Trimetrexate is a novel lipophilic folate antagonist that causes growth inhibition, inhibition of nucleic acid biosynthesis, and cytotoxicity at nanomolar concentrations in tissue cultures. The potency of trimetrexate cytotoxicity against most cell lines is greater than that of methotrexate. Trimetrexate has antitumor activity in vivo in several murine leukemia and solid tumor systems, including tumors in which methotrexate is inactive. Antitumor activity was seen following oral, intravenous, or intraperitoneal administration. Trimetrexate causes a pronounced and early depression in incorporation of deoxyuridine into DNA. In tumor cell lines resistant to methotrexate because of a drug transport defect, trimetrexate retains activity. In many such cases the methotrexate-resistant tumors show collateral sensitivity to trimetrexate. In methotrexate-resistant cells with impaired drug transport, trimetrexate sensitivity was even more pronounced when cells were grown in folate-free medium supplemented with physiological levels of tetrahydrofolate cofactor. In the human tumor stem cell colony assay, trimetrexate, at concentrations achievable in vivo, gave activity against many human tumors, including samples that were unresponsive to methotrexate. Trimetrexate crosses the blood-brain barrier, and at very high doses may cause neurotoxicity. At conventional doses the primary toxic effects in mice are gastrointestinal. This toxicity is reversible at therapeutic doses. Unlike earlier lipophilic antifolates, trimetrexate has rapid plasma clearance (t1/2 in mice of 45 minutes). Trimetrexate is a tight-binding competitive inhibitor of dihydrofolate reductase. The Ki,slope for inhibition of the human enzyme was 4 X 10(-11) M. A dose-dependent decrease in cellular purine ribonucleotide pools is given by trimetrexate. Pyrimidine ribonucleotide pools tend to increase in treated cells. Trimetrexate caused a marked depression of cellular pools of dTTP and dGTP, and a lesser depression in dATP. Cytotoxicity of trimetrexate in vitro was prevented by leucovorin. Leucovorin also protected mice from trimetrexate toxicity. Thymidine protected cells from lethal effects of low concentrations of trimetrexate, but not from high concentrations. The combination of thymidine and hypoxanthine completely protected cells from low and high concentrations of trimetrexate. A new, stable and highly water-soluble formulation of trimetrexate has been developed. Because of the interesting biochemical and pharmacological properties of trimetrexate, and its experimental antitumor activity, clinical trials are planned.

OBJECTIVE

This phase I study was designed to determine the optimally tolerated regimen (OTR), safety, and clinical activity of lapatinib in combination with FOLFOX4 [oxaliplatin/leucovorin/5-fluorouracil (5-FU)] in patients with solid tumors. Furthermore, the pharmacokinetics of lapatinib, oxaliplatin, and 5-FU when given alone and in combination were evaluated.

METHODS

This study was conducted in two parts. Part 1 was designed to determine the OTR and part 2 was the pharmacokinetic part of the study. Lapatinib was administered once daily for the entire duration of the study. Leucovorin and oxaliplatin were given concurrently over 2 h as an i.v. infusion, after which 5-FU was given as a bolus followed by continuous infusion over 22 h on day 1. 5-FU and leucovorin administration were repeated in an identical manner on day 2. Cycles were repeated every 2 weeks. Once the OTR was determined, it was to become the dose level for patients included in the pharmacokinetic part of the study.

RESULTS

A total of 34 patients was treated in this study. No dose-limiting toxicities were observed and the OTR was established at 1,500 mg/d lapatinib in combination with the standard FOLFOX4 regimen. Nonhematologic toxicities consisted mainly of nausea, diarrhea, vomiting, fatigue, neuropathy, and mucositis. The most important hematologic toxicity was neutropenia. No drug-drug interactions between lapatinib and the FOLFOX4 regimen were observed.

CONCLUSIONS

Lapatinib can be safely administered in combination with the standard FOLFOX4 regimen. Further studies are warranted to explore the potential additive antitumor effect of lapatinib in combination with the FOLFOX4 regimen.

BACKGROUND

Oxaliplatin stop and go in combination with leucovorin and 5-fluorouracil has been successfully used in a previous study (OPTIMOX1) in metastatic colorectal cancer (MCR). Celecoxib is an anti-cyclooxygenase-2 drug with anti-neoplastic properties. In the present study, celecoxib was evaluated in combination with FOLFOX7 regimen and as a single agent in maintenance therapy.

METHODS

This phase II study examined for previously untreated MCR patients the stop-and-go procedure [six cycles of folinic acid, 5FU and oxaliplatin (FOLFOX7) followed by chemotherapy-free intervals (CFIs) and reintroduction at progression] with continuous administration of celecoxib (800 mg/day).

RESULTS

Forty-four patients were included, 42 eligible: performance status (%) 0/1/2=45/40/15, median age 60 (31-76) years. Response rate (RR) was 43% (95% CI 28%-58%). Median progression-free survival (PFS) was 6 months; median overall survival was 15.8 months. Grade 3/4 toxicity criteria were neurotoxicity 9.5%, thrombocytopenia 21.4%, neutropenia 7.1%, diarrhea 7.1%, nausea 4.8% and vomiting 2.4%. Median CFI 1 (n=27) duration was 3.9 months (range 2-39 months).

