Background Elderly patients have been often excluded from or underrepresented in the study populations of combination chemotherapy trials. The primary end point of this study was to determine the response rate and the toxicity of the weekly oxaliplatin, 5-fluorouracil and folinic acid (OXALF) regimen in elderly patients with advanced gastric cancer. The secondary objective was to measure the time to disease progression and the survival time. Methods Chemotherapy-naive patients with advanced gastric cancer aged 70 or older were considered eligible for study entry. Patients received weekly oxaliplatin 40 mg/m2, fluorouracil 500 mg/m2 and folinic acid 250 mg/m2. All drugs were given intravenously on a day-1 schedule. Results A total of 42 elderly patients were enrolled. Median age was 73 years and all patients had metastatic disease. The response rate according to RECIST criteria was 45.2% (95% CIs: 30%–56%) with two complete responses, 17 partial responses, 13 stable diseases and 10 progressions, for an overall tumor rate control of 76.2% (32 patients). Toxicity was generally mild and only three patients discontinued treatment because of treatment related adverse events. The most common treatment-related grade 3/4 adverse events were fatigue (7.1%), diarrhoea (4.8%), mucositis (2.4%), neurotoxicity (2.4%) and neutropenia (4.8%). The median response duration was 5.3 months (95% CIs: 2.13 – 7.34), the median time to disease progression was 5.0 months (95% CIs: 3.75 – 6.25) and the median survival time was 9.0 months (95% CIs: 6.18 – 11.82). Conclusion OXALF represents an active and well-tolerated treatment modality for elderly patients with locally advanced and metastatic gastric cancer.

12016 Background: Combination of C and G has been demonstrated to be well tolerated, with apparent efficacy in patients with advanced cancers. To determine the toxicity of C plus Fixed Dose Rate (FDR) G in metastatic cancer patients, a phase I trial was conducted. Methods: This is an open-label, single-center, dose-escalating phase I study. C was administered orally according to the standard 21-day schedule: bid in equal doses (650 mg/m2 bid) for 14 days every 21 days. G was administered at a FDR of 10 mg/m2 per min in escalating durations of infusion on days 1 and 8 every 21 days. The doses of G explored were 600, 700, 800 mg/m2 infused at FDR in 60, 70 and 80 minutes, respectively. 15 pts (10 female, 5 male), aged 37–70 yr (median 66) with a variety of advanced solid tumors have been treated (11 peri-ampullary cancers, 3 colorectal cancers and 1 ovarian cancer). The FDR G dose was escalated when 3 patients in a cohort had completed two cycles of treatment without experiencing dose-limiting toxicities (DLT). The MTD was defined as the dose level at which no more than one of nine patients experienced a DLT. Results: No DLT occurred at doses of 600 and 700 mg/m2 in any of the 3 patients included at each level. At 800 mg/m2, 1 of 9 patients experienced DLT (neutropenia grade 4 with fever). The non-haematological toxicities have been generally mild or moderate in all patients (grade 2 stomatitis: 4 patients; grade 2 fatigue: 3 patients; grade 2 nausea/vomiting: 2 patients). 2 patients showed one episode of grade 4 neutropenia spontaneously regressed in 3 days. 2 patients showed one episode of grade 2 thrombocytopenia. The recommended dose for further studies is C bid in equal doses (650 mg/m2 bid) for 14 days (28 doses) plus FDR G at 800 mg/m2 infused in 80 minutes on days 1 and 8 every 21 days. Other patients with periampullary carcinoma are being evaluated at the same dose level, with an ongoing evaluation of cumulative (all cycles) toxicity and efficacy. In terms of response, we have observed 2 PR and 3 SD in the 6 pancreatic cancer patients evaluated for response after the first 3 cycles. Conclusions: C plus FDR G combination seems to be a feasible and safety approach which has demonstrated promising clinical activity. No significant financial relationships to disclose.

