PATIENT CONCERNS: We report a rare case of pancreatic carcinosarcoma involving a 44-year-old woman. The patient complained of discomfort associated with the upper abdomen and jaundice of skin and sclera for 1 week.
DIAGNOSES: After hospitalization, relevant examinations were completed. The disease was diagnosed as carcinoma of the pancreatic head.
INTERVENTIONS: Whipple procedure was conducted in May 2013. Intraoperative exploration indicated 2 components of the tumor: a fish-shaped gray matter and a hard structure similar to cancellous bone. Histopathological examination showed adenocarcinoma and osteosarcoma. After surgery, the patient received 8 cycles of chemotherapy with gemcitabine and raltitrexed.
OUTCOMES: Previous studies indicated poor prognosis for pancreatic carcinosarcoma. However, our patient survived for 31 months with no recurrence till date.
LESSONS SUBSECTIONS: Coexistence of pancreatic adenocarcinoma and osteosarcoma is very rare. Our case was also an exception in manifesting longer survival than expected.

AIM: The aim of this study was to evaluate the pathological response of locally advanced rectal cancer after preoperative concurrent two-drug chemotherapy and intensified radiation therapy (RT) with concomitant boost.
PATIENTS AND METHODS: Patients with T4 tumor or local recurrence were included. A trial based on two-stage Simon's design was planned. RT was performed with 3D-conformal technique. The dose to the mesorectum and pelvic lymph nodes was 45 Gy (1.8 Gy/fraction). A concomitant boost was delivered to Gross Tumor Volume (GTV) 2 cm margin to a total dose of 55 Gy (2.2 Gy/fraction). The following concurrent chemotherapy was administered: Raltitrexed (3 mg/m(2)) and oxaliplatin (130 mg/m(2)) on days 1, 17, and 35 of RT. Pathological response was evaluated according to the Mandard classification. Toxicities were scored according to the Common Terminology Criteria for Adverse Events v3.0 scale.
RESULTS: Eighteen patients (median age=64.5 years) were enrolled. The median follow-up was 22 months (range=2-36 months). After chemoradiation treatment, 16 patients underwent surgical resection (seven anterior resections and nine abdominal-perineal amputation); two patients did not undergo surgery due to early metastatic progression or refusal. R0 resection was achieved in all patients who underwent surgery. Five patients had pathological complete response [27.7%; 95% confidence interval (CI)=9.7-53.5%] and two patients showed only microscopic residual disease (11.1%; 95% CI=0.1-34.7%). Mandard grades 1 and 2 were detected in seven patients (38.9%; 95% CI=17.3-64.3%). Acute grade 3 or more toxicity was found in eight patients (44.4%; 95% CI=21.5-69.2%): one leucopenia-neutropenia, one liver, one skin and five cases of gastrointestinal toxicities. No patient had local tumor recurrence. One-, 2- and 3-year cumulative disease-free survival were 93.8%. One-, 2- and 3-year cumulative overall survival were 92.3%.
CONCLUSION: Concurrent chemoradiation with concomitant boost in patients with advanced rectal cancer allows complete or near-complete pathological response in more than 38% of patients. However, severe acute toxicity was reported in more than one-third of patients.

Electrochemical biosensors using five anticancer drug and lipid molecules attached on the conducting polymer layer to obtain the orientation of drug molecules toward cancer cells, were evaluated as sensing materials and their performances were compared. Conjugation of the drug molecules with a lipid, phosphatidylcholine (PC) has enhanced the sensitivity towards leukemia cells and differentiates cancer cells from normal cells. The composition of each layer of sensor probe was confirmed by electrochemical and surface characterization experiments. Both impedance spectroscopy and voltammetry show the enhanced interaction of leukemia cells using the drug/lipid modified sensor probe. As the number of leukemia cells increased, the charge transfer resistance (Rct) in impedance spectra increased and the amine oxidation peak current of drug molecules in voltammograms decreased at around 0.7-1.0V. Of test drug molecules, raltitrexed (Rtx) showed the best performance for the cancer cells detection. Cancer and normal cell lines from different origins were examined to evaluate the degree of expression of folate receptors (FR) on cells surface, where cervical HeLa cell line was found to be shown the highest expression of the receptor. Impedance and chronoamperometric experiments for leukemia cell line (Jurkat E6-1) showed linear dynamic ranges of 1.0×10(3)-2.5×10(5) cells/mL and 1.0×10(3)-8.0×10(3) cells/mL with detection limits of 68±5 cells/mL and 21±3 cells/mL, respectively.

Malignant pleural mesothelioma (MPM) is a rare aggressive cancer of the pleura. Asbestos exposure (through inhalation) is the most well established risk factor for mesothelioma. The current standard of care for patients suffering from MPM is a combination of cisplatin and pemetrexed (or alternatively cisplatin and raltitrexed). Most patients, however, die within 24 months of diagnosis. New therapies are therefore urgently required for this disease. Lysine acetyltransferases (KATs) including KAT5 have been linked with the development of cisplatin resistance. This gene may therefore be altered in MPM and could represent a novel candidate target for intervention. Using RT-PCR screening the expression of all known KAT5 variants was found to be markedly increased in malignant tumors compared to benign pleura. When separated according to histological subtype, KAT5 was significantly overexpressed in both the sarcomatoid and biphasic subgroups for all transcript variants. A panel of MPM cell lines including the normal pleural cells LP9 and Met5A was screened for expression of KAT5 variants. Treatment of cells with a small molecule inhibitor of KAT5 (MG-149) caused significant inhibition of cellular proliferation (p<0.0001), induction of apoptosis and was accompanied by significant induction of pro-inflammatory cytokines/chemokines.