CONCLUSIONS

With an acceptable safety profile, celecoxib combined with FOLFOX7 achieved RR and PFS in the lower range of that obtained with FOLFOX7 alone. These results indicate the lack of synergy between FOLFOX7 and celecoxib. PFS of 6 months appears lower than PFS obtained in OPTIMOX1 study with simplified LV5FU2 in maintenance therapy.

OBJECTIVE

To determine the incidence of new chorioretinal lesions in patients with congenital toxoplasmosis who were treated throughout their first year of life.

METHODS

Prospective longitudinal observation of a cohort.

METHODS

One hundred thirty-two children were studied as part of the longitudinal observation.

METHODS

One hundred thirty-two children were treated during their first year of life with pyrimethamine, sulfadiazine, and leucovorin. They had eye examinations at prespecified intervals.

METHODS

New chorioretinal lesions on fundus examination and fundus photographs.

RESULTS

The mean age (+/- standard deviation) is 10.8+/-5.1 years (range, 0.2-23). One hundred eight children have been evaluated for new chorioretinal lesions. Thirty-four (31%; 95% confidence interval, 23%-41%) of 108 children developed at least one chorioretinal lesion that was previously undetected. These occurred at varying times during their follow-up course. Fifteen children (14%) developed new central lesions, and 27 (25%) had newly detected lesions peripherally. Ten (9%) had more than one occurrence of new lesions developing, and 13 (12%) had new lesions in both eyes. Of those who developed new lesions, 14 children (41%) did so at age 10 or later.

CONCLUSIONS

New central chorioretinal lesions are uncommon in children with congenital toxoplasmosis who are treated during their first year of life. This finding contrasts markedly with earlier reports in the literature for untreated children or those treated for only 1 month near birth, in whom new lesions were much more prevalent >>/=82%). Our observation that 14 (41%) of the 34 children with new chorioretinal lesions had occurrences when they were 10 years or older indicates that long-term follow-up into the second decade of life is important in assessing the efficacy of treating toxoplasmosis during infancy.

Information concerning the pulmonary toxicity of oxaliplatin with infusional 5-fluorouracil plus leucovorin (FOLFOX) is very limited. We herein report the case of a patient with FOLFOX-induced interstitial pneumonia. An 82-year-old man with unresectable colon cancer liver metastases was referred to our department for chemotherapy with the FOLFOX protocol. After the administration of ten cycles, he visited our outpatient clinic with a 2-week history of coughing and shortness of breath; he was afebrile. A chest radiograph showed reticular shadows with ground-glass opacities mainly involving the middle and lower zones of the right lung. Computed tomography depicted ground-glass opacities with superimposed reticulation in the right lung. A diagnosis of FOLFOX-induced interstitial pneumonia was made based on the clinical course and imaging findings. The symptoms disappeared within 3 days after the cessation of the FOLFOX regimen and the initiation of high-dose corticosteroid treatment. Two months after the initiation of the corticosteroid treatment, complete remission of the radiological abnormalities was confirmed; thereafter, interstitial pneumonia did not recur despite the reintroduction of 5-fluorouracil/leucovorin alone, suggesting that 5-fluorouracil/leucovorin alone was not responsible for the development of the interstitial pneumonia. Thus, oxaliplatin, alone or in combination with 5-fluorouracil/leucovorin, may have caused the interstitial pneumonia in this patient. Once interstitial pneumonia has occurred, cessation of the regimen is mandatory, and high-dose corticosteroid treatment is commonly given to rescue patients from this potentially lethal complication.

Primary effusion lymphoma (PEL) is a rare KSHV/HHV8-associated high-grade non-Hodgkin's lymphoma (NHL) of B-cell origin, characterized by serous effusions in body cavities. Most patients are HIV-infected homosexual men with severe immunosuppression and other KSHV/HHV8-associated diseases such as Kaposi's sarcoma (KS). The prognosis is poor with a median survival of less than 6 months in most cohorts. The achievement of a sustained complete remission is rare. High-dose chemotherapy regimens are warranted to improve complete remission rate and survival. Seven patients with AIDS-associated PEL were treated with a combined chemotherapy including high-dose methotrexate followed by leucovorin rescue. In all cases, KSHV/HHV8 sequences were detected in the effusion samples using quantitative PCR assays. Five patients had a pre-existing KS, associated in three cases with multicentric Castleman's disease (MCD). Upon diagnosis, 6 patients received antiretroviral therapy, which was maintained during chemotherapy in 5 of them. At time of analysis, 3 out of 7 patients were in complete remission 18, 26, and 78 months after PEL diagnosis. Three patients died with a progressive PEL at 22, 67, and 153 days after diagnosis, and 1 patient died 9 months after PEL diagnosis with a MCD-associated plasmablastic NHL. Complete remission was obtained in 3 out of 7 patients treated for AIDS-associated PEL with combined chemotherapy containing high-dose methotrexate.

