Aspirin, one of the most widely used drugs in the world, consistently produces gastric mucosal injury, but the pathogenic mechanisms are incompletely understood. The present study was designed to determine the role of neutrophils in aspirin-induced acute gastric mucosal injury. Gastric mucosal lesions induced by acidified aspirin (300 mg/kg) were completely prevented in rats that had been rendered profoundly neutropenic by anti-neutrophil serum. Aspirin-induced acute gastric mucosal lesions were also significantly, albeit incompletely, reduced in rats that had been rendered moderately neutropenic by methotrexate. Moreover, in the methotrexate-induced neutropenia model, the neutropenia-associated mucosal protection against aspirin-induced injury could be reversed by leucovorin rescue. Aspirin caused a marked and statistically significant reduction in gastric mucosal 6-ketoprostaglandin F1 alpha synthesis, but no significant changes in gastric mucosal leukotriene synthesis. Thus no gastric mucosal lesions were observed in profoundly neutropenic rats that were treated with aspirin, despite the marked inhibition of prostaglandin synthesis. These findings demonstrate that aspirin-induced acute gastric mucosal injury is a neutrophil-dependent process.

The objectives of this study were to determine prognostic factors for response to treatment, freedom-from-relapse (FFR) survival, and overall survival of 737 aggressive malignant lymphoma patients treated with the doxorubicin, cyclophosphamide, vindesine, bleomycin, methylprednisolone, methotrexate with leucovorin, ifosfamide, etoposide, asparaginase, and cytarabine (LNH-84) regimen; to construct a prognostic index with factors isolated by multivariate analyses; and to validate this prognostic index with another set of patients. Complete response (CR) was reached in 75% of LNH-84 patients, and 30% of them relapsed. With a median follow-up of 36 months, median FFR survival and median overall survival were not reached. Low serum albumin level, high tumoral mass, weight loss, bone marrow involvement, greater than or equal to 2 extranodal sites, and increased lactic dehydrogenase (LDH) level were associated with a low response rate. Advanced stage, increased LDH level, and nonlarge-cell histologic subtypes (diffuse mixed, lymphoblastic, and small non-cleaved) were statistically associated with a high relapse rate and short FFR survival. Increased LDH level, low serum albumin level, tumoral mass larger than 10 cm, greater than or equal to 2 extranodal sites, advanced stage, and age older than 65 years were statistically associated with short overall survival. Four of these parameters, namely, LDH level, stage, number of extranodal sites, and tumoral mass, were put together to construct a prognostic index. This index partitioned LNH-84 patients into three subgroups of good, intermediate, and poor prognosis (P less than .00001): CR rates of 93%, 83%, and 61%; relapse rates of 12%, 25%, and 45%; 3-year FFR survival of 87%, 73%, and 53%, and 3-year survival of 88%, 71%, and 41%, respectively. This prognostic index was applied to a test set of patients: 155 patients treated on protocols of the Nebraska Lymphoma Study Group. Using this index, these patients had 3-year FFR survival of 70%, 40%, and 22% (P = .0002) and 3-year survival of 79%, 52%, and 31% (P = .005). In patients with aggressive lymphomas, this simple prognostic index could distinguish between patients requiring intensive treatment such as autologous bone marrow transplantation in first complete remission and those who could be treated with standard regimens.

OBJECTIVE

The present study was conducted to evaluate the efficacy and safety of the combination of Oxaliplatin, Leucovorin and 5-FU as second line therapy, following relapse to Gemcitabine, in patients with advanced adenocarcinoma of the pancreas.

METHODS

Patients with advanced pancreatic cancer previously treated with Gemcitabine were included in the study. All patients had histologically or cytologically confirmed adenocarcinoma of the pancreas that was unresectable, locally advanced or metastatic. Treatment consisted of Oxaliplatin 50 mg/m(2) (2-hour iv infusion), followed by Leucovorin 50 mg/m(2) (i.v. bolus) and 500 mg/m(2) 5-FU (1-hour iv infusion), administered weekly, until unacceptable toxicity or disease progression. Objective tumour response and toxicity were evaluated according to World Health Organisation (WHO) criteria.