BACKGROUND: To compare the efficacy of three chemotherapeutic combinations for laparoscopic hyperthermic intraperitoneal perfusion chemotherapy (HIPPC) in the treatment of malignant ascites secondary to unresectable gastric cancer (GC).
MATERIALS AND METHODS: From January 2010 to December 2013, 38 GC patients were randomly divided into three groups and treated by laparoscopic HIPPC with one of the three following chemotherapy combinations: raltitrexed (Ra) with oxaliplatin [trans-(±)-diaminocyclohexane oxalatoplatinum (l-OHP)], Ra with cisplatin (DDP), and Ra with mitomycin C (MMC). Perioperative complications, patients' quality of life, and survival were recorded and compared among the three groups.
RESULTS: The intraoperative course was successful in all patients, and no perioperative death or complication related to laparoscopic HIPPC was documented. The median follow-up period was 9 months, and the median survival was 7.5 months for all patients. Patients in the Ra/l-OHP group had a median survival of 8.7 months, the Ra/DDP group had a median survival of 5.6 months, and the Ra/MMC group had a median survival of 7.5 months. Patients' median survival in the Ra/l-OHP group and Ra/MMC group was significantly longer than in the Ra/DDP group (P < .05). No significant difference was found in total remission rate of ascites, increase in the Karnofsky Performance Scale, and incidence rate of port-site metastases among the three groups.
CONCLUSIONS: Laparoscopy-assisted HIPPC provides modest yet encouraging efficacy for malignant ascites secondary to disseminated GC. Our preliminary data indicate that the chemotherapeutic combination of Ra/l-OHP and Ra/MMC might be more beneficial compared with Ra/DDP in terms of patients' survival.

Retrorectal cystic hamartomas are rare congenital presacral lesions and malignancy is extremely rare. Although surgical excision is the essential for treatment, a unique feature of our case compared with previously reported tailgut cysts is that this patient's blood irregular antibodies are positive with higher operational risks.A 44-year-old woman presented to our department complaining of pelvic and perineal pain for 6 months. Computed tomography (CT) scan of the abdomen and pelvis demonstrated a well-demarcated hypodense, multilocular cystic lesion, 10 cm in size, in the presacral region of the right of the midline. We found her blood irregular antibodies were positive in the preoperative examination. So she quitted surgery. Exploratory laparotomy and incision and drainage of pelvic tumor were operated. Postoperative routine pathology showed: (retroperitoneal tumors) moderately differentiated adenocarcinoma. Combined with clinical symptom and imaging, malignant transformation of retrorectal cystic hamartomas (tailgut cysts) was diagnosed. Taking into account that cyst is not sensitive to radiotherapy, so tumor necrosis factor (TNF) and raltitrexed were infused into the cysts and 3 cycles oxaliplatin (130 mg/m) were completed. Now although the lesion is shrink, but yellow, viscous mucus still secrete constantly, 100 ml/w.Given surgical excision is the essential for treatment, complete surgical excision should be implemented as far as possible. But if surgery cannot be carried out like the presented case, systemic chemotherapy and local radiotherapy are also available, which can alleviate the symptoms of oppression and improve the quality of life partly.

We defined the stem cell profile of K562 line, demonstrating the expression of the Embryonic Transcription Factors Oct3/4, Sox2, Klf4 and Nanog. This profile was associated with a high vulnerability to the physiological oxidizable substrate pyruvate. remarkably, this substrate was shown to be innocuous, even at the highest doses, to normal differentiated cells. This vulnerability is based on a complex metabolic trim centered on the cellular redox state expressed by the NADP/NADPH ratio geared by the mitochondrial respiratory chain. Flow cytometry revealed that the inhibition of this chain by antimycin A produced cell accumulation in the S phase of cell cycle and apoptosis. This block negatively interferes with the aerobic synthesis of purines, without affecting the anaerobic synthesis of pyrimidines. This imbalance was reproduced by using two antifolate agents, LY309887 and raltitrexed (TDX), inhibitors of purine or pyrimidine synthesis, respectively. All this revealed the apparent paradox that low doses of TDX stimulated, instead of inhibiting, leukemia cell growth. This paradox might have significant impact on therapy with regard to the effects of TDX during the intervals of administration, when the drug concentrations become so low as to promote maintenance of dormant cancer cells in hypoxic tissue niches.

