OBJECTIVE

Long-term adverse neurobehavioral sequelae frequently are observed in pediatric patients treated for acute lymphoblastic leukemia (ALL). To clarify the relative contribution of cranial irradiation (CRT) therapy and drug therapy to these outcomes, we evaluated neuropsychologic outcomes associated with different doses of CRT and intravenous (IV) methotrexate (MTX) in long-term survivors.

METHODS

Fifty-one patients treated for ALL on Dana-Farber Cancer Institute protocol 81-01 were evaluated by standardized cognitive and academic achievement tests. These children had been assigned at diagnosis to a standard-risk (SR) or high-risk (HR) group and received 1,800 cGy or 2,800 cGy CRT, respectively. A subgroup of these patients was randomized to receive MTX during remission induction, either as a single low dose (LD; 40 mg/m2) or a single high dose (HD; 4 g/m2) with leucovorin rescue.

RESULTS

Sex and MTX randomization jointly predicted the intelligence quotient (IQ). Fifty percent of girls versus 14% of boys exhibited low IQ (less than 90; P = .01); 80% of girls who received HD MTX versus 25% of girls who received LD MTX exhibited low IQ (P = .03). In contrast, risk group better predicted performance on tasks sensitive to verbal memory and/or coding.

CONCLUSIONS

We conclude that (1) significant neurotoxicity occurred principally in girls; (2) increased dose intensity of IV MTX was associated with lower IQ, but only in girls; and (3) increased dose of CRT may have been associated with impairment of verbal memory and coding.

BACKGROUND

The current prospective, multicenter study sought to identify single nucleotide polymorphisms of voltage-gated sodium channels (SCNAs) genes that might confer susceptibility to an increased incidence and severity of oxaliplatin-induced peripheral neuropathy (OXAIPN) in patients treated with either leucovorin, 5-fluorouracil, and oxaliplatin (FOLFOX) or oxaliplatin plus capecitabine (XELOX) for colorectal cancer (CRC).

METHODS

A total of 200 patients with CRC were genotyped with real-time polymerase chain reaction using locked nucleic acid hydrolysis probes or allele-specific primers. All patients had received oxaliplatin-based chemotherapy, either in the adjuvant or metastatic setting. The incidence and severity of cumulative OXAIPN was graded using the clinical version of the Total Neuropathy Score and the neurosensory National Cancer Institute Common Toxicity Criteria (version 3.0). The incidence of acute OXAIPN was assessed using a descriptive questionnaire (yes/no response format) at each clinical evaluation. Acute OXAIPN was present in 169 of 200 patients (84.5%), whereas after treatment discontinuation, the cumulative/chronic form of neurotoxicity occurred in 145 of 200 patients (72.5%).

RESULTS

In the logistic regression analysis adjusted for confounding factors, the overdominant model (CT vs CC + TT) of 2 single nucleotide polymorphisms (ie, SCN4A-rs2302237 and SCN10A-rs1263292) emerged as being significantly associated with an increased incidence of acute OXAIPN (rs2302237: odds ratio of 2.62 [95% confidence interval (95% CI), 1.15-6.00]; P = .019; and rs12632942: OR of 0.39 [95% CI, 0.17-0.88]; P = .023). However, only SCN4A-rs2302237 emerged as also being predictive of the clinical severity of acute OXAIPN (OR, 2.50 [95% CI, 1.35-4.63]; P = .0029) and the occurrence of cumulative/chronic OXAIPN (OR, 2.47 [95% CI, 1.04-5.85]; P = .037).

CONCLUSIONS

The results of the current study provide evidence to support a causal relationship between SCNA polymorphisms and OXAIPN. However, further studies from independent groups are warranted to confirm these results.

BACKGROUND

Two phase III trials of neoadjuvant treatment in T3-4 rectal cancer established that adding chemotherapy (CRT) to radiotherapy (RT) improves pathological complete response (pCR) and local control (LC). We combined trials to assess the clinical benefit of CRT on overall (OS) and progression free survival (PFS) and to explore the surrogacy of pCR and LC.

METHODS

Individual patient data from European Organisation for Research and Treatment of Cancer (EORTC) 22921 (1011 patients) and FFCD 9203 (756 patients) were pooled. Meta-analysis methodology was used to compare neoadjuvant CRT to RT for OS, PFS LC and distant progression (DP). Weighted linear regression was used to estimate trial-level association (surrogacy R(2)) between treatment effects on candidate surrogate (pCR, LC, DP) and OS.

