Antitumor Benefit Research Articles

The BC Cancer Agency experience with gefitinib in advanced non-small cell lung cancer (NSCLC)

3104 Background: Institutional series suggest specific patient subgroups; female, Asian, non-smokers, respond preferentially to gefitinib. Vancouver, BC, has a large Asian population and therefore is an ideal location to study this differential effect. We performed a retrospective analysis of patients treated with single agent gefinitib to determine if our experience reflects this observation. Methods: Between April 2002 and August 2003, 31 patients were treated with gefitinib. Pathology, radiology, laboratory investigations and clinical records were reviewed. Partial radiologic response was defined as per SWOG response criteria. Symptom responses were subjectively evaluated from chart review. Tumor markers assessed included CEA, Ca 15.3, Ca 19–9 and Ca 125. Results: Baseline characteristics at diagnosis; 61% Caucasian, 39% Asian, male 45%, smokers 55%, non-smokers 39%, ECOG 0/1 87%. The tumor histology: 55% adenocarcinoma, 19% bronchoalveolar variant, 6.5% large cell, 3% squamous, 16.5% other. Median treatment length was 2 months. On radiologic review, 6 patients had a response, 13 had stable disease, 9 progressed, and 3 unknown. Fourteen patients reported improved symptoms, 6 had no change, and 9 had symptom progression. Tumor marker data was available in 18 patients: 7 had decrease in marker values, 4 had marker stabilization, and 7 had an increase. Toxicity was minimal; 1 patient had grade 3 hepatotoxicity that resolved with treatment cessation. There were 5 Asian female non-smokers; 2 had a response, 2 had stable disease and 1 progressed. Of the 6 radiological responders, 5 had ECOG 0/1, 4 were female, 5 non-smokers, 4 adenocarcinoma and 2 bronchoalveolar variant. A multivariate analysis of radiologic responders and those with stable disease is underway. Conclusions: At the BCCA, in a select number of patients with advanced NSCLC, gefitinib demonstrated clinical and radiologic anti-tumor benefit with minimal side effects. The molecular basis of the improved response rate observed in the subset of female, Asian, non-smokers with adenocarcinoma or bronchoalveolar variant warrants further exploration. No significant financial relationships to disclose.

Combination of a poxvirus-based vaccine with a cyclooxygenase-2 inhibitor (celecoxib) elicits antitumor immunity and long-term survival in CEA.Tg/MIN mice.

The present study was designed to determine whether: (a) chronic administration of dietary celecoxib (Celebrex), a potent nonsteroidal anti-inflammatory drug, which targets the cyclooxygenase-2 (COX-2) enzyme, negatively impacts host immunity; and (b) celecoxib can be coupled with a poxvirus-based vaccine to impact tumor burden in a murine tumor model of spontaneous adenomatous polyposis coli. Naive mice fed the celecoxib-supplemented diets developed eosinophilia with lowered plasma prostaglandin E(2) levels and reduced COX-2 mRNA expression levels in their splenic T cells. Responses of splenic T, B, and natural killer cells to broad-based and antigen-specific stimuli were, for the most part, unchanged in those mice as well as COX-2 knockout mice; exceptions included: (a) reduced IFN-gamma production by concanavalin A- or antigen-stimulated T cells; and (b) heightened lipopolysaccharide response of naive B cells from mice fed a diet supplemented with 1000 ppm of celecoxib. When transgenic mice that express the human carcinoembryonic antigen (CEA) gene (CEA transgenic) were bred with mice bearing a mutation in the Apc(Delta850) gene (multiple intestinal neoplasia mice), the progeny (CEA transgenic/multiple intestinal neoplasia) spontaneously develop multiple intestinal neoplasms that overexpress CEA and COX-2. Beginning at 30 days of age, the administration of a diversified prime/boost recombinant CEA-poxvirus-based vaccine regimen or celecoxib (1000 ppm)-supplemented diet reduced the number of intestinal neoplasms by 54% and 65%, respectively. Combining the CEA-based vaccine with the celecoxib-supplemented diet reduced tumor burden by 95% and significantly improved overall long-term survival. Both tumor reduction and improved overall survival were achieved without any evidence of autoimmunity directed at CEA-expressing or other normal tissues. Celecoxib is prescribed for the treatment of familial adenomatous polyposis in humans, and the CEA-based vaccines have been well tolerated and capable of eliciting anti-CEA host immune responses in early clinical studies. The results suggest that the administration of a recombinant poxvirus-based vaccine is compatible with celecoxib, and this combined chemoimmuno-based approach might lead to an additive therapeutic antitumor benefit not only in patients diagnosed with familial adenomatous polyposis but, perhaps, in other preventive settings in which COX-2 overexpression is associated with progression from premalignancy to neoplasia.