BACKGROUND: We have previously shown that an intensified preoperative regimen including oxaliplatin plus raltitrexed and 5-fluorouracil/folinic acid (OXATOM/FUFA) during preoperative pelvic radiotherapy produced promising results in locally advanced rectal cancer (LARC). Preclinical evidence suggests that the scheduling of bevacizumab may be crucial to optimize its combination with chemo-radiotherapy.
PATIENTS AND METHODS: This non-randomized, non-comparative, phase II study was conducted in MRI-defined high-risk LARC. Patients received three biweekly cycles of OXATOM/FUFA during RT. Bevacizumab was given 2 weeks before the start of chemo-radiotherapy, and on the same day of chemotherapy for 3 cycles (concomitant-schedule A) or 4 days prior to the first and second cycle of chemotherapy (sequential-schedule B). Primary end point was pathological complete tumor regression (TRG1) rate.
RESULTS: The accrual for the concomitant-schedule was early terminated because the number of TRG1 (2 out of 16 patients) was statistically inconsistent with the hypothesis of activity (30%) to be tested. Conversely, the endpoint was reached with the sequential-schedule and the final TRG1 rate among 46 enrolled patients was 50% (95% CI 35%-65%). Neutropenia was the most common grade ≥ 3 toxicity with both schedules, but it was less pronounced with the sequential than concomitant-schedule (30% vs. 44%). Postoperative complications occurred in 8/15 (53%) and 13/46 (28%) patients in schedule A and B, respectively. At 5 year follow-up the probability of PFS and OS was 80% (95%CI, 66%-89%) and 85% (95%CI, 69%-93%), respectively, for the sequential-schedule.
CONCLUSIONS: These results highlights the relevance of bevacizumab scheduling to optimize its combination with preoperative chemo-radiotherapy in the management of LARC.

BACKGROUND: Studies of clinical outcomes of elderly patients treated with neoadjuvant chemoradiation (nCRT) for locally advanced rectal cancer (LARC) are limited. Our aim was to assess the impact of age on clinical outcomes in a large multi-institutional database.
PATIENTS AND METHODS: Data for patients diagnosed with LARC who received nCRT and curative-intent surgery between 2005 and 2012 were collected from five major Canadian cancer centers. Age was analyzed as a continuous and dichotomous variable (< 70 versus ≥ 70 years) and correlated with disease-free survival (DFS), cancer-specific survival (CSS) and overall survival (OS). Cox regression models were used to adjust for important prognostic factors.
RESULTS: Of 1172 patients included, 295 (25%) were ≥ 70 years, and they were less likely to receive adjuvant chemotherapy (ACT; 60% versus 79%, P < 0.0001), oxaliplatin-based ACT (12% versus 31%, P < 0.0001), less likely to complete nCT (76% versus 86%, P < 0.001), and more likely to be anemic at initiation of nCRT (42% versus 30%, P = 0.0004). In multivariate analyses, age ≥ 70 years was associated with similar DFS [hazard ratio (HR) 0.93, 95% confidence interval (CI) 0.68-1.26, P = 0.63], similar CSS (HR 0.81, 95% CI 0.46-1.41, P = 0.45), and similar OS (HR 1.28, 95% CI 0.88-1.86, P = 0.20), compared with the younger age group. As a continuous variable, increasing age was not predictive of DFS (HR 1.00, 95% CI 0.99-1.02, P = 0.49) or CSS (HR 1.002, 95% CI 0.98-1.02, P = 0.88); however, it correlated with an inferior OS (HR 1.02, 95% CI 1.00-1.03, P = 0.04).
CONCLUSIONS: Elderly patients (≥ 70 years) who receive nCRT followed by surgery appear to have similar outcomes compared with younger patients. Decisions regarding eligibility for nCRT and surgery should not be based on age alone.

BACKGROUND: Peritoneal implantation metastasis of gastric cancer is the major reason for cancer recurrence after radical operations. As a new chemotherapeutic agent, raltitrexed has been widely used in intravenous chemotherapy for many kinds of cancers. However, no study has reported the efficacy and safety of raltitrexed in intraperitoneal chemotherapy. This study aimed to explore the safety of intraperitoneal chemotherapy with raltitrexed during gastric cancer operation compared to normal saline (NS) rinsing of the abdominal cavity.
METHODS: In this prospective study, 91 gastric cancer patients undergoing surgery and reconstruction were consecutively enrolled and randomly assigned into two groups. Raltitrexed in NS (500 ml) was injected into the abdominopelvic cavity for the patients in the RT group (n = 48), while for the patients in the group NS (n = 43), only NS (500 ml) was injected. The postoperative complications, gas passage time, and adverse effects, according to NCI-CTCAE v3.0, were compared between the two groups.
RESULTS: There were no significant differences in age, sex, cancer pathological type, clinical stage or operation method between the two groups (all P >0.05). No significant difference was observed in adverse effects and postoperative complications between the two groups (all P >0.05). No significant change was found in the levels of red blood cells, white blood cells, platelets, lactate dehydrogenase, blood urea nitrogen, and alanine aminotransferase before and after the operation for both groups (all P >0.05). All adverse events were mild or moderate by NCI-CTCAE v3.0 (National Cancer Institute common terminology criteria for adverse events) grade.
CONCLUSIONS: The findings of the present study demonstrate that intraperitoneal chemotherapy with raltitrexed after gastric cancer operation is safe and could be used for patients.