RESULTS

The median follow-up was 5.6 years. Compared to RT (881 pts), CRT (886 pts) did not prolong OS, DP or PFS. The 5-y OS-rate was 66.3% with CRT versus 65.9% in RT (hazard ratios (HR) = 1.04 {0.88-1.21}). CRT significantly improved LC (HR = 0.54, 95%confidence interval (CI): 0.41-0.72). PFS was validated as surrogate for OS with R(2) = 0.88. Neoadjuvant treatment effects on LC (R(2) = 0.17) or DP (R(2) = 0.31) did not predict effects on OS.

CONCLUSIONS

Preoperative CRT does not prolong OS or PFS. pCR or LC do not qualify as surrogate for PFS or OS while PFS is surrogate. Phase III trials should use OS or PFS as primary endpoint.

The oral, tumour-selective fluoropyrimidine capecitabine represents a major new strategy for the treatment of colorectal cancer. Pooled results from two large, multicentre, open-label, phase III studies comparing oral capecitabine (1250 mg/m2 twice daily for 14 days every 3 weeks) with the Mayo Clinic regimen (5-fluorouracil [5-FU] 425 mg/m2 plus leucovorin 20 mg/m2 days 1-5, every 4 weeks) provide information on over 1200 patients receiving first-line chemotherapy for metastatic colorectal cancer. Analysis of all randomised patients demonstrated a significantly superior overall response rate as assessed by the investigator for capecitabine compared with 5-FU/leucovorin (25.7% versus 16.7%, P<0.0002), reinforcing the individual trial results. Median time to disease progression, overall survival and duration of response were equivalent in the two treatment groups. Furthermore, capecitabine showed a superior safety profile compared with 5-FU/leucovorin, with a significantly lower incidence (P<0.001) of diarrhoea, stomatitis, nausea and alopecia, together with a reduced treatment-related hospitalisation rate. In addition, the incidence of neutropenic fever/sepsis was significantly lower in patients receiving capecitabine.

OBJECTIVE

The aim of this study was to analyze the impact of hepatic arterial infusion (HAI) of oxaliplatin with systemic 5-Fluorouracil and leucovorin on patients with isolated unresectable liver metastases.

METHODS

A total of 87 patients treated in our hospital with HAI of oxaliplatin with systemic 5-Fluorouracil and leucovorin for isolated unresectable colorectal liver metastases from May 1999 to May 2007 were extracted from a prospective database and analyzed. The resectability rate, perioperative findings, postoperative outcomes, and long-term follow-up were evaluated.

RESULTS

HAI was delivered after failure of previous systemic chemotherapy in 69 patients (79%). The main criterion for unresectability was massive liver involvement (86% of patients). Most patients had synchronous (85%), bilateral metastases (89%). The median number of HAI courses was 8 (0-25). About 31 patients experienced technical catheter-related problems, which were responsible for withdrawal of HAI in only 7 patients (8%). Finally, a total of 23 patients (26%) were operated on, and resection or radiofrequency ablation was performed in 21 patients (24%). No postoperative mortality was observed and the morbidity rate was 35%. Five-year overall survival was 56% in the surgery group versus none in the nonsurgery group (P < 0.0001). After a median follow-up of 63 months, intrahepatic recurrence occurred in 10 patients among the 23 operated patients.

CONCLUSIONS

HAI of oxaliplatin with systemic 5-Fluorouracil and leucovorin offers a second chance to remove initially unresectable isolated colorectal liver metastases in 24% of patients, and appears to be more efficient when performed as first-line therapy. Long-term overall survival can be obtained with this approach.

This phase II study examined a regimen (FOLFOX7) of leucovorin (LV), high-dose intensity oxaliplatin, and 5-fluorouracil (5-FU), as second-line therapy for metastatic colorectal cancer. 48 patients were enrolled - 36 refractory and 12 resistant to prior therapy with LV-5-FU. Oxaliplatin (130 mg/m2) was infused with LV (400 mg/m2) over 2 h on day 1, followed by bolus 400 mg/m2 and a 46-h infusion (2400 g/m2) of 5-FU, every 2 weeks. Patients who responded or were stable received eight cycles. Patients were evaluated every 2 months. 20 patients (42%) had partial responses (95% confidence interval (CI): 28-56%), 19 (40%) had stable disease and 9 (19%) progressed. Median progression-free survival (PFS) was 6 months and median survival 16.1 months. Toxic effects of National Cancer Institute-Common Toxicity Criteria (NCI-CTC) grade 3/4 were: peripheral neuropathy 15%, nausea 8%, diarrhoea 11%, neutropenia 9%, thrombocytopenia 11%. Overall, 38% of patients experienced grade 3/4 toxicities, and 64% received 90% or more of the scheduled oxaliplatin dose intensity during the first four cycles. FOLFOX7 was highly active, with good tolerability, in pretreated patients resistant to LV-5-FU [corrected].