Good progress has been made to modernize traditional Chinese medicines by obtaining active components from natural herbs. In this review, some recent works on procuring active components and modernizing traditional Chinese medicines will be covered. In addition, some recent works on drug design using modern drug design tools have been described. With some well defined targets, the traditional Chinese medicine databases have been screened so as to identify those compounds for which the potential as a drug candidate was not known before. Among these studies, two have been selected as examples to be discussed in details. First, new anti-HIV candidates have been detected, namely leucovorin and agaritine derivatives. Subsequently, GTS-21 is proved to be a good candidate for Alzheimer's disease. All these findings may provide useful information for finding effective drug candidates with lower cost.

BACKGROUND

Taurolidine (TRD) is a novel agent with multimodal antineoplastic effects. We present the case of a tumor remission after intravenous administration of taurolidine in a patient with gastric cancer re-recurrence.

METHODS

A 58 years old male patient suffering from a gastric adenocarcinoma was submitted to partial gastrectomy and partial liver resection (pT2, pN1, pM1L (liver segment 2), N0, V0). 24 months later a local recurrence was diagnosed and the patient was reoperated. Postoperatively the patient underwent a palliative chemotherapy with eloxatin, FU, and leucovorin. A subsequent CT-revealed a liver metastasis and a recurrence adjacent to the hepatic artery. After successful radiofrequency ablation of the liver metastasis the patient was intravenously treated with 2% taurolidine. The patient endured the therapy well and no toxicity was observed. CT-scans revealed a stable disease without a tumor progression or metastatic spread. After 39 cycles the patient was submitted to left nephrectomy due to primary urothelial carcinoma and died 2 days later due to myocardial infarction. Postmortem histology of the esophageal-jejunal anastomosis and liver revealed complete remission of the known metastasized gastric adenocarcinoma.

CONCLUSIONS

The intravenous treatment with 2% taurolidine led to a histological remission of the tumor growth without any toxicity for the patient.

Two of the most promising new targets in the treatment of colorectal cancer are the epithelial growth factor receptor (EGFR) and the vascular endothelial growth factor (VEGF). Agents that inhibit the EGFR or bind to VEGF have demonstrated clinical activity as single agents and in combination with chemotherapy in phase II and phase III clinical trials. The most promising of these agents are cetuximab, which blocks the binding of EGF and transforming growth factor alpha (TGF-alpha) to EGFR, and bevacizumab, which binds free VEGF. Cetuximab and irinotecan have been evaluated in two clinical studies in the USA (IMCL CP02-0141 and IMCL CP02-9923). Study IMCL CP02-0141 evaluated the antitumor activity of single-agent cetuximab in patients with irinotecan-refractory, EGFR-positive metastatic colorectal carcinoma. There were 6 partial responses in 57 treated patients, for a response rate of 10.5%. Study IMCL CP02-9923 evaluated the combination of cetuximab and irinotecan in a total of 139 patients enrolled at 27 study sites. In this trial 22.5% of patients with progressive disease on irinotecan achieved an objective response (19% by investigator assessment) showing that the combination of cetuximab and irinotecan has antitumor activity in this population. A large randomized phase II trial evaluating similar study populations in Europe confirmed these findings, demonstrating response rates for cetuximab/irinotecan and cetuximab alone of 22.9% and 10.8%, respectively. The other promising agent bevacizumab is a humanized variant of the anti-VEGF monoclonal antibody. VEGF is produced by healthy and neoplastic cells. Its activities are mediated by two receptor tyrosine kinases. VEGF signaling is often a rate-limiting step in physiologic and pathologic angiogenesis. Bevacizumab has been studied as an antiangiogenic cancer therapeutic as a single agent and in combination with chemotherapy in patients with stage III and IV colon cancer. In addition to its direct antiangiogenic effects, bevacizumab may allow more efficient delivery of chemotherapy by altering tumor vasculature and decreasing the elevated interstitial pressure common in tumors. In this regard, some of the most robust phase II data using bevacizumab are from a randomized study of chemotherapy [fluorouracil (5-FU) and leucovorin (LV)] with or without bevacizumab in metastatic colorectal cancer. In this study, treatment with bevacizumab plus 5-FU/LV resulted in higher response rates, longer median time to disease progression, and longer median survival. Recently, a phase III, multicenter, double-blind, randomized, placebo-controlled trial was designed to investigate the addition of bevacizumab to first-line irinotecan, 5-FU, and LV chemotherapy (IFL). The trial showed a higher response rate, longer time to tumor progression, and prolonged overall survival in patients with metastatic colorectal cancer. It was the first large, randomized, phase III survival trial to assess the importance of targeting VEGF and tumor angiogenesis for the treatment of human cancer. Integration of novel agents targeting VEGF and EGFR with irinotecan-based chemotherapy has shown clinical activity in patients with metastatic colorectal cancer. The goal in the future will be to predict which specific chemotherapy and targeted agent combination will most likely benefit individual patients.

BACKGROUND

Previous studies have shown that the taxane, docetaxel, is effective in treating gastric cancer. The aim of this study was to assess the efficacy and safety of docetaxel in combination with 5-fluorouracil (5-FU) and leucovorin (LV).