Zoledronic acid (Zometa, ZOL) is increasingly used to treat tumour-induced bone disease, and is also reported to have antiangiogenic properties in vivo. In this study, we have investigated the correlations between changes in the proangiogenic cytokine, vascular endothelial growth factor (VEGF), and markers of bone resorption in a cohort of patients with metastatic bone disease, following a single infusion of ZOL. Twenty-four consecutive selected cancer patients with scintigraphic and radiographic evidence of bone metastases were treated for the first time with a single infusion of 4 mg ZOL. Patients were considered ineligible if they had received any steroid therapy, radiotherapy, chemotherapy, immunotherapy or haemopoietic growth factors in the 4 weeks before or during the study period. Circulating levels of VEGF and beta crosslinked type I collagen C-telopeptide (betaCTX) were measured at base-line and at 1, 2, 7 and 21 days following ZOL infusion. The majority of our patients (23/24) developed a significant reduction in circulating levels of betaCTX at just 1 day after the single zoledronic acid infusion, median percentage decrease 67.05% (95% CI, 52.39%; 76.27%). This reduction persisted at all following time points in almost all subjects in our patient population (day 2, 95.8%; day 7, 100%; day 21, 91.7%). The median decrease at day 2 was 85.67% (95% CI, 78.23%; 90.16%); at day 7, 67.38% (95% CI, 67.38%; 86.98); and at day 21, 76.89% (95% CI, 35.00%; 83.16%). Moreover, a linear regression model with variance analysis demonstrated a statistically significant correlation between median VEGF and betaCTX circulating levels at each of the time points (1, 2, 7 and 21 days after ZOL infusion). The present work demonstrates that a single infusion of ZOL was able to induce a rapid and long lasting decrease of betaCTX plasma levels in the majority (23/24) of the included cancer patients. Furthermore, we found that there is a correlation between the levels of VEGF and betaCTX following ZOL treatment. Future clinical trials should be designed to prospectively evaluate the prognostic role of reduction of betaCTX and VEGF in response to ZOL to predict clinical and skeletal outcome.

3706 Background: We retrospectively evaluated the relevance of TS expression and DPD in normal colonic mucosa as predictive factors of toxicity in colorectal cancer patients receiving adjuvant 5-FU based chemotherapy. Methods: TS and DPD expression were immunohistochemically assessed on normal colonic mucosa from 64 patients with colorectal cancer Dukes’ stages B (35 patients) and C (29 patients) treated with 5-fluorouracil (5-FU) based adjuvant chemotherapy. Results: The incidence of grade 2–3 diarrhoea and stomatitis (according to WHO) was demonstrated to be significantly higher in patients with low nuclear TS expression in normal mucosa than in those with high TS expression (P<0.0001). Moreover, patients with low DPD expression in normal colonic mucosa developed more commonly grade 2–3 diarrhoea (55% vs 23%, p=0.062) and stomatitis (48% vs 23%, p=0.013). Furthermore, considering the concomitant expression of TS and DPD, we identified three groups of patients (group 1: TS + and DPD +, group 2: TS - and DPD -, group 3: only one +). The incidence of grade 2–3 diarrhoea and stomatitis were statistically significant higher in group 2 than in groups 1 and 3 (diarrhoea; 76% vs 24%, P<0.0001; stomatitis: 76% vs 24%; P<0.0001). Conclusions: Immunohistochemical TS and DPD expression in normal colonic mucosa and their combination, may represent two important predictive parameters for identifying a subset of patients with high risk of developing severe 5FU- related toxicities. No significant financial relationships to disclose.

Aims: There is considerable evidence that links COX-2 to the development of cancer. The aim of our study was to assess, by immunohistochemistry, COX-2 expression in ductal carcinoma in situ (DCIS) and its possible correlation with HER-2/neu, vascular endothelial growth factor (VEGF) expression and other common immunohistochemical parameters (p53, ER, PGR, Ki67).Methods and results: Tissue samples of 49 archival cases of DCIS without any invasive component were analysed for COX-2, HER-2/neu, VEGF, oestrogen and progesterone receptors, Ki67 and p53 by immunohistochemistry using specific antibodies. COX-2 expression was detected in 43 (87.8%) tissue samples, of which 12 (24.5%) were graded as weak, 22 (44.9%) as moderate and nine (8.4%) as high expression. Only six (12.2%) lesions were negative for COX-2 expression. VEGF expression was detected in 93.8% of samples; 66.7% of lesions were found to be positive for HER-2/neu expression. Furthermore, COX-2 expression was significantly correlated with VEGF expression (P = 0.003). A significant positive correlation was also observed between COX-2 and HER-2/neu expression (P < 0.0001).Conclusions: Our results suggest that COX-2 is highly expressed in DCIS and takes part in the molecular pathway implicated in progression of breast cancer and may provide a rationale for targeting COX-2 in preinvasive breast cancer therapy.