OBJECTIVE

Panitumumab monotherapy is approved for KRAS wild-type (WT) metastatic colorectal cancer (mCRC) progressing after standard chemotherapy. This study evaluated first-line panitumumab plus FOLFIRI in patients with mCRC.

METHODS

In this phase II, single-arm study, panitumumab (6 mg/kg) and FOLFIRI [irinotecan (180 mg/m(2)) and leucovorin (400 mg/m(2)) followed by a 5-fluorouracil 400 mg/m(2) bolus and a 2,400-3,000 mg/m(2) continuous infusion] were administered every 14 days until progression. Data were analysed descriptively overall and by tumour KRAS status.

RESULTS

KRAS data were available for 145/154 (94%) patients: 59% KRAS WT and 41% mutant (MT); mean follow-up was 39.5 versus 35.8 weeks, respectively. Objective responses occurred in 49% of patients: 56% versus 38% in the KRAS WT versus MT groups [(18% difference (95% CI 1-35%); odds ratio 2.1 (95% CI 1.0-4.4)]; median duration of response was 13.0 versus 7.4 months. More patients in the WT group underwent R0 resection (8% vs. 5%); median progression-free survival also favoured this group (8.9 vs. 7.2 months). The most common adverse events (any grade) were integument toxicities (98%), diarrhoea (79%) and stomatitis/oral mucositis (51%).

CONCLUSIONS

As expected, consistently favourable efficacy was observed in patients with KRAS WT versus MT tumours receiving first-line panitumumab plus FOLFIRI treatment.

We examined the patterns of induction of apoptosis, Fas expression, and the influence of the status of the p53 tumor suppressor gene, in response to treatment of human colon carcinoma cell lines to 5-fluorouracil (FUra) combined with leucovorin (LV) under conditions of both DNA-directed (HT29, VRC5/c1, and RKO) and RNA-directed (HCT8 and HCT116) cytotoxicity. Acute apoptosis was induced in cell lines expressing wtp53 (RKO, HCT8, and HCT116), independent of the mechanism of FUra action. In HT29 cells that expressed mp53, apoptosis was a delayed event. Cell lines undergoing DNA-directed FUra cytotoxicity demonstrated marked accumulation of cells in S-phase (HT29 and RKO), whereas those lines undergoing RNA-directed cytotoxicity (HCT8 and HCT116) demonstrated marked cell cycle phase arrest in G2-M, both reversible by dThd. dThd partially protected HCT8 and HCT116 cells from FUra-LV-induced apoptosis but had no influence on FUra-LV-induced loss in clonogenic survival. In cells expressing wtp53, the Fas death receptor was induced in response to FUra-LV treatment. FUra-LV sensitized RKO cells to the anti-Fas monoclonal antibody CH-11 that was completely reversed by dThd, demonstrating the involvement of DNA damage in FUra-LV-induced, Fas-dependent sensitization to CH-11. In contrast, FUra-LV sensitized HCT116 cells to CH-11-induced apoptosis, which was not dThd reversible. Transduction of HT29 cells with Ad-wtp53 induced elevated Fas expression and sensitized the cells to FUra-LV-induced apoptosis. Data indicate that the presence of a wtp53 gene determines FUra-LV-induced Fas expression, the kinetics of FUra-LV-induced apoptosis and not the extent of apoptosis induced, both being independent of the mechanism of FUra action. Therefore, in colon carcinomas that express wtp53, the approach to sensitize tumors to Fas-mediated apoptosis may be further enhanced from the effect of FUra-LV in elevating Fas expression in a p53-dependent manner.

OBJECTIVE

In the current study, we examine the effects of a novel proteasome inhibitor, NPI-0052 (salinosporamide A), on proteasome function and nuclear factor-kappaB activation and evaluate its ability to enhance treatment response in colon cancer xenografts when administered orally.

METHODS

The effects of treatment on nuclear factor-kappaB activation, cell cycle regulation, and apoptosis were determined. The pharmacodynamic effect of NPI-0052 on 20S proteasome function was assayed in vivo following oral and i.v. drug administration and compared with treatment with bortezomib. The effect of combined treatment with chemotherapy was determined in a colon cancer xenograft model.

RESULTS

We found that NPI-0052 is a potent, well-tolerated proteasome inhibitor that has pharmacodynamic properties distinct from bortezomib in that it achieves significantly higher and more sustained levels of proteasome inhibition. When combined with chemotherapy, NPI-0052 increases apoptosis and shifts cells toward G2 cell cycle arrest. When added to chemotherapy in vivo [using combinations of 5-fluorouracil (5-FU), CPT-11, Avastin (bevacizumab), leucovorin, and oxaliplatin], NPI-0052 significantly improved the tumoricidal response and resulted in a 1.8-fold increased response to CPT-11, 5-FU, and leucovorin triple-drug combination (P=0.0002, t test), a 1.5-fold increased response to the oxaliplatin, 5-FU, and leucovorin triple-drug combination (P=0.013, t test), and a 2.3-fold greater response to the CPT-11, 5-FU, leucovorin, and Avastin regimen (P=0.00057).