METHODS

Thirty patients with histologically proven locally advanced and/or metastatic gastric cancer with WHO performance status 0-2 were enrolled and received either 75 or 100 mg/m(2) docetaxel as a 1-h intravenous infusion on day 1 every 28 days. All patients also received 5-FU (1800 mg/m(2)) plus LV (500 mg/m(2)), by continuous intravenous infusion over 24 h on days 1, 8, and 15 every 28 days. Chemotherapy was given for at least two cycles.

RESULTS

Of the 25 evaluable patients, 3 showed a complete response, 4 showed a partial response, and 11 patients had stable disease. The overall response rate was 28.0% (95% confidence interval [CI], 10.4, 45.6). The median time to progression was 5.9 months (95% CI, 5.4, 6.5), and the median overall survival was 7.7 months (95% CI, 7.2, 8.3) for the intent-to-treat population. The most frequent grade III and IV hematological toxicities were neutropenia and anemia. Febrile neutropenia was observed in 10% of patients and 2.4% of cycles. The prophylactic use of granulocyte colony-stimulating factor (G-CSF) in 3 patients reduced the incidence and severity of neutropenia. Other hematological toxicities were rare.

CONCLUSIONS

Docetaxel in combination with weekly 5-FU and LV is effective in treating patients with advanced/metastatic gastric cancer. This new docetaxel-containing combination shows promise as a third-generation treatment option for gastric cancer.

OBJECTIVE

The primary outcome was sphincter preservation. No benefit was found with chemoradiation. The aim of this report is to analyse postoperative complications, which were the secondary outcome.

METHODS

Patients with resectable T3-4 low rectal carcinoma were randomised to receive either pre-operative 5 x 5 Gy irradiation with subsequent total mesorectal excision (TME) performed within 7 days or chemoradiation (50.4 Gy, 1.8 Gy per fraction plus bolus 5-fluorouracil and leucovorin) followed by TME after 4-6 weeks.

RESULTS

Three hundred and five patients (153 in 5 x 5 Gy group and 152 in chemoradiation group) were analysed. The rates of patients with postoperative complications for the 5 x 5 Gy group and for the chemoradiation group were 27 vs 21%, respectively (P = 0.27). If the values were expressed in terms of number of complications, the rates were 31 vs 22%, respectively (P = 0.06). The corresponding values for severe complications were 10 vs 11% (P = 0.85) of patients with complications and 12 vs 11% (P = 0.85) of events.

CONCLUSIONS

The study did not demonstrate a statistically significant difference in the rate of postoperative complications after short-course pre-operative radiotherapy compared with full course chemoradiation.

OBJECTIVE

Early intensification with methotrexate (MTX) is a key component of acute lymphoblastic leukemia (ALL) therapy. Two different approaches to MTX intensification exist but had not been compared in T-cell ALL (T-ALL): the Children's Oncology Group (COG) escalating dose intravenous MTX without leucovorin rescue plus pegaspargase escalating dose, Capizzi-style, intravenous MTX (C-MTX) regimen and the Berlin-Frankfurt-Muenster (BFM) high-dose intravenous MTX (HDMTX) plus leucovorin rescue regimen.

METHODS

COG AALL0434 included a 2 × 2 randomization that compared the COG-augmented BFM (ABFM) regimen with either C-MTX or HDMTX during the 8-week interim maintenance phase. All patients with T-ALL, except for those with low-risk features, received prophylactic (12 Gy) or therapeutic (18 Gy for CNS3) cranial irradiation during either the consolidation (C-MTX; second month of therapy) or delayed intensification (HDMTX; seventh month of therapy) phase.

RESULTS

AALL0434 accrued 1,895 patients from 2007 to 2014. The 5-year event-free survival and overall survival rates for all eligible, evaluable patients with T-ALL were 83.8% (95% CI, 81.2% to 86.4%) and 89.5% (95% CI, 87.4% to 91.7%), respectively. The 1,031 patients with T-ALL but without CNS3 disease or testicular leukemia were randomly assigned to receive ABFM with C-MTX (n = 519) or HDMTX (n = 512). The estimated 5-year disease-free survival ( P = .005) and overall survival ( P = .04) rates were 91.5% (95% CI, 88.1% to 94.8%) and 93.7% (95% CI, 90.8% to 96.6%) for C-MTX and 85.3% (95% CI, 81.0%-89.5%) and 89.4% (95% CI, 85.7%-93.2%) for HDMTX. Patients assigned to C-MTX had 32 relapses, six with CNS involvement, whereas those assigned to HDMTX had 59 relapses, 23 with CNS involvement.

CONCLUSIONS

AALL0434 established that ABFM with C-MTX was superior to ABFM plus HDMTX for T-ALL in approximately 90% of patients who received CRT, with later timing for those receiving HDMTX.

BACKGROUND

Inactivation of the p53 gene has been reported to be associated with resistance to chemotherapy. The authors evaluated the significance of p53 status to the clinical outcomes of patients with locally advanced, unresectable gastric carcinoma (LAGC) who received chemotherapy.

METHODS

Thirty chemotherapy-naive patients with LAGC received weekly administration of cisplatin 40 mg/m2, epi-doxorubicin 35 mg/m2, 5-fluorouracil 500 mg/m2, 6S-leucovorin 250 mg/m2, and glutathione 1500 mg/m2. After eight administrations of these agents, patients were assessed for response. Biopsy specimens of primary tumors were analyzed for p53 status using monoclonal antibody Bp53-12.

