Abstract: Adjuvant chemoradiotherapy does not represent the standard of care in patients with resected high-risk gastric cancer; however, results from phase 2 and randomized trials suggest improvement in overall survival. We assessed the feasibility and toxic effects of chemoradiotherapy as adjuvant treatment in locally advanced gastric cancer.
Abstract: Surgery is the only curative therapy for gastric cancer. In the metastatic setting the objective of treatment is to manage symptoms, improve quality of life and prolong survival, but current treatment options have limited efficacy and some of them exhibit unfavourable toxicity profiles. Fluoropyrimidine, taxanes and platinum-based regimens are used most frequently and offer a response rate of 30-50% with a median overall survival of =1 year. These discouraging data support the need for new therapeutic strategies based on targeted drugs. Trastuzumab, a monoclonal antibody against HER2, has shown survival benefits when given with chemotherapy in all setting of HER2-positive breast cancer patients. The ToGA trial, the first study evaluating the efficacy and safety of adding trastuzumab to chemotherapy in HER-2 positive advanced gastric cancer, showed a significant superiority of combination over chemotherapy alone. Based on these results trastuzumab combined with a cisplatin and fluoropyrimidine regimen appear the new reference treatment for HER-2 positive metastatic gastric cancer.
Abstract: We evaluated the association of a weekly cisplatin (35 mg/mq) and paclitaxel (45 mg/mq) regimen with radiotherapy (46 Gy) as primary treatment in locally advanced esophageal cancer (LAEC). The main end point was the activity in terms of pathologic complete response (pathCR) rate. Thirty-three LAEC patients received chemoradiation therapy during weeks 1-6 followed by esophagectomy. A pathCR was observed in 10/33 patients; 20/33 and 3/33 patients showed PR and SD, respectively. The EUS maximal transverse cross sectional area reduction >50% significantly correlated with pathCR. Three-year survival rate was 35%. These results support the activity and mild toxicity of this regimen.
Abstract: The understanding of the molecular mechanisms which regulate cancer cell sensitivity to epidermal growth factor receptor (EGFR) inhibitors is necessary for the optimal use of these drugs in cancer treatment. We developed an in vitro model of acquired resistance to two EGFR tyrosine kinase inhibitors (TKI), erlotinib and gefitinib, by continuously treating the human non-small cell lung cancer (NSCLC) cell line CALU-3 with escalating doses of each drug. In these two EGFR inhibitor-resistant cancer cell lines a significant increase in the expression of activated, phosphorylated AKT and of survivin compared to parental cells was observed. Treatment with several agents known to target directly or indirectly the AKT signalling pathway did not affect significantly EGFR inhibitor-resistant cancer cell proliferation. In contrast, bortezomib, a proteasome inhibitor, induced a significant inhibition of cancer cell growth and an increase in apoptosis in EGFR inhibitor-resistant cancer cells as compared to treatment with LY294002, a PI3K inhibitor, suggesting that, in addition to interference with AKT signalling, other mechanisms are involved in the pro-apoptotic effects of bortezomib. Bortezomib treatment activated endoplasmic reticulum (ER) stress-mediated apoptosis, as demonstrated by the induction of GADD153, an ER stress-inducible transcription factor, and of the death receptor DR5, in EGFR inhibitor-resistant cells, but not in parental cells. This effect resulted in the activation of the extrinsic apoptotic pathway, as shown by caspase 8 dependent-PARP and bid cleavage. Bortezomib significantly inhibited the growth of EGFR inhibitor-resistant CALU-3 cells which were established as subcutaneous tumor xenografts in athymic nude mice. These results suggest that bortezomib treatment could be a useful approach to overcome resistance to anti-EGFR therapies.
Abstract: BACKGROUND: Gastrointestinal anastomotic complications represent serious events; methods to evaluate anastomotic integrity seem to be suboptimal. Since endoscopic intraoperative anastomotic testing allows direct visualization of anastomosis, complication rates may be theoretically reduced by the use of this technique. METHODS: A prospective study involving 118 consecutive oncologic patients undergoing endoscopically tested gastrointestinal stapled anastomoses was carried out. As controls, 148 historical patients without anastomotic testing were used for comparisons. RESULTS: In the study group, anastomotic testing revealed 16 defects: 11 (9.3%) air leaks and five (4.3%) bleeding anastomoses. All leaks were oversewn and secured. Bleeding anastomoses were managed under direct visualization, and one non-patent anastomosis was redone. Forty-one (15.4%) postoperative anastomotic complications were observed: eight (3%) bleeding anastomoses, seven (2.6%) stenoses, and 26 (9.8%) clinical leaks. No early dehiscence or bleeding occurred if anastomoses were intraoperatively checked, while these complications were significantly more frequent in non-checked anastomoses (6.1% and 5.4%, respectively). Conversely, late leak and stenosis rates were similar between the two groups. CONCLUSION: Endoscopic anastomotic testing was a safe and reliable method to assess integrity of gastrointestinal anastomoses, to correct any defect under direct visualization, and to avoid early complications. However, this method seemed inadequate to predict late anastomotic complications.
Abstract: Cancer cell survival, invasion, and metastasis depend on cancer cell proliferation and on tumor-induced angiogenesis. We evaluated the efficacy of the combination of sorafenib and erlotinib or cetuximab.
Abstract: Although the incidence of gastric cancer has been declining in Western countries, it is still a major health problem and a leading cause of cancer mortality. Surgery is the mainstay of treatment for gastric adenocarcinoma. However, even among patients undergoing gastrectomy with curative intent, 5-year survival rates are disappointing due to locoregional relapse and distant metastases. This emphasizes the importance of multidisciplinary management of patients with gastric cancer. In contrast to the preoperative approach, several phase III trials have been carried out in the adjuvant setting, but postoperative chemotherapy has not proven to be superior to surgery alone. Therefore, at present the routine use of adjuvant therapy should be regarded as an investigational approach. Improved clinical trial designs with standardized surgical techniques and the incorporation of newer active drugs are needed.