Objectives: We retrospectively evaluated the relevance of thymidylate synthase (TS) expression in normal colonic mucosa as a predictive factor of toxicity in colorectal cancer patients receiving adjuvant fluorouracil (5-FU)-based chemotherapy. Methods: TS expression was immunohistochemically assessed on normal colonic mucosa from 50 patients with colorectal cancer Dukes’ stages B (15 patients) and C (35 patients) treated with 5-FU-based adjuvant chemotherapy. Results: The incidence of grade 2–3 diarrhea and stomatitis (according to WHO) was demonstrated to be significantly higher in patients with low nuclear TS expression in normal mucosa than in those with high TS expression (p < 0.0001). Moreover, patients with low TS expression in normal colonic mucosa developed weight loss and worsening of the performance status (according to ECOG score) more commonly than patients with high TS expression (p = 0.005 and p = 0.02, respectively). Furthermore, low TS expression in normal colonic mucosa significantly correlated with a higher rate of a delay of chemotherapy courses, dose reduction and treatment discontinuation. Conclusions: Immunohistochemical TS expression in normal colonic mucosa may represent an important predictive parameter for identifying a subset of patients with a high risk of developing severe 5-FU-related toxicities.

Bisphosphonates are endogenous pyrophosphate analogs in which a carbon atom replaces the central atom of oxygen. They are indicated in non-neoplastic diseases including osteoporosis, corticosteroid-induced bone loss, Paget disease, and in cancer-related diseases such as neoplastic hypercalcemia, multiple myeloma and bone metastases secondary to breast and prostate cancer. There is now extensive in vitro evidence suggesting a direct antitumor effect of bisphosphonates at different levels of action. Some new in vitro and in vivo studies support the cytostatic effects of bisphosphonates on tumor cells, and the effects on the regulation of cell growth, apoptosis, angiogenesis, cell adhesion, and invasion, with particular attention to biological properties. Well designed clinical trials are necessary to investigate whether the antitumor potential of bisphosphonates may be clinically relevant. On the basis of their effects on macrophages, we may divide bisphosphonates into two distinct categories: aminobisphosphonates, which sensitize macrophages to an inflammatory stimulus inducing an acute-phase response, and non-aminobisphosphonates that can be metabolized into macrophages and that may inhibit the inflammatory response of macrophages. There is evidence of aminobisphosphonate-induced pro-inflammatory response, in particular, related to modifications of the cytokine network. Several in vivo studies have demonstrated an acute-phase reaction after the first administration of aminobisphosphonates, with a significant increase in the main pro-inflammatory cytokines. However, a peculiar aspect concerning the action of non-aminobisphosphonates seems to be an anti-inflammatory activity caused by the inhibition of the release of inflammatory mediators from activated macrophages, such as interleukin (IL)-6, tumor necrosis factor-alpha and IL-1. The inhibition of inflammatory responses is demonstrated in both in vivo and in vitro models. This activity suggests the use of non-aminobisphosphonates in several inflammatory diseases characterized by macrophage-mediated production of acute-phase cytokines, as prevention of erosions in rheumatoid arthritis, and of loosening of joint prostheses, as well as possibly in osteoarthritis, ankylosing spondylitis, myelofibrosis, and hypertrophic pulmonary osteoarthropathy.

Colorectal cancer represents a major health problem in the western world. A lot of drugs have been employed in treatment of this disease, but only few data are available about predictive factors for response to anticancer treatments in colorectal cancer. Aim of this paper is to review the main data about this investigation field. Using a Medline database search (1966-2003) we reviewed all the relevant papers that investigate clinical and molecular predictors for response to the main drugs used in the treatment of colorectal cancer patients, both in adjuvant and in advanced setting. Moreover we comprehensively reviewed all the data published in abstract form during the most significant international meetings. Our review put in evidence the most important predictive factors for response in colorectal cancer patients treated with anticancer chemotherapy both in adjuvant and in advanced setting. The predictive factors are clustered on the basis of the different anticancer drugs. The results of this review provide the rationale basis for personalizing anticancer treatment in colorectal cancer patients by molecular and clinical features, aiming to improve response rate and reduce toxicities.

