCLC, followed by rIFN-alpha2a and megestrol acetate maintenance therapy, was reasonably well tolerated. The complete and overall response rates and duration of remission and survival appear to be similar to those generally obtained with EP alone in similar patients.

Phase II trial of uracil and tegafur plus oral leucovorin: an effective oral regimen in the treatment of metastatic colorectal carcinoma.

PURPOSE: To determine the activity and evaluate the toxicity of uracil and tegafur in a 4:1 molar concentration (UFT; Taiho Pharmaceutical Ltd, Tokyo, Japan) plus oral calcium leucovorin in the treatment of patients with advanced colorectal carcinoma. PATIENTS AND METHODS: Forty-five patients with advanced, bidimensionally measurable metastatic colorectal carcinoma were enrolled onto the trial. None of the patients had received prior chemotherapy or biologic therapy for advanced disease. Patients received either 350 or 300 mg/m2/d UFT plus 150 mg/d leucovorin administered orally in divided daily doses every 8 hours for 28 days followed by a 7-day rest period. Response was evaluated after two courses of therapy. RESULTS: Eighteen patients (three treated at 350 mg/m2/d and 15 at 300 mg/m2/d) had partial responses, and one patient had a complete response (response rate, 42.2%; 95% confidence interval, 28% to 58%). Responses were observed in sites that included liver (n = 18), lung (n = 6), and bone (n = 1). Of seven patients who received 350 mg/m2 UFT, prolonged grade 3 diarrhea developed in five; this resulted in a reduction in the UFT starting dose to 300 mg/m2/d in the remaining 38 patients. Grade 1 or 2 toxic effects included diarrhea, nausea, vomiting, abdominal cramping, anorexia, fatigue, oral mucositis, excessive lacrimation, and rash. Among 38 patients who received the 300-mg/m2/d dose, grade 3 toxic reactions included diarrhea (n = 4), vomiting (n = 2), abdominal cramping (n = 1), and fatigue (n = 2). CONCLUSION: UFT 300 mg/m2/d plus oral leucovorin 150 mg/d administered for 28 days demonstrated significant activity against metastatic colorectal carcinoma. This oral regimen was well tolerated and devoid of the neutropenia or significant oral mucositis that complicates intravenous schedules of fluorouracil (5-FU) plus leucovorin. The results of this clinical trial will serve as the basis for a randomized phase III study to compare this oral schedule of UFT plus leucovorin with intravenous 5-FU plus leucovorin to determine the relative efficacy, impact on quality of life, and cost of the two regimens.

Phase I and plasma pharmacokinetic study of infusional fluorouracil combined with recombinant interferon alfa-2b in patients with advanced cancer.

PURPOSE: Enhanced fluorouracil (FUra) cytotoxicity caused by recombinant interferon alfa-2b (rIFN-a) has been reported, but the mechanism, optimal dose, and schedule remain unknown. Therefore, a phase I and pharmacokinetic study of FUra with escalating doses of rIFN-a was initiated. PATIENTS AND METHODS: FUra (750 mg/m2/d) was given by continuous intravenous (IV) infusion for 5 days. rIFN-a (0.1 to 15 x 10(6) U/m2/d) was given subcutaneously (SC) daily for 5 days concurrent with FUra. Courses were repeated every 14 to 21 days. Forty-four patients were enrolled; 39 received at least two courses. During the first course of therapy, FUra levels before and after administration of rIFN-a were quantitated in 26 patients by high-pressure liquid chromatography. RESULTS: The maximum-tolerated dose of rIFN-a was 10 x 10(6) U/m2/d. Stomatitis was dose-limiting. Three partial and five minor responses occurred. Interpatient pharmacokinetics showed that rIFN-a did not alter steady-state plasma concentration (Css; range, 0.77 +/- 0.35 mumol/L to 1.85 +/- 0.48 mumol/L), elimination half-life (t1/2; mean, 9.7 +/- 4.3 minutes), area under the concentration-versus-time curve (AUC; range, 93 to 224 mumol/L x hours), total-body clearance (CI; range, 1,172 to 3,236 mL/min), or volume of distribution (range, 11.9 to 49.2 L) of FUra. Intrapatient data evaluation revealed a dose-independent effect of rIFN-a. The mean FUra Css after rIFN-a administration (1.31 mumol/L) was greater than that before rIFN-a administration (1.02 mumol/L, P < .0001). FUra Cl after rIFN-a administration was reduced by 20% to 35% compared with use of FUra alone (P < .0001). Patients with a greater than 20% decrease in FUra Cl had a fourfold greater incidence of diarrhea. CONCLUSION: rIFN-a reduces FUra Cl and, consequently, increases FUra-associated toxicity. Phase II studies of FUra and rIFN-a seem to be warranted.