OBJECTIVE: To explore the effectiveness and safety of raltitrexed/cisplatin with concurrent radiotherapy in treating of patients with advanced cervical cancer.
PATIENTS AND METHODS: Sixty-five patients with stage IIB-IVA cervical cancer enrolled in this study, received raltitrexed/cisplatin with concurrent radiotherapy. The treatment consisted of raltitrexed 3 mg/m2 iv 15 min, d1; cisplatin 60 mg/m2 iv 60 min, d1, and pelvic radiotherapy, using three-dimensional conformal radiotherapy. The radiotherapy was implemented over Elekta accelerator (Model Type Precise), with 2.0 Gy per fraction for the whole pelvic or pelvic extension field. Central lead shield was used if the dose reached 30 Gy to produce a total dosage of 50 Gy. Following radiation therapies of full pelvic field or extended-field, additional radiation with the dose of 56-60 Gy was administrated to the lymph node metastases. Brachytherapy of iridium 192 was completed in our hospital, with the dose of 7Gy per fraction for point A, once a week, with six fractions for internal radiations during the full treatment course of eight weeks.
RESULTS: A total of 65 patients completed radiotherapy with two cycles of concurrent chemotherapy. Amongst them, chemotherapy was delayed for a week due to hypoleukocytosis for seven of the patients. Total response rate, three-year disease-free survival, and three-year overall survival OS were 95.4%, 75.4%, and 90.7%. High-grade (≥3) acute toxicities were hypoleukocytosis (23.1%) and thrombocytopenia (6.2%) with a prevalence of high-grade (≥3) late toxicities at 1.5%. One patient received surgical resection because of a partial intestinal obstruction after 8 months of radiotherapy.
CONCLUSIONS: Raltitrexed/cisplatin combined with concurrent radiotherapy is effective in treating advanced cervical cancer.

Raltitrexed is a thymidylate synthase inhibitor belonging to the antimetabolite class of cytotoxic drugs. It is also effective in colorectal cancer (CRC) both as a single agent and in combination with other drugs, in particular in those patients with cardiologic risk factors or previous cardiotoxicity. The efficacy of first-line raltitrexed-based chemotherapy containing oxaliplatin (TOMOX) and irinotecan (TOMIRI) was investigated in this systematic review. Studies that enrolled advanced CRC patients for first-line therapy with TOMOX/TOMIRI combinations were identified using electronic databases (Pubmed, SCOPUS, Web of Science, EMBASE, and the Cochrane Library). A systematic analysis was carried out using Comprehensive Meta Analysis (version 2.2.064) software to calculate the pooled response rate and 95% confidence limits. The median pooled overall survival and progression-free survival were also calculated. Results for TOMOX and TOMIRI studies were compared using the two-sided Student's t-test. We tested for significant heterogeneity using Cochran's χ-test and I index. Twelve studies published between 2001 and 2012 were eligible for this analysis and a total of 735 patients were enrolled in these studies. The overall response rate was 40% (95% confidence interval 34-46%): 43.9% for TOMOX and 34.1% for TOMIRI arms. The weighted median overall survival and progression-free survival times were 14.6 and 6.7 months, respectively. Neutropenia and liver toxicity were more frequent with TOMOX, whereas neutropenia and diarrhea were more frequent with TOMIRI. However, compared with historical FOLFOX and FOLFIRI trials, raltitrexed-based doublets are associated with less neutropenia and gastrointestinal toxicity and uncommon cardiotoxicity. TOMOX and TOMIRI doublets are active as first-line chemotherapy for advanced CRC and seem useful in particular when the use of 5-fluorouracil is contraindicated for cardiac comorbidity.

BACKGROUND: There is no standard treatment for patients with colorectal cancer (CRC) progressing after irinotecan and oxaliplatin treatment. Here we aimed to retrospectively evaluate the efficacy and tolerability of raltitrexed in combination with oral 5-fluoropyrimidine (uracil tegafur-UFT) or mitomycin C as salvage therapy in mCRC patients.
MATERIALS AND METHODS: A total of 62 patients who had received raltitrexed combined with UFT or mitomycin C were identified between December 2008 and June 2013. They were given raltitrexed 2.6 mg/m2 (max 5 mg) i.v. on day 1 in combination with either oral UFT 500 mg/day on days 1-14 every 3 weeks (group A) or mitomycin C 6 mg/m2 i.v. on day every 3 weeks (group B).
RESULTS: Forty-two patients (67.7%) were in group A and 20 (32.2%) in group B. In 15 patients (24%) grade 3/4 toxicity was observed, resulting in dose reduction, and in 13 patients (20.9%) dose delay was necessary. The median progression free survival (PFS) was 3 months (95%CI 2.65-3.34) and median overall survival (OS) was 6 months (95%CI 2.09-9.90) in the whole group. Median PFS was 3 months (95%CI 2.60-3.39) in group A vs 3 months (95%CI 1.64-4.35) in group B (p=0.90). Median OS was 6 months (95%CI 2.47-9.53) in group A vs 12 months (95%CI 2.83-21.1) in group B (p=0.46).
CONCLUSIONS: The combination of raltitrexed with UFT or mitomycin C seem to be a salvage therapy option due to safety profile and moderate clinical activity in heavily-pretreated mCRC patients.

No standard chemotherapy regimen has been established for metastatic colorectal cancer (mCRC) after progression on 5-fluorouracil, oxaliplatin, and irinotecan. Here, we report the combination of raltitrexed and bevacizumab as a salvage regimen for the treatment of three heavily pretreated patients with KRAS mutant mCRC. All three patients had stable disease (SD) according to response evaluation criteria in solid tumors (RECIST) criteria, progression free survival (PFS) were 3.0, 3.2 months for the first two patients and have not been reached for over 5 months for the third patient and no severe adverse effect was observed. The combination of raltitrexed plus bevacizumab in mCRC seems worthy of further investigation.