Abstract: Several trials show a relationship between skin toxicity, response rate, and overall survival in cetuximab-treated patients. We analyzed our database to evaluate the importance of skin rash as a surrogate marker of favorable outcome in cancer patients referred to our institution in the last three years. We retrospectively analyzed 90 cetuximab-treated patients: 57 colon cancer patients, 10 NSCLC patients, 14 locally advanced esophageal cancer patients, and 9 miscellaneous. A significant correlation was observed between skin rash and response to therapy. Skin rash was experienced by 93% of PR and 100% of CR patients. The mean TTP was 184 days in patients showing skin rash and 94 days in patients without skin rash, respectively. On multivariate analysis, skin rash was demonstrated to be the only independent prognostic variable with regard to TTP. Patients who did not develop skin rash had a 2-fold greater likelihood to manifest tumor progression significantly earlier than patients who developed skin rash. In our series, a statistically significant correlation between rash, response rate, and TTP was demonstrated in 90 cetuximab-treated patients. Skin toxicity was confirmed as the only clinical variable able to predict the response to cetuximab.
Abstract: Gastric cancer still represents a leading cause of death worldwide. Several cytotoxic agents have demonstrated activity and combination regimens improve progression-free survival, overall survival and quality of life. Nevertheless, now there is no standard therapy for advanced gastric cancer patients.
Abstract: The number of harvested (LNs) and metastatic nodes (LNs+) represents the most significant factor to define postoperative treatment and prognosis in colon cancer. However, its assessment may be inadequate causing an incorrect cancer staging. The lymph node ratio (LNR: the ratio between metastatic and resected nodes) has shown prognostic significance in many tumors; however, its role in colon cancer is not clearly elucidated. This study investigated LNR as a prognostic factor in node-positive colon cancers.
Abstract: The epidermal growth factor receptor (EGFR) is a transmembrane tyrosine kinase receptor involved in the proliferation and survival of cancer cells. EGFR is the first molecular target against which monoclonal antibodies (mAb) have been developed for cancer therapy. Here we review the mechanisms underlying the effects of EGFR-specific mAb in cancer therapy. The efficacy of EGFR-specific mAb in cancer occurs thanks to inhibition of EGFR-generated signalling; furthermore, the effects of antibodies on the immune system seem to play an important role in determining the overall anti-tumour response. In this review, attention is focused on cetuximab and panitumumab, two mAb introduced recently into clinical practice for treatment of metastatic colorectal and head and neck cancer which target the external part of EGFR.
Abstract: Unlike other human tumors, gastric cancer remains a great therapeutic challenge since no standardized postoperative treatment exists. Knowledge of molecular pathways determining the behavior of individual gastric tumors seems to be crucial for therapeutic decisions, and evaluation of vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) expression might be critical for prognosis, assessment, and identification of patients that could be treated with tailored therapies.
Abstract: Vascular endothelial growth factor (VEGF) is a potent stimulator of angiogenesis, associated with unfavorable clinical characteristics in breast cancer. The aim of this study was to evaluate different angiogenic markers in endocrine-positive breast cancer patients. The authors analyzed serum and tumor samples from 71 patients with endocrine-positive operable primary breast cancer to determine the expression and the possible relationship between circulating serum VEGF levels, tumor VEGF expression, microvessel density (MVD), and other immunohistochemical parameters. Basal VEGF serum levels were significantly higher in breast cancer patients than in healthy controls. A significant correlation was observed between basal VEGF serum concentrations, microvessel density (p = 0.01) and p53 status (p = 0.004). Intratumoral VEGF expression was significantly associated with neoplastic embolization (p = 0.041) and circulating VEGF levels (p = 0.047). The results confirm that in primary endocrine-positive breast cancer serum VEGF levels are elevated and show a positive relationship with tumor VEGF and p53 overexpression.
Abstract: Bowel resection followed by chemotherapy is a better management strategy than immediate chemotherapy in asymptomatic patients with colorectal cancer and unresectable liver-only metastases at presentation.
Abstract: In gastric cancer, the recurrence rate is high even after curative surgery. A relevant issue is the identification of independent prognostic factors to select high-risk patients; such features can be used as predictive factors for tailored therapies. In this study we have investigated the role of epidermal growth factor receptor (EGFR) expression as a prognostic marker for predicting cancer behavior and clinical outcome in gastric cancer patients undergoing potentially curative surgery.
Abstract: Hepatoid adenocarcinoma (HAC) is a peculiar type of extrahepatic adenocarcinoma generally characterized by adenocarcinomatous and hepatocellular carcinoma (HCC)-like foci. Stomach is the most frequent site where hepatoid adenocarcinoma occurs, although it has been described in many other organs. On the other side, liposarcoma is a rare, malignant tumor that develops from fat cells.
Abstract: This randomized, multicenter, phase III trial evaluated the efficacy and safety of the combination of epirubicin, leucovorin, 5-fluorouracil and etoposide (ELFE regimen) as adjuvant therapy for radically resected gastric cancer patients.
Abstract: Gastric cancer is still a major health problem and a leading cause of cancer mortality despite a worldwide decline in incidence. Surgery is the primary curative treatment of locoregional gastric cancer. In Western countries, however, at the time of resection, most patients are expected to have regional lymph node involvement with poor prognostic implications. To improve these results, different trials have been carried out in the adjuvant or neo-adjuvant setting. Many phase III trials of adjuvant therapy have been conducted; however, postoperative treatment modalities have not proven to be superior to postsurgical observation alone. Therefore, at present the routine use of adjuvant therapy should be regarded as an investigational approach. Improved clinical trial designs with standardized surgical techniques and the incorporation of newer active drugs are needed. On the contrary, neo-adjuvant chemotherapy has shown promising results as suggested by the final results of UK Medical Research Council Adjuvant Gastric Infusional Chemotherapy trial.