RESULTS

Characteristics of patients were as follows: The median age was 66 years (range, 44-70 years); 18 were males and 12 were females. Eastern Cooperative Oncology Group performance status was 0 for 14 patients and 1 for 16. Histology was intestinal for 13 patients; for 17, it was diffuse. The site of the primary tumor was the cardia in 8 patients, the body of the stomach in 13, and the antrum in 9. The response rate (assessed with CT scan and endoscopy) for patients with p53 negative tumors was significantly higher than for those with overexpression of p53 (71% vs. 12%, P=0.004).

CONCLUSIONS

p53 status analyzed before chemotherapy seems to be associated with response to treatment in patients with LAGC. This may provide a useful guide to selecting neoadjuvant chemotherapy for these patients.

OBJECTIVE

The treatment of gastric cancer has been rapidly evolving with the emergence of new cytotoxic drugs and targeted biologic agents. The purpose of this review is to provide an update in the treatment of localized and metastatic gastric cancer.

RESULTS

Although the overall incidence of gastric cancer has been declining in the United States, the disease continues to be a devastating problem worldwide. Complete surgical resection offers the chance of cure for localized gastric cancer. However, local and distant recurrences are common. Adjuvant chemoradiation with 5-fluorouracil/leucovorin significantly improves disease-free survival and overall survival as demonstrated by the US Intergroup INT-116 study. Most recently, the UK Medical Research Council Adjuvant Gastric trial showed survival benefit with perioperative chemotherapy. Preoperative chemotherapy and chemoradiation have also been explored in several small randomized studies with encouraging results. However, this approach needs to be further confirmed in a large randomized phase III study. Finally, novel molecular targeting agents have been incorporated into the multimodality treatment and shown promising response rate and progression-free survival.

CONCLUSIONS

Gastric cancer remains one of the most clinically challenging cancers among all gastrointestinal malignancies. Mutimodality approach clearly offers survival benefit over surgery alone. In the United States, preoperative chemoradiation or postoperative adjuvant chemoradiation is widely practiced in major centers.

OBJECTIVE

To investigate mechanism-directed regimens in maximizing the efficacy of fluorouracil (5-FU) in advanced colorected cancer.

METHODS

Based on promising phase II data, a randomized comparison of various methods for the biochemical modulation of 5-FU was undertaken in patients with advanced colorectal cancer. The control group received single-agent 5-FU as a 24-hour infusion weekly. Patients (N = 1,120) with no prior chemotherapy for metastatic disease were randomized to one of the following arms: arm A, 5-FU 2,600 mg/m2 by 24-hour infusion, weekly; arm B, N-phosphonoacetyl-l-aspartic acid 250 mg/m2 day l, 5-FU 2,600 mg/m2 by 24-hour infusion day 2, weekly; arm C, 5-FU 600 mg/m2 with oral leucovorin (LV) 125 mg/m2 hourly for the preceding 4 hours, weekly; arm D, 5-FU 600 mg/m2 with intravenous (IV) LV 600 mg/m2, weekly; arm E, 5-FU 750 mg/m2/d IV by continuous infusion for 5 days, then 750 mg/m2 weekly, and recombinant interferon alfa-2a 9 million units subcutaneously three times weekly. Median follow-up was 4.8 years.

RESULTS

Of the 1,098 assessable patients, 57% had measurable disease. The toxicity of all the regimens was tolerable. Grade 4 or worse toxicity occurred in 11%, 11%, 30%, 24%, and 22% on each arm, respectively; diarrhea was the most common adverse effect. These toxicity patterns favored significantly (P <.001) the 24-hour infusion arms. Median survival (months) by arm was A, 14.8; B, 11.9; C, 13.5; D, 13.6; and E, 15.2. These survival durations did not differ significantly.

CONCLUSIONS

We conclude that a weekly infusion regimen of 5-FU is significantly less toxic than and as effective as 5-FU bolus regimens modulated by either LV or interferon in patients with metastatic colorectal cancer.

OBJECTIVE

Ethnic diversity of genetic polymorphism can result in individual differences in the efficacy and toxicity of cancer chemotherapy.

METHODS

We analyzed 20 germline polymorphisms in 10 genes (TS, MTHFR, ERCC1, XPD, XRCC1, ABCC2, AGXT, GSTP1, GSTT1 and GSTM1) from prospectively enrolled 292 Korean patients treated with adjuvant oxaliplatin plus leucovorin plus 5-fluorouracil (FOLFOX) for colon cancer.