AIMS: To evaluate the efficiency and safety profile of raltitrexed-based chemotherapy in the treatment of advanced colorectal cancer.
METHODS: An electronic search was undertaken to identify randomized controlled trials comparing raltitrexed-based regimen to 5-fluorouracil-based regimen in patients with advanced colorectal cancer. The outcomes included overall survival, overall response rate and toxicities.
RESULTS: This meta-analysis included 11 studies with 4622 patients. Overall, there were no significant differences between the two regimens in terms of overall survival (HR=1.06, 95% CI: 0.96-1.17, P=0.23) or overall response rate (RR=1.09, 95% CI: 0.86-1.38, P=0.47). In subgroup analysis, patients in raltitrexed/oxaliplatin group had significantly higher partial response (RR=1.53, 95% CI: 1.17-2.00, P=0.002), overall response rate (RR=1.42, 95% CI: 1.10-1.82, P=0.006), disease control rate (RR=1.16, 95% CI: 1.04-1.29, P=0.009) and lower progressive disease (RR=0.61, 95% CI: 0.45-0.84, P=0.002) when compared to 5-fluorouracil/leucovorin/oxaliplatin group. Occurrence of severe anemia (RR=2.23, 95% CI: 1.38-3.59, P=0.0001), asthenia (RR=2.29, 95% CI: 1.36-3.84, P=0.002), hepatic disorders (RR=7.51, 95% CI: 1.30-43.56, P=0.02), and nausea/vomit (RR=1.70, 95% CI: 1.03-2.81, P=0.04) were significantly higher with the raltitrexed arm treatment, while frequencies of grade 3/4 alopecia (RR=0.36, 95% CI: 0.26-0.50, P<0.00001) and stomatitis/mucositis (RR=0.14, 95% CI: 0.07-0.31, P<0.00001) were increased in the 5-fluorouracil group.
CONCLUSIONS: Raltitrexed-based chemotherapy regimen leads to an equivalent overall survival and response rates with acceptable toxicities compared to traditional 5-fluorouracil-based regimen in patients with advanced colorectal cancer. Raltitrexed can be a treatment option for these patients when 5-fluorouracil-based regimens are not tolerated or inappropriate.

BACKGROUND: Cardiac toxicity an uncommon but serious side-effect of some fluoropyrimides. Cardiac toxicity from raltitrexed is rarely reported. With this background, we initiated this study to investigate the incidence of cardiac events in patients who had switched to raltitrexed following cardiac toxicity from fluoropyrimidines (5-fluorouracil or capecitabine).
PATIENTS AND METHODS: Pharmacy records were used to identify patients receiving raltitrexed from January 2004 till March 2012. Medical records were then reviewed to confirm the use of raltitrexed after cardiac toxicity from 5-fluorouracil or capecitabine. The primary end point was the rate of further cardiac events after commencing raltitrexed.
RESULTS: Forty-two patients were identified and the majority had colorectal cancer. Prior regimens included 5-fluorouracil ± leucovorin, capecitabine alone, FOLFOX, FOLFIRI, epirubicin/cisplatin/5-fluorouracil, and capecitabine/oxaliplatin. Seven patients (17%) had bolus 5-fluorouracil regimens, 26 patients (62%) had infusion 5-fluorouracil regimens, and 9 patients (21%) had capecitabine alone or in combination. Angina was the most common cardiac toxicity from 5-fluorouracil or capecitabine and usually occurred in the first or the second cycle. Four patients after their first cardiac event continued with the same 5-fluorouracil or capecitabine regimen with the addition of nitrates and calcium antagonists but still had further cardiac events. After changing to raltitrexed, either as a single agent or a continuing combination regimen, no patients experienced further cardiac toxicity.
CONCLUSION: Raltitrexed is associated with no significant cardiac toxicity in patients who have experienced prior cardiac toxicity from 5-fluorouracil or capecitabine. Raltitrexed, alone or in combination with oxaliplatin or irinotecan, provides a safe option in terms of cardiac toxicity for such patients.

PURPOSE: The purpose of the study is to analyze the relationship between tumor thymidylate synthase (TS) mRNA expression levels and raltitrexed/pemetrexed/5-FU sensitivity.
PATIENTS AND METHODS: We collected freshly removed colorectal tumor specimens from 50 patients. Chemosensitivities to anticancer drugs were evaluated by histoculture drug response assay. We adopted quantitative reverse transcription polymerase chain reaction for TS mRNA detection and immunohistochemical staining for assessing TS expression in tumor tissues.
RESULTS: There is a significant relationship between TS mRNA expression levels and in vitro chemosensitivity of freshly removed colorectal tumor specimens to pemetrexed (P < 0.001)/raltitrexed (P = 0.004)/5-FU (P = 0.007).
CONCLUSIONS: TS mRNA expression levels can predict pemetrexed and raltitrexed sensitivity in colorectal cancer.

INTRODUCTION: 5-fluorouracil continues to be the cornerstone of treatment for colorectal cancer. Although fluoropyrimidines are generally considered as well-tolerated drugs, severe toxicities can be a major clinical problem, and the recommended prolonged infusion of 5-fluorouracil provokes discomfort in patients. Raltitrexed (Tomudex), a quinazoline analogue of folinic acid, is a selective and direct thymidylate synthase (TS) inhibitor with a convenient 3-weekly schedule of administration.
AREAS COVERED: In this review, through critical insight into the mechanism of action and main clinical experiences, the authors suggest the necessity to reconsider raltitrexed as a valuable anticancer drug and as a suitable option for colorectal cancer. The authors highlight its emerging therapeutic role in clinical practice for patients with fluoropyrimidine-induced cardiotoxicity or a significant history of cardiac disease.
EXPERT OPINION: This review discusses if TS could still be a relevant target for colorectal cancer in the era of molecular therapy and if raltitrexed should still be considered a drug with a life-threatening toxicity. Furthermore, this review discusses the principal combination clinical experiences of raltitrexed and its emerging therapeutic role in clinical practice as a suitable option for colorectal cancer patients with fluoropyrimidine-induced cardiotoxicity or a significant history of cardiac disease.