CONCLUSIONS

The high level of proteasome inhibition achieved by NPI-0052 is well tolerated and significantly improves the tumoricidal response to multidrug treatment in a colon cancer xenograft model. Further evaluation of this novel proteasome inhibitor in clinical trials is indicated.

BACKGROUND

New chemotherapeutic regimens have improved survival for stage IV pancreatic ductal adenocarcinoma and occasionally major response of liver metastases can be observed. Aim of this work is to analyze the outcomes of patients undergoing primary chemotherapy for liver metastases from pancreatic cancer and to evaluate the results of surgical resection.

METHODS

Retrospective analysis.

METHODS

patients with extra-hepatic metastases, patients with Eastern Cooperative Oncology Group performance status ≥3, patients undergoing supportive care alone.

RESULTS

127 patients were identified. Liver metastases were unilobar in 28.5% of patients. Chemotherapy regimens included gemcitabine alone or in association with other agents (44%), oxaliplatin, irinotecan, fluorouracil and leucovorin (FOLFIRINOX 8%), and cisplatin, gemcitabine plus capecitabine and epirubicin (PEXG) or capecitabine and docetaxel (PDXG) or epirubicin and fluorouracil (PEFG) (48%). 56 patients (44%) had a complete (7%) or partial response (37%). surgical resection was carried out in 11 patients (8.5%). Median overall survival was 11 months for the entire cohort and 15 months for those with partial/complete response. In this sub-group median survival was significantly longer (46 versus 11 months) for patients undergoing resection (P < 0.0001). Independent predictors of overall survival were chemotherapy with multiple agents (HR: 0.512), surgical resection (HR: 0.360), >5 liver metastases at diagnosis (HR: 3.515), and CA 19.9 reduction < 50% of baseline value (HR: 2.708).

CONCLUSIONS

Surgical resection of primary pancreatic tumor with or without residual liver disease can be considered in selected cases after primary chemotherapy and it is associated with improved survival.

Colorectal cancer is one of the leading causes of death from malignant diseases in the Western world. Worldwide, approximately 50% of patients who present with colorectal cancer will develop metastatic disease and eventually die from this malignancy. Recently, significant advances have been made in the medical treatment of advanced colorectal cancer with the introduction of novel cytotoxic drugs, such as irinotecan and oxaliplatin. Based on the results of recent Phase III trials, combination regimens of infusional 5-fluorouracil/leucovorin and oxaliplatin (FOLFOX) have emerged as a new standard of care in the palliative and adjuvant treatment of colorectal cancer. The addition of biological agents targeting angiogenesis or oncogenes such as epidermal growth factor receptor (EGFR) to FOLFOX will conceivably further enhance the activity of treatment regimens. Making use of all available active therapeutic options in the course of disease has significantly improved median overall survival of metastatic colorectal cancer into a chronic disease, with implications for treatment strategies and pharmacoeconomic considerations.

OBJECTIVE

To compare efficacy in terms of pathologic response in LARC patients treated with preoperative chemoradiation, with or without a short-intense course of induction oxaliplatin.

METHODS

From 05/98 to 10/02, 114 patients were treated with preoperative chemoradiation (4500-5040 cGy + oral Tegafur 1200 mg/day) for cT(3)-(4)N(+/x)M(0) rectal cancer. Starting 05/01, 52 consecutive patients additionally received induction FOLFOX-4, oxaliplatin (85 mg/m(2) iv d1), 5-FU (400 mg/m(2) iv bolus d1) and 600 mg/m(2) iv continuous infusion in 22 h with leucovorin (200 mg iv) d1 and d2, every 15 days (2 cycles), followed by the previously described Tegafur chemoradiation regime. Surgery was performed in 5-6 weeks. Pathological assessment investigated post-treatment T and N status in the rectal wall and peri-rectal tissues.

RESULTS

Patients, tumor and treatment characteristics were comparable between groups. Incidence of pT(0) specimens was significantly increased by induction FOLFOX-4 (P = 0.006). Total T and N downstaging were 58% versus 75% and 42% versus 40%, respectively (P = ns). T downstaging of>> or =2 categories was significantly superior in FOLFOX-4 group (P = 0.029).

