Adoptive immunotherapy of human cancer: the cytokine cascade and monocyte activation following high-dose interleukin 2 bolus treatment.

Serum concentration kinetics of gamma-interferon (IFN-gamma), neopterin, 2'-5' A synthetase and tumor necrosis factor alpha were determined in five cancer patients undergoing adoptive immunotherapy with high-dose interleukin 2 (IL-2) bolus infusion and lymphokine-activated killer cells according to the National Cancer Institute, NIH protocol. In all cases a significant increase of these markers was observed after IL-2 treatment. This suggests that the antitumor effect of high-dose IL-2 bolus administration may be in part mediated by activation of a cascade of endogenous cytokines including IFN-gamma and tumor necrosis factor alpha. After IL-2 bolus injection, the kinetics of neopterin was similar but delayed when compared to that of IFN-gamma: this suggests that macrophages, the specific source of neopterin, become activated by IFN-gamma following IL-2-mediated lymphocyte induction, thus implying a possible role for macrophages in the antitumor effects mediated by IL-2 and lymphokine-activated killer cells.

Intraperitoneal recombinant alpha-2-interferon alternating with cisplatin as salvage therapy for minimal residual-disease ovarian cancer: a phase II study.

A phase II study was initiated in March 1987 at the Regina Elena National Cancer Institute of Rome to evaluate the efficacy of alternating intraperitoneal (IP) recombinant alpha-2-interferon (r-alpha 2-IFN) and cisplatin (DDP) as salvage therapy for less than or equal to 5 mm residual-disease (RD) ovarian carcinoma. Fourteen assessable patients entered the study. All had received prior chemotherapy (11 with DDP-based regimens); five patients had macroscopic RD (less than or equal to 5 mm), and nine had microscopic RD (histologically positive random biopsies and/or positive cytology and immunocytochemical tests). The response to IP immunochemotherapy was evaluated by laparotomy. Pathologic complete remissions (PCRs) were achieved in seven patients (50%) who have remained free of disease with a median follow-up of 22+ months (range, 11+ to 30+ months). Six patients achieved a stable disease and one presented disease progression. With the exception of chemical peritonitis-induced adhesions, no limiting toxicity was observed. The results obtained in this small, highly selected series demonstrate that a high PCR rate may be obtained with IP immunochemotherapy with DDP and r-alpha 2-IFN as salvage therapy in residual ovarian carcinoma less than or equal to 5 mm after first-line chemotherapy also including intravenous (IV) DDP. Larger comparative studies must be conducted to establish the potential role of IP DDP and r-alpha 2-IFN as compared with either of the single treatments.

Prognostic factors for chemotherapy response and survival using combination chemotherapy as initial treatment of advanced head and neck squamous cell cancer.

Between May 1981 and December 1987, 152 consecutive patients with locally advanced and previously untreated head and neck squamous cell cancer (HNSCC) received two or three courses of neoadjuvant chemotherapy (NAC) prior to surgery and/or radiotherapy. Eighteen percent of patients achieved a complete response and 45% a partial response (PR), for an overall response rate of 63%. A variety of pretreatment patient and tumor characteristics were analyzed for both the tumor response to NAC and survival rate. Significantly higher CR rates were found in patients with a World Health Organization (WHO) performance status (PS) of 0 to 1 than in those patients with a PS of 2 (P = .03). Patients with stage III disease were significantly more likely to respond than those with stage IV (P = .006). Evaluation of all parameters through multivariate analysis identifies the tumor classification (P = .001) and the primary site (P = .006) as the most significant in predicting CR. The overall 5-year survival rate of the entire group of patients was 18% (median survival, 14.3 months). Analysis by PS (P = .001), stage (P = .002), and tumor (P = .001), and node (P = .01) classes showed significant differences. Patients achieving a CR after NAC had a significantly improved survival rate as compared with those with residual disease at assessment (P = .0003). With the multistep regression analysis, the tumor (P = .005) and node (P = .007) classifications, and the sex (P = .03) were significant factors, but CR (P = .0004) remained the most important and independent predictive factor. Randomized prospective trials are requested to clearly establish the role of NAC on survival rates.