RESULTS

A total of 30 patients, 20 men and 10 women, median age 63 years (range 52-71 years) and Karnofsky Performance Status (PS) of>> or =50 entered the study. The majority of patients (96%) had locally advanced disease. A total of 380 doses of chemotherapy were delivered, a median of 12 doses per patient. Partial responses were observed in 7 patients (PR 23.3%), stable disease in 9 (SD 30.0%), while 14 patients progressed (PD 46.7%). Improved PS was observed in 18 (42.8%) patients. Patients that had responded to first-line Gemcitabine treatment were found more likely to respond or stabilize their disease with second-line treatment. The median duration of response was 22 weeks, and median overall survival was 25 weeks, Grade 3/4 toxicity expressed per chemotherapy dose included leukopenia 16%, anemia 3.2%, thrombocytopenia 3.2%, diarrhea 14.2%, fatigue 16.1% and neurotoxicity 4.2%. Eight patients (27%) suffered a febrile neutropenic event managed successfully with oral antibiotic home therapy, while 17 patients required G-CSF support. There were no treatment related deaths.

CONCLUSIONS

The combination of Oxaliplatin, Leucovorin and 5-FU was tolerated with manageable toxicity, offering encouraging activity as second-line treatment of patients with advanced or metastatic pancreatic adenocarcinoma, previously treated with Gemcitabine. Additional studies are warranted with this regimen in Gemcitabine relapsed pancreatic cancer patients.

BACKGROUND

Recently, there has been considerable interest in neoadjuvant chemotherapy for colorectal liver metastases. However, there is little information that defines how much liver should be removed after a favorable response.

METHODS

Liver metastases from 2 groups of patients were analyzed: 25 metastases were evaluated from a group that did not receive chemotherapy and 26 lesions were studied from patients who had received systemic chemotherapy before resection. All patients except for 1 had 5-fluorouracil (5-FU), leucovorin (LV), and irinotecan (CPT-11); 1 had 5-FU and LV alone. The average duration of chemotherapy was 2.9+/-0.7 months. Separate assessments of the histopathologic features of the central and peripheral portions of each tumor were made. The pathologist was blinded to all clinical information.

RESULTS

All of the untreated metastases had well-circumscribed borders. Irregular borders were seen in 6 of the postchemotherapy lesions (26%), which was particularly prominent in lesions that had significantly contracted. After chemotherapy, discrete islands of viable tumor cells outside of the main tumor mass were seen in 4 patients, but all were close to the peripheral margin of the tumor mass. Viable tumor cells were more frequent in the periphery of metastases, regardless of chemotherapy exposure. Central necrosis was prominent in untreated metastases, but disappeared after chemotherapy. In lesions treated with chemotherapy, central fibrosis was greater compared with untreated lesions.

CONCLUSIONS

After a partial response to chemotherapy, liver metastases shrank in a generally concentric fashion. These findings support the practice of removing less liver after downsizing with chemotherapy.

OBJECTIVE

To study the impact of preoperative radiation dose escalation and postoperative adjuvant chemotherapy on the outcome of tethered and fixed rectal carcinoma.

METHODS

We have treated 156 patients with 3 consecutive preoperative chemoradiation protocols with escalating treatment intensity. Schedule 1 consisted of 40 Gy radiation with concurrent 5-fluorouracil (5-FU) infusion and mitomycin C. Schedule 2 used a sandwich design with preoperative (40 Gy) and postoperative (18 Gy) radiation with concomitant 5-FU infusion, leucovorin, and mitomycin C. In schedule 3, the preoperative radiation dose was increased to 50 Gy and adjuvant 5-FU/leucovorin chemotherapy was added following surgery. There were 54, 27, and 75 patients treated in schedules 1, 2, and 3, respectively.

RESULTS

The resectability was 91% for schedule 1 and 100% for both schedules 2 and 3. A dose-response relationship was observed between the radiation dose and the tumor downstaging and local control. The pathological complete response (T0N0M0) rates for schedules 1, 2, and 3 were 4%, 15%, and 25%, respectively. The respective rates of tumor downstaging were 41%, 33%, and 68%, respectively. The 5-year local relapse-free rates were 67% for schedule 1 (40 Gy), 96% for schedule 2 (58 Gy), and 92% for schedule 3 (50 Gy) (p = 0.0011). The addition of postoperative chemotherapy appeared to improve both the survival and the relapse-free survival. The 5-year survival was increased from 52% to 84% (p = 0.0004) and the 5-year progression-free survival was improved from 48% to 74% (p = 0.0008).

CONCLUSIONS

Preoperative 5-FU infusion, leucovorin, mitomycin C, and 50-Gy pelvic radiation, followed by postoperative bolus 5-FU/leucovorin chemotherapy, appeared to be an effective treatment for tethered/fixed rectal cancers. However, its therapeutic efficacy could only be validated in randomized studies.