CONCLUSIONS

Short-intense induction FOLFOX-4 significantly improves pathologic complete response in LARC patients treated with tegafur-sensitized preoperative chemoradiation. The 44% rate of pT(0)-(1) specimens observed in the oxaliplatin group should impulse innovative surgical approaches to promote ano-rectal sphincter conserving protocols.

OBJECTIVE

Fluorouracil plus leucovorin (FU + LV) adjuvant chemotherapy reduced the risk of recurrence and death across all time points in a pooled analysis of 20,898 patients with colon cancer from 18 randomized studies. The impact of oxaliplatin added to FU + LV on the time course of recurrence and survival remains unknown.

METHODS

A total of 12,233 patients enrolled to the randomized trials C-07, C-08, N0147, MOSAIC (Adjuvant Treatment of Colon Cancer), and XELOXA (Adjuvant XELOX) were pooled to examine the impact of oxaliplatin and tumor-specific factors on the time course of recurrence and death. For each end point, continuous-time risk was modeled over 6 years post treatment in all oxaliplatin-treated patients and patients concurrently randomized to FU + LV with or without oxaliplatin; the latter analyses supported time-dependent treatment comparisons.

RESULTS

Addition of oxaliplatin significantly reduced the risk of recurrence within the first 14 months post treatment for patients with stage II disease and within the first 4 years for patients with stage III disease. Oxaliplatin also significantly reduced risk of death from 2 to 6 years post treatment for patients with stage III disease, with no differences in timing of outcomes between treatment groups (ie, oxaliplatin did not simply postpone recurrence or death compared with FU + LV alone). Patients with stage II disease receiving oxaliplatin did not exhibit a significant reduction in risk of death in the first 6 years post treatment. Recurrence risk peaked near 14 months for both treatments, and risk of recurrence and death increased with increased tumor and nodal burden.

CONCLUSIONS

These analyses support the addition of oxaliplatin to fluoropyrimidine-based adjuvant therapy in patients with stage III disease and underscore the need for adequate surveillance of patients with colon cancer during the first 3 years after adjuvant therapy.

OBJECTIVE

The combination of radiation therapy with fluorouracil (5-FU)-based chemotherapy is generally accepted as appropriate postoperative therapy for patients with adenocarcinomas of the rectum that extend through the bowel wall or with lymph nodes positive for tumor. We attempted to determine whether the efficacy of this postoperative therapy could be improved by the addition of leucovorin and/or levamisole.

METHODS

A total of 1,696 patients were randomized and eligible for treatment with one of four treatment schemes. All patients received two cycles of bolus 5-FU-based systemic chemotherapy followed by pelvic radiation therapy with chemotherapy and two more cycles of the same systemic chemotherapy. Chemotherapy was either 5-FU alone, 5-FU with leucovorin, 5-FU with levamisole, or 5-FU with leucovorin and levamisole.

RESULTS

With a median follow-up duration of 48 months, there is no statistically significant advantage to any of the treatment regimens compared with bolus 5-FU alone. There is evidence of increased gastrointestinal toxicity with the three-drug combination compared with bolus 5-FU alone. Statistical analysis suggests it is very unlikely that either levamisole-containing combination will be shown to be of value with further follow-up evaluation.

CONCLUSIONS

There is no evidence at present for a beneficial effect of levamisole in the adjuvant treatment of rectal cancer. Definitive evaluation of the effect of the addition of leucovorin to 5-FU and pelvic radiation will require further follow-up evaluation.

OBJECTIVE

To determine whether the side effects of methotrexate can be decreased by the concurrent use of leucovorin, without affecting the efficacy of the methotrexate.

METHODS

We conducted a multicenter randomized, double-blind, placebo-controlled trial of leucovorin administration, 2.5-5.0 mg orally, to be given 24 hours after the single, weekly, oral dose of methotrexate. Every 3 weeks for 52 weeks, patients were evaluated for rheumatic disease activity and side effects. Dosage adjustments for both methotrexate and leucovorin were made as needed, according to a defined protocol. The primary outcome evaluated was the frequency of study withdrawals because of side effects and/or inefficacy. Secondary outcomes evaluated included the frequency of side effects and the relative efficacy of methotrexate in the leucovorin and placebo treatment groups.

RESULTS

Ninety-two evaluable patients were analyzed (44 took leucovorin and 48 placebo). Twenty-two patients withdrew early because of side effects unresponsive to our protocol, and 1 because of inefficacy; 17 had been taking placebo and 6 had been taking leucovorin (35% versus 14%, P < 0.02). The number of visits during which side effects were reported was reduced by almost 50% in the leucovorin treatment group (P < 0.001). There were significant reductions in the frequencies of all common side effects. At 52 weeks, disease activity was similar in both patient groups.