Abstract: The recent successful development of monoclonal antibodies that target key components of biological pathways has expanded the armamentarium of treatment options for patients with colorectal cancer (CRC). In particular, the epidermal growth factor receptor (EGFR), a tyrosine kinase growth factor receptor involved in CRC development and progression, is exploited by the newest monoclonal antibody that is available for use in CRC patients. Cetuximab, the first chimeric monoclonal antibody, which has been generated against the EGFR, is currently registered in USA, Europe and worldwide, in combination with irinotecan in the treatment of metastatic CRC patients who have progressed on irinotecan containing chemotherapy. Cetuximab is well tolerated and does not exacerbate the toxicity of concomitant chemotherapy. Furthermore, a series of phase III clinical trials are currently evaluating the combination of cetuximab with standard chemotherapy regimens in the first-line treatment chemotherapy-naïve patients with metastatic CRC.
Abstract: Historically, radiotherapy has been occasionally used in the treatment of gastric cancer. More recently, the results of INT-0116 trial have shown an improvement of disease-free and overall survival by chemoradiation with a significant impact on the management of this tumor. Based on these data, there has been an increasing interest in radiotherapy and its association with chemotherapy for patients with locoregional disease as a part of an adjuvant treatment after surgery in high-risk patients. However, many questions remain to evaluate; first of all the toxicity of this approach and its efficacy after adequate surgery.
Abstract: As a significant number of curatively treated gastric cancer patients will ultimately relapse, there is an urgent need to investigate new prognostic markers for identification of high-risk patients. In this study, we investigated the possible role of molecular markers involved in cell cycle regulation (B1 and D3 cyclins, and p27) and cell protection (metallothionein, MT) in predicting tumor behavior and clinical outcome in gastric cancer patients.
Abstract: To investigate the role of epidermal growth factor receptor (EGFR) expression as a prognostic marker for prediction of cancer behavior and clinical outcomes in colon cancer patients undergoing potentially curative surgery.
Abstract: We have evaluated the activity and safety of gefitinib, a small-molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, in combination with docetaxel as first-line treatment of women with metastatic breast cancer (MBC). In total, 41 patients with MBC were enrolled in a first-line combination therapy study with oral gefitinib (250 mg day(-1)) and intravenous docetaxel (75 mg m(-2), the first 14 patients; or 100 mg m(-2), the following 27 patients, on day 1 of a 3-week cycle). Out of 41 patients, 38 received at least one cycle of therapy. There were no differences in activity or tolerability between the two docetaxel doses. G3/4 toxicities were neutropenia (49%), diarrhoea (10%), acne-like rash (5%), and anaemia (2%). Complete plus partial responses (CR+PR) were observed in 22 out of 41 patients with a 54% response rate (95% confidence interval (CI) 45-75%). The 22 patients that achieved a response following six cycles of docetaxel plus gefitinib continued gefitinib monotherapy (median duration, 24 weeks; range, 2-108+ weeks). Two patients with PR following combination therapy achieved a CR during gefitinib monotherapy. Complete plus partial responses correlated with oestrogen receptor (ER) status, since they occurred in 19 out of 27 (70%) patients with ER-positive tumours as compared to three out of 14 (21%) patients with ER-negative tumours (P=0.01).
Abstract: Capecitabine and docetaxel have demonstrated preclinical antitumor synergy and activity in advanced gastric cancer. We assessed the clinical activity and the toxicity of weekly docetaxel in combination with capecitabine in untreated patients with advanced gastric cancer.
Abstract: Over the last decade, the concept of targeted biological therapy for the treatment of cancer has emerged. However, a better understanding of these targets and their role in tumor cells and in the surrounding stromal cells is required. Two interesting biological targets are the epidermal growth factor receptor (EGFR) and the vascular endothelia growth factor (VEGF) and its receptors. A number of agents that target these pathways have been described. Many of these are currently in clinical trials and a few have recently been approved by the regulatory authorities in USA and in the European Union. The molecular pathways involved in the proliferation of cancer cells and in tumor-related angiogenesis are very complex and the interference with only a single step of these pathways may often reveal an insufficient therapeutic approach. Moreover, cancer cells have an inherent ability to harness different growth factor signaling pathways for growth advantage and cell survival, a process that may even be facilitated by the use of selective targeted agents. Because of these escape mechanisms, monotherapy with selective targeted agents is unlikely to be a fully effective cancer treatment. For these reasons, targeting different pathways is an attractive and effective therapeutic strategy with a strong rationale for investigating this approach in the clinic. This review focuses on the preclinical rationale of combining targeted agents such as EGFR and VEGF inhibitors in the treatment of cancer and on the clinical trials that have emerged from these studies.
Abstract: The aim of the study was to assess the toxicity and the clinical activity of biweekly oxaliplatin in combination with infusional 5-fluorouracil (5-FU) and folinic acid (FA) administered every 2 weeks (FOLFOX-4 regimen) in patients with advanced gastric cancer (AGC). A total of 61 previously untreated AGC patients were treated with oxaliplatin 85 mg m(-2) on day 1, FA 200 mg m(-2) as a 2 h infusion followed by bolus 5-FU 400 mg m(-2) and a 22 h infusion of 5-FU 600 mg m(-2), repeated for 2 consecutive days every 2 weeks. All patients were assessable for toxicity and response to treatment. Four (7%) complete responses and 19 partial responses were observed (overall response rate, 38%). Stable disease was observed in 22 (36%) patients, with progressive disease in the other six (10%) patients. Median time to progression (TTP) and median overall survival (OS) were 7.1 and 11.2 months, respectively. National Cancer Institute Common Toxicity Criteria grade 3 and 4 haematologic toxicities were neutropenia, anaemia and thrombocytopenia in 36, 10 and 5% of the patients, respectively. Grade 3 peripheral neuropathy was recorded in three (5%) patients. FOLFOX-4 is an active and well-tolerated chemotherapy. Response rate (RR), TTP and OS were comparable with those of other oxaliplatin-based regimens, suggesting a role for this combination in gastric cancer.