Thymidylate synthase (TS) is a key enzyme in the synthesis of 2'-deoxythymidine-5'-monophosphate, an essential precursor for DNA biosynthesis. For this reason, this enzyme is a critical target in cancer chemotherapy. As the first TS inhibitor in clinical use, 5-fluorouracil (5-FU) remains widely used for the treatment of colorectal, pancreatic, breast, head and neck, gastric, and ovarian cancers. The reduced folate, leucovorin, has been shown to enhance the activity of 5-FU in colorectal cancer. However, response rates of the combination remain in the 25%-30% range, and much effort has been focused on designing new, more potent TS inhibitors. Raltitrexed is a folate analogue that is approved as first-line therapy for advanced colorectal cancer in Europe, Australia, Canada, and Japan, although it remains an investigational agent in the United States. Pemetrexed is an antifolate analogue that has shown promising activity in several solid tumor types, including mesothelioma. ZD9331, a highly specific TS inhibitor that dose not require polyglutamation for its activation, has shown activity in patients with refractory ovarian and colorectal cancer. Capecitabine is an oral fluoropyrimidine carbamate that was designed to generate 5-FU preferentially in tumor cells; this agent was recently approved by the US Food and Drug Administration as first-line therapy for patients with advanced colorectal cancer. As the number of TS inhibitors available for general clinical use increases, further research is needed to elucidate the critical molecular and biochemical elements that determine the efficacy and tumor specificity of each compound.

OBJECTIVE

To evaluate the efficacy and tolerance of irinotecan (CPT-11) in combination with oxaliplatin (L-OHP) plus fluorouracil (5-FU)/leucovorin (LV) (de Gramont regimen) as first-line treatment of metastatic colorectal cancer (MCC).

METHODS

Thirty-one patients with MCC who had not received prior therapy for metastatic disease were enrolled. Their median age was 60 years; performance status (World Health Organization) was 0 in 12, 1 in 14, and 2 in five patients; 19 patients (61%) had prior surgery, and 14 (45%) had adjuvant chemotherapy. CPT-11 was administered on day 1 at 150 mg/m(2) as a 90-minute intravenous (IV) infusion; L-OHP was administered on day 2 at 65 mg/m(2) as a 2-hour IV infusion; and on days 2 and 3, LV 200 mg/m(2) preceded 5-FU administration of 400 mg/m(2)/d initial IV bolus dose followed by 600 mg/m(2)/d 22-hour IV continuous infusion. The regimen was repeated every 2 weeks.

RESULTS

All patients were assessable for toxicity and 30 for response to treatment. Complete response was achieved in two patients (6.5%) and partial response in 16 (51.6%) (overall response rate, 58.1%; 95% confidence interval, 40.7% to 75.4%); eight patients (25.8%) had stable disease, and five (16.1%) had disease progression. The median duration of response was 9 months, and the median time to disease progression was 13 months. Neutropenia grade 3 to 4 occurred in 14 patients (45%) and febrile neutropenia in two (6%). Diarrhea grade 3 to 4 was observed in 10 patients (32%), neurotoxicity grade 3 to 4 in three (9%), and asthenia grade 3 in two (10%). No treatment-related death has occurred.

CONCLUSIONS

The triplet combination of 5-FU/LV + CPT-11 + L-OHP is a highly active regimen with manageable toxicity as front-line treatment in MCC.

OBJECTIVE

With the emergence of new chemotherapies and biologic agents in the treatment of metastatic colorectal cancer (mCRC), the optimal combination and sequencing of these therapies are yet to be determined. This study examined the extent and pattern of chemotherapy and biologic therapy use by line of treatment. Biologic continuation and dose escalation were also examined.

METHODS

This study used an integrated electronic medical record database of 91 US oncology practices. Records were analyzed for 1,655 adult patients with mCRC who were treated from January 1, 2004 to January 31, 2008 with systemic therapy and could be observed for ≥ 3 months beyond their diagnosis of metastatic disease. Combination and sequence of individual drugs and regimens were examined.

RESULTS

For first-line therapy, the most common chemotherapy backbone was infused fluorouracil, leucovorin, and oxaliplatin (FOLFOX; 40.5% of patients), and the most common treatment regimen was FOLFOX plus bevacizumab (26.2%). For second-line therapy, fluorouracil, leucovorin, and irinotecan (FOLFIRI) was the most common chemotherapy backbone (25.7%), and FOLFIRI plus bevacizumab was the most common treatment regimen (18.3%). Across the study period, 68.6%, 22%, and 7% of patients received bevacizumab, cetuximab, and panitumumab, respectively. Among 412 patients receiving bevacizumab-containing regimens as first-line therapy who then received second-line therapy, 58% continued receiving bevacizumab, with dose escalation observed in 44%.