In this issue

In this issue

The angiogenic factor CYR61 in breast cancer: molecular pathology and therapeutic perspectives.

CYR61 (CNN1), a member of the cysteine rich 61/connective tissue growth factor/nephroblastoma overexpressed (CYR61/CTFG/NOV) family of growth regulators (CNN), is a pro-angiogenic factor that mediates diverse roles in development, cell proliferation, and tumorigenesis. We have recently shown that CYR61 is overexpressed in invasive and metastatic human breast cancer cells. Accordingly, elevated levels of CYR61 in breast cancer are associated with more advanced disease. Unfortunately, the exact mechanisms by which CYR61 promotes an aggressive breast cancer phenotype are still largely unknown. This review examines the functional role of CYR61 in breast cancer disease, presenting evidence that CYR61 signaling may play a major role in estrogen- as well as growth factor-dependent breast cancer progression. We also emphasize the functional significance of the molecular connection of CYR61 and its integrin receptor alpha(v)beta(3) enhancing breast cancer aggressiveness. Moreover, we describe experimental evidence that establishes a novel role for CYR61 determining the protection of human breast cancer cells against chemotherapy-induced apoptosis through its interactions with the integrin receptor alpha(v)beta(3). All these findings delineate a new noteworthy function of a CYR61/alpha(v)beta(3) autocrine-paracrine signaling pathway within both angiogenesis and breast cancer progression, which would allow a dual anti-angiogenic and anti-tumor benefit with a single drug.

Use of the Anti-idiotype Breast Cancer Vaccine 11D10 in Conjunction with Autologous Stem Cell Transplantation in Patients with Metastatic Breast Cancer

The results of cytotoxic therapy, including dose-intensive therapy requiring autologous stem cell transplantation (ASCT), have been disappointing in patients with metastatic breast cancer, as almost all patients eventually experience disease progression. There has been a renewed interest in immunotherapeutic strategies in this disease, including evaluation of several breast cancer vaccines. In the current study, we describe the results of a program in which the anti-idiotype breast cancer vaccine 11D10 (TriAb®) was administered before and after ASCT in patients with metastatic breast cancer chemosensitive to previous conventional therapy. The toxicity of this approach was acceptable, and idiotype-specific humoral and T-cell proliferative responses were observed in the majority of patients within a few weeks post-ASCT. The actuarial 3-year overall survival rate was 48% (95% CI, 32%-64%), while the progression-free survival rate was 32% (95% CI, 19%–45%). Multivariate analysis identified achievement of a strong antibody and cellular immune response to the vaccine as the only significant prognostic factors for outcome. The ability to reliably produce robust immune responses after ASCT is encouraging. Further studies are required to determine if the immune response mediates an antitumor benefit in these patients.