Delay in progression of bone metastases in breast cancer patients treated with intravenous pamidronate: results from a multinational randomized controlled trial. The Aredia Multinational Cooperative Group.

PURPOSE: Bone metastases are a major cause of morbidity in breast cancer, resulting in complications that include pain, loss of mobility, pathologic fracture, and tumor-induced hypercalcemia (TIH). Inhibition of osteoclast-mediated bone destruction using bisphosphonates represents a promising new management approach. PATIENTS AND METHODS: Breast cancer patients with bone metastases were randomly allocated to receive chemotherapy alone (152 patients) or chemotherapy plus pamidronate 45 mg in 250 mL of saline as a 1-hour intravenous infusion every 3 weeks (143 patients). Whenever possible, treatment continued until progression of disease (PD) in bone appeared on radiographs or bone scan. Time to PD in bone and pain reduction according to a self-assessment six-point scale were selected as primary end points. PD in bone was verified during extramural review (EMR) of all imaging studies by blinded observers, and these data were used as the main efficacy criterion. Analgesic intake, World Health Organization (WHO) performance status, and complications of bone metastases (radiotherapy, TIH, fractures, orthopedic surgery) were also compared in the two groups. RESULTS AND CONCLUSION: At EMR, median time to PD in bone was increased by 48% in patients who received pamidronate (249 v 168 days; P = .02, Wilcoxon test). Marked pain relief, defined as a two-point decrease lasting for > or = 6 weeks, was reported by 44% of pamidronate patients and by 30% of controls (P = .025, chi 2 test). The infusions (median, nine per patient; range, 0 to 39) were well tolerated, with no major toxicities reported. Pamidronate by repeated infusion can significantly slow the progression of bone metastases and reduce attendant morbidity.

High-dose chemotherapy followed by autologous bone marrow transplantation versus dexamethasone, cisplatin, and cytarabine in aggressive non-Hodgkin's lymphoma with partial response to front-line chemotherapy: a prospective randomized italian multicenter study.

PURPOSE: To evaluate, in a prospective multicentric study, the efficacy of a conventional salvage chemotherapy (dexamethasone, cisplatin, and cytarabine [DHAP]) versus high-dose chemotherapy (carmustine, etoposide, cytarabine, and cyclophosphamide [BEAC]) followed by autologous bone marrow transplantation (ABMT) in patients with aggressive non-Hodgkin's lymphoma (NHL) in clinical partial response (PR) after two thirds of a conventional front-line therapy. PATIENTS AND METHODS: From August 1988 to August 1991, 286 patients with aggressive NHL were randomized in seven Italian institutions to receive fluorouracil, methotrexate, cytarabine, cyclophosphamide, doxorubicin, vincristine, and prednisone (F-MACHOP) or methotrexate with leucovorin, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin (MACOP-B) as front-line therapy. Of the 286 patients enrolled onto the trial, 77 (27%) were considered in PR after two thirds of the front-line therapy, and 49 of 77 (64%) were randomized: 27 to receive DHAP chemotherapy and 22 to receive BEAC followed by ABMT. RESULTS: The response after second-line treatment was as follows: in the DHAP group, four patients (15%) achieved a complete remission (CR), 12 (44%) remained in stable PR, and 11 (41%) showed progressive disease; in the ABMT group, three patients (14%) obtained a CR, 18 (82%) obtained a stable PR, and one (4%) progressed, with an overall response (CR + stable PR) of 59% and 96% (P < .001) in the DHAP and ABMT groups, respectively. The overall survival was 59% versus 73% and the progression-free survival (PFS) was 52% versus 73% in the DHAP and ABMT groups, respectively (P, not significant). The toxicity was mild, particularly in the ABMT group, and no treatment-related deaths occurred in either group. CONCLUSION: Because of the small number of patients randomized, we were unable to determine whether ABMT or a standard salvage regimen (DHAP) is superior for PR patients. However, we confirmed that myeloablative treatment is a safe and well-tolerated procedure in this category of patients and this may enable us to evaluate its role as part of a front-line treatment in poor-risk NHL patients.

