BACKGROUND

S-1 is an oral fluoropyrimidine whose antitumor effects have been demonstrated in treating various gastrointestinal cancers, including metastatic colon cancer, when administered as monotherapy or in combination chemotherapy. We conducted a randomized phase III study investigating the efficacy of S-1 as adjuvant chemotherapy for colon cancer by evaluating its noninferiority to tegafur-uracil plus leucovorin (UFT/LV).

METHODS

Patients aged 20-80 years with curatively resected stage III colon cancer were randomly assigned to receive S-1 (80-120 mg/day on days 1-28 every 42 days; four courses) or UFT/LV (UFT: 300-600 mg/day and LV: 75 mg/day on days 1-28 every 35 days; five courses). The primary end point was disease-free survival (DFS) at 3 years.

RESULTS

A total of 1518 patients (758 and 760 in the S-1 and UFT/LV group, respectively) were included in the full analysis set. The 3-year DFS rate was 75.5% and 72.5% in the S-1 and UFT/LV group, respectively. The stratified hazard ratio for DFS in the S-1 group compared with the UFT/LV group was 0.85 (95% confidence interval: 0.70-1.03), demonstrating the noninferiority of S-1 (noninferiority stratified log-rank test, P < 0.001). In the subgroup analysis, no significant interactions were identified between the major baseline characteristics and the treatment groups.

CONCLUSIONS

Adjuvant chemotherapy using S-1 for stage III colon cancer was confirmed to be noninferior in DFS compared with UFT/LV. S-1 could be a new treatment option as adjuvant chemotherapy for colon cancer.

UNASSIGNED

NCT00660894.

Thirty-one assessable patients with metastatic adenocarcinoma of the gastrointestinal tract were entered onto a pilot study designed to assess the impact of recombinant interferon alpha-2a (rIFN alpha-2a) on the toxicity and pharmacokinetics of fluorouracil (5-FU) and leucovorin (LV). Patients received an initial cycle of 5-FU (370 or 425 mg/m2/d) with LV (500 mg/m2/d) for 5 days. If tolerated, the patient received the same dose of 5-FU/LV for the second cycle on days 2 to 6, with rIFN alpha-2a at 5 x 10(6) or 10 x 10(6) U/m2/d on days 1 to 7, or with 3 x 10(6) U/m2/d on days 1 to 14. In 26 matched cycles, rIFN alpha-2a administration was associated with an increased incidence of dose-limiting mucositis and diarrhea and a significantly lower median platelet nadir; rIFN alpha-2a did not significantly affect the median WBC or granulocyte nadir. Dose-limiting toxicity occurred in all six patients entered at 425 mg/m2/d of 5-FU/LV within two cycles. The majority of patients treated with 370 mg/m2/d of 5-FU/LV and 10 x 10(6) U/m2/d rIFN alpha-2a experienced grade 3 to 4 mucositis and diarrhea, whereas patients receiving 3 x 10(6) and 5 x 10(6) U/m2/d rIFN alpha-2a had acceptable toxicity. Administration of rIFN alpha-2a was associated with a dose-dependent decrease in 5-FU clearance. The increase in the area under the 5-FU concentration-time curve (AUC) was 1.3-fold and 1.5-fold in patients receiving 5 x 10(6) and 10 x 10(6) U/m2/d rIFN alpha-2a, respectively. Thus, the increase in 5-FU toxicity with rIFN alpha-2a may be explained by alterations in 5-FU pharmacokinetics. In 22 patients without prior 5-FU therapy, three complete (13.6%) and seven partial (31.8%) responses were seen, for an overall response rate of 45.4% (95% confidence interval, 24.4% to 67.8%). Since the 5 x 10(6) U/m2/d dose of rIFN alpha-2a increased the 5-FU drug exposure and was associated with acceptable toxicity, we recommend its further evaluation as given on days 1 to 7 in combination with 5-FU 370 mg/m2/d, with high-dose LV given on days 2 to 6.

BACKGROUND

The complete resection of macroscopic colorectal peritoneal carcinomatosis (PC), followed by intraoperative intraperitoneal chemohyperthermia (IPCH) to treat residual microscopic disease, leads to cure in some patients. We report preliminary results on survival in a phase II study using oxaliplatin (LOHP).

METHODS

Twenty-four patients with macroscopic colorectal PC underwent complete resection of the PC followed by IPCH with LOHP performed in an open abdominal cavity. The dose of LOHP was 460 mg/m(2) in 2 l/m(2), during 30 min at 43 degrees C, at a flow rate of 2 l/min. During the hour preceding IPCH, they received an intravenous administration of 5-fluorouracil (400 mg/m(2)) and leucovorin (20 mg/m(2)).