RESULTS

In contrast to previous studies in Caucasians, neutropenia (grade 3-4, 60.5 %) was frequently observed, whereas only 16.4 % experienced grade 2 or more sensory neuropathy. Neutropenia was more frequent in MTHFR 677TT [adjusted odds ratio (OR) 2.32, 95 % confidence interval (CI) 1.19-4.55] and ERCC1 19007TT (adjusted OR 4.58, 95 % CI 1.20-17.40) genotypes. Patients harboring XRCC1 23885GG experienced less grade 2-4 neuropathy [adjusted OR 0.52, 95 % CI 0.27-0.99]. MTHFR 677TT (p = 0.002) and XRCC1 23885GG (p = 0.146) genotypes were also more prevalent in Koreans compared to Caucasians. TS 'low' genotype (adjusted HR 1.83, 95 % CI 1.003-3.34) was significantly related to shorter disease-free survival. Overall survival was not significantly different according to the polymorphisms.

CONCLUSIONS

Polymorphisms in MTHFR, XRCC1 and TS are related to toxicities and disease-free survival in patients with colon cancer. The ethnic differences in frequencies of genotypes may explain the ethnic difference in toxicity profile following adjuvant FOLFOX chemotherapy.

OBJECTIVE

The rationale for using adjuvant chemotherapy in colorectal cancer is to achieve better disease control and thus reduce the high rates of tumor recurrence and mortality in patients who undergo curative surgery. The current literature, including relevant abstracts, on clinical trials of fluorouracil (5-FU) in combination with high-dose leucovorin as adjuvant chemotherapy for colorectal cancer is reviewed. The intent is not to present new data, but to present the reader with a broad perspective and larger patient experience on which to base well-reasoned treatment decisions.

METHODS

Published clinical trials and abstracts presented at the 1996 American Society of Clinical Oncology (ASCO) meeting that assessed 5-FU in combination with high-dose leucovorin as adjuvant chemotherapy for colorectal cancer were surveyed. End points of interest were disease-free survival (DFS), overall survival, and toxicity.

RESULTS

In randomized trials that used high-dose leucovorin at doses that ranged from daily-times-five 200 mg/m2 to weekly 500 mg/m2 in combination with 5-FU, significant improvements in both DFS and overall survival were observed over surgery alone (control). In patients treated with high-dose leucovorin/5-FU, DFS rates ranged from 71% to 77% compared with control (58% to 64%). A similar trend was seen in overall survival, with a range of 75% to 84% compared with control (63% to 77%). Toxicities observed for high-dose leucovorin administered on a weekly or daily-times-five schedule were diarrhea, stomatitis, myelosuppression, and nausea.

CONCLUSIONS

Overall, the results of these randomized trials support the use of high-dose leucovorin/5-FU as adjuvant therapy for colorectal cancer. Longer follow-up studies are needed to compare the benefits of these different regimens in terms of survival and to characterize adverse effects, especially those that may not be immediately evident. Adjuvant therapy with high-dose leucovorin/5-FU is an effective regimen that is well tolerated by many patients with colorectal cancer.

BACKGROUND

Somatic mutations in PIK3CA (phosphatidylinositol-4,5-bisphosphonate 3-kinase [PI3K], catalytic subunit alpha gene) activate the PI3K-AKT signaling pathway and contribute to pathogenesis of various malignancies, including colorectal cancer.

METHODS

We examined associations of PIK3CA oncogene mutation with relapse, survival, and treatment efficacy in 627 stage III colon carcinoma case subjects within a randomized adjuvant chemotherapy trial (5-fluorouracil and leucovorin [FU/LV] vs irinotecan [CPT11], fluorouracil and leucovorin [IFL]; Cancer and Leukemia Group B 89803 [Alliance]). We detected PIK3CA mutation in exons 9 and 20 by polymerase chain reaction and pyrosequencing. Cox proportional hazards model was used to assess prognostic and predictive role of PIK3CA mutation, adjusting for clinical features and status of routine standard molecular pathology features, including KRAS and BRAF mutations and microsatellite instability (mismatch repair deficiency). All statistical tests were two-sided.

RESULTS

Compared with PIK3CA wild-type cases, overall status of PIK3CA mutation positivity or the presence of PIK3CA mutation in either exon 9 or 20 alone was not statistically significantly associated with recurrence-free, disease-free, or overall survival (log-rank P>> .70; P>> .40 in multivariable regression models). There was no statistically significant interaction between PIK3CA and KRAS (or BRAF) mutation status in survival analysis (P(interaction)>> .18). PIK3CA mutation status did not appear to predict better or worse response to IFL therapy compared with FU/LV therapy (P(interaction)>> .16).

CONCLUSIONS

Overall tumor PIK3CA mutation status is not associated with stage III colon cancer prognosis. PIK3CA mutation does not appear to serve as a predictive tumor molecular biomarker for response to irinotecan-based adjuvant chemotherapy.

BACKGROUND

The high recurrence rate after surgery for colorectal cancer liver metastasis (CLM) remains a crucial problem. The aim of this trial was to evaluate the efficacy of adjuvant therapy with uracil-tegafur and leucovorin (UFT/LV).

METHODS

In the multicenter, open-label, phase III trial, patients undergoing curative resection of CLM were randomly assigned in a 1:1 ratio to either the UFT/LV group or surgery alone group. The UFT/LV group orally received 5 cycles of adjuvant UFT/LV (UFT 300mg/m2 and LV 75mg/day for 28 days followed by a 7-day rest per cycle). The primary endpoint was recurrence-free survival (RFS). Secondary endpoints included overall survival (OS).