This review aims to provide insight into treatment of malignant pleural mesothelioma (MPM) considering effects on survival, quality of life (QoL) and costs, in order to determine the value of pemetrexed in MPM treatment. Cisplatin in combination with pemetrexed or raltitrexed increased survival in MPM, whereas vinorelbine and gemcitabine have led to good response rates. None of these appear to have any detrimental effect with respect to symptoms and global QoL. The cost-effectiveness of pemetrexed-cisplatin was found to be acceptable in advanced MPM compared with cisplatin, but raltitrexed-cisplatin was found to be a more cost-effective treatment option. This may also apply for gemcitabine and vinorelbine, since in contrast to pemetrexed, both agents can be obtained from generic manufacturers. As yet platinum-doublet therapy is the most effective palliative treatment of MPM. To provide a more cost-effective treatment approach for advanced MPM, further research should include randomized controlled trials comparing the recommended pemetrexed-cisplatin directly with platinum doublets with raltitrexed, gemcitabine, or vinorelbine.

AIM: Fluoropyrimidines are the backbone of the majority of approved chemotherapy regimens for colorectal cancer (CRC). However, there are reports of fluoropyrimidine treatments being associated with cardiotoxicity which have led to permanent cardiovascular damage and even death. Raltitrexed is indicated for palliative treatment of advanced CRC where 5-fluorouracil (5-FU) is not tolerated or inappropriate. A systematic review was undertaken to determine the incidence of cardiotoxicity associated with 5-FU, capecitabine and raltitrexed.
METHODS: An electronic search of PubMed was undertaken to identify articles relating to cardiotoxicity associated with 5-FU, capecitabine or raltitrexed, published between January 1991 and August 2011. Additionally, a retrospective review of cardiotoxicity associated with raltitrexed at our treatment centres was conducted.
RESULTS: Twenty studies were examined. The overall incidence of cardiotoxicity associated with 5-FU/capecitabine varied between 0.55% and 19% (mean: 5.0%, median: 3.85%). No published data were identified reporting cardiotoxicity associated with raltitrexed. A retrospective review at our treatment centres revealed that the incidence was 4.5% amongst high-risk patients treated with raltitrexed (n=111) for advanced gastrointestinal cancer with a significant cardiac history and/or previous cardiotoxicity with 5-FU or capecitabine.
CONCLUSION: The incidence of cardiotoxicity associated with raltitrexed in patients with advanced CRC treated is favourable in a highly skewed, at-risk patient population, all of whom had documented cardiotoxicity with other fluoropyrimidines or were unable to tolerate capecitabine due to cardiac history. Raltitrexed is therefore a suitable option for patients with fluoropyrimidine-induced cardiotoxicity or significant cardiovascular risk factors.

The pyrimidine analogue 5-fluorouracil (5FU) is used as a treatment for solid tumors, but its mechanism of action is not fully understood. We have used mass spectrometry to study the mechanism of action of 5FU, and we have measured the effects of this drug on the composition and on the turnover of the proteome of RKO cancer cells. We have identified novel potential targets of 5FU that are affected after very short exposure times. We have also shown that 5FU has a massive effect on the proteins involved in RNA metabolism. After only 1 h of treatment, 5FU causes a post-transcriptional reduction in the abundance of components of the translation machinery (mostly ribosomal proteins), and this reduction is accompanied by a down-regulation of the translational capacity of the cells. Neither rapamycin nor raltitrexed, two drugs that also block cell proliferation, reduce the abundances of ribosomal proteins as 5FU does, which suggests that the down-regulation of ribosomal proteins is coupled to the mechanism of action of 5FU. Some of our observations conflict with previous reports based on RNA quantification. This shows how important it is to complement RNA profiling studies with analyses of drug toxicity at the protein level.

BACKGROUND: Carcinoembryogenic antigen (CEA) is useful in the evaluation of chemotherapy response of metastatic colorectal cancer (CRC). We studied weekly CEA during one fluorouracil-based chemotherapy cycle, correlated with long-term (8-12 week interval) computed tomography (CT) and CEA responses.
PATIENTS AND METHODS: CEA, liver function tests and inflammatory parameters were measured prospectively at baseline, day 7, day 14, and after the cycle (day 21/28), in 60 patients with metastatic CRC.
RESULTS: CEA non-significantly decreased at day 7 and was increased on day 14. In progressive disease, CEA increased significantly during the evaluation cycle (55.4 μg/l vs. 148.2 μg/l; p=0.024), but the level was stable in patients with disease control (10.6 μg/l vs. 17.8 μg/l; p=0.58). CEA fluctuation correlated neither with liver function test nor with inflammatory parameters. Correlation of long-term response was most evident in progressive disease.
CONCLUSION: CEA should not be measured during 5-fluorouracil-based oral chemotherapy nor within two weeks from intravenous chemotherapy administration.