Phase III randomized study of fluorouracil, epirubicin, and cyclophosphamide v fluorouracil, doxorubicin, and cyclophosphamide in advanced breast cancer: an Italian multicentre trial.

From February 1983 to January 1985, 497 patients with advanced breast cancer were randomly allocated to receive either epirubicin or doxorubicin in the following combination chemotherapy regimen: fluorouracil (5-FU) 500 mg/m2 intravenous (IV) on days 1 and 8; epirubicin or doxorubicin 50 mg/m2 IV on day 1; cyclophosphamide 500 mg/m2 IV on day 1 (FEC or FAC). Cycles were repeated every 21 days until progression or to cumulative doses of 700 mg/m2 for epirubicin and 550 mg/m2 for doxorubicin. Dose reductions were applied according to the standard criteria. Activity was evaluated in 443 patients (222 in the FEC arm and 221 in the FAC arm). The two experimental groups were comparable in age, performance status, menopausal status, histology, previous treatments, and site of the disease. The overall response rate (complete response and partial response [CR + PR]) was not significantly different: 53.6% for FEC and 56.5% for FAC. The median time to progression was 273 days for FEC and 314 days for FAC; the median survival time was 591 and 613 days, respectively. Leukopenia, anemia, nausea, and vomiting were significantly lower in patients treated with FEC. As for cardiotoxicity, four cases of congestive heart failure (CHF) were recorded among patients treated with FAC while only one was observed in the FEC group. These results indicate that epirubicin in a combination chemotherapy regimen is as active as doxorubicin and is significantly less toxic.

Prospective randomised trial comparing fluorouracil versus doxifluridine for the treatment of advanced colorectal cancer.

Doxifluridine (dFUR) is a fluoropyrimidine derivative that has shown activity on a variety of solid tumours. The purpose of this study was to compare its therapeutic effect with a standard fluorouracil (FU) regimen in patients with locally advanced or metastatic colorectal cancer. 222 previously untreated patients were randomised to receive dFUR (4000 mg/m2) or FU (500 mg/m2) daily for 5 days every 28 days. The primary tumour originated in the colon in two-thirds of the cases in both groups; approximately 90% of patients had metastatic extension, and liver involvement was present in 69% of the patients in the dFUR and FU groups. A good performance status (ECOG 0-1) was recorded in 90% of cases in both arms. A median of five cycles was administered to the patients (range 1-12). Only one partial response among 110 patients in the FU arm and one complete response and five partial responses out of 112 evaluable patients in the dFUR group were observed. Time to progression was significantly longer in the dFUR group (P = 0.02); overall survival, while longer in the dFUR arm (48 weeks vs. 39 weeks), was not significantly so (P = 0.08). Toxicity was acceptable in both arms, although grade 3-4 neurological side-effects and leukopenia were more common after dFUR infusion. Despite the low response rate, our results indicate that dFUR may be a superior alternative to FU. The possibility of enhancing significantly the activity of dFUR with biochemical modulators should be further investigated.

Fluorouracil, doxorubicin, and cyclophosphamide versus fluorouracil, doxorubicin, and cyclophosphamide plus lonidamine for the treatment of advanced breast cancer: a multicentric randomized clinical study.