Venous Thromboembolism (VTE) in cancer patients recognizes a multifactorial pathogenesis, depending on endogeous and esogenous factors. However, the relationship among VTE and laboratoristic thrombophilic alterations in cancer patients is not clearly known. Aim of our trial has been to evaluate changes in the levels of physiological coagulation inhibitors and some thrombophilic acquired factors in a cohort of gastrointestinal tumours patients considering four timepoints of their medical history. All patients over 18 years with a new diagnosis of malignant gastrointestinal neoplasm observed in the Surgery department of the University Hospital “Campus Bio-Medico” from October 2002 to June 2004 have been included in this trial. Patients with antineoplastic previous treatment, anticoagulant current therapies, autoimmune or hematological diseases were not included. The following physiological coagulation inhibitors have been tested: Protein C, Protein S, Antithrombin III. Moreover, we tested also the presence of Lupus Anticoagulant by mean of Silica Clotting Time (SCT), Diluted Russel Viper Venom Test (DRVVT) and Anticardiolipin Antibodies of IgG type (ACA IgG). Furthermore, we investigated also the levels of homocysteine and annexin V as well as the presence of activated Protein C resistance. Tests were performed on samples taken just before and after surgery as well as before and at the end of the chemotherapeutic protocols. In addiction, VTE's prevalence has been evaluated. A total of 102 patients (60 males and 42 females) have been included; median age was 67 years (range 28–92). A significant modification in the values of DRVVT, ACA IgG, PS, ATIII has been observed in the samples taken just after surgery (P <.001) and just before chemotherapy (P <.004). Moreover, PC levels were significantly reduced only after surgery (P <.000); SCT was significantly prolonged before starting chemotherapy (P <.003) while homocysteine levels were significantly reduced (P <.001) just after the end of the chemotherapeutic protocols. In this cohort of patients, VTE's prevalence has been 7,8% (8/102) of these, 5/8 (62,5%) were treated with FU-based therapies and 3/8 (37,5%) had a Central Venous Catheter. None of the thrombophilic parameters tested was correlated with the development of VTE, while an advanced disease (P<.024) was strongly correlated to VTE. These preliminar results agree with other published trials as for the reduction in physiological coagulation inhibitors after surgery and VTE's prevalence in cancer patients. Moreover, as expected, patients with advanced inoperable disease experience more easily VTE. Surprisingly, FU-based therapies reduce the levels of homocysteine in this cohort of patients. Increasing the number of studied patients may better clarify which are, in addiction to advanced disease, the more useful parameters for identifying those patients with gastrointestinal cancers at risk of VTE who may, therefore, benefit of a correct VTE prophylaxis.

BACKGROUND:Liver toxicity can be observed during treatment with most chemotherapic agents, and represents one of the principal causes of dose reduction or chemotherapy delays. S-Adenosylmethionine (AdoMet) plays a critical role in the synthesis of polyamines and provides cysteine for the production of glutathione (GSH), the major endogenous hepatoprotective agent. Our study was aimed at assessing the protective effect of AdoMet supplementation in cancer chemotherapy-induced liver toxicity.PATIENTS AND METHODS:Fifty cancer patients who developed, for the first time, anticancer chemotherapy-induced liver toxicity were studied. Enrolled patients received oral AdoMet supplementation.RESULTS:AST, ALT and LDH levels recorded at the moment of the recognition of liver toxicity were significantly reduced after one week of AdoMet therapy (respectively p: 0.009, 0.0005 and 0.012). AST, ALT and LDH decrease was confirmed after two weeks of treatment. Furthermore, the effect on these enzyme levels persisted in the following chemotherapy courses, permitting our patients to perform the scheduled chemotherapy courses with a minimal number of dose reductions or administration delays. The efficacy of AdoMet supplementation was not influenced by the presence of liver metastases, and no appreciable side-effects were recognized.CONCLUSION:The results of our study clearly demonstrate a protective effect of AdoMet in cancer chemotherapy-induced liver toxicity. Further large phase III studies are required to assess the real clinical benefit associated with AdoMet supplementation.