A hypoxia-selective oncolytic adenovirus for cancer therapy

Purpose/Objective: The goal for this study is to develop a novel adenovirus gene therapy vector that can selectively replicate in and subsequently lyse hypoxic tumor cells, which are usually more resistant to radiation and a major stimulator of tumor angiogenesis. Materials/Methods: Our strategy is based on the understanding that the Hif1a transcription factor is the most important molecular factor that appears to be universally activated in hypoxic tumor cells. We attempted to exploit this unique feature of hypoxic tumor cells to design conditionally replicative adenovirus vectors that will target hypoxic regions of tumors. The approach we have taken is to engineer adenovirus vectors with their E1 genes, which are essential for virus replication, under the control of hypoxia-activated promoter. This promoter is an artificial promoter that can be activated hundreds of fold when tumor cells are subject to hypoxia. It is based on the Hif1a-binding sequence in the vascular endothelial growth factor gene (VEGF). Results: -We have successfully engineered a series of vectors that encode various reporter and therapeutic genes. -Our data in tissue culture indicate that these vectors can indeed replicate and lyse hypoxic tumor cells with a differentiation factor of at least 100:1 in hypoxic vs normoxic tumor cells. -We have also obtained data that demonstrate significant hypoxia-specific replication and anti-tumor efficacy in vivo. Both virus infection and gene expression efficiency of the hypoxia-selective virus vector are several hundred fold higher compared to conventional non-replicative virus vectors. -Preliminary data indicate that our vectors had significant anti-tumor efficacy either alone or in combination with radiotherapy. Conclusions: Our hypoxia-selective oncolytic adenovirus gene therapy approach is a promising way to target hypoxic tumor cells. It may provide significantly anti-tumor benefits when combined with ionizing radiation.

RETINOID THERAPY OF CHILDHOOD CANCER

In vitro studies that showed RA could cause growth arrest and differentiation of myelogenous leukemia and neuroblastoma led to clinical trials of retinoids in APL and neuroblastoma that increased survival for both of those diseases. In the case of APL, ATRA has been the drug of choice, and preclinical and clinical data support direct combinations of ATRA with cytotoxic chemotherapy. For neuroblastoma, a phase I study defined a dose of 13-cis-RA, which was tolerable in patients after myeloablative therapy, and a phase III trial that showed postconsolidation therapy with 13-cis-RA improved EFS for patients with high-risk neuroblastoma. Preclinical studies in neuroblastoma indicate that ATRA or 13-cis-RA can antagonize cytotoxic chemotherapy and radiation, so use of 13-cis-RA in neuroblastoma is limited to maintenance after completion of cytotoxic chemotherapy and radiation. A limitation on the antitumor benefit of ATRA in APL is the marked decrease in drug levels that occurs during therapy as a result of induction of drug metabolism, resulting in a shorter drug half-life and decreased plasma levels. Although early studies sought to overcome the pharmacologic limitations of ATRA therapy in APL, the demonstration that ATO is active against APL in RA-refractory patients has led to a focus on studies employing ATO. Use of 13-cis-RA in neuroblastoma has avoided the decreased plasma levels seen with ATRA. It is likely that recurrent disease seen during or after 13-cis-RA therapy in neuroblastoma is due to tumor cell resistance to retinoid-mediated differentiation induction. Studies in neuroblastoma cell lines resistant to 13-cis-RA and ATRA have shown that they can be sensitive, and in some cases collaterally hypersensitive, to the cytotoxic retinoid fenretinide. Fenretinide induces tumor cell cytotoxicity rather than differentiation, acts independently from RA receptors, and in initial phase I trials has been well tolerated. Clinical trials of fenretinide, alone and in combination with ceramide modulators, are in development.

Thalidomide: dual benefits in palliative medicine and oncology.

Thalidomide is an immunomodulator, anti-angiogenic agent, anti-cytokine, and anti-integrin. Alone or in combination with other drugs, thalidomide has also demonstrated anti-cachexin and anti-neoplastic properties. Anorexia and cachexia are common symptoms of advanced cancer. Since certain cytokines also promote tumor growth, we may have a class of agents with palliative and anti-tumor benefits in combination with anti-neoplastics and anti-cytokines, such as thalidomide.

Preoperative intraperitoneal chemotherapy for gastric cancer, with special reference to delayed peritoneal complications.