Experimental models have demonstrated the Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH)-potentiating activity of lonidamine. Phase II clinical trials on advanced breast cancer have shown that this drug induced a 16% objective response rate. Present multicentric randomized trial was conducted to verify whether lonidamine can potentiate the antineoplastic effects of conventional fluorouacil, Adriamycin, cyclophosphamide (FAC) chemotherapy in advanced breast cancer. From January 1987 to December 1989, 265 patients were enrolled in this study, and 231 are evaluable for response. After stratification according to institution and ECOG performance status (PS), the patients were randomly allocated to receive either standard FAC therapy (group A) or FAC plus lonidamine (600 mg orally daily three times a day) (group B). After three FAC courses, the patients with no progressive disease were further randomized to either receive continuous treatment up to the time of tumor progression (maximum: 10 courses) or to discontinue therapy when a response "plateau" was reached. In this latter group, the same therapy was restarted at relapse or disease progression. Objective response (complete response plus partial response) was significantly higher in group B (66.3%) compared to group A (42.3%). The actuarial median times to disease progression was also significantly longer (P less than 0.0001) in group B (median 9 months) than in group A (median 6 months). Other than myalgia and gastric pain, no increased toxicity was observed in the lonidamine. The analysis of second randomization are yet available because of the longer follow-up time required. Present findings suggest an interesting additive effect of lonidamine when combined with FAC chemotherapy and warrant further investigation in other therapeutic regimens and in other neoplastic diseases.

Biological response modifiers.

Biological response modifiers (BRMs) of current clinical interest may be divided into two categories: immunomodulating agents and colony stimulating factors (CSFs). The first are employed to potentiate the host defences towards the tumor but results have proved disappointing in non-small cell lung cancer (NSCLC). With regard to the second, the real dose increment which may be ascribed to CSFs is not sufficient to overcome chemoresistance of NSCLCs. CSFs can, however, reduce the hematologic toxicity of chemotherapy, which represents the most significant result.

A combination of ifosfamide and mitoxantrone as salvage therapy in patients with advanced ovarian cancer.

Ifosfamide (IFX) and mitoxantrone (MXN) have been found to be effective against advanced epithelial ovarian cancer. The combination of these two agents has not yet been tested in this setting but seems to be rational, given the different action mechanisms of these drugs and their not completely overlapping side effects. Between June 1987 and November 1991, 37 patients with advanced ovarian carcinoma recurrent or refractory to primary cisplatin-based chemotherapy entered the study. Therapy consisted of MXN, given i.v. at 10 mg/m2 on day 1 and IFX given i.v. at 2,000 mg/m2 per day on days 1-3 with mesna. The cycles were repeated every 3 weeks. Four patients achieved a complete remission and three achieved a partial remission, for response rates of 18.9% [95% confidence interval (CI) 6.3-31.5%] in the whole sample and 38.8% (95% CI 16.3-61.3%) in the subset of 18 patients responding to first-line cisplatin. No response was obtained in the remaining patients, whose disease was refractory to primary platinum-based chemotherapy. Clinically significant toxicity (WHO grades 3-4) included leukopenia in 46% of the patients and anemia in 32.5%. The non-hematologic toxicity was mild, except for reversible alopecia (57%) and nausea and vomiting (48.5%). This regimen seems attractive for patients who have either failed or not received platinum retreatment, especially when limiting neurotoxicity occurs. Further studies are warranted to establish the relative impact of both of these agents.

Surgical-adjuvant chemotherapy with AMSA in Lewis lung carcinoma bearing mice.

The effect of 4'-(9-Acridinylamino) methanesulfon-m-anisidide (AMSA) in combination with surgery was studied on Lewis lung carcinoma-bearing mice. The surgical removal of the primary tumor was performed at a late stage of growth and the drug was administered i.p. according to different schedules. Results of the present study indicate that the AMSA-surgery combination displays a modest effect against the Lewis lung carcinoma, slightly improved when chemotherapy is given before tumor removal, and that double courses of AMSA, given both before and after surgery, prove to be equally effective as a single preoperative chemotherapy.

Schedule-dependent effectiveness of ADM and multiple cycles of DDP on a murine reticulum sarcoma.