Raltitrexed is an inhibitor of thymidylate synthase (TS) with demonstrated activity in colorectal, breast, pancreatic, nonsmallcell lung and refractory ovarian cancer.[[1]] The dose-limiting toxici...

Oxaliplatin-containing regimens are now considered standard therapeutic options for patients with metastatic colorectal cancer (1). Oxaliplatin has a very good safety profile, and the doselimiting toxicity of oxaliplatin is neurosensory toxicity (2). In approximately 90% of patients, oxaliplatin is associated with acute reversible neurotoxicity that is characterized by the rapid onset of cold-induced distal dysesthesia and/or paresthesia, jaw pain, eye pain, pain in the arm used for drug infusion, ptosis, leg cramps, and visual and vocal changes (3–5). At high cumulative doses of oxaliplatin, persistent and chronic sensory neuropathy can develop, with continuous, non–cold-related paresthesiae, superficial and deep sensory loss, and eventually sensory ataxia and functional impairment (4). We present six case reports of patients with oxaliplatin-associated neurotoxicity who also had atypical and similar acute neurosensory symptoms characterized by recurrent episodes of involuntary masticatory spasms. All patients with metastatic colorectal carcinoma received the same chemotherapy regimen containing continuous infusion of oxaliplatin (70 mg/m for 12 hours on days 1 and 8) plus oral capecitabine (2000 mg/m per day). After each oxaliplatin infusion, all patients reported recurring paroxysmal episodes of painful involuntary masticatory spasms that were characterized by mouth opening or lateral shift of the mandible followed by muscle relaxation failure. These episodes started 6–24 hours after the beginning of each oxaliplatin administration, recurred several times a day, and lasted for 48–72 hours. These spasms were easily provoked by mouth movements, such as eating and talking, and caused difficulties in speech or mastication. They usually lasted only a few seconds and were not induced or exacerbated by cold. No episode was associated with hypocalcemia or hypomagnesemia. After a complete oto-rhino-laryngology examination, oromandibular dystonia and temporomandibular dysfunction were completely excluded in each patient. No patient had a history of limited mouth opening, typical of temporomandibular disorders, or had previous neurologic diseases. One patient had previously received eight cycles of a 2-hour oxaliplatin infusion without reporting an episode of masticatory spasm. The infusion time was reduced to 2 hours in two patients, and no masticatory spasm episode was reported. The acute neurotoxicity seen with oxaliplatin is related to acute peripheral nerve hyperexcitability (6). Moreover, recent data indicate that oxaliplatin may act on the voltage-gated sodium channel to increase the excitability of sensory neurons (6). For these reasons, we postulate that a possible abnormal and prolonged oxaliplatin-induced hyperexcitability state of trigeminal fibers results in the described paroxysmal episodes of painful involuntary occlusion of the jaw. This hypothesis is supported by the demonstration that the remodeling of voltage-gated sodium channels in the neuronal membrane has been proposed as a mechanism of trigeminal ectopic hyperexcitability that occurs in several types of masticatory spasms (7). We suggest that prolonged exposure to oxaliplatin induces a prolonged abnormal function of voltage-gated sodium channels in the neuronal membrane of trigeminal nerve. Thus, we believe that the high incidence of the described neurotoxicity in our patients (six of 13 patients treated with continuous infusion of oxaliplatin) is strictly related to the duration of drug infusion.