Preoperative intraperitoneal (IP) chemotherapy was performed in 23 patients with gastric malignancies to inhibit peritoneal recurrence. Cis-diamminedichloroplatinum (CDDP) and mitomycin C (MMC) were administered intraperitoneally 3 days prior to surgery, at which time a very viscid peritoneum and mucinous intraperitoneal fluid were found in 100% and 83% of the patients, respectively. Inflammatory changes were microscopically observed in the subserosal layer of the resected stomachs and in the intraperitoneal fluid, but degenerative changes characteristic of cancer cells could not be seen. The 3-year survival rate of the stage III patients was 55.6%, and peritoneal recurrence was found in three of six patients with recurrence. Extensive adhesions were found in eight patients (34.8%) as a delayed peritoneal complication, and chronic bowel obstruction resulting from the adhesion developed in five patients (21.7%). Thus, we conclude that the administration of this IP chemotherapy demonstrated no definite antitumor effects or survival benefits, but was frequently associated with delayed peritoneal complications.

Molecular Mechanisms of Resistance to Tamoxifen Therapy in Breast Cancer

Clinical data suggest that the use of adjuvant tamoxifen citrate (Nolvadex) for a minimum of 5 years, and possibly indefinitely, will result in maximal antitumor benefit. There is concern that long-term tamoxifen maintenance therapy may result in the induction of drug resistance. This article reviews the potential molecular mechanisms of resistance to tamoxifen and explores the possibility of tamoxifen-stimulated tumor growth.

Antitumor Effect and Survival Benefit of Chemotherapy for Unresectable Advanced Gastric Cancer

The "Criteria for Evaluating the Efficacy of Chemotherapy/Radiation Therapy in the Treatment of Gastric Cancer" are now widely used in Japan. To assess the validity of the criteria, the relation between the antitumor effect evaluated by the criteria and the survival of patients with gastric cancer was analyzed. The subjects were 169 patients with unresectable advanced gastric cancer who were entered into a randomized comparative trial of tegafur plus mitomycin C, or UFT (a combination of uracil and tegafur in a 4:1 molar ratio) plus mitomycin C. Irrespective of their performance status, disease extent and chemotherapy regimen, responding patients showed improved survival over non-responding patients. If the primary gastric lesion responded to chemotherapy, prolongation of survival was noted in patients with a measurable gastric lesion as well as in those with a non-measurable but evaluable gastric lesion. No improvement in survival was recognized among patients having a primary gastric lesion which did not respond to chemotherapy, even if the metastases showed a response. The results obtained in the present study indicate the validity of the criteria, except for diffusely infiltrating gastric lesions.

Effect of oxygen level on the enhancement of tumor response to radiation by perfluorochemical emulsions or a bovine hemoglobin preparation

Attempts to correct tumor hypoxia with oxygen-carrying solutions have used high concentrations of inspired oxygen (Fi0 2 100% or 95%). In the clinic, however, obtaining such high levels of FiO 2 using mask ventilation in older patients or in children may be difficult. Since lower levels of F102 had not been previously tested, we examined the antitumor efficacy of FiO. levels of 65, 85, and 95% breathed for 1 hr prior to and during irradiation used with the concentrated perfluorochemical emulsion F44E, the less concentrated emulsion, FluosolDA, or a new preparation consisting of purified bovine hemoglobin solution, PBHS. When tested in mice bearing the Lewis lung carcinoma with 2, 3, or 4 Gy daily for 5 days, daily Fluosol-DA produced only a small increase in the slope of the tumor growth delay versus irradiation alone, when used with 85% FiO 2 (dose modifying factor [DMF] 1.3), but produced a DMF of 2.1 with 95% FiO 2 Various concentrations of F44E (2, 4, or 8 g PFC/kg) each required a 95% FiO 2 for full effect but the 8 g/kg dose had a discernable effect with an FiO 2 of 65% and 85% (DMF 1.25 and 1.30, respectively). For PBHS, in contrast, a DMF of 1.6 was observed at 20% FiO 2 but surprisingly this increased further to 2.1 with 95% FiO 2 Further investigations of PBHS with irradiation demonstrated that daily administration of PBHS (12 ml/kg) 1 hr before single Xray fractions of 5, 10, 15, or 20 Gy with 20% FiO, resulted in a DMF of 1.6–1.7 in the FSaIIC fibrosarcoma compared with irradiation alone when ascertained by tumor cell excision assay. These results indicate that to achieve maximum antitumor benefit with these oxygen-carrying solutions with radiation therapy, care must be taken to insure that FiO 2 levels near 100% are achieved.