Intraperitoneal catheters: percutaneous placement with fluoroscopic guidance.

PURPOSE: The authors reviewed their experience with percutaneous placement of catheters into the peritoneal cavity for the administration of intraperitoneal chemotherapy to determine if their approach resulted in a lower complication rate than the reported 12%-16% rate and to demonstrate the technical advantages over surgically placed catheters. PATIENTS AND METHODS: Seventy-six patients with gastrointestinal or gynecologic malignancies underwent 152 procedures during a 20-month period. The catheters were used to deliver antineoplastic agents and, in some patients, to drain ascites. Catheter insertion was performed with local anesthesia and a modified Seldinger technique. A 5-F catheter was used in 89% of procedures; in the remainder, the catheter was of a larger caliber. RESULTS: The procedure was successful in 145 (95%) instances and failed in seven (5%) attempts because of peritoneal adhesions. The catheters remained in place for less than 2 days in 56%, 2-10 days in 25%, and more than 10 days in 19% of patients. One catheter remained in place for 15 weeks. Complications occurred in seven procedures (5%). Four cases of mild peritonitis responded to a brief course of intravenously administered antibiotics, and severe pain in two patients required premature catheter removal. A single case of inadvertent transcolonic catheter placement occurred without adverse sequelae to the patient. CONCLUSIONS: Intraperitoneal catheterization can be performed with local anesthesia by using a simple technique with a very low complication rate. The catheters can remain in place for prolonged periods without significant risks.

Phase II study of etoposide and alpha-interferon in patients with advanced measurable colorectal carcinoma.

Based on encouraging in vitro and in vivo data, 14 consecutive patients with measurable metastatic previously untreated colorectal carcinoma were treated with a combination of intravenous etoposide and subcutaneous alpha-interferon. Etoposide was given at 60 mg/m2 intravenously on days 1-5 and alpha-interferon at 5 million units/m2 subcutaneously on days 1-5; courses were repeated every 21 days. All 14 patients were evaluable for response and toxicity. None of the patients achieved a complete or partial remission. Toxicity of this combination was moderate. Our data suggest that this combination is ineffective against colorectal carcinoma.

Suppression of chronic myelogenous leukemia colony growth by interleukin-4.

Interleukin-4 (IL-4) is a cytokine with pleiotropic activities. In normal bone marrow cultures grown in the presence of either granulocyte-macrophage colony-stimulating factor (GM-CSF) or interleukin-3 (IL-3), IL-4 suppresses granulocyte-macrophage colony-forming unit (CFU-GM) proliferation but it enhances the colony-stimulatory effect of granulocyte colony-stimulating factor (G-CSF). We studied the effect of IL-4 on chronic myelogenous leukemia (CML) bone marrow or peripheral blood cells from 30 patients using the CFU-granulocyte-erythrocyte-monocyte-megakaryocyte colony culture assay. In several repetitive experiments, IL-4 inhibited CFU-GM colony replication by 24 to 65% in a dose-dependent fashion at concentrations ranging from 0.01 to 10 micrograms/ml when patients' cells were cultured in the presence of erythropoietin alone or with phytohemagglutinin-conditioned medium, GM-CSF, or IL-3. The addition of 100 U/ml of IL-1 beta to the CML cultures partially reversed the inhibitory effect of IL-4. Incubation of CML low-density peripheral blood cells with IL-4 resulted in down-regulation of IL-1 beta and IL-6 production in three of four samples, suggesting that the suppressive effect of IL-4 is mediated by inhibition of IL-1 and by other mechanisms including inhibition of IL-6 production. In contrast to the stimulatory effect exerted by IL-4 on G-CSF-dependent CFU-GM progenitor proliferation in normal marrow, the addition of IL-4 to CML cultures grown in the presence of G-CSF resulted in a divergent effect: suppression of CML CFU-GM in two, stimulation in three, and no significant effect in two CML patients' samples. It is therefore possible that IL-4 may have an in vivo antiproliferative effect in a subpopulation of CML patients.