RESULTS

Mean peritoneal tumoral extension (Sugarbaker's Index) was 16.9 +/- 9.5, median operative duration was 490 min and median blood loss was 965 ml. There were two postoperative deaths (8%) by intracerebral hemorrhage, and morbidity rate was 41.6%. Minimal follow-up was 18 months and median follow-up was 27.4 months (range 18.3-49.6). At 1, 2 and 3 years, overall survival rates were 83%, 74% and 65%, and disease-free survival rates were 70%, 50% and 50%, respectively. Only 32% of the 22 postoperative living patients presented a peritoneal recurrence. A peritoneal index >24 influenced survival, with a 17% recurrence rate at 2 years versus 63% when it was <24 (P = 0.005).

CONCLUSIONS

This new modality of treatment, when feasible, gives encouraging preliminary results, with a promising 3-year survival rate of 65%.

One hundred ninety-three patients with stage II, III, or IV follicular large-cell, diffuse large-cell, diffuse mixed, immunoblastic, or diffuse small noncleaved-cell (non-Burkitt's) lymphoma were randomized to receive either cyclophosphamide 650 mg/m2 intravenously (IV), doxorubicin 25 mg/m2 IV, etoposide 120 mg/m2 IV on day 1, mechlorethamine 6 mg/m2 IV, vincristine 1.4 mg/m2 (no cap at 2 mg total dose) IV on day 8, prednisone 60 mg/m2 orally daily days 1 through 14, procarbazine 100 mg/m2 orally daily days 8 through 14, and methotrexate 500 mg/m2 IV on day 15 with leucovorin 50 mg/m2 orally every 6 hours for four doses beginning 24 hours after methotrexate with cycles repeated every 28 days (ProMACE-MOPP) or same day-1 treatment as ProMACE-MOPP plus cytarabine 300 mg/m2 IV, bleomycin 5 U/m2 IV, vincristine 1.4 mg/m2 (no cap at 2 mg total dose) IV, and methotrexate 120 mg/m2 IV on day 8, leucovorin 25 mg/m2 orally every 6 hours for four doses beginning 24 hours after methotrexate, and prednisone 60 mg/m2 orally daily days 1 through 14 with cycles repeated every 21 days (ProMACE-CytaBOM). Co-trimoxazole two double-strength tablets orally twice daily throughout the period of treatment was added to the ProMACE-CytaBOM regimen when an increased risk of Pneumocystis carinii pneumonia was found in the first 35 patients receiving this combination. Median follow-up is 5 years. Among the 99 patients treated with ProMACE-MOPP, 73 achieved a complete remission (CR) (74%), 30 complete responders have relapsed (41%), and 45 patients have died (45%), including two (2%) of treatment-related causes. Among the 94 patients treated with ProMACE-CytaBOM, 81 achieved a CR (86%), 22 complete responders have relapsed (27%), and 31 patients have died (33%). The complete response rate (P2 = .048) and survival (P2 = .046) were significantly higher for patients treated with ProMACE-CytaBOM. The mortality of ProMACE-CytaBOM treatment overall was six of 94 patients (6.4%). There was no treatment-related mortality among patients treated with prophylactic co-trimoxazole (n = 59). ProMACE-CytaBOM combination chemotherapy with co-trimoxazole prophylaxis is a safe and effective treatment for patients with aggressive histology malignant lymphoma and is superior to ProMACE-MOPP.

BACKGROUND

To increase the knowledge about the palliative effects of chemotherapy in patients with symptomatic advanced colorectal cancer, physician- and patient-rated "quality of life" was studied in a randomized multicenter trial comparing a regimen of methotrexate/5-fluorouracil (5-FU) followed by leucovorin rescue (MFL) with a regimen of 5-FU/leucovorin (FLV).

METHODS

Between January 1989 and December 1990, 70 patients completed a quality of life questionnaire at randomization and after every fourth treatment course. At one of the hospitals, the evaluation was done as an interview (interview group, n = 24), whereas a questionnaire was used at the other hospitals (questionnaire group, n = 46).

RESULTS

Objective responses (complete response plus partial response) were obtained in 15 (21%) patients, subjective responses in 29 (41%) patients, and an overall improved quality of life in 25 (36%) patients. In addition, 16 (23%) patients had unchanged quality of life during at least 4 months. There was a correlation between objective responses, subjective responses, and improvements in quality of life, although discrepancies were noticed, particularly in patients with only slight symptoms. Response rates were higher in the interview group than in the questionnaire group (P < 0.01). This difference could be related to a more favorable outcome when 5-FU was given as a bolus injection, rather than as a short-term infusion (more than 5 minutes).