CONCLUSIONS

The most commonly used chemotherapy backbones for mCRC treatment were first-line FOLFOX and second-line FOLFIRI. Bevacizumab was the most frequently administered biologic therapy. Continuation and dose escalation with bevacizumab were frequently observed across lines of therapy.

Bevacizumab, a monoclonal antibody against vascular endothelial growth factor, has shown clinical activity in metastatic colorectal cancer patients when used as either a first-line or second-line treatment. Here, we evaluated the efficacy and safety of bevacizumab plus FOLFIRI (irinotecan, 5-fluorouracil, and leucovorin) or FOLFOX (oxaliplatin, 5-fluorouracil, and leucovorin) in metastatic colorectal cancer cases after failure to FOLFIRI and FOLFOX. Between October 2004 and February 2007, the data on 42 patients with metastatic colorectal cancer after failure of FOLFIRI and FOLFOX were reviewed retrospectively. All patients were treated with bevacizumab plus FOLFIRI or FOLFOX. The median patient age was 57.0 years. The ECOG performance status was 0 or 1 in 27 patients (64.3%). The number of previous chemotherapy regimens was>>/=3 in 35 patients (83.3%). Thirty-nine patients were evaluable for response. Four patients had partial responses (PRs) and no patient had a complete response (CR), giving an overall response rate of 9.5%. Twenty-two patients (52.4%) had stable disease and 13 patients (31.0%) showed progressive disease. With a median follow-up time of 12.9 months (range 1.0-30.0 months), the median progression-free survival time and the median overall survival time were 5.3 and 9.5 months, respectively. Grade 3 or 4 neutropenia developed in 18 patients (42.9%), including febrile neutropenia in 4 patients (9.5%). Common non-hematologic toxicities were fatigue (21.4%), neuropathy (21.4%), and mucositis (21.4%). Grade 2 or 3 hypertension occurred in 4 patients (9.6%), and grade 1 or 2 proteinuria was seen in 16 patients (38.1%). The frequencies of adverse events related BV, such as bleeding, thrombosis, and gastrointestinal perforation, were within the ranges of previous reports. However, there were no treatment-related deaths. The combination of bevacizumab plus FOLFIRI or FOLFOX showed modest activity and was relatively tolerable in patients with metastatic colorectal cancer refractory to both FOLFIRI and FOLFOX.

PHY906 is a novel Chinese herbal preparation that has been used in the Orient for over 1800 years to treat a wide range of gastrointestinal side effects including diarrhea, abdominal cramps, vomiting, fever, and headache. Preclinical and clinical studies were conducted to further investigate the biologic and clinical activities of this herbal medicine. To ensure standardization and maintain interbatch reliability of PHY906, high performance liquid chromatography (HPLC) was used to establish a "chemical fingerprint" of PHY906. In vivo preclinical studies using the murine Colon 39 tumor model showed that PHY906 protected against the weight loss associated with irinotecan treatment. In the presence of PHY906, mice were able to tolerate otherwise lethal doses of irinotecan. Significantly improved antitumor activity and overall survival were observed in animals treated with the combination of irinotecan and PHY906 versus irinotecan alone. The combination of PHY906 with irinotecan, 5-fluorouracil (5-FU), and leucovorin (LV) also resulted in at least additive antitumor activity with no increased host toxicity. Based on these in vivo studies, a phase I multicenter, double-blind, randomized, placebo-controlled, dose escalation, cross-over study of PHY906 as a modulator of the weekly, bolus regimen of irinotecan, 5-FU, and LV (IFL) in the first-line treatment of patients with advanced colorectal cancer (CRC) was conducted. The specific objectives of this clinical trial were to determine the safety and tolerability of PHY906 when administered concomitantly with the bolus, weekly IFL regimen. Treatment with PHY906 did not alter the pharmacokinetics of 5-FU, irinotecan, or the irinotecan metabolite SN-38.

OBJECTIVE

To assess the economics of various chemotherapeutic regimens for advanced gastric cancer (AGC), and to select the best cost-effective regimen for the common Chinese patients.

METHODS

Data source used in this study was the Chinese Biomedical Disk Database. Patients were diagnosed as AGC and any regimen was eligible. Outcome measures included median survival time (MST) and percentage of complete and partial response (CR+PR). Economic statistics was per capita direct medical cost (DMC) of a single cycle. TreeAge Pro Healthcare 2007 software was used to carry out cost-effectiveness and incremental cost-effectiveness analysis. Sensitivity analyses were applied by altering willingness-to-pay and annual discount rate, and also re-analyzed by excluding the studies with apparent heterogeneity.