Surgery following response to interferon-alpha-based therapy for residual renal cell carcinoma.

The role of aggressive surgery for metastatic renal cancer in the era of biological therapy is not clear. Therefore, we reviewed 17 patients who, between February 1987 and August 1990, underwent surgical resection of residual masses following initial response to interferon-alpha-based therapy. Viable tumor persisted in 15 patients (88%), whereas only inflammatory response was detected in 2. Of the patients 11 (65%) remained disease-free at a median of 12 months postoperatively (range 5 to 29), with an overall median survival of 26 months (range 6 to 34) from treatment initiation. These data suggest that surgery may be of therapeutic benefit in select patients with renal cell carcinoma who do not meet traditional criteria for surgical resection. Prospective trials are being performed to determine whether there is a role for aggressive surgical resection of persistent disease in patients with advanced renal cell carcinoma who have previously responded to interferon-alpha-based therapy.

Novel tumor necrosis factor toxic effects. Pulmonary hemorrhage and severe hepatic dysfunction.

Recombinant human tumor necrosis factor is an investigational antitumor agent currently undergoing clinical trials. Previous reports of pulmonary and hepatic toxicities include mild reversible decline in pulmonary diffusing capacity and mild elevation of bilirubin and transaminases. This report describes two novel toxicities in patients receiving their first intravenous dose of tumor necrosis factor: pulmonary hemorrhage and severe hepatic dysfunction. These patients received no other antitumor therapy for at least 4 weeks before tumor necrosis factor treatment and no additional antitumor therapy concomitant with tumor necrosis factor. An analysis of the possible pathogenesis is presented.

Immunological properties of melanoma tumor-infiltrating lymphocytes before and after IL-2-based biotherapies.

Immunological properties of melanoma TILs before and/or after IL-2-based biotherapies were investigated. TILs harvested before therapies, including those for adoptive transfer, proliferated well in culture with IL-2 and displayed cytotoxicity relatively restricted to autologous tumor cells. In contrast, TILs during or at the end of IL-2 based therapies did not proliferate in culture with IL-2. TILs from tumors even harvested 45 days after the end of IL-2 therapy modestly proliferated in culture with IL-2 and showed MHC-nonrestricted cytotoxicity. The number of live tumor cells that were yielded from melanomas during or at the end of IL-2-based therapies significantly decreased in all nine patients with metastatic melanomas, regardless of their clinical responses (2 PR, 2 MR, 2 SD, and 3 PD). Collectively, these results suggest that current IL-2-based therapies resulted in both transient nonresponsiveness of TILs to IL-2 and transient decrease in the number of live tumour cells in most melanoma patients.

Study of tumor-infiltrating lymphocytes for adoptive therapy of renal cell carcinoma (RCC) and metastatic melanoma: sequential proliferation of cytotoxic natural killer and noncytotoxic T cells in RCC.

We investigated the immunological properties of interleukin-2 (IL-2)-activated tumor-infiltrating lymphocytes (TIL), which were used for adoptive therapy of renal cell carcinoma (RCC) (seven patients) by focusing on natural killer (NK) cells, and metastatic melanoma (six patients) by focusing on cytotoxic T lymphocytes. TIL from five of seven cases proliferated well in culture with AIM-V serum-free medium and 1000 U/ml rIL-2 in 3-L gas permeable bags, whereas TIL from two RCCs exhibited delayed proliferation. Proliferation of CD3-CD56+ NK cells with major histocompatibility complex-nonrestricted cytotoxicity in RCC-TIL (n = 6, mean = 651-fold, ranging from 39- to 3450-fold) for the first 2-4 weeks was 63 times higher than that of noncytotoxic CD3+ T cells (n = 6, 10.3-fold ranging from 0.8 to 35-fold). Thereafter, CD3+ T cells predominantly proliferated, and proliferation of CD3+ T cells (n = 5, 743-fold) for 5-6 weeks were 24 times higher than that of CD3-CD56+ NK cells (n = 5, 31-fold). Significant numbers of RCC-TIL became adherent to the surfaces of the bags several weeks after initiation of culture. These adherent TIL consisted of more CD3-CD56+ NK cells and exhibited higher cytotoxicity than did nonadherent TIL. Adherent RCC-TIL produced interferon (IFN)-gamma, while nonadherent TIL did not. These results suggest that initially cytotoxic CD3-CD56+ NK cells and, later, noncytotoxic CD3+ T cells proliferated in culture of RCC-TIL for adoptive therapy. These noncytotoxic TIL were primarily transferred to RCC patients, who also received cyclophosphamide, IL-2, and IFN-alpha. In contrast to RCC-TIL, IL-2-activated melanoma TIL consisting of all CD3+ T cells displayed modest levels of cytotoxicity, primarily restricted to autologous melanoma cells in all cases tested. The cytotoxic melanoma TIL were adoptively transferred to melanoma patients. Three of seven RCC patients responded to the adoptive therapy.