CONCLUSIONS

Improvements or prolonged stabilization of disease in quality of life can be achieved in at least half of the patients with tumor-related symptoms. However, factors related to the administration of chemotherapy may influence this proportion.

While many patients with early-stage colon cancer are cured with surgery alone, the standard of care remains a uniform approach to adjuvant chemotherapy based primarily on tumor stage. Recently, increasing awareness of the need for more individualized decision-making in cancer care has led to the development of several potential prognostic and predictive markers in colon cancer. While adjuvant chemotherapy with 5-fluorouracil, leucovorin and oxaliplatin is clearly beneficial to patients with stage III disease, well-validated molecular markers might help define which patients with stage II disease are likely to benefit from adjuvant therapy as well. Here, we review the data on the clinical development of molecular markers to individualize adjuvant therapy in colon cancer.

Results from five completed and two ongoing Phase III trials comparing 5-fluorouracil (5-FU) with 5-FU and leucovorin (LV) for the treatment of advanced, previously untreated colorectal carcinoma are reviewed. In five of these studies, 5-FU/LV was shown to provide a significantly higher response rate than 5-FU alone. Partial response rates resulting from the combination ranged from 16% to 45%, while those obtained with 5-FU alone were 5% to 18%. Complete responses with either treatment occurred in 0% to 8% of the patients treated. In two of the studies, 5-FU treatment prolonged median survival by 3 and 6 months. The planned dose intensities (DI) for single-agent 5-FU ranged from 463 to 760 mg/m2/week, and the actual delivered DI, established in two of the trials, were 531 and 533 mg/m2/week. The planned 5-FU DI for the 5-FU/LV combination ranged from 463 to 600 mg/m2/week compared with the delivered DI of 461 and 463 mg/m2/week. When used with LV, 5-FU cannot be administered at the single-agent maximum tolerated dose because of unacceptable toxicity. Nevertheless, lower doses of 5-FU, when combined with LV, had higher response rates than 5-FU alone. Significant toxicity occurred with 5-FU and with the combination. The addition of LV to 5-FU changed the type of toxicity that resulted; that toxicity varied with the schedule followed. The real, but modest improvement that resulted from the combination of 5-FU with the metabolic modulator LV offers the possibility that the administration of 5-FU/LV in the adjuvant setting will prolong survival and increase the percentage of patients cured of their disease. Furthermore, other compounds that modulate the effects of 5-FU may be capable of providing additional therapeutic benefits.

Fifty-four patients with metastatic adenocarcinoma received i.v. bolus 5-fluorouracil, 500 mg/m2, prior to surgical biopsy of tumor at 20-400 min, for analysis of biochemical parameters of resistance to thymidylate synthase (TS) inhibition. The majority of patients, 37, had colon or rectal adenocarcinoma, five had breast cancer, five had gastric primary disease, four had pancreatic adenocarcinoma, and three had hepatocellular adenocarcinoma. Fluorodeoxyuridylate (FdUMP) was assayed by isotope dilution of [3H]FdUMP binding to bacterial TS; free and total TS was determined by [3H]FdUMP binding; and deoxyuridylate (dUMP) was assayed by conversion to [14C]thymidylate. Free levels of TS were lower in breast cancers, 0.08 +/- 0.06 pmol/g, than in other histologies (overall average, 1.41 +/- 2.25), associated with significantly greater percentages of TS inhibition (88.6% versus 62.0% overall). Colorectal tumors showed significantly greater FdUMP levels than other gastrointestinal malignancies, associated with somewhat lower free TS values. Plots of FdUMP levels, or (FdUMP/dUMP) x 100 values versus percentages of TS inhibition suggested minima of 75 pmol/g and 0.10, respectively, for achieving maximal enzyme inhibition. Analyses of normal tissues showed: poor TS inhibition in liver and normal colonic mucosa, related to low FdUMP levels; and very high dUMP levels in bone marrow leukocytes suggestive of reactive increases in dUMP as an important mechanism of recovery in this tissue. Among the 30 of the 37 colorectal tumors that showed suboptimal (less than 85%) inhibition of TS, 16 (53%) showed FdUMP levels less than 75 pmol/g, 8 (27%) showed relatively high dUMP levels (over 35 nmol/g), and 16 (53%) showed poor efficiency of inhibition of TS, with the major overlap between these mechanisms of resistance being high dUMP and poor binding in 6 (20%). These data provide a strong rationale for administration of leucovorin to the majority of patients receiving 5-fluorouracil, since increased intratumoral reduced folates potentially can overcome multiple mechanisms of resistance including low FdUMP, high dUMP, and high total TS levels, in addition to that caused by isolated folate deficiency.