CONCLUSIONS

The methotrexate-leucovorin protocol used significantly reduces common side effects of methotrexate therapy without significantly altering efficacy.

BACKGROUND

Cancer chemotherapy with folate antimetabolites has been traditionally targeted at the enzyme dihydrofolate reductase and is based on the requirement of dividing tumor cells for a supply of thymidylate and purines. However, a new compound, 5,10-dideazatetrahydrofolate (DDATHF, whose 6R diastereomer is also known as Lometrexol), has become available that prevents tumor cell growth by inhibiting the first of the folate-dependent enzymes involved in de novo purine synthesis, glycinamide ribonucleotide formyltransferase.

OBJECTIVE

We investigated the toxicity and therapeutic activity of DDATHF in a phase I clinical trial.

METHODS

DDATHF was given at one of the following dose levels to 33 patients (16 females and 17 males) with malignant solid tumors: 3.0 mg/m2 per week (level A) to 10 patients, 4.5 mg/m2 per week (level B) to 13 patients, or 6.0 mg/m2 per week (level C) to 10 patients. Each drug cycle consisted of three weekly injections of DDATHF followed by a 2-week rest prior to redosing in the next cycle.

RESULTS

Of 33 patients, 27 received at least one full cycle of DDATHF. Thrombocytopenia was the major dose-limiting toxicity, and it was severe in one of 10 patients during the first cycle and in two of four patients during the second cycle. Because of cumulative toxicity at 6.0 mg/m2, second or later cycles were abbreviated to two weekly doses. Stomatitis was generally mild, but it was dose-limiting in one patient. Neutropenia was infrequent and mild, and normocytic anemia requiring blood transfusion was common with repeat dosing. Leucovorin was given for grade 2 or greater thrombocytopenia and resulted in hematologic recovery within 1 week in all eight patients so treated. Without leucovorin, the thrombocytopenia lasted from 7 to 49 days in three patients. A partial response was noted in one patient with non-small-cell lung cancer and a minor response in one patient with breast cancer. Three patients with colorectal cancer achieved stable disease for greater than 3 months with improvement in carcinoembryonic antigen levels in one patient.

CONCLUSIONS

DDATHF has an unusual pattern of toxicity with repetitive dosing, and humans with advanced cancer are considerably more sensitive than would be predicted from previous animal studies. Although doses of 6.0 mg/m2 per week on our schedule have been determined to be safe, repeated cycles require careful monitoring because of cumulative toxic effects.

CONCLUSIONS

Additional phase I studies of DDATHF that relate toxicity to folate intake and tissue folate pools appear warranted.

Many patients with early-stage colon cancer are cured with surgery alone, even if the standard of care remains an uniform approach to adjuvant chemotherapy based primarily on tumour stage. Consequently, it is important to individualize decision-making in this subset of patients with the aim to identify potential prognostic and predictive markers in colon cancer. While 5-fluorouracil, leucovorin, and oxaliplatin are widely known as gold treatment in the post-operative of stage III, well-validated molecular markers might help define which patients with stage II disease are likely to benefit from adjuvant therapy as well. Herein we review the use of adjuvant chemotherapy in colon cancer and analyzed the date on the clinical development of molecular markers to individualize another therapeutic approach in colon cancer.

Standard therapy for advanced or metastatic colorectal cancer consists of 5-fluorouracil plus leucovorin (5-FU/LV) administered intravenously (i.v.). Capecitabine (Xeloda), an oral fluoropyrimidine carbamate which is preferentially activated by thymidine phosphorylase in tumour cells, mimics continuous 5-FU and is a recently developed alternative to i.v. 5-FU/LV. The choice of oral rather than intravenous treatment may affect medical resource use because the two regimens do not require the same intensity of medical intervention for drug administration, and have different toxicity profiles. Here we examine medical resource use in the first-line treatment of colorectal cancer patients with capecitabine compared with those receiving the Mayo Clinic regimen of 5-FU/LV. In a prospective, randomised phase III clinical trial, 602 patients with advanced or metastatic colorectal cancer recruited from 59 centres worldwide were randomised to treatment with either capecitabine or the Mayo regimen of 5-FU/LV. In addition to clinical efficacy and safety endpoints, data were collected on hospital visits required for drug administration, hospital admissions, and drugs and unscheduled consultations with physicians required for the treatment of adverse events. Capecitabine treatment in comparison to 5-FU/LV in advanced colorectal carcinoma resulted in superior response rates (26.6% versus 17.9%, P=0.013) and improved safety including less stomatitis and myelosuppression. Capecitabine patients required substantially fewer hospital visits for drug administration than 5-FU/LV patients. Medical resource use analysis showed that patients treated with capecitabine spent fewer days in hospital for the management of treatment related adverse events than did patients treated with 5-FU/LV. In addition, capecitabine reduced the requirement for expensive drugs, in particular antimicrobials fluconazole and 5-HT3-antagonists to manage adverse events. As anticipated with an oral home-based therapy patients receiving capecitabine needed more frequent unscheduled home, day care, office and telephone consultations with physicians. In the light of clinical results from the phase III trial demonstrating increased efficacy in terms of response rate, equivalent time to progression (TTP) and survival (OS), and a superior safety profile, the results from this medical resource assessment indicate that capecitabine treatment of colorectal cancer patients results in a substantial resource use saving relative to the Mayo Clinic regimen of 5-FU/LV. This benefit is derived principally from the avoidance of hospital visits for i.v. drug administration, less expensive drug therapy for the treatment of toxic side-effects, and fewer treatment-related hospitalisations required during the course of therapy for adverse drug reactions in comparison to patients treated with 5-FU/LV.