Granulocyte-macrophage colony-stimulating factor mitigates the neutropenia of combined interferon alfa and zidovudine treatment of acquired immune deficiency syndrome-associated Kaposi's sarcoma.

The combined use of zidovudine (ZDV) and interferon (IFN) alfa-2a has been shown to have antiretroviral and antitumor potential benefit in the treatment of acquired immune deficiency syndrome (AIDS)-associated Kaposi's sarcoma (KS). However, the clinical use of this combination is frequently complicated by the overlapping myelotoxicity of these agents. We report here the results of a phase I/II study in which granulocyte-macrophage colony-stimulating factor (GM-CSF) was used for those KS patients who became neutropenic while receiving ZDV (1,200 mg/d) and IFN (9 x 10(6) U/d). Nineteen of 29 patients (66%) developed an absolute neutrophil count (ANC) of less than 1,000 cells per cubic millimeter and were begun on GM-CSF. All experienced a prompt increase in the ANC. Those patients receiving GM-CSF/ZDV/IFN alfa-2a had an improved end of study ANC when compared with the ZDV/IFN alfa-2a group, but did not have an increased rate of tumor response, end of study CD4 cell count, or improvement in any other hematologic variable. The use of GM-CSF was not associated with increased toxicity and, in particular, was not associated with a change in serum human immunodeficiency virus (HIV) p24 antigen. Tumor response was noted in 50% of the assessable patients (33% overall) despite "high-risk" characteristics in 80%. Of the responding patients, seven were on GM-CSF and might have otherwise required an alteration in ZDV/IFN alfa-2a dose level. Further study of GM-CSF as an alternate to dose modification of this (ZDV/IFN alfa-2a) and other combination therapies for AIDS patients is warranted.

Combined effects of chemotherapy and interleukin 2 in the therapy of mice with advanced pulmonary tumors : Papa MZ, Yang JC, Vetto JT, Shiloni E, Eisenthal A, Rosenberg S.A. Surgery Branch, National Cancer Institute, Bethesda, MD 20892. Cancer Res 1988;48:122-9

We have evaluated the effects of chemotherapeutic agents on the toxicity and antitumor benefit of therapy of established murine tumors by high-dose interleukin 2 (IL-2). Cyclophosphamide (Cy), doxorubicin, and bischloroethylnitrosourea were given to normal mice prior to IL-2 administration to test the effects of these agents on IL-2-induced toxicity. Cy at doses of 100 mg/kg and 150 mg/kg completely protected mice from a 100% lethal dose of IL-2, and doses of 50 mg/kg and 150 mg/kg allowed the administration of a median of 4.5 and 10.0 more doses of IL-2, respectively, before death from IL-2 toxicity occurred. Doxorubicin at 8 mg/kg and bischloroethylnitrosourea at 20 mg/kg did not impact on toxicity in IL-2-treated mice. In mice bearing pulmonary metastases of the weakly immunogenic MCA-105 sarcoma, IL-2 increased median survival time from 33 (no IL-2) to greater than 60 days for all doses of IL-2 tested when combined with a single injection of Cy at 75 mg/kg (P less than 0.002). Increasing doses of either Cy or IL-2 produced increasing benefits on survival which were always greater than either treatment alone. These effects of Cy and IL-2 were also seen in mice bearing the nonimmunogenic MCA-101 sarcoma and a murine adenocarcinoma (MCA-38). Doxorubicin and bischloroethylnitrosourea did not consistently enhance the effects of IL-2 treatment. Cy appears to reduce the yield of in vivo generated lymphokine-activated killer cells, but these lymphokine-activated killer cells are still lytic for fresh tumor targets in vitro. Thus, the mechanism of this synergy does not appear to involve stimulation of lymphokine-activated killer cell activity, but may in part involve reduction of tumor burden by the chemotherapeutic agent, an increase in susceptibility of tumor to cellular immune lysis, and/or a decrease in suppressor cell activity mediated by the chemotherapy.