OBJECTIVE

To assess toxicity and long-term results of preoperative chemoradiotherapy in rectal cancer.

METHODS

Between 1989 and 1997, as a phase II study, 66 patients with T3 M0, rectal cancer received preoperatively a 45 Gy dose pelvic radiotherapy (XRT) combined with two 5-day chemotherapy courses (CT) of 5-Fluorouracil (5-FU) and Leucovorin (LV) delivered the first and fifth week of XRT. For each CT course, LV:20 mg/m2/d1-d5,. While the 5-FU dose was variable from 450 to 350 mg/m2/d first course and 370 to 350 mg/m2/d second course. Surgery was planned 3 weeks later.

RESULTS

XRT-CT was stopped in 1 patient due to progressive disease. CT was stopped in 1 patient due to toxicity. Grades 2 and 3 diarrhea were observed in 8 and 3 patients, respectively. One patient died from acute diarrhea due to deviation from recommendations; 60 patients went to surgery. Among the 58 patients operated on for cure, 5 had an R1-resection. After a 4.5-year median follow-up, the 5-year pelvic disease-free survival was 92% for the whole group and 96% in the R0-resection group.

CONCLUSIONS

Preoperative combined XRT-5-FU-LV is feasible if optimal XRT and patients are carefully managed. The recommended 5-FU daily dose is 350 mg/m2 for both CT courses. This approach is currently tested in a large EORTC phase III trial.

To evaluate toxicity and efficacy of chemotherapy in elderly patients >> or = 65 years of age) with advanced colorectal cancer, data from two consecutive trials conducted between 1984 and 1995 at the National Institute for Cancer Research were analysed comparing the results of treatment in those 65 years of age or older and in those younger than 65 years. Of 215 patients recruited, 82 elderly patients (median age 70 years, median performance status 1) received one of the following regimens based on 5-fluorouracil (5-FU): (1) weekly 5-FU 600 mg/m2 i.v. bolus (30 patients); (2) weekly 5-FU 600 mg/m bolus plus leucovorin (LV) 500 mg/m2 2-h i.v. infusion (28 patients); (3) Weekly 5-FU 2600 mg/m2 24-h continuous i.v. infusion plus LV 100 mg 4-h i.v. infusion and 50 mg orally every 4 h for five doses (24 patients). Overall, 1071 chemotherapy cycles were administered with a median number of 12 courses per patient. The main side effects were diarrhoea, observed in 38% of patients, stomatitis in 24% of patients and hand-foot syndrome in 13% of patients, and haematological toxicity affected only 15% of patients. No patient suffered grade IV toxicity. In three patients chemotherapy was discontinued because of toxicity (two patients suffered grade III diarrhoea, one patient grade III hand-foot syndrome). No significant difference in toxicity was evident between patients older than or younger than 65 years. Analysis of median dose intensity demonstrated no difference between the two groups. Overall objective response was observed in 18% (95% confidence limits 11-29) of elderly patients (15/82) in comparison with 23% (95% CL 17-32) of patients < 65 years of age (31/133 pts). In conclusion, chemotherapy in elderly patients with advanced colorectal cancer is a safe and effective treatment with acceptable toxicity and comparable objective response rates.