RESULTS

Seven retrospective economics studies on 760 patients were included. 5-fluorouracil-based regimens were universal, and also some new agents were involved, such as docetaxel, paclitaxel, and oxaliplatin. By processing analysis, we could recommend etoposide, leucovorin and 5-fluorouracil (ELF) regimen as preference, with a DMC/MST ratio of 2543 RBM/11.7 mo and a DMC/CR+PR ratio of 2543 RMB/53.3%. Uracil-tegafur, etoposide and cisplatin (FEP) or 5-fluorouracil, adrimycin/epirubin and mitomycin (FAM) regimens could be regarded as optional first-line chemotherapy for AGC in common Chinese patients. With no regard for willingness-to-pay, the docetaxel, cisplatin and 5-fluorouracil (DCF) regimen could be chosen as either a first- or a second-line chemotherapy, with a DMC/CR+PR ratio of 9979 RMB/56.3%.

CONCLUSIONS

5-fluorouracial regimens are still considered the mainstream for AGC, while new agents such as taxanes are optional. More randomized clinical trials are required before any mandatory recommendation of certain regimens for patients with AGC in China is made.

It is almost 50 years since antimetabolites were first found to have clinical antitumour activity, with Farber's discovery that aminopterin could cause remission in acute leukaemia. In the following 10 years, methotrexate, 6-mercaptopurine and 5-fluorouracil (5-FU) found their way into clinical practice. Subsequently, cytosine arabinoside was found to have activity in acute leukaemia, but, until recently, other significant developments have involved optimizing the efficacy of existing antimetabolites, including the use of leucovorin with methotrexate or 5-FU. Recently, new antimetabolites have become a fertile area for anti-cancer drug research. Gemcitabine (GEMZAR) has emerged as an important new agent in several tumour types, including pancreatic, non-small-cell lung, bladder, breast and ovarian cancers. Capecitabine is an intriguing new prodrug, offering tumour selectivity and prolonged tumour exposure to 5-FU. More potent thymidylate synthase inhibitors have also emerged; raltitrexed is now commercially available for the treatment of colorectal cancer. Others under development include LY231514, which has other sites of action, hence the acronym MTA (multi-targeted antifolate). A novel target is glycinamide ribonucleotide formyltransferase (GARFT) and LY309887 and AG2034 are undergoing clinical investigation as GARFT inhibitors. A critical element with LY309887 appears to be co-administration of folate. It seems entirely possible that several novel antimetabolites will establish themselves in clinical practice in future for the treatment of solid tumours.

Twenty-two patients with advanced colorectal carcinoma were enrolled in this study. Ten patients had received prior chemotherapy that included the combination of fluorouracil (5-FU) and leucovorin (LV). All patients required subcutaneous port insertion and portable external infusion pumps to allow outpatient treatment. 5-FU (2,600 mg/m2) was administered concurrently with LV (500 mg/m2) over 24 hours of continuous infusion. The mean steady-state plasma concentration of 5-FU was 10 mumol/L (range, 7 to 14 mumol/L). The 5-FU dose was based on our previous phase I study, in which maximum-tolerated dose (MTD) of 5-FU was determined to be 2,600 mg/m2 in combination with a fixed dose of LV at 500 mg/m2. The treatment was repeated weekly. Twenty-two patients received a total of 560 courses of treatment. Eleven instances of grade 2-3 toxicity were observed: diarrhea (five), stomatitis (three), hand/foot syndrome (three). The overall objective response was 45% (10 of 22) and among previously untreated patients was 58%. Three of the responders achieved complete response (CR), with lung and liver as the metastatic sites. The median duration of survival for the previously untreated patients was not reached at 22 months, and was 10 months for the previously treated patients. These results suggest that short-term infusional therapy of 5-FU and LV in patients with advanced metastatic colorectal cancer generates acceptable toxicity, with equivalent or superior survivability in previously treated and untreated patients versus alternative methods of administration of the two agents.

OBJECTIVE

The results of a survey to characterize oncology drug shortages across the United States and the impact of shortages on clinical practice, patient safety, clinical trials, and health care costs are presented.

METHODS

A 34-item online survey was distributed to 1672 members of the Hematology/Oncology Pharmacy Association and other organizations to gather information on shortages of oncology drugs (i.e., all drugs essential in the care of cancer patients, including supportive care agents).