The therapeutic index of adriamycin (ADM) and cisplatin (DDP) combination versus repeated sequences of the more active drug (DDP) was investigated on a murine reticulum cell sarcoma of ovarian origin (M5) implanted i.m. in C57BL/6 mice. The antitumor efficacy of multiple cycles of DDP according to different regimens at a prefixed time (every 7 days) or at tumor regrowth was also evaluated. Our data demonstrate that the ADM-DDP combination did not improve the antitumoral efficacy of DDP as single agent, while repeated cycles of DDP led to a significant increase in the host life span. Differences in therapeutic effect were elicited by the two schedules: the regimen at a prefixed time showed a major effect on local tumor control, although the regimen at tumor regrowth was better tolerated.

Antiemetic activity of high-dose metoclopramide combined with methylprednisolone versus metoclopramide alone in dacarbazine-treated cancer patients. A randomized double-blind study of the Italian Oncology Group for Clinical Research.

In a double-blind randomized trial, we compared the efficacy and tolerability of high-dose (2 mg/kg X 4) intravenous metoclopramide (MTC) versus metoclopramide plus high-dose (250 mg X 2) intravenous methylprednisolone (MP) administered for the first 2 days in untreated patients submitted to dacarbazine chemotherapy for 5 days. Thirty-four patients entered the study. Complete protection from nausea and vomiting was achieved in the majority of patients all through the study period with both antiemetic treatments, with slightly greater efficacy at day 2 for the combination. However, after suspension of the antiemetic therapy, there was a relapse of vomiting in patients. Side effects were not different between the two treatments, but extrapyramidal reactions were significantly increased on the second day of antiemetic therapy. In conclusion, high-dose MTC with or without MP can give good antiemetic protection and the combination seems to be slightly more efficacious. However, the relapse of vomiting after discontinuing antiemetic treatment and the high incidence of extrapyramidal reactions justify further studies to find a better antiemetic treatment.

Paclitaxel as salvage therapy in advanced pretreated ovarian cancer: a phase II study.

The response rate to salvage chemotherapy in advanced ovarian cancer has been disappointing in patients who do not respond or who relapse after platinum-containing regimens. In these cases, the identification of new drugs is a substantial challenge. The efficacy of one of these, paclitaxel, has already been assessed in many phase II trials. From July 1993 to October 1995, 33 patients with advanced ovarian cancer, recurrent or refractory after platinum-based regimens, entered our study. Paclitaxel was given by 3-hour intravenous infusion every 3 weeks. All the patients were evaluable for toxicity and 27 for response. Nine patients (33.3%) responded: 6 complete (22.2%) and 3 partial responses (11.1%). Six responses (35.3%) were observed in the 17 platinum-resistant patients and 3 (30%) in the 10 platinum-responders. World Health Organization (WHO) grade 3-4 neutropenia was common (13/33 patients, 39.4%) and peripheral neurotoxicity was observed in 29 patients (87.8%), but was WHO grade 3 in four cases (12.1%). Alopecia was ubiquitous, whereas other toxic effects were not significant. The overall response rate to paclitaxel in this study is similar to that reported in others and the high complete response (CR) rate should be emphasized. These data confirm the significant activity and safety of this drug in patients with advanced ovarian cancer, even in platinum-resistant cases.

Chemotherapeutic activity and histopathologic feature of BCNU + 5-FU effect on Lewis lung carcinoma.

In this study we investigated the effects of BCNU + 5-FU on the intramuscularly implanted Lewis lung carcinoma and on its spontaneous lung metastases. Chemotherapeutic agents were given i. v. either alone and in combination seven days after transplantation of 2.5 x 10(5) viable tumor cells, when the average weight of the primary tumor was 500 mg. The analysis of the following parameters: T/C, T--C, of %-metastases reduction, indicates that the simultaneous administration of BCNU + + 5-FU induces a more relevant response on the Lewis lung carcinoma than single drug therapy, especially evident at level of lung metastases.

Cyclophosphamide and iphosphamide against Lewis lung carcinoma: evaluation of toxic and therapeutic effects.