Most chemotherapy regimens in colorectal cancer treatment are 5-fluorouracil (5-FU)/leucovorin or capecitabine-based. Cardiotoxicity is a less common but potentially lethal complication of 5-FU or capecitabine treatment, and some physicians might be unfamiliar with treatment alternatives. Rechallenging should be avoided because it carries a high risk of recurrence of the cardiac symptoms and prophylactic treatment is not always protective. Possible alternative treatment options to be considered are to replace the oral capecitabine or intravenous 5-FU by a 5-FU bolus regimen, by uracil-tegafur or tegafur/gimeracil/oteracil, both oral fluoropyrimidines combining a 5-FU prodrug with a dihydropyrimidine dehydrogenase (DPD) inhibitor, or by raltitrexed, a thymidilate synthase inhibitor whose metabolism is independent of DPD. Patients with advanced colorectal cancer and fluoropyrimidine-induced cardiotoxicity can be treated with other non-fluoropyrimidine related chemotherapy, either as a single agent, combined, or in combination with biological agents. In this report we discuss the different alternative treatment options.

PURPOSE: The aim of the present study is to prospectively evaluate the prognostic value of previously defined [(18)F]2-fluoro-2-deoxy-D-glucose positron emission tomography (FDG PET) criteria of early metabolic response in patients with locally advanced rectal cancer (LARC) after long-term follow-up.
METHODS: Forty-two patients with poor prognosis LARC underwent three biweekly courses of chemotherapy with oxaliplatin, raltitrexed and 5-fluorouracil modulated by levofolinic acid during pelvic radiotherapy. FDG PET studies were performed before and 12 days after the beginning of the chemoradiotherapy (CRT) treatment. Total mesorectal excision (TME) was carried out 8 weeks after completion of CRT. A previously identified cutoff value of ≥52 % reduction of the baseline mean FDG standardized uptake value (SUV(mean)) was applied to differentiate metabolic responders from non-responders and correlated to tumour regression grade (TRG) and survival.
RESULTS: Twenty-two metabolic responders showed complete (TRG1) or subtotal tumour regression (TRG2) and demonstrated a statistically significantly higher 5-year relapse-free survival (RFS) compared with the 20 non-responders (86 vs 55 %, p = .014) who showed TRG3 and TRG4 pathologic responses. A multivariate analysis demonstrated that early ∆SUV(mean) was the only pre-surgical parameter correlated to the likelihood of recurrence (p = .05).
CONCLUSION: This study is the first prospective long-term evaluation demonstrating that FDG PET is not only an early predictor of pathologic response but is also a valuable prognostic tool. Our results indicate the potential of FDG PET for optimizing multidisciplinary management of patients with LARC.

INTRODUCTION: The aim of this study was to compare TOMOX versus FOLFOX4 as first-line treatment of advanced colorectal cancer (CRC).
MATERIALS AND METHODS: 191 chemotherapy-naïve patients were randomized to receive TOMOX or FOLFOX4. Patients were evaluated every 3 months and chemotherapy was continued until disease progression or unacceptable toxicity. Overall response rate was the primary endpoint.
RESULTS: 183 patients were included in the intent-to-treat analysis (92 TOMOX and 91 FOLFOX4). Overall response rate was 45.6 and 36.3 % (p = 0.003) for TOMOX and FOLFOX4, respectively. No statistically significant differences were observed in overall survival (15.6 and 17.2 months; p = 0.475); progression-free survival (7.7 and 8.7 months; p = 0.292), and response duration (6.4 and 7.6 months; p = 0.372) for TOMOX and FOLFOX4, respectively. Grades 3 and 4 neutropenia (p < 0.0001) and leukopenia (p = 0.028) were more common with the FOLFOX4 regimen, while hepatic disorders and asthenia were higher in TOMOX group (p = ns). There were two treatment-related deaths in the FOLFOX4 arm and one in the TOMOX arm. Quality of life analysis based on the SF-36 revealed differences between the two regimens for physical and mental composite scores after 6 weeks, and for body pain and emotional role functioning after 6 and 12 weeks; all of these favored the FOLFOX4 arm (p ≤ 0.05).
CONCLUSIONS: TOMOX and FOLFOX4 seem to have similar efficacy and are well tolerated in the first-line treatment for advanced CRC with different profiles of toxicity. The convenient TOMOX regimen may offer an alternative to fluoropyrimidine-based regimens.

Different chemotherapeutic agents currently available are effective only in certain subsets of patients. Predictive biomarkers will be helpful in choosing those agents and can improve the clinical efficiency by a more personalized chemotherapeutic approach. Raltitrexed is a novel water-soluble quinazoline folate analogue and can improve the efficiency of gastric cancer treatment, but its predictive biomarker remains unclear. The aim of our study was to investigate the role of plasma and tumor thymidylate synthase (TS) mRNA levels as predictive biomarkers for raltitrexed in gastric cancer. In total, 125 freshly removed gastric tumor specimens and corresponding blood samples before surgery were collected. Raltitrexed sensitivity was determined by histoculture drug response assay procedures. TS mRNA levels in tumor and plasma were determined by quantitative reverse transcription polymerase chain reaction. Plasma TS mRNA level in cancer patients was significantly higher than in healthy subjects (p = 0.009) and was significantly correlated with TS mRNA level in tumor tissues (r = 0.665, p < 0.001). Tumor and plasma TS mRNA expression levels were significantly lower in raltitrexed-sensitive group than in resistant group (p = 0.007 and 0.013, respectively). The sensitivity and accuracy of raltitrexed sensitivity prediction based on plasma TS mRNA levels were 82 and 60%, respectively, whereas the prediction based on tumor TS mRNA reached 70% sensitivity and 68% accuracy. These results indicate that TS mRNA level in plasma can mirror tumor TS mRNA level, and both of them can be used to predict raltitrexed sensitivity in gastric cancer.