Pretreatment of L1210 cells with methotrexate in concentrations which produced free intracellular methotrexate and near maximal inhibition of dihydrofolate reductase resulted in an enhancement of intracellular 5-fluorouracil (FUra) accumulation. This enhancement of FUra accumulation was maximum (5-fold increase) after a 6-h exposure to 100 microM methotrexate. The nucleotide derivatives of FUra, including a 5-fluoro-2'-deoxyuridylate, and 5-fluorouridine-5'-triphosphate were also increased nearly 5-fold following methotrexate treatment. In cells pretreated with methotrexate, there was an increase in intracellular 5-phosphoribosyl-1-pyrophosphate pools which ranged from 2 to 8 times control values following concentrations of methotrexate between 0.1 microM and 10 microM. Both the increase in 5-phosphoribosyl-1-pyrophosphate and FUra accumulation could be prevented by the addition of Leucovorin (N5-formyltetrahydrofolate) at concentrations which rescued cells from the inhibitory effects of methotrexate. Pretreatment with 6-methylmercaptopurine riboside, which inhibits amidophosphoribosyltransferase, the first committed step in de novo purine synthesis, also resulted in a similar elevation in 5-phosphoribosyl-1-pyrophosphate pools and enhancement of FUra accumulation. If the 5-phosphoribosyl-1-pyrophosphate pools were reduced following methotrexate pretreatment by the addition to the cultures of hypoxanthine, which utilizes 5-phosphoribosyl-1-pyrophosphate for the conversion to IMP, the intracellular accumulation of FUra was not enhanced. Also, if the inhibitor of 5-phosphoribosyl-1-pyrophosphate synthetase, 7-deazaadenosine, was given to cultures with methotrexate, there was no increase in 5-phosphoribosyl-1-pyrophosphate pools, nor enhancement of FUra accumulation. In addition, when 5-fluoro-2'-deoxyuridine was added with the methotrexate to cell cultures, there was no increase in 5-phosphoribosyl-1-pyrophosphate pools, nor enhancement of intracellular FUra accumulation. These results indicate that the ability of methotrexate to enhance FUra accumulation was probably the consequence of the antipurine effect of methotrexate which resulted in a reduction of the complex feedback inhibition on 5-phosphoribosyl-1-pyrophosphate synthesis and utilization. The resultant increased 5-phosphoribosyl-1-pyrophosphate pools were then capable of being utilized for the conversion of FUra to 5-fluorouridylate, the possible rate-limiting step in FUra intracellular metabolism and the major determinant of the rate of intracellular FUra accumulation. When methotrexate preceded FUra, there was synergistic cell killing as determined by soft agar cloning. The exact mechanism of this sequential synergistic antitumor activity may be the result of the enhanced incorporation of FUra into RNA, since the increased 5-fluoro-2'-deoxyuridylate which is formed is unlikely to increase substantially the inhibition of dTMP synthesis induced by methotrexate pretreatment.

OBJECTIVE

The primary goal of this multicenter phase III trial was to determine whether overall survival (OS) of fluorouracil (FU) -refractory patients was noninferior when treated with second-line infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4; arm B) versus irinotecan (arm A). Cross-over to the other treatment on disease progression was mandated.

METHODS

Patients who experienced treatment failure with one prior FU-based therapy and had not received prior irinotecan or oxaliplatin, either for metastatic disease or within 6 months of adjuvant FU therapy, were randomly assigned to arm A (irinotecan 350 or 300 mg/m(2) every 3 weeks) or arm B (FOLFOX4).

RESULTS

A total of 491 patients were randomly assigned (arm A, n = 245; arm B, n = 246); 288 (59%) had experienced treatment failure with FU for metastatic colorectal cancer. Two hundred twenty-seven patients (46%) received protocol-mandated third-line therapy (arm A, 43%; arm B, 57%). Median survival was 13.8 months (95% CI, 12.2 to 15.0 months) for initial treatment with FOLFOX4 and 14.3 months (95% CI, 12.0 to 15.9 months) for irinotecan (P = .38; hazard ratio = 0.92; 95% CI, 0.8 to 1.1). Response rates (RR; 28% v 15.5%; P = .0009) and time to progression (TTP; 6.2 v 4.4 months; P = .0009) were significantly superior with FOLFOX4. In the nonrandom subset of patients who crossed over, RR and TTP improvements with FOLFOX4 continued into third-line treatment. Irinotecan therapy was associated with more grade 3 nausea, vomiting, diarrhea, and febrile neutropenia; FOLFOX4 was associated with more neutropenia and paresthesias.

CONCLUSIONS

In patients who experienced treatment failure with front-line FU therapy, OS does not significantly differ whether second-line therapy begins with irinotecan or FOLFOX4. FOLFOX4 produces higher RR and longer TTP. Both arms had notable OS in patients who experienced treatment failure with first-line FU therapy.

OBJECTIVE

Complete resection of macroscopic colorectal peritoneal carcinomatosis (PC), followed by intraoperative intraperitoneal chemohyperthermia (IPCH) to treat residual microscopic disease achieves cure in some patients. We report long-term results concerning survival of a phase II study using oxaliplatin (LOHP).

METHODS

From June 1998 to December 2003, thirty patients with macroscopic colorectal PC underwent complete resection of PC followed by IPCH with LOHP performed in an open abdominal cavity. The dose of LOHP was 460 mg/m2 in 2 L/m2 of iso-osmotic 5% dextrose, over 30 min at an intraperitoneally homogenous temperature of 43 degrees C and at a flow rate of 2 L/min in the continuous closed circuit. During the hour preceding IPCH, patients received 5-fluorouracil (400 mg/m2) and leucovorin (20 mg/m2) intravenously. All patients received neoadjuvant and adjuvant systemic chemotherapy.