In the present report, investigations have been carried out to evaluate toxic and therapeutic effects of cyclophosphamide vs its isomer iphosphamide. Cytostatic action of the 2 drugs was assayed on the murine Lewis lung carcinoma (3LL). It has been observed that iphosphamide is less toxic as compared to cyclophosphamide (LD50 IP LD50 CP = 1.5); on the other hand, to reach the same therapeutic effectiveness on 3LL, an iphosphamide dose 1.6 - 2 times higher than that of its parent compound is necessary.

Interleukin-2, interferon-alpha and interleukin-2 plus interferon-alpha in renal cell carcinoma. A randomized phase II trial.

BACKGROUND: The purpose of the present study was to investigate the therapeutic effectiveness of interleukin-2 (IL-2) and interferon (IFN), either alone or in combination, in comparable groups of patients affected by advanced renal cell carcinoma (RCC). PATIENTS AND METHODS: In order to limit selection biases, treatment was allocated on a random basis. Patients randomized to IL-2 alone were scheduled to receive eight rlL-2 24-hour i.v. infusion cycles, days 1 to 4, at a daily dose of 18 x 10(6) lU/m2 for a total of 25 weeks. Patients randomized to IFN alone were scheduled to receive rIFN-alpha at a daily dose of 6 x 10(6) IU/m2, days 1, 3 and 5, every week for a total of 52 weeks. Patients randomized to the combination of IFN and IL-2 were given the same drugs at the same daily doses for a total of 24 weeks. Drug dose was modified according to toxicity. RESULTS: Twenty-three percent (95% CI:+/-17.5) of patients treated with IL-2 alone showed an objective response to treatment (9% CR). The corresponding figures in patients treated with IFN alone or IFN plus IL-2 were 9% (95% CI:+/-11.9) and 9% (95% CI:+/-11.9), respectively. Complete responses were observed only in patients treated with IL-2. The median duration of response in the IL-2 arm was 18 months (range, 9.5-24). The duration of the two responses achieved by IFN alone was seven and nine months, respectively. The corresponding figures in the two patients responding to the combination of IFN with IL-2 were 19 and 27 months, respectively. Total IL-2 dose appeared to be a major predictor of response. Only a minority of patients experienced grade 3-4 toxicity, the incidence being higher in those treated with IL-2 or IL-2 plus IFN. CONCLUSIONS: Neither IFN nor IL-2 or the combination of the two appear to be very active in patients with advanced RCC, even when trial entry was restricted to patients with relatively indolent disease. This stresses the need for the development of new approaches.

LH-RH analogue Zoladex in the treatment of pre- and perimenopausal women with metastatic breast cancer (results of the Italian Cooperative Study).

From May 1987 to May 1989 sixty one pre- and perimenopausal women with advanced or recurrent breast cancer entered in an open non comparative study. They were treated, as a first-line therapy, with goserelin (Zoladex ICI-118630) a long acting gonadotropin-releasing hormone (LH-RH)-analogue in a depot formulation. Fifty three patients were evaluable for response; median age at entry was 41 years (range 28-56). Serum concentrations of 17 beta estradiol, LH and FSH were significantly suppressed within the first four weeks of therapy and remained suppressed for the whole duration of treatment. Subjective responses were observed, such as pain reduction and/or performance status improvement in 58% of patients. Overall objective response (CR + PR) occurred in 16 (30.2%) patients in all major sites of disease with a median time to response of 12 weeks (range 8 to 48 weeks) and a lifetable median duration of response of 36 weeks (range 16 to 76 weeks). The lifetable median time to progression was 17 weeks (range 5 to 76 weeks). Goserelin depot was well tolerated with no withdrawal due to possible adverse reactions. The observed subjective and objective response rates are comparable to those induced by surgical oophorectomy. Goserelin provides a well tolerated medical alternative to ovarian ablation, without the morbidity associated to surgery. In conclusion the present paper suggests that this innovative chemical estrogen deprivation, in premenopausal breast cancer patients, might be favorably investigated as an adjuvant therapy in future clinical trials.