RESULTS

Between February 2004 and December 2010, 180 patients (90 in each group) were enrolled into the study. Of these, 3 patients (2 in the UFT/LV group and 1 in the surgery alone group) were excluded from the efficacy analysis. Median follow-up was 4.76 (range, 0.15-9.84) years. The RFS rate at 3 years was higher in the UFT/LV group (38.6%, n = 88) than in the surgery alone group (32.3%, n = 89). The median RFS in the UFT/LV and surgery alone groups were 1.45 years and 0.70 years, respectively. UFT/LV significantly prolonged the RFS compared with surgery alone with the hazard ratio of 0.56 (95% confidence interval, 0.38-0.83; P = 0.003). The hazard ratio for death of the UFT/LV group against the surgery alone group was not significant (0.80; 95% confidence interval, 0.48-1.35; P = 0.409).

CONCLUSIONS

Adjuvant therapy with UFT/LV effectively prolongs RFS after hepatic resection for CLM and can be recommended as an alternative choice.

BACKGROUND

UMIN Clinical Trials Registry C000000013.

BACKGROUND

This study evaluated the effectiveness and safety of preoperative chemoradiotherapy with capecitabine in patients with locally advanced resectable rectal cancer. This report summarizes the results of the phase II study together with long-term (5-year) follow-up.

METHODS

Between June 2004 and January 2005, 57 patients with operable, clinical stage II-III adenocarcinoma of the rectum entered the study. Radiation dose was 45 Gy delivered as 25 fractions of 1.8 Gy. Concurrent chemotherapy with oral capecitabine 825 mg/m² twice daily was administered during radiotherapy and at weekends. Surgery was scheduled 6 weeks after the completion of the chemoradiotherapy. Patients received four cycles of postoperative chemotherapy comprising either capecitabine 1250 mg/m² bid days 1-14 every 3 weeks or bolus i.v. 5-fluorouracil 425 mg/m²/day and leucovorin 20 mg/m²/day days 1-5 every 4 weeks (choice was at the oncologist's discretion). Study endpoints included complete pathological remission, proportion of R0 resections and sphincter-sparing procedures, toxicity, survival parameters and long-term (5-year) rectal and urogenital morbidity assessment.

RESULTS

One patient died after receiving 27 Gy because of a pulmonary embolism. Fifty-six patients completed radiochemotherapy and had surgery. Median follow-up time was 62 months. No patients were lost to follow-up. R0 resection was achieved in 55 patients. A complete pathological response was observed in 5 patients (9.1%); T-, N- and overall downstaging rates were 40%, 52.9% and 49.1%, respectively. The 5-year overall survival rate, recurrence-free survival, and local control was 61.4% (95% CI: 48.9-73.9%), 52.4% (95% CI: 39.3-65.5%), and 87.4% (95% CI: 75.0-99.8%), respectively. In 5 patients local relapse has occurred; dissemination was observed in 19 patients and secondary malignancies have occurred in 2 patients. The most frequent side-effect of the preoperative combined therapy was dermatitis (grade 3 in 19 patients). The proportion of patients with severe late (SOMA grade 3 and 4) rectal, bladder and sexual toxicity was 40%, 19.2% and 51.7%, respectively.

CONCLUSIONS

This study confirms data from other non-randomised studies that capecitabine-based preoperative chemoradiation is a feasible treatment option for locally advanced rectal cancer, with positive 5-year overall survival, recurrence-free survival, and local control rates.

BACKGROUND

Our current protocol for treatment of childhood acute lymphoblastic leukemia (ALL) was designed to assess the efficacy of methotrexate (MTX) plus L-asparaginase and of etopisode (VP-16) plus cytarabine (ARA-C) during intensive consolidation and continuation therapies and to determine the feasibility of intensifying MTX therapy by the use of divided oral doses of MTX. The protocol was associated with unexpected acute neurotoxicity. There are few reports of such toxic effects during therapy for ALL.

OBJECTIVE

This report describes these toxic effects and outlines our successful approach to the problem.

METHODS

The standard four-drug induction regimen consisted of vincristine, L-asparaginase, daunorubicin, and prednisone. In consolidation therapy, oral MTX was given in divided doses (dMTX) of 25 mg/m2 every 6 hours four times daily in four weekly courses concomitant with weekly triple intrathecal therapy--MTX, ARA-C, and hydrocortisone--plus one dose of leucovorin 24 hours after triple intrathecal therapy. Consolidation treatment ended with three daily doses of intravenous VP-16 and ARA-C. The first 16 months of continuation therapy included 6-week cycles of dMTX and L-asparaginase, both given every other week for 5 weeks, with 6-mercaptopurine nightly, and then two doses of VP-16 plus ARA-C and one dose of triple intrathecal therapy.

RESULTS

Twenty-five of the 138 patients evaluated had acute neurotoxicity. Ten of the first 72 experienced a seizure or episode of transient neurological deficit 9-11 days following the administration of intravenous ARA-C, VP-16, and triple intrathecal therapy. Despite discontinuation of intrathecal ARA-C, which eliminated simultaneous intravenous and intrathecal treatment with ARA-C, acute neurotoxicity was observed in six previously unaffected patients and six of 42 patients treated after the elimination of intrathecal ARA-C. Therefore, as a second amendment, oral leucovorin was given 24 and 36 hours after dMTX and intrathecal MTX in continuation therapy. No acute neurotoxicity has been seen in 24 patients subsequently entered in the study.