RESULTS

Two hundred forty-three completed responses, almost all from pharmacists (97%), were analyzed. Delays in chemotherapy administration or changes in treatment regimens due to drug shortages were reported by 93% of survey participants; 85% of respondents reported increased costs, and 10% reported reimbursement challenges related to drug shortages. At 34% of represented institutions, at least 1000 hours of additional labor annually was needed to manage shortages. Changes in therapy leading to near-miss errors were reported by 16% of participants, with 6% reporting one or more actual medication errors attributable to a drug shortage. The oncology medications most frequently reported to be in short supply during the preceding 12 months were fluorouracil, leucovorin, liposomal doxorubicin, and paclitaxel. The conduct of clinical trials was affected by drug shortages at 44% of represented institutions.

CONCLUSIONS

A survey of U.S. oncology pharmacists indicated that oncology drug shortages occurred frequently in the first half of 2011. Shortages led to delays in chemotherapy and changes in therapy, complicated the conduct of clinical research, increased the risks of medication errors and adverse outcomes, and increased medication costs.

The human reduced folate carrier (hRFC) mediates the membrane transport of reduced folates and classical anti-folates into mammalian cells. RFC is characterized by 12 transmembrane domains (TMDs), internally oriented N and C termini, and a large central linker connecting TMDs 1-6 and 7-12. By co-expression and N-hydroxysuccinimide methotrexate (Mtx) radioaffinity labeling of hRFC TMD 1-6 and TMD 7-12 half-molecules, combined with endoproteinase GluC digestion, a substrate binding domain was previously localized to within TMDs 8-12 (Witt, T. L., Stapels, S. E., and Matherly, L. H. (2004) J. Biol. Chem. 279, 46755-46763). In this report, this region was further refined to TMDs 11-12 by digestion with 2-nitro-5-thiocyanatobenzoic acid. A transportcompetent cysteine-less hRFC was used as a template to prepare single cysteine-replacement mutant constructs in which each residue from Glu-394 to Asp-420 of TMD 11 and Tyr-435 to His-457 of TMD 12 was replaced individually by a cysteine. The mutant constructs were transfected into hRFC-null HeLa cells. Most of the 50 single cysteine-substituted constructs were expressed at high levels on Western blots. With the exception of G401C hRFC, all mutants were active for Mtx transport. Treatment with sodium (2-sulfonatoethyl) methanethiosulfonate (MTSES) had no effect on hRFC activity for all of the cysteine mutants within TMD 12 and for the majority of the cysteine mutants within TMD 11. However, MTSES inhibited Mtx uptake by the T404C, A407C, T408C, T412C, F416C, I417C, V418C, and S419C mutants by 25-65%. Losses of activity by MTSES treatment for T404C, A407C, T412C, and I417C hRFCs were appreciably reversed in the presence of excess leucovorin, a hRFC substrate. Our results strongly suggest that residues within TMD 11 are likely critical structural and/or functional components of the putative hRFC transmembrane channel for anionic folate and anti-folate substrates.

A clinical trial for patients with measurable, disseminated colorectal cancer is being conducted to determine: (1) if intratumoral expression of thymidylate synthase (TS) affects response to protracted-infusion 5-fluorouracil (5FU); and (2) whether intratumoral expression of TS increases when clinical resistance is found after response to 5-FU. Polymerase chain reaction technology is employed to determine TS expression. Using beta-actin as an internal standard, TS expressions for 26 patients range from 0.5 x 10(-3) to 22.6 x 10(-3). Currently, 22 patients are evaluable for response and TS quantitation of their measurable tumour. 8 patients (36%) have had partial responses; 3 responding patients had been previously treated with 5-FU. A strong statistical association between TS expression and resistance to therapy has been found (P = 0.004). No patient with TS expression of 4.0 x 10(-3) or greater has responded. On average, patients previously treated with 5-FU have slightly higher levels of TS expression in their measurable tumours (P = 0.4). Whether responding patients will develop increased expressions of TS upon clinical progression of their cancer remains to be determined. Confirmation of these results in a larger cohort could lead to a scientific rationale for deciding upon specific therapy for patients with disseminated colorectal cancers.

BACKGROUND

Since 1990, the recommended adjuvant therapy for patients with surgically resected node-positive colon cancer has been 5-fluorouracil (5-FU), usually in combination with leucovorin or levamisole. The purpose of this study is to assess the distribution of adjuvant 5-FU treatment in the elderly.

METHODS

The Surveillance, Epidemiology and End Results-Medicare database provides population-based information on cancer patients, representing approximately 14% of the United States population, along with health care utilization data from Medicare claims files. We studied patients with node-positive colon cancer diagnosed between 1992 and 1996 who survived at least 120 days beyond diagnosis (N = 4998).