RESULTS

Mean peritoneal tumor extension (Sugarbaker's Score) was 14.3 +/- 3.8, median operative duration, 450 min, and median blood loss, 940 mL. Eleven (37%) patients had associated extra-peritoneal lesions which were resected during the same procedure. There were no postoperative deaths and grade 2-3 morbidity (requiring specific treatment) was 40%. Median follow-up was 55 months (range: 31-84). Twenty-two patients (73%) relapsed after a median interval of 14 months, but 7 of them (32%) were amenable to curative repeat surgery. At 3 and 5 years, overall survival rates (95% confidence interval) were 53% (9-72), and 48.5% (31-66) respectively. At 3 and 5 years, disease-free survival rates were 41.5% (27-59), and 34% (19-52) respectively. Median survival was 60.1 months.

CONCLUSIONS

When feasible, this treatment modality yields a 5-year survival rate of 48.5%, with median survival attaining 60.1 months.

BACKGROUND

To improve the poor prognosis of patients with advanced incurable gastric cancer, intensive chemotherapy combined with radical surgery was used.

METHODS

Thirty patients with incurable gastric cancer were treated with a combination of 5-fluorouracil (370 mg/m2) and leucovorin (30 mg/person), given intravenously for five consecutive days, followed by cisplatinum (70 mg/m2) and etoposide (70 mg/m2) on days 6 and 20, delivered through a catheter placed either in the aorta with its tip at the level of the ninth thoracic vertebra or in the celiac artery. This treatment (FLEP therapy) was repeated twice every 5 weeks. Radical or palliative surgery followed chemotherapy.

RESULTS

The overall response rate to the chemotherapy was 50.0% (15 of 30 patients, 95% confidence limit 0.305-0.671). Nineteen patients (15 with a partial response, three showing no change, and one with progressive disease) underwent surgery. Of these, nine underwent curative surgery and 10 palliative surgery. The median survival time was 6.5 months overall, 12.7 months for responders, and 4.7 months for nonresponders. Long-term survivors were exclusively found among patients with distant lymph node metastasis treated by curative surgery (55.6% at 5 years).

CONCLUSIONS

Favorable results of this small phase II study justify a phase III trial.

Our group previously reported on the synthesis and characterization of a novel (99m)Tc-based folate-peptide chelator called EC20. This agent was found to bind folate receptor (FR)-positive cells and tissues with high affinity and was deemed useful for radiodiagnostic applications. In this study, we investigated the effect of D-amino acid substitution within EC20 on its tissue biodistribution. Expanded in vivo studies were also performed with unmodified (99m)Tc-EC20 to determine the effect of tumor FR expression, tumor size, tumor location, route of dose administration, and rodent diet on the agent's tissue biodistribution pattern.

METHODS

EC20 and EC53, the all-D-isomer of EC20, were synthesized and radiolabeled with (99m)Tc. The relative affinity of EC53 to the FR with respect to EC20 was then determined in cultured tumor cells. The ability of (99m)Tc-EC20 and (99m)Tc-EC53 to target tumors in vivo was examined using BALB/c mice with subcutaneously inoculated M109 or 4T1 cells, yielding 0.1- to 0.5-g tumors in 20 d.

RESULTS

The D-amino acid substitutions of EC20 were found to reduce the uptake of the agent into tumor and major organs. Subsequent studies using the original (99m)Tc-EC20 agent confirmed that its net tumor uptake was specific and proportional to FR expression levels in tumor cells as well as linear with respect to the overall tumor size. Further, (99m)Tc-EC20 uptake was found to be independent of both solid tumor location (intraperitoneal vs. subcutaneous) and the route of administration (intraperitoneal vs. intravenous). Interestingly, leucovorin supplementation of a commonly used folate-deficient laboratory chow had no effect on the agent's overall tissue biodistribution pattern. But, tumor-to-nontumor ratios could be increased up to 2.7-fold when 1 equivalent of free folic acid was coinjected with (99m)Tc-EC20.

CONCLUSIONS

Taken together, these results confirm that (99m)Tc-EC20 has the potential to be a clinically useful noninvasive radiodiagnostic agent for detecting the locus of FR-positive cancers.