CONCLUSIONS

These findings suggest that folate replacement due to administration of leucovorin modulated MTX toxicity and/or modified an interaction among VP-16, ARA-C, intrathecal therapy, and the central nervous system.

Chemotherapy for treatment of osteosarcoma was demonstrated to be effective in eradicating primary tumor and pulmonary metastases in the mid-twentieth century. The first agents that held promise were doxorubicin and high-dose methotrexate with leucovorin (citrovorin factor) in the mid-1970s. Since then, other agents that can eliminate or cause regression of tumor have been discovered: cis-diamminedichloroplatinum II (cisplatin) and the oxazaphosphorines ifosfamide and cyclophosphamide. Additional agents await further study to define their potential. The effective agents have been utilized in various combination regimens and have escalated the survival rate from <10 to 75 %. They have also enabled pulmonary metastectomy in patients with persistent and/or recurrent pulmonary metastases and tumor ablation and limb salvage in 80 % of newly diagnosed patients. Unfortunately, however, despite these impressive advances no change in survival expectancy of patients with osteosarcoma during the past 40 years has occurred. There have been no new chemotherapeutic agents effective in addressing disease that is resistant to current agents; the few that have been introduced await further study to substantiate their efficacy. This also includes attempts at alternate administration of chemotherapy (intra-arterial and inhalation therapy.) In this chapter, we provide an account of the sequential introduction of the chemotherapeutic agents, review the results of their application in selected regimens, and discuss the role of neoadjuvant chemotherapy.

Bevacizumab is an anti-VEGF human monoclonal antibody suitable for chemotherapy for patients with metastatic colorectal cancer (mCRC). This study investigated the efficacy and safety of using bevacizumab plus irinotecan, 5-fluorouracil, and leucovorin (FOLFIRI) as second-line chemotherapy option for patients with mCRC in China. Patients with mCRC, who had been previously treated with oxaliplatin-based chemotherapy, but not bevacizumab, were randomly assigned to two groups to receive bevacizumab plus FOLFIRI (FOLFIRI-B) or FOLFIRI alone. In FOLFIRI-B group, patients were given 10 mg/kg bevacizumab plus FOLFIRI every 2 weeks. The primary endpoints were response rates and survival rates. Between June 2010 and May 2014, 65 patients were assigned to FOLFIRI-B group and 77 to FOLFIRI alone group. The median progression-free survivals were 8.5 months (95 % CI 5.8-10.5 months) for FOLFIRI-B and 5.1 months (95 % CI 2.7-9.8 months) for FOLFIRI alone; median overall survivals were 15.2 months (95 % CI 11.8-19.4 months) for FOLFIRI-B and 11.3 months (95 % CI 6.7-16.5 months) for FOLFIRI alone. Incidence rates of grade 3 and 4 adverse events were observed and comparable between FOLFIRI-B and FOLFIRI alone groups. Chinese patients with mCRC treated with second-line chemotherapy of FOLFIRI-B had better survivals than those patients treated with FOLFIRI alone.

OBJECTIVE

To investigate the sequence effect of irinotecan and a 48-hour infusion of fluorouracil (5-FU) modulated by leucovorin (LV) on the plasma pharmacokinetics of irinotecan and its metabolites, the toxicity profile of this combination, and irinotecan's maximum-tolerated dose (MTD).

METHODS

Thirty-three metastatic colorectal cancer patients were randomized to receive a 60-minute infusion of irinotecan before or after a 48-hour infusion of 5-FU modulated by LV. The reverse sequence was used after 21 days for the second cycle. 5-FU 3,500 mg/m2 was preceded by l-LV 250 mg/m2. Irinotecan 150 mg/m2 (starting dose) was administered to the first three patients. The dose was escalated by 50 mg/m2 in subsequent groups of three to six patients to determine the MTD for both sequences. Pharmacokinetic analysis of irinotecan and its metabolites was performed after each cycle.

RESULTS

Toxicities were affected by the sequence of administration of irinotecan and 5-FU, with an improved tolerability for irinotecan followed by 5-FU. The irinotecan MTD was reached at 300 mg/m2 when irinotecan followed 5-FU and at 450 mg/m2 when it preceded 5-FU. In seven of 23 patients who received both sequences at identical irinotecan doses, the dose-limiting toxicity was observed only when irinotecan followed 5-FU. Pharmacokinetic analysis revealed that the administration sequence significantly affected the SN-38 area under the concentration-versus-time curve (AUC), which was 40.1% lower (P <.05) when irinotecan preceded 5-FU.

CONCLUSIONS

The sequence of treatment with irinotecan and infusional 5-FU affects the tolerability of this combination. This can be explained in part by a reduced SN-38 AUC when irinotecan preceded infusional 5-FU. Well-defined 5-FU/irinotecan regimens are needed because the administration sequence or the interval between the agents might affect treatment tolerance and perhaps also activity.