RESULTS

About 50% of elderly patients received 5-FU within 4 months of diagnosis. The proportion of patients treated with 5-FU increased by about 10% from 1992 to 1996. In a multiple logistic regression model, 5-FU treatment was less likely to be given to older patients (compared with those aged 65-69 years, the odds ratio (OR) [95% CI] was 0.82 [0.67-1.00] for ages 70 to 74 years, 0.47 [0.39-0.57] for ages 75 to 79, 0.17 [0.13-0.20] for ages 80 to 84, and 0.04 [0.03-0.05] for ages 85 to 88 years. Non-Hispanic black patients were less likely to be treated than non-Hispanic white patients (OR 0.46 [0.36-0.59]); patients with more than three positive lymph nodes were more likely to be treated than those with three or less, and those with comorbid conditions were less likely to be treated than those without such conditions.

CONCLUSIONS

Despite its proven efficacy in reducing colon cancer mortality, 5-FU-based chemotherapy is not widely used among apparently eligible patients over age 65. Efforts are needed to ensure that elderly and non-Hispanic black patients receive appropriate treatment.

BACKGROUND

We evaluate the long-term survival of patients with peritoneal carcinomatosis (PC) treated with systemic chemotherapy regimens, and the impact of the of the retrospective peritoneal disease severity score (PSDSS) on outcomes.

METHODS

One hundred sixty-seven consecutive patients treated with PC from colorectal cancer between years 1987-2006 were identified from a prospective institutional database. These patients either received no chemotherapy, 5-FU/Leucovorin or Oxaliplatin/Irinotecan-based chemotherapy. Stratification was made according to the retrospective PSDSS that classifies PC patients based on clinically relevant factors. Survival analysis was performed using the Kaplan-Meier method and comparison with the log-rank test.

RESULTS

Median survival was 5 months (95% CI, 3-7 months) for patients who had no chemotherapy, 11 months (95% CI, 6-9 months) for patients treated with 5 FU/LV, and 12 months (95% CI, 4-20 months) for patients treated with Oxaliplatin/Irinotecan-based chemotherapy. Survival differed between patients treated with chemotherapy compared to those patients who did not receive chemotherapy (p = 0.026). PSDSS staging was identified as an independent predictor for survival on multivariate analysis [RR 2.8 (95%CI 1.5-5.4); p < 0.001].

CONCLUSIONS

A trend towards improved outcomes is demonstrated from treatment of patients with PC from colorectal cancer using modern systemic chemotherapy. The PSDSS appears to be a useful tool in patient selection and prognostication in PC of colorectal origin.

OBJECTIVE

To reveal the present status and future directions of colorectal cancer in Asia.

METHODS

The Working Group consisted of oncologists from six Asian countries (Japan, Korea, Hong Kong, China, Taiwan, Singapore and Philippines) discussed colorectal cancer in the 30th Asia-Pacific Cancer Conference and made a consensus report.

RESULTS

The incidence of colorectal cancer has been increasing rapidly in recent decades, and mortality has also increased except in Japan and Singapore. Colorectal screening with fecal occult blood tests is a national policy in Taiwan, Japan and Korea. Total colonoscopy is the most common examination for diagnosing colorectal cancers and neoplasms. However, there are differences in the macroscopic classification used. Laparoscopic surgery for colon cancer is extensively used, although the indication varies. Adequate lymph node harvesting of more than 12 nodes is performed in most countries. Neoadjuvant chemoradiation therapy is not routinely done for T2 or T3 rectal cancer. Total mesorectal excision is the standard surgery for rectal cancer. Survival rate data are unavailable for many countries and should be compiled in all. The differences in the health-care delivery systems affect the treatment choices for unresectable colorectal cancer. Infusional 5-FU plus leucovorin plus oxaliplatin (FOLFOX) is the most popular first-line regimen. Cetuximab is mainly used as a second- or third-line regimen with reference to k-ras mutation. Oxaliplatin-based adjuvant chemotherapy is commonly used for stage III disease, whereas the clinical practice for stage II disease varies.

CONCLUSIONS

Further clinical cooperation is needed to optimize the management of colorectal cancer in Asia.