Abstract: Gastric cancer is still a major health problem and a leading cause of cancer mortality despite a worldwide decline in incidence. Surgical resection with curative potential is the only treatment modality of scientific proven effectiveness. Many phase III trials of adjuvant therapy have been conducted, however, postoperative treatment modalities have not proven to be superior to pos-surgical observation alone. Therefore, at present the routine use of adjuvant therapy should be regarded as an investigational approach. Improved clinical trial designs with standardized surgical techniques and the incorporation of newer active drugs are needed.
Abstract: The role of epidermal growth factor receptor (EGFR)-driven signaling in different stages of colorectal carcinogenesis, as well in the acquisition of therapy resistance, has been established. Multiple strategies have been developed for the therapeutic targeting of EGFR. Cetuximab is a chimeric monoclonal antibody selective for EGFR with efficacy alone or in combination with irinotecan in the treatment of metastatic colorectal cancer patients, who have progressed to using irinotecan-containing chemotherapy. Cetuximab is well tolerated and does not exacerbate the toxicity of concomitant chemotherapy. Based on this data, the combination of cetuximab with standard chemotherapy regimens such as irinotecan/ 5-FU/folinic acid (FA) or oxaliplatin/5-FU/FA are currently being investigated in Phase III trials for chemotherapy-naive patients with metastatic colorectal cancer.
Abstract: Epidermal growth factor receptor (EGFR) inhibitors are in clinical development in cancer treatment. Preclinical studies have shown potential antitumor efficacy of these agents in combination with chemotherapy or with radiotherapy. However, controversial results have been obtained in different clinical trials.
Abstract: The epidermal growth factor receptor is a cell membrane receptor that plays a key role in cancer development and progression. Ligand-activated epidermal growth factor receptor-dependent signaling is involved in cell proliferation, apoptosis, angiogenesis, invasion, and metastasis. Targeting the epidermal growth factor receptor represents a promising molecular approach in cancer treatment. Several antiepidermal growth factor receptor agents are in clinical development. This review focuses on the available clinical data on epidermal growth factor receptor-targeting drugs in the treatment of nonsmall cell lung cancer.
Abstract: Conventional staging procedures are often unable to precisely predict prognosis in colorectal cancer (CRC). In this study, we set out to investigate the possible role of molecular/structural indicators involved in cell cycle regulation (p27 and p53), apoptosis (p53 and p27), and tumor neoangiogenesis [p53, vascular endothelial growth factor (VEGF), and microvessel count] in predicting tumor behavior and clinical outcome in CRC patients
Abstract: To the authors' knowledge, little is known to date regarding the prognostic relevance of measuring serum levels of vascular endothelial growth factor (VEGF), a potent stimulator of angiogenesis, in patients with colon carcinoma who undergo surgery.
Abstract: Anthracyclines are among the most active antineoplastic drugs developed to date, used both in the treatment of solid cancers, such as breast and ovarian cancer and sarcomas, and of hematologic cancers. However, their clinical use is limited by cardiotoxicity, which is observed at a range of 0.4-41%. The risk of this side effect can be minimized by using cardioprotective agents, planning dosing schedules to lower the anthracycline peak plasma concentration, identifying and monitoring high-risk patients, keeping in mind that early anthracycline-induced histologic changes may be identified successfully by cardiac biopsy. Nonetheless, the challenge to increase the tumor response to chemotherapy while keeping low the cardiac risk may be now met by the use of a recently introduced polyethylene glycol-coated (pegylated) liposomal doxorubicin (PLD). Here, we review the pharmacologic properties of PLD as well as the results of phases I, II and III trials demonstrating activity and low cardiac toxicity associated with the use of this novel drug.
Abstract: Early-stage colon cancer patients (Dukes A or B; pT1-T3 pNO pMO) are excluded from adjuvant chemotherapy following potentially curative surgery because they are expected to have good long-term survival. However, 20 percent to 30 percent of these patients ultimately succumb from recurrent disease. This indicates that the conventional staging procedures may be unable to precisely predict cancer prognosis.
Abstract: A giant cystic lesion of the left upper abdomen associated with a smaller ovarian cyst in a young female patient is reported. Laboratory data revealed elevated serum levels of carbohydrate antigen 19-9 (CA 19-9), carcino-embryonic antigen (CEA), cancer antigens 50 and 125, and tissue polypeptide antigen. In contrast, the serum levels of interleukin 10, a cytokine involved in modulating immune responses and produced by many cancer histotypes, were normal. Since ovarian cancer or cystic adenocarcinoma of the tail of the pancreas were not ruled out, the patient underwent laparotomy. After splenectomy and ovariectomy, the tumour marker serum levels normalized. Histology and immunohistochemical analysis revealed a true splenic cyst with the inner epithelium strongly positive for CA 19-9 and CEA and high levels of cancer antigens in the fluid. The ovarian lesion was a serous cystadenoma. The inner epithelium showed no immunoreactivity for tumour markers which were not measurable in the fluid. True cysts of the spleen are rare; in a few cases, high serum levels of CA 19-9 and CEA have been reported. In such instances, cyst resection or splenectomy is indicated to rule out malignant lesions and to remove the cancer antigen producing epithelium. The reported case shows that the epithelium lining true splenic cysts may produce, besides CA 19-9 and CEA, other tumour markers, in particular cancer antigens 50 and 125. In addition, normal serum values of interleukin 10 correctly predicted the benign nature of the lesion.