BACKGROUND

In patients with metastatic colorectal carcinoma (MCC), capecitabine has demonstrated a superior response rate (RR), equivalent disease progression-free (PFS) and overall survival (OS), and an improved overall tolerability profile compared with bolus 5-fluorouracil/leucovorin (5-FU/LV). The FOLFOX4 regimen, combining oxaliplatin with LV and bolus plus infusional 5-FU (LV5FU2), has been shown to improve RR and PFS versus LV5FU2, and it was more effective and less toxic than irinotecan plus bolus 5-FU/LV. Capecitabine (an oral fluoropyrimidine) may be an effective, well tolerated, and more convenient alternative to 5-FU/LV in combination with oxaliplatin, especially in older patients.

METHODS

Elderly >> or = 70 years) patients with MCC were treated with a 3-weekly regimen of oxaliplatin at an initial dose of 85 mg/m(2) intravenously on Day 1 plus capecitabine 1000 mg/m(2) orally twice daily from Days 2 to 15 (XELOX regimen). In the absence of Grade>> or = 2 hematologic toxicity, oxaliplatin was increased to 100 mg/m(2) in the second cycle, and in the absence of Grade>> or = 2 nonhematologic adverse events during Cycle 2, capecitabine was increased to 1250 mg/m(2) twice daily in the third and subsequent cycles. After the first 35 patients (first series), the treatment protocol was amended so that only an oxaliplatin increase to 110 mg/m(2) and 130 mg/m(2) during Cycles 2 and 3, respectively, was planned in the remaining 41 patients (second series).

RESULTS

Seventy-six patients with a median age of 75 years (range, 70-82 years) entered the current study. In the first series, the oxaliplatin dose was increased in 18 (51%) patients, and the capecitabine dose was increased in 4 (11%) patients. In the second series, the oxaliplatin dose was increased to 110 mg/m(2) in 26 (63%) patients, and to 130 mg/m(2) in 19 (46%) patients. In all, 2 complete and 29 partial responses were observed, for an overall RR of 41% (95% confidence interval [CI], 30-53%). The median PFS was 8.5 months (95% CI, 6.7-10.3 months), and the median OS was 14.4 months (95% CI, 11.9-16.9 months). In a multivariate analysis, the presence of disease symptoms affected both PFS and OS, whereas OS also was independently affected by male gender and disease spread. Age had no independent effect on PFS or OS. Five percent of patients developed Grade>> or = 3 hematologic toxicity during treatment, Grade 3 peripheral neuropathy occurred in 8% of patients, and severe hand-foot syndrome in 13% of patients.

CONCLUSIONS

Fit elderly patients with MCC showed a good RR to XELOX with only mild toxicity observed in most patients. XELOX, should, therefore be considered as an important therapeutic option for elderly patients with MCC.

Metastatic colorectal cancer has traditionally been treated with i.v. 5-fluorouracil (5-FU), with or without leucovorin (LV). 5-FU is administered as either an i.v. bolus or a protracted infusion. Although schedules using the latter method offer efficacy benefits (objective response rate, time to disease progression), protracted infusion schedules are often associated with medical complications, inconvenience, high costs, and poor quality of life. Issues such as quality of life and convenience have influenced treatment decisions, but the availability of oral fluoropyrimidines represents a new development in this domain. Studies have confirmed that the majority of patients prefer oral to i.v. chemotherapy. Questionnaire-based studies have also demonstrated a preference for home-based rather than hospital-/clinic-based therapy. This preference was one of the driving forces behind the development of the oral fluoropyrimidines capecitabine (Xeloda) and uracil plus tegafur (UFT). Oral agents offer patients a more convenient treatment option that can be administered at home, providing patients with a greater sense of control over their therapy, while avoiding the medical complications and psychological distress associated with venous access. This article highlights some of the problems associated with i.v. therapy and reviews the available data on patient preference, including results of a recent, randomized, phase II study. It also provides a critical evaluation of the efficacy and safety profiles of the only two oral fluoropyrimidines approved for prescription, capecitabine and UFT/LV (UFT/LV not available in Germany and the U.S.), compared with those of two infused, 5-FU-based regimens. Finally, the results of an interactive debate exploring the opinions of approximately 400 oncologists on the issues of oral versus i.v. therapy are presented.