After i.v. administration of d,l-, 1-5-formyltetrahydrofolate (d,l-CHO-THF) CHO-THF was rapidly cleared from the plasma by conversion to 5-methyltetrahydrofolate (5-CH3-THF) and urinary excretion, whereas d-CHO-THF, which was not metabolized and was slowly excreted in the urine, persisted in plasma at concentrations greatly exceeding those of l-CHO-THF and 5-CH3-THF. The plasma half-life (beta) of the unnatural (d) isomer was 451 +/- 24 (S.E.) min compared to 31.6 +/- 1.1 min for the natural (l) isomer, and 227 +/- 20 min for its active metabolite, 5-CH3-THF. The half-lives and volumes of distribution of each of the three compounds were independent of dose over a range of 25 to 100 mg, indicating that mechanisms for distribution, metabolism, and excretion are not saturable over the dose range tested. The urinary clearance of l-CHO-THF or 5-CH3-THF differed only slightly from creatinine clearance, whereas urinary clearance of d-CHO-THF was only one-fifth creatinine clearance, indicating that d-CHO-THF was extensively reabsorbed. Absorption of d,l-CHO-THF after p.o. administration was stereoselective in that absorption of the l-isomer was approximately 5 times that of the d isomer. Thus, p.o. administration resulted in a more favorable ratio of active to inactive folates in plasma. At a dose of 25 mg, absorption approached 100% for l-CHO-THF compared to 20% for d-CHO-THF. However, absorption was saturable, and lower percentages of both compounds were absorbed at doses of 50 and 100 mg.

BACKGROUND

In a previous phase I-II study we demonstrated that the FOLFOXIRI regimen [irinotecan 125-175 mg/m2 day 1, oxaliplatin 100 mg/m2 day 1, l-leucovorin (l-LV) 200 mg/m2 day 1, 5-fluorouracil (5-FU) 3800 mg/m2 as a 48-h chronomodulated continuous infusion starting on day 1, repeated every 2 weeks] has promising activity and efficacy in metastatic colorectal cancer. However, this regimen required a chronomodulated infusion of 5-FU, and because neutropenia occurred in 32% of cycles, granulocyte colony-stimulating factor (G-CSF) was used and the delivered dose intensity was only approximately 78% of planned. Therefore, we conducted the present phase II study in order to develop a simplified FOLFOXIRI regimen that could be more easily administered in clinical practice as well as in multicenter settings.

METHODS

A total of 32 patients with unresectable metastatic colorectal cancer received irinotecan 165 mg/m2 day 1, oxaliplatin 85 mg/m2 day 1, l-LV 200 mg/m2 day 1 and 5-FU 3200 mg/m2 as a 48-h continuous (not chronomodulated) infusion starting on day 1, repeated every 2 weeks.

RESULTS

All 32 patients were evaluated for safety and the incidence of grade 3-4 toxic effects, and the use of G-CSF seemed to be lower than with the previous FOLFOXIRI regimen: grade 4 neutropenia (34%), grade 3 diarrhea (16%), grade 3 stomatitis (6%) and grade 2-3 peripheral neurotoxicity (37%) were reported, and G-CSF was used in 23% of cycles. Delivered dose intensity was 88% of that planned, and no toxic deaths occurred. The intention-to-treat analysis for activity showed four complete responses, 19 partial responses, seven stable disease and two progressive disease, for an overall response rate of 72% (95% confidence interval 53% to 86%). Eight (25%) patients with residual liver or lung metastases were radically resected after chemotherapy. After a median follow-up of 18.1 months, the median progression-free survival is 10.8 months and median survival is 28.4 months.

CONCLUSIONS

This simplified FOLFOXIRI combination can be delivered easily in outpatient settings, with manageable toxic effects, and has very promising antitumor activity. While the safety profile seems to be improved in comparison with our previous FOLFOXIRI regimen, antitumor activity and efficacy appear to be maintained.

Adjuvant treatment of colon cancer is a relatively new concept, having been first validated less than 20 years ago. Fluoropyrimidines including 5-fluorouracil (5-FU), introduced in clinical trials in the 1950s, are an integral component of the treatment of colon cancer in the adjuvant setting. Whereas both irinotecan and oxaliplatin have demonstrated clinical activity in metastatic colorectal cancer, only oxaliplatin has demonstrated efficacy in the adjuvant setting when added to 5-FU-based therapy. Irinotecan, despite showing a survival advantage in the second-line metastatic cancer setting and a survival advantage when added to first-line metastatic cancer treatment, has failed to show a survival or disease-free survival benefit in the adjuvant setting. In contradistinction, the addition of oxaliplatin to 5-FU plus leucovorin has improved disease-free survival in 2 large randomized adjuvant trials. Oxaliplatin/5-FU/leucovorin should therefore be regarded as a reference standard for adjuvant therapy. This comprehensive review of adjuvant therapy for colon cancer will cover the role of fluoropyrimidines and oxaliplatin, the controversies of adjuvant therapy for patients with stage II cancer, and the ongoing clinical trials that will define the future role, or lack thereof, of newer agents in adjuvant therapy.