Abstract: True cysts of the spleen are rare. In a few cases, high serum levels of carbohydrate antigen (CA) 19-9 and carcinoembryonic antigen (CEA) have been reported. It has been suggested that they are produced by inner epithelium of the cyst. In such instances, cyst resection or splenectomy is indicated to rule out malignant lesions and to remove cancer antigen-producing epithelium. Furthermore, a high serum level of interleukin (IL)-10, an immunosuppressive cytokine, has been described in many neoplastic diseases, suggesting it as a potential new diagnostic method. Giant cystic lesion of the left upper abdomen associated with ovarian tumor was diagnosed in a young patient. Laboratory data revealed elevated serum levels of several tumor markers [CA 19-9, CEA, cancer antigens (CA) 125 and 50, and tissue polypeptide antigen]. In contrast, IL-10 serum level was normal. After splenectomy and ovariectomy, tumor marker serum levels normalized. Histology and immunohistochemical analysis revealed true splenic cyst with inner epithelium strongly positive for CA 19-9, CEA, and high levels of cancer antigens in fluid. Ovarian lesion was a serous cystoadenoma; its inner epithelium showed no immunoreactivity for tumor markers that were not measurable in fluid. The reported case showed that epithelium lining true splenic cysts may produce, in addition to CA 19-9, CEA, and other tumor markers, in particular CA 125 and CA 50. When malignant disease is suspected, IL-10 serum level could be useful to correctly predict the nature of the lesion.
Abstract: The epidermal growth factor receptor (EGFR) is a cell membrane receptor that plays a key role in cancer development and progression. Ligand-activated EGFR-dependent signalling is involved in cell proliferation, apoptosis, angiogenesis and metastatic spread. Targeting the EGFR, therefore, represents a promising molecular approach in cancer treatment. Several anti-EGFR agents are in clinical development. Three drugs are currently in Phase II and III development as single agents, or in combination with other anticancer modalities: IMC-225 (cetuximab/Erbitux; ImClone), a chimaeric human-mouse monoclonal IgG(1) antibody, which blocks ligand binding and functional activation of the EGFR; OSI-774 (erlotinib/Tarceva; Genentech/OSI/Roch) and ZD1839 (gefitinib/Iressa; AstraZeneca), two small molecule EGFR-selective inhibitors of tyrosine kinase enzymatic activity, which prevent EGFR autophosphorylation and activation. Iressa is the first EGFR-targeting agent to be registered as an anticancer drug in Japan, in Australia and in the US for the third-line treatment of chemoresistant non-small cell lung cancer (NSCLC) patients. This review will focus on the preclinical background and on the results from the first series of clinical trials with these drugs. Furthermore, continuing clinical trials and a series of open clinical issues for the development of optimal strategies of using EGFR-targeting agents will be discussed.
Abstract: The prognostic significance of IL-10 and IL-6 serum levels in colon cancer patients undergoing surgery was investigated. To this end, 50 candidate patients with colon cancer for surgery were admitted to the study. Of these, 30 could be subjected to a potentially curative surgery. Cytokine serum levels at several time points before and after surgery were measured by ELISA. Circulating levels of IL-10 and IL-6 were found to be elevated in cancer patients with respect to controls. Both IL-10 and IL-6 serum levels were demonstrated to predict the likelihood of curative surgery (predictive accuracy, 83.3%). IL-10 serum levels returned to normal in all but 6 patients who underwent curative surgery. These latter had tumor recurrence (predictive accuracy, 100%). In contrast, IL-6 serum levels significantly decreased in all patients, regardless of whether cure was surgically achieved, but did not normalize. On multivariate analysis, basal IL-10 serum levels were found to be among the variables significantly predicting the disease-free survival rate. Stepwise regression selected tumor stage, basal IL-10 serum level, and basal CEA serum level as the best combination of variables for prediction of the likelihood of tumor recurrence. In conclusion, preoperative serum levels of IL-10 were shown to be useful markers for predicting both likelihood to perform curative surgery and, in combination with the 16th postoperative day IL-10 serum levels, tumor recurrence (predictive accuracy, 73.6 and 96%, respectively). IL-6 serum levels were found to have a more limited prognostic role.
Abstract: Elevated interleukin-10 (IL-10) and IL-6 serum levels in advanced gastrointestinal cancer patients have been shown previously. To investigate the behavior and the prognostic role of IL-10 and IL-6 serum levels in gastric and colon cancer patients undergoing surgery, we studied the relationship between these cytokine levels and surgical radicality and outcome. Seventy-eight patients with gastric or colon cancer were admitted to the study, and 50 underwent radical surgery. Cytokine serum levels were measured by ELISA the day before surgery and 16 days after surgery. Circulating levels of IL-10 and IL-6 were found to be higher in cancer patients than in controls. Both IL-10 and IL-6 serum levels were demonstrated to be able to predict likelihood to perform radical surgery. IL-10 serum levels returned to normal in all but 8 radically resected patients. These 8 patients had tumor recurrence. In contrast, IL-6 serum levels were shown to significantly decrease in all patients but not to normalize regardless of the radicality of the operation. On multivariate analysis, basal IL-10 serum levels were found to be among the variables significantly affecting the disease-free survival rate. Stepwise regression selected tumor stage, number of metastatic resected nodes, and basal IL-10 serum level as the best combination of variables for prediction of likelihood of tumor recurrence. Preoperative IL-10 serum levels may be a useful marker to predict likelihood of performing radical surgery. Abnormally high postoperative IL-10 values negatively affected disease-free survival and tumor recurrence. IL-6 serum levels were found to have a more limited prognostic role.
Abstract: Interleukin-8 (IL-8) is a pleiotropic cytokine that has also been shown to exert effects relevant to cancer growth and progression. Cancer progression is believed to be contributed to by the ability of this cytokine to promote angiogenesis and mitogenic effects. As IL-8 production at the tumor site may determine elevated serum levels of this cytokine because of hematogenous leakage, it is conceivable that patients with high IL-8 serum levels may have tumors actively producing this cytokine. The aim of this study was, therefore, to assess IL-8 serum levels in 60 non-small cell lung cancer (NSCLC) patients undergoing chemotherapy and to correlate them with prognosis. IL-8 serum levels were found to be significantly elevated in cancer patients with respect to controls. Moreover, IL-8 serum levels were shown to be significantly increased in stage IV patients compared with stage III patients. When basal IL-8 serum levels in cancer patients were analyzed according to response to chemotherapy, responders were shown to have significantly lower IL-8 serum levels than nonresponders. On univariate analysis, the IL-8 serum level was included among the variables capable of affecting both overall survival (OS) and time to treatment failure (TTF). However, multivariate analysis failed to demonstrate an independent prognostic significance for IL-8 serum levels. In conclusion, this study showed that IL-8 serum levels were elevated in advanced NSCLC patients and correlated with both OS and TTF, but they were shown not to be an independent prognostic factor.