OBJECTIVE

The purpose of the present study was to evaluate the activity and the tolerability of the FOLFIRI regimen, administered as second-line chemotherapy in patients with locally advanced or metastatic pancreatic cancer after the failure of a gemcitabine-based regimen.

METHODS

Patients with locally advanced/metastatic disease who received a first-line chemotherapy (one line only) with gemcitabine ± platinoid (cisplatin, oxaliplatin) and who had measurable disease conform with the RECIST criteria were eligible for the study. FOLFIRI consists of irinotecan 180 mg/m(2) i.v. on day 1, leucovorin (l-form) 200 mg/m(2) i.v. on day 1 and 2, 5-FU 400 mg/m(2) i.v. bolus on days 1 and 2, and 5-FU 600 mg/m(2) i.v. by ci for 22 h on days 1 and 2, repeated every 2 weeks. The primary end point was the response rate.

RESULTS

Among the 50 enrolled patients, 4 partial responses (PR) (8%) and 14 stable diseases were observed, for a disease control rate of 18/50 (36%). Forty-one patients (82%) have been pretreated with cisplatin/oxaliplatin+gemcitabine as first-line chemotherapy. The median progression-free and overall survivals were 3.2 and 5 months, respectively. The 6-month survival rate was 32%. Grade 3-4 neutropenia and diarrhea occurred in 10 (20%) and 6 (12%) patients, respectively.

CONCLUSIONS

The FOLFIRI regimen showed a modest clinical activity in this quite heavily pretreated patients' population with locally advanced or metastatic pancreatic cancer with a manageable toxicity profile.

BACKGROUND

Cell physiology is regulated along the 24-h time scale by a circadian timing system composed of molecular clocks within each cell and a central coordination system in the brain. The mammalian molecular clock is made of interconnected molecular loops involving at least 12 circadian genes. The cellular clocks are coordinated by the suprachiasmatic nuclei, a hypothalamic pacemaker which also helps the organism adjust to environmental cycles. The rest-activity rhythm is a reliable marker of the circadian system function in both rodents and man. This circadian organization is responsible for predictable changes in the tolerability and efficacy of anticancer agents, and possibly also in tumor promotion or growth.

METHODS

Expected least toxic times of chemotherapy were extrapolated from experimental models to human subjects with reference to the rest-activity cycle. The clinical relevance of the chronotherapy principle, i.e. treatment administration as a function of rhythms, has been demonstrated in randomized multicenter trials.

RESULTS

Chronotherapeutic schedules have been used to safely document the activity of the association of oxaliplatin, 5-FU and leucovorin against metastatic colorectal cancer and to set up a new medicosurgical management of this disease which achieved unprecedented long term survival.

CONCLUSIONS

The chronotherapy concept offers further promises for improving current cancer treatment options as well as for optimizing the development of new anticancer or supportive agents.

The use of dendritic cells (DC) loaded with tumor antigen is one of the most advanced approaches in cancer immunotherapy. CpG motifs within microbial DNA detected by toll-like receptor 9 are responsible for the favorable properties of CpG oligodeoxynucleotides (ODN) as immune modulators. In this study, mature antigen-pulsed DC or peritumoral injections of CpG ODN, both effective for the treatment of small established tumors, were almost ineffective against large established tumors (1-cm diameter) in a syngeneic murine colon carcinoma model. For large tumors, the antitumor activity of mature antigen-pulsed DC was strongly increased by coinjection of CpG ODN, resulting in a transient control of tumor growth. Rejection of large tumors and long-term cure of mice was achieved by combining injection of antigen-pulsed DC plus CpG ODN at a site distant to the tumor with peritumoral injections of CpG ODN. Depletion of CD8 T cells abrogated the therapeutic activity. Large numbers of DEC-205-positive DC infiltrated the tumor in treated mice. Therapy with 5-fluorouracil and leucovorin was unable to control tumors of the same size. In conclusion, we demonstrate that the immune system, provided that appropriate stimulation with DC and CpG ODN is given, has the potential to cure animals of large solid tumors in situations where even chemotherapy is not efficient.