Four separate groups of patients have been studied: (1) The effect of high-dose methotrexate (MTX) administration on glomerular filtration rate was determined by pre- and posttreatment inulin and creatinine clearances in nine patients. Measurements were made prior to and 24-40 hr after drug administration. Inulin and creatinine clearances both decreased a mean of 43%. No signs of systemic toxicity occurred. (2) Three other patients given high-dose courses of MTX developed MTX toxicity. Their creatinine clearance decreased an average of 61%. (3) In a separate group of five patients undergoing weekly MTX treatment, comparison of serum MTX pharmacokinetics with and without alkalinization of the urine demonstrated no significant difference in peak serum MTX levels or serum MTX decay. (4) Eight additional patients with severe renal dysfunction secondary to MTX were treated with increased doses of leucovorin and a continuous infusion of thymidine (8 g/m2/day) once renal failure was recognized. When high-dose leucovorin and thymidine were begun 48-72 hr after the MTX infusion, severe toxicity in the form of leukopenia, thrombocytopenia, diffuse mucositis, stomatitis, or skin rash was averted. We concluded the following: (1) high-dose MTX causes a subclinical decrease in glomerular filtration rate with each administration, even in nontoxic courses; (2) alkalinization of the urine with sodium bicarbonate does not alter plasma MTX decay, while volume expansion (hydration) is maintained constant; and (3) rigorous monitoring of serum creatinine and serum MTX levels 24-48 hr after MTX administration allows for the institution of rescue measures, including leucovorin and thymidine, which will abort the systemic toxicity that accompanies MTX-induced renal failure.

Colorectal cancer (CRC) is one of the leading causes of cancer-related death in the elderly. However, elderly patients with CRC tend to be under-presented in clinical trials and undertreated in clinical practice. Advanced age alone should not be the only criteria to preclude effective therapy in elderly patients with CRC. The best guide about optimal cancer treatment can be provided by comprehensive geriatric assessment. Elderly patients with stage III colon cancer can enjoy the same benefit from adjuvant chemotherapy with 5-fluorouracil/leucovorin or capecitabine as younger patients, without a substantial increase in toxicity. With conflicting results of retrospective studies and a lack of data available from randomized studies, combined modality treatment should be used with great caution in elderly patients with locally advanced rectal cancer. Combination chemotherapy can be considered for older patients with metastatic CRC. For elderly patients who are frail or vulnerable, however, monotherapy or a stop-and-go strategy may be desirable. The use of targeted therapies in older patients with metastatic CRC appears to be promising in view of their better efficacy and toxicity. Treatment should be individualized based on the nature of the disease, the physiologic or functional status, and the patient's preference.

The aim of this study was to determine the pathological complete remission (pCR) rate, and its relationship to clinical outcome, in patients with adenocarcinoma of the stomach or oesophagogastric junction receiving preoperative 5-fluorouracil, leucovorin, oxaliplatin and docetaxel (FLOT) every 2 weeks. Data from these patients who received at least one cycle of preoperative FLOT followed by surgery were prospectively collected in three German centres. Outcome analyses were conducted and tumour samples were evaluated for pathological remission by a central pathologist. A total of 46 patients were included in this analysis. All patients had clinical T3- and/or N+-stages and 11 (23.9%) had distant metastases (M1). After a median of 4 (range 2-8) preoperative cycles, 8 of 46 patients (17.4%) achieved a pCR. The pCR rate was highest in tumours of intestinal type histology (30.8%) and in those located in the oesophagogastric junction (30.4%) and lowest in patients with diffuse/mixed type tumours (0%) or tumours located in the stomach (4.3%; p < 0.05 for both comparisons). Patients with pCR had 100% probability of overall and disease-free survival (DFS) during the observation period, which was significantly higher (p = 0.037 and p = 0.009, respectively) than the survival probability in patients without pCR. In conclusion, treatment intensification using FLOT was associated with significant pCR rates in patients with oesophagogastric cancer. The distribution of pCR appeared to be significantly different according to histological type and location of the tumours.

While 5-fluorouracil used as single agent in patients with metastatic colorectal cancer has an objective response rate around 20%, the administration of combinations of irinotecan with 5-fluorouracil/folinic acid or oxaliplatin with 5-fluorouracil/folinic acid results in significantly increased response rates and improved survival. However, the side effects of systemic therapy such as myelotoxicity, neurotoxicity or gastrointestinal toxicity may lead to life-threatening complications and have a major impact on the quality of life of the patients. Therefore, biomarkers that would be instrumental in the choice of optimal type, combination and dose of drugs for an individual patient are urgently needed. The efficacy and toxicity of anticancer drugs in tumor cells is determined by the effective concentration in tumor cells, healthy tissues and by the presence and quantity of the drug targets. Enzymes active in drug metabolism and transport represent important determinants of the therapeutic outcome. The aim of this review was to summarize published data on associations of gene and protein expression, and genetic variability of putative biomarkers with response to therapy of colorectal cancer to 5-fluorouracil/leucovorin/oxaliplatin and 5-fluorouracil/leukovorin/irinotecan regimens. Gaps in the knowledge identified by this review may aid the design of future research and clinical trials.