Malignant pleural mesothelioma is a rare malignancy with a dismal prognosis. The clinical management of most of the patients with this disease is quite challenging, and, overall, the therapeutic strategy has not yet benefited from the recent advances in molecular biology. Randomized evidence supports the use of cisplatin in combination with pemetrexed or raltitrexed as first-line treatments. In elderly patients with comorbidities cisplatin may be replaced by carboplatin because of a lesser burden of toxicities. The role of second-line chemotherapy is unproven, although pemetrexed can be regarded as the standard option in pemetrexed-naive patients and therapeutic rechallenge with pemetrexed may be considered in selected patients with prolonged disease control after first-line therapy. Targeted therapies failed to demonstrate any substantial activity; however, immunotherapies may complement other treatment strategies. In summary, there is an unmet clinical need and innovative approaches to select new potentially active drugs are highly warranted.

The incidence of human malignant pleural mesothelioma (hMPM) is still increasing worldwide. hMPM prognosis is poor even if the median survival time has been slightly improved after the introduction of the up-to-date chemotherapy. Nevertheless, large phase II/III trials support the combination of platinum derivatives and pemetrexed or raltitrexed, as preferred first-line schedule. Better understanding of the molecular machinery of hMPM will lead to the design and synthesis of novel compounds targeted against pathways identified as crucial for hMPM cell proliferation and spreading. Among them, several receptors tyrosine kinase show altered activity in subsets of hMPM. This observation suggests that these kinases might represent novel therapeutic targets in this chemotherapy-resistant disease. Over these foundations, several promising studies are ongoing at preclinical level and novel molecules are currently under evaluation as well. Yet, established tumour cell lines, used for decades to investigate the efficacy of anticancer agents, although still the main source of drug efficacy studies, after long-term cultures tend to biologically diverge from the original tumour, limiting the predictive potential of in vivo efficacy. Cancer stem cells (CSCs), a subpopulation of malignant cells capable of self-renewal and multilineage differentiation, are believed to play an essential role in cancer initiation, growth, metastasization and relapse, being responsible of chemo- and radiotherapy refractoriness. According to the current carcinogenesis theory, CSCs represent the tumour-initiating cell (TIC) fraction, the only clonogenic subpopulation able to originate a tumour mass. Consequently, the recently described isolation of TICs from hMPM, the proposed main pharmacological target for novel antitumoural drugs, may contribute to better dissect the biology and multidrug resistance pathways controlling hMPM growth.

Mesotheliomas are aggressive and lethal neoplasms arising from mesothelial cells lining the pleura, peritoneum, tunica vaginalis testis and pericardium. Malignant peritoneal mesothelioma accounts for about 30% of all mesotheliomas. Asbestos is the main known cause of the disease. Presenting symptoms in these patients include: ascites, abdominal pain, asthenia, weight loss, anorexia, abdominal mass, fever, diarrhea and vomiting. Electron microscopy, immunohistochemistry, computed tomography scan, echotomography, magnetic resonance imaging, positron emission tomography and laparoscopy are used in diagnosis and follow-up. Chemotherapy alone is considered as a palliative treatment for these patients who are not eligible for radical surgery. The most promising non-surgical approach today in the management of peritoneal mesothelioma is the use of the combination chemotherapy regime of an antifolate (pemetrexed and raltitrexed) and a platinum based (cisplatin) agent with a median survival of about 12-14 months. Due to peritoneal confinement of malignant mesothelioma and low occurrence of metastasis, a locoregional approach consisting of cytoreductive surgery and perioperative intraperitoneal chemotherapy has been introduced as a curative treatment option over the last decade with an overall 5-year survival rate of 29-63%. In this locoregional approach, surgery can separate the adhesions and remove the bulky tumor, leaving microscopic residual tumors much more susceptible to the killing effect of chemotherapeutic drugs. Here in St. George hospital, cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (using cisplatin and doxorubicin) resulted in significant survival advantage. This article describes how the prognosis of the disease has changed over the last decade.

Raltitrexed is a cytotoxic agent, rationally designed to inhibit a specific molecular target, thymidylate synthase. In contrast to other agents, raltitrexed inhibits thymidylate synthase directly and specifically in a mixed, noncompetitive manner, which may lead to an improved toxicity profile. After promising Phase II trials exploring the activity of raltitrexed either as a single agent or in combination with a platinum agent, a Phase III randomized study demonstrated that the combination of raltitrexed and cisplatin improves overall survival in malignant pleural mesothelioma (MPM) and is superior compared with cisplatin alone, without harmful effect on health-related quality of life. Moreover, the cost-effectiveness analysis found raltitrexed plus cisplatin to be cost effective compared with cisplatin and compared with active supportive care. Based on these results, raltitrexed is registered for the treatment of MPM in several European countries. MPM is hard to treat and has a poor prognosis. New treatment options, such as a combination of cisplatin and raltitrexed, which improve patient outcomes with no detrimental effect on quality of life, are a welcome addition to our therapeutic portfolio.