Abstract: This study evaluated the concurrent treatment of chemoradiation followed by esophagectomy in the management of locoregional esophageal carcinoma. The main end points were to determine the resectability of the tumor and the pathologic tumor response. An accessory aim was to evaluate the survival rate.
Abstract: Interleukin-6 (IL-6) is a pleiotropic cytokine that has been shown to regulate immune defense mechanisms and hematopoiesis. In addition, IL-6 may also be involved in malignant transformation and tumor progression. A poor prognosis in patients with multiple myeloma, renal cell carcinoma, ovarian cancer, or prostate cancer has been associated consistently with elevated IL-6 serum levels. The aim of this study was, therefore, to assess IL-6 serum levels in 68 advanced gastrointestinal cancer patients and to correlate them with prognosis. IL-6 serum levels were found to be significantly elevated in cancer patients with respect to controls. Moreover, patients with disseminated cancer displayed significantly higher IL-6 serum levels than patients without apparent metastases. On univariate analysis, both overall survival (OS) and time to disease progression (TTP) were shown to be affected by IL-6 serum levels. However, multivariate analysis failed to demonstrate an independent prognostic significance for IL-6 serum levels while confirming the role of previously established variables, such as performance status, carcinoembryonic antigen (CEA) serum levels, and distant metastases. In conclusion, this study showed that IL-6 serum levels were elevated in advanced gastrointestinal cancer patients and correlated with both OS and TTP. However, they were shown not to be an independent prognostic factor.
Abstract: The aim of this phase II multicenter trial was to evaluate the activity of a novel combination of gemcitabine (GEM) and epirubicin (EPI) in advanced pancreatic cancer patients. Clinical benefit and response rate were the main efficacy end-points. From December 1997 to October 1999, 30 consecutive patients with measurable advanced pancreatic cancer were enrolled. Gemcitabine was administered intravenously in 30 min at a dose of 800 mg/m2 on days 1, 8, 15 followed by i.v. injection of epirubicin 25 mg/m(2); treatment was repeated every 28 days. With regard to clinical benefit response, 8/21 patients (38%) experienced significant palliation of tumor-related symptoms; the median symptom control time was 25 weeks. No complete responses were recorded while 6 patients achieved a partial remission, for an overall response rate of 20%; 10 patients (30%) had a stable disease and 14 (46%) had progressive disease. The median time to progression was 14 weeks. Median survival was 26 weeks, with 6 patients (20%) having long-term survival at 46 weeks. In general, chemotherapy was well tolerated; 9 patients (30%) suffered from WHO grade 3-4 haematological toxicity and 5 patients (16.6%) suffered from grade 3 non-haematological toxicity. In conclusion, the GEM plus EPI regimen represent a feasible approach for improvement of clinical benefit in advanced pancreatic cancer patients, but confirmatory investigations are required.
Abstract: The aim of this study was to assess the protective effect and the safety profile of amifostine in 16 esophageal cancer patients undergoing neoadjuvant chemo-radiation therapy (group A) compared to 21 matched patients (group B), treated with the same schedule without receiving amifostine, and considered as controls. Haematological and extra-haematological toxicity were evaluated according to WHO criteria and considered as result of amifostine activity. The bone marrow toxicity was globally lower in group A than in group B. We recorded 4 cases of mucosities in group B compared to 1 case in group A. amifostine-related side effects were few (2 cases of hypotension and 1 of vomiting), mild, and well controlled. In conclusion, amifostine seems to be effective and safe when used as protective agent also in esophageal cancer.
Abstract: Interleukin (IL)-10 is a Th2 type pleiotropic cytokine that has been found to be produced at the tumor site and to be increased in sera of patients suffering from different types of cancer. IL-10 has been shown to hinder a number of immune functions, i.e., T lymphocyte proliferation, Th1 type cytokine production, antigen presentation, and lymphokine-activated killer cell cytotoxicity. To assess its prognostic value, we measured serum levels of IL-10 in 118 patients with advanced solid tumors before treatment, after completion of therapy, and during follow-up. Other prognostic variables, to which IL-10 results were compared, were analyzed as well. IL-10 serum levels were found significantly elevated in cancer patients with respect to healthy controls. Of interest, a significant decrease in IL-10 serum levels was observed in the responder group, whereas a significant increase was recorded in the non-responder group. Using univariate and multivariate analyses, a significant relationship was shown between IL-10 serum levels and both overall survival (OS) and time to treatment failure (TTF). Stepwise regression analysis selected IL-10 serum level, performance status (PS), and stage as the best association of variables with significant impact on OS and TTF. In conclusion, this study shows that IL-10 has an independent prognostic significance in patients with advanced solid tumors and may be useful for monitoring disease progression.
Abstract: To determine the maximum tolerated dose of oxaliplatin (L-OHP) given as a two-hour infusion followed by raltitrexed (Tomudex [TOM]) administered as a 15-min infusion on day 1, and bolus 5-fluorouracil (5-FU) modulated by a fixed dose of levo-folinic acid (LFA) 250 mg/m2 on day 2, recycling every two weeks, and to have preliminary evidence of activity of this combination in pretreated advanced colorectal cancer patients.