Effect of recombinant human interleukin 4 on human monocyte activity.

Recombinant human interleukin 4 (rhuIL-4), a lymphokine that reportedly stimulates tumoricidal activity in mouse macrophages, is currently undergoing clinical studies to determine its efficacy in the treatment of cancer. IL-4 is known to participate with other cytokines to regulate growth and differentiation of various hematopoietic cells as well as modulate the immune response. Little is known about the effect of rhuIL-4 on human monocyte tumoricidal activity. The purpose of these studies was to examine the effect of rhuIL-4 on human peripheral blood monocytes. Peripheral blood monocytes isolated from normal donors failed to demonstrate tumoricidal activity or interleukin 1 secretion after treatment with rhuIL-4 in vitro. Furthermore, monocyte-mediated cytotoxicity induced by recombinant human gamma-interferon plus muramyl dipeptide was suppressed in a dose-dependent manner by rhuIL-4. This reduction in cytotoxicity corresponded to a reduction in IL-1 production and secretion. Further investigation of rhuIL-4 and its role in the cytokine network is necessary for the development of effective immunotherapy in cancer patients.

Interleukin-2 alone and in combination with other cytokines in melanoma: the investigational approach at the University of Texas M.D. Anderson Cancer Center.

The clinical data that have been accumulated so far suggests a significant influence of IL-2 dose and schedule on the immunobiological effects and clinical toxicities observed with this cytokine. Consequently, the series of Phase I and Phase II clinical trials conducted at the University of Texas M. D. Anderson Cancer Center in patients with advanced malignant melanoma investigating the use of IL-2 in combination with other cytokines, monoclonal antibodies, or ex vivo activated effector cells have used a common dose and schedule of IL-2 administration for which abundant immunobiological information already exists. This approach allows cross-trial comparison of experience with toxicities, immunobiological observations and clinical activity by a group of investigators within a single institution, and more rapid and valid evolution towards combination biological therapy, which preclinical data suggest will have greater activity than single agent therapy.

A phase II study of interleukin-2 and lymphokine-activated killer cells in patients with metastatic malignant melanoma.

Thirty-six patients with metastatic melanoma were entered into a study of the therapeutic efficacy of adoptive immunotherapy with high-dose interleukin-2 (IL-2) and lymphokine-activated killer (LAK) cells. Thirty-two patients who received all components of the therapy are evaluable for response, and all patients are evaluable for toxicity. Sites of disease included lung, liver, subcutaneous nodules, and intra-abdominal metastases. One complete response (CR) and five partial responses (PRs) resulted from treatment (19% response rate). The median response duration was 5 months, with the durable CR continuing at 31+ months and one durable PR continuing for 13 months. Sites of response included lung, liver, subcutaneous nodules, and lymph nodes. Response, response duration, or site of response did not correlate with the total dose of IL-2 administered, rebound lymphocytosis, or the number of LAK cells infused. Toxicity included hypotension, fluid retention with a "capillary leak syndrome" in most patients, and transient multiorgan dysfunction that resolved promptly after the completion of therapy. Adverse cardiac events occurred in 16% of patients, with one myocardial infarction leading to a death. This study confirms the activity of the initial IL-2/LAK cell regimen in metastatic melanoma reported by Rosenberg et al, supporting the concept of adoptive immunotherapy as an important new treatment approach for this disease.