British Journal of DermatologyVolume 149, Issue 6 p. 1306-1307 Dramatic improvement of psoriasis with gemcitabine monotherapy D. Landi, D. Landi Medical Oncology, Campus Bio-Medico University, Via Emilio Longoni 83, 00155 Rome, ItalySearch for more papers by this authorD. Santini, D. Santini Medical Oncology, Campus Bio-Medico University, Via Emilio Longoni 83, 00155 Rome, ItalySearch for more papers by this authorB. Vincenzi, B. Vincenzi Medical Oncology, Campus Bio-Medico University, Via Emilio Longoni 83, 00155 Rome, ItalySearch for more papers by this authorA. La Cesa, A. La Cesa Medical Oncology, Campus Bio-Medico University, Via Emilio Longoni 83, 00155 Rome, ItalySearch for more papers by this authorC. Dianzani, C. Dianzani Medical Oncology, Campus Bio-Medico University, Via Emilio Longoni 83, 00155 Rome, ItalySearch for more papers by this authorG. Tonini, G. Tonini Medical Oncology, Campus Bio-Medico University, Via Emilio Longoni 83, 00155 Rome, ItalySearch for more papers by this author D. Landi, D. Landi Medical Oncology, Campus Bio-Medico University, Via Emilio Longoni 83, 00155 Rome, ItalySearch for more papers by this authorD. Santini, D. Santini Medical Oncology, Campus Bio-Medico University, Via Emilio Longoni 83, 00155 Rome, ItalySearch for more papers by this authorB. Vincenzi, B. Vincenzi Medical Oncology, Campus Bio-Medico University, Via Emilio Longoni 83, 00155 Rome, ItalySearch for more papers by this authorA. La Cesa, A. La Cesa Medical Oncology, Campus Bio-Medico University, Via Emilio Longoni 83, 00155 Rome, ItalySearch for more papers by this authorC. Dianzani, C. Dianzani Medical Oncology, Campus Bio-Medico University, Via Emilio Longoni 83, 00155 Rome, ItalySearch for more papers by this authorG. Tonini, G. Tonini Medical Oncology, Campus Bio-Medico University, Via Emilio Longoni 83, 00155 Rome, ItalySearch for more papers by this author First published: 11 December 2003 https://doi.org/10.1111/j.1365-2133.2003.05667.xCitations: 4 Daniele Santini, E-mail: d.santini@unicampus.it Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Citing Literature Volume149, Issue6December 2003Pages 1306-1307 RelatedInformation

In this minireview the authors examine and discuss the radioprotective compounds and the new combination therapies for the prophylaxis of radiation-induced emesis. Radiation-induced emesis is an important secondary effect of this anticancer treatment and it represents one of the causes of therapy interruption and decay of life quality before the introduction of optimal control of radiation-induced emesis with new antiemetic drugs which ensure the continuance of radiotherapy and avoid time breaks, that could negatively influence the efficacy of anticancer treatment. The incidence, the severity or the latency of radiotherapy-induced nausea and vomiting are correlated both with the treatment features (fractions, total dose, irradiation site) and with the main clinical characteristics of the patients. In contrast to the very extensive literature on the prevention of chemotherapy-induced emesis, relatively few studies about the prevention of nausea and vomiting in patients submitted to radiotherapy have been published. Among antiemetic drugs for the prevention of emesis, benzamides and in particular metoclopramide, are widely used in clinical practice. The introduction of selective 5-HT3 antagonists in clinical practice produced an important improvement in control of chemotherapy induced emesis, but few published studies were aimed at evaluating the efficacy of these drugs in the prophylaxis of nausea and vomiting due to radiation exposure. We herewith present a brief summary of Clinical practice guidelines for the use of antiemetics in anticancer therapy recently published by ASCO (American Society of Clinical Oncology).

Bisphosphonates are now well established as successful agents for the prevention and treatment of postmenopausal osteoporosis, corticosteroid-induced bone loss and Paget's disease. Bisphosphonates have also recently become important in the management of cancer-induced bone disease, and they now have a widely recognized role for patients with multiple myeloma and bone metastases secondary to breast cancer and prostate cancer. Recent studies suggest that, besides the strong antiosteoclastic activity, the efficacy of such compounds in the oncological setting could also be due also to direct antitumor effect, exerted at different levels. Here, after a brief analysis of the chemical structure, we will review the antineoplastic and biological properties of bisphosphonates. We will start from well estabilished mechanisms of action and go on to discuss the latest evidence and hypotheses. In particular, we will review the antiresorptive properties in malignant osteolysis and the recent evidence of a direct antitumor effect. Furthermore, this review will analyze the influence of bisphosphonates on cancer growth factor release, their effect on cancer cell adhesion. invasion and viability, the proapoptotic potential on cancer cells, the antiangiogenic effect, and, finally, the immunomodulating properties of bisphosphonates on the gammadelta T cell population.