Abstract: Interleukin(IL)-2 is a T helper (Th) 1 type cytokine that has been shown to play an important role in antitumour immune responses. In this study, the prognostic significance of serum IL-2 levels was investigated in 60 advanced non-small-cell lung cancer (NSCLC) patients. IL-2 serum levels were determined before chemotherapy, at the end of chemotherapy and during follow-up, using a commercially available enzyme-linked immunoadsorbent assay kit. The results were analysed according to the response to therapy and were used to generate a model predicting overall survival and time to treatment failure. All 60 patients were shown to have higher IL-2 serum levels than controls (P < 0.0001). Stage IV patients had significantly lower IL-2 levels than stage III patients (P < 0.0001), although they were still significantly higher than controls (P < 0.0001). It is interesting that, when patients were divided into responders and non-responders according to the response to therapy, the former were shown to have significantly higher pre-chemotherapy levels than the latter (P < 0.0001). Moreover, a further significant increase in IL-2 serum levels (P = 0.004) and a significant decrease (P < 0.0001) were shown in responders and non-responders, respectively at the end of the therapy. Using univariate and multivariate analyses, both overall survival and time to treatment failure were shown to be affected by the mean pathological levels of IL-2. Furthermore, the prognostic significance of the serum level of IL-2 was confirmed by the stepwise regression analysis. In conclusion, determination of pre-treatment IL-2 serum levels was shown to be of independent prognostic utility in patients with advanced NSCLC; therefore, its possible use for prediction of outcome is proposed.
Abstract: Thirty-four patients with gastric cancer in stage II and III were enrolled, after curative resection, in a pilot study to assess the feasibility and the impact on relapse of a double modulation of 5-Fluorouracil (5FU) by Methotrexate (MTX) and 1-Leucovorin (LFA) as adjuvant chemotherapy.
Abstract: To determine the maximum tolerable doses (MTDs) of irinotecan (CPT-11) and 5-fluorouracil (5-FU) plus levofolinic acid (LFA) administered together every two weeks, to define the toxicity profile of this regimen, and to have a preliminary evidence of its activity in the first-line management of advanced colorectal cancer patients.
Abstract: Patients receiving systemic cancer chemotherapy must often have their dose intensity of therapeutic agents reduced, because a broad range of organs are adversely affected. Therefore, research and the development of agents protecting the normal tissues from the toxicity of antineoplastic therapy, without reducing the antitumour efficacy, are very important. Amifostine, a prodrug that forms an activated free thiol, when dephosphorylated by alkaline phosphatase, appears selective in its entry in non-malignant cells, and exerts a protective effect from toxicity induced by chemo- or radiotherapy on normal tissues, through free radical scavenging, hydrogen donation and inhibition of DNA damage. Studies in vitro and experimental models have confirmed the protective properties of amifostine in normal cells. In clinical trials pretreatment with amifostine reduced the frequency of cyclophosphamide induced neutropenia and nephro-, oto- and neurotoxicity of platinum compounds. In some cases the use of amifostine have also potentiated the effects of several drugs, such as alkylating agents and, in recent studies, taxanes. The main potentially dose-limiting adverse effect is hypotension, that is often asymptomatic. Amifostine is thus usefully employed in order to obtain a better quality of life in patients receiving oncologic treatments.
Abstract: Interleukin-10 (IL-10) is a cytokine with immunosuppressive properties. In this study, the authors investigated the prognostic significance of IL-10 levels in the sera of 58 patients with advanced gastric or colorectal carcinoma.
Abstract: Based on our previous experience in doxorubicin-treated patients, in whom we observed a significant increase of ventricular recovery time indexes, we analyzed these non- invasive parameters of myocardium electrical instability in forty-three 5-fluorouracil-treated patients, to test the hypothesis of a mechanoelectrical disarrangement occurring in 5-fluorouracil (5FU) cardiotoxicity. All patients enrolled were studied at the first presentation and following chemotherapy. The study showed the absence of any significant changes in recovery time indexes or in other electrocardiographic parameters. Our data suggest that 5FU does not interfere with electrical properties of myocardial fibers.
Abstract: Intercellular adhesion molecule-1 has been implicated in tumor progression and metastasis. Like soluble forms of other membrane receptors, a circulating form of intercellular adhesion molecule-1 (sICAM-1) has been identified in the serum of healthy subjects and it has been found in malignant diseases at increased levels. This study evaluated the serum concentration of sICAM-1 in 112 patients with non-small cell lung cancer (NSCLC). Soluble ICAM-1 levels were significantly higher in all patients when compared with the controls; serum concentration of sICAM-1 correlated with clinical stage and tumor progression. These results suggest that elevated levels of serum ICAM-1 could be of prognostic importance in patients with NSCLC.
Abstract: Serum levels of interleukin-6 (IL-6) were evaluated in a group of advanced non-small cell lung cancer (NSCLC) patients using an enzyme-linked immunosorbent assay. The data were related to clinical status and to cisplatin-based chemotherapy response. The mean IL-6 concentrations were higher than the controls (p<0.0001); patients with metastatic tumor had higher levels than those with undisseminated disease (p<0.006). Tumor progression was associated with an increase of IL-6 levels. Patients who responded to chemotherapy had lower serum IL-6 levels compared with unresponsive patients (p<0.0001). These data suggest that NSCLC patients with high levels of IL-6 have a worse clinical outcome and may manifest resistance to cisplatin chemotherapy.
Abstract: Tumor necrosis factor (TNF)-alpha has been shown to induce shedding of ICAM-1. Experimental studies report that soluble intercellular adhesion molecule-1 (sICAM-1) may interfere with the host immunesurveillance system. Serum levels of TNF-alpha and sICAM-1 were determined by ELISA in 112 non-small cell lung cancer (NSCLC) patients. Serum concentration of TNF-alpha and sICAM-1 were related to tumor burden and progression; a significant correlation was observed between circulating levels of TNF-alpha and sICAM-1. Our study suggests that ICAM-1 could be a marker of TNF-alpha activity and that high levels of these molecules may have a prognostic value in lung cancer.
Abstract: To assess the relationship between serum concentrations of proinflammatory cytokines and prognosis of non small cell lung cancer (NSCLC), we evaluated the serum levels of tumor necrosis factor-alpha (TNF-alpha), interleukin-1-beta (IL-1-beta) and interleukin-6 (IL-6) in 60 patients with untreated advanced NSCLC. Mean cytokines concentrations in patients were significantly higher than in the control population. Patients with metastatic disease had higher levels than those with undisseminated disease. Finally, in patients with tumor progression we observed an increase of cytokines serum levels. These results suggest that in NSCLC elevated serum levels of proinflammatory cytokines may have prognostic value being associated with a worse prognosis.
Abstract: High levels of soluble lymphocyte antigens have been described in a large number of tumors and, particularly, in hematopoietic neoplasms. As previously reported, many antitumor immune responses are IL-2 dependent: clinical observations indicate that a worse survival in advanced tumor patients is related with a decrease of soluble IL-2 levels. A soluble form of CD8 has been described: as found in Hodgkin's disease and acute lymphoblastic leukemia, sCD8 levels have a prognostic value. To explain the significance of these soluble molecules in solid tumors, we a) determinated sIL-2R and sCD8 in 84 patients; b) correlated the expression of p55 chain of IL-2R and CD8 antigen on the cell-surface of peripheral lymphocytes to sIL-2R and sCD8 levels; c) analyzed endogenous IL-2R levels in patients with lung cancer. An increase of sIL-2R was found in 82% of cases, while high levels of sCD8 were observed in 32%; no correlation was observed between sIL-2R and the expression of p55 on the surface of peripheral lymphocytes: IL-2 levels in patients with NSCLC were significatively reduced, when compared to healthy controls, with an inverse relationship between endogenous IL-2 concentration and sIL-2R levels. Whatever may be the physiopathological mechanism of the increase of sIL-2 observed in solid tumors, this rise may contribute to the immunodepression correlated to neoplastic disease. Therefore, higher levels of sIL-2R/IL-2 ratio has a negative biologic prognostic significance. We think that determinating CD8 antigen in the serum can offer a more sensitive and specific measurement of activation of suppressor/cytotoxic T-lymphocytes.
Abstract: The anthracyclines, doxorubicin and daunorubicin, are antibiotics effective in the treatment of many malignancies. However, their usefulness is limited by the development of potentially fatal cardiotoxicity. Cardiac monitoring by a noninvasive test capable of identifying patients at high risk of cardiac damage, before the ejection fraction deteriorates would have clinical utility. Electrocardiograms and echocardiograms are routinely utilized for noninvasive assessment of myocardial function. However, of the ECG abnormalities described, none has been noted to be of consistent predictive value for cardiotoxicity. The aim of this study was to assess the effects of doxorubicin on ventricular repolarization time indexes, as they have been shown to be effective in the identification of electrical myocardial instability and, hence, in the identification of risk for either arrhythmia or heart failure. For this reason, electrocardiograms were compared in 35 cancer patients at the first presentation (drug-free state) and after 29.4 +/- 37.65 weeks of treatment with doxorubicin. The results of the present study showed that after only a short period of treatment with doxorubicin there was a significant increase in ventricular recovery time dispersion indexes (QTc, JT, and JTc dispersion, and their "adjusted" values). Thus, increased regional variation in ventricular repolarization could be, in the absence of a significant modification of the echocardiographic parameters, an early marker of an electropathy, due to the early cardiotoxic action of doxorubicin on myocardial cells, eventually leading to heart failure.
Abstract: Intestinal malignant neoplasms are extremely rare (1% of all solid tumours) and leiomyosarcomas represent 20% of them. The authors report the experience of 5 cases (M:F ratio = 0.6), aged 30-69 yrs old, treated in the period 1985-95. The best results have been obtained in 2 cases, characterized by low grading and submitted to curative resections. The others presented local and distant (mostly hepatic) extensions with a poorer prognosis (1-3 yrs. survival). Leiomyosarcomas are particularly binding because of their rarity and aspecific symptomatology, determining late diagnosis in most cases. The clinical course, the surgical and complementary management, the istology and the prognosis have been analysed. Nowadays 5 yrs-survival is very low and the prognosis remains severe because of local and distant metastases, already present at laparotomy. New chances may come out from better diagnostic techniques and from new complementary chemotherapeutical associations.
Abstract: Wilms' tumor in an adult is rare and no treatment guidelines have been established, although all authors recommend aggressive therapy based on surgery, radiotherapy, and multiagent chemotherapy.
Abstract: Thromboembolic complications are common in patients with cancer and represent the second cause of death in patients with overt malignant disease. The aim of this study was to investigate the activated protein C pathway in cancer.
Abstract: Primary lymphoma of the parotid gland is uncommon: we report a case in an 82-year-old man, classified according to the Working Formulation as a low-grade lymphoma. After parotidectomy the patient was treated with radiation therapy and, subsequently, with polychemotherapy (endoxan, vincristine and prednisone) for six cycles. At follow-up examination one year after, the patient is in complete remission. The major problem encountered was the correct diagnosis that became possible only when the surgical specimen was available. The authors review the pathological features of this extranodal form of lymphoma and discuss the treatment.
Abstract: Doxorubicin is a common antitumoral agent, widely used to treat patients with a variety of neoplastic diseases: acute and severe dose-related chronic cardiotoxicity is the major limitation to optimal use of anthracycline antibiotics. Cancer patients with clinically important heart disease are thus generally not eligible for anthracycline therapy. This review discusses the clinical aspects and possible underlying pathogenetic mechanisms of cardiac damage. Also described is the diagnostic evaluation necessary for early warning of a cardiac event during anthracycline therapy as well as the means to prevent it. The authors also discuss the anthracycline derivatives, verapamil, and dexrazoxane (ICRF-187), a new cardioprotector agent.
Abstract: The authors report a case of 17-years-old woman suffering from a Ki-1 lymphoma with retroperitoneal bulky disease, extranodal involvement, poor performance status and high level of LDH. Due to the unfavorable prognosis, after complete remission obtained with aggressive induction therapy, the patient received high dose of therapy based on busulfan and etoposide followed by autologous bone marrow transplantation (ABMT) as consolidation therapy. Toxicity was mild, particularly neutrophil recovery was hastened with G-CSF. After 22 months from ABMT she is alive without evidence of disease.