The prognosis of metastatic colorectal cancer remains poor despite advances made in recent years, particularly with new treatments directed towards molecular targets. Cetuximab, a chimeric immunoglobulin (Ig)G1 monoclonal antibody that targets the ligand-binding domain of the epidermal growth factor receptor (EGFR), is active in metastatic colorectal cancer. As an IgG1 antibody, cetuximab may exert its antitumour efficacy through both EGFR antagonism and antibody-dependent cell-mediated cytotoxicity. The benefits of cetuximab in metastatic colorectal cancer are well documented in clinical trials and are acknowledged in the approval and licensing of this agent. There is evidence of the role of cetuximab not only in irinotecan-refractory or heavily pretreated patients, but also of the efficacy and safety of the addition of this agent to FOLFIRI (irinotecan/5-fluorouracil/leucovorin) in first-line metastatic colorectal cancer, with an enhanced effect in 5-fluorouracil patients with Kirsten rat sarcoma (KRAS) wild-type tumours. In these patients, a recent meta-analysis of the pooled Cetuximab Combined with Irinotecan in First-Line Therapy for Metastatic Colorectal Cancer (CRYSTAL) and Oxaliplatin and Cetuximab in First-Line Treatment of mCRC (OPUS) patient populations confirms that the addition of cetuximab to first-line chemotherapy achieves a statistically significant improvement in the best overall response, overall survival time, and progression-free survival (PSF) compared with chemotherapy alone. In nonresectable colorectal liver metastases, cetuximab plus FOLFOX-6 (oxaliplatin/5-fluorouracil/leucovorin) or cetuximab plus FOLFIRI increased significantly resectability of liver metastases, including R0 resections. Also, preliminary data indicate that cetuximab can be administered in a more convenient 2-week schedule in combination with standard chemotherapy. Cetuximab is generally well tolerated. Acne-form rash is the most frequent toxicity. Up to the present time, the results obtained with targeted therapy combinations are not as encouraging as initially expected. The identification of biomarkers associated with disease control, including KRAS and BRAF mutation status in patients treated with cetuximab, is changing the current management of metastatic colorectal cancer. Clinical and molecular predictive markers of response are under active evaluation in order to better select patients who could benefit from cetuximab treatment, with the aim of both optimising patient outcomes and avoiding unnecessary toxicities.

Cancers of the biliary tract are rare, and remain a major challenge to surgical, medical, and radiation oncologists. Unfortunately, the large majority of these tumors are not resectable at the time of initial diagnosis, and patients with advanced disease face a dismal prognosis. The efficacy of conventional palliative systemic chemotherapy (eg, with 5-fluorouracil, mitomycin-C, and cisplatin) seems negligible, and there is presently no agreement on the best chemotherapeutic regimen. Gemcitabine is among several different new anticancer drugs under investigation in the treatment of advanced biliary tract cancer. Apart from its favorable toxicity profile, this novel nucleoside analog has shown activity in many solid tumors, including pancreatic adenocarcinoma. In view of the histogenetic affinity between the pancreas and the biliary tract, and several case reports describing the efficacy of gemcitabine in advanced gallbladder or cholangiocellular carcinoma, a number of phase II investigations have been undertaken. In the majority of these trials a conventional gemcitabine dose regimen of 1,000 to 1,200 mg/m(2) given over 30 minutes on 3 consecutive weeks followed by a week of rest has been used. In a total of seven studies involving 167 assessable patients, objective response rates up to 60% (36% in the largest trial composed of 39 evaluable patients), abrogation of progressive disease (complete response + partial response + stable disease) in 50% to 93%, and overall survival times ranging from 6.3 to 16 months, have been reported. The consensus is that the tolerance of treatment was remarkable with only exceptional patients (< or = 5%) experiencing grade 4 hematologic toxicities. Nonhematologic side effects were infrequent and almost exclusively mild to moderate. In three of the trials, a formal clinical benefit analysis was included, suggesting that a considerable proportion of symptomatic patients will experience relief of tumor-related symptoms and/or weight gain. Possible options currently being investigated to further improve the therapeutic results of gemcitabine monotherapy include modifications of the dose regimen as well as combinations with other potentially synergistic anticancer drugs. In the latter approach, preliminary data have been reported for gemcitabine plus cisplatin, oxaliplatin, docetaxel, mitomycin-C, and continuous-infusion 5-fluorouracil/leucovorin. Objective response rates as high as 53% (for gemcitabine/cisplatin), and median survival times>> or = 11 months with only a slight increase in frequency and severity of side effects have been reported. In conclusion, while the best available chemotherapeutic treatment for advanced biliary tract cancer remains to be determined, accumulating data from recent phase II trials suggest that single-agent gemcitabine represents an active and very well-tolerated treatment option. It may also be safely combined with other drugs, though further improvements in response activity and survival warrant confirmation in future randomized studies.

Until recently, fluorouracil (F) and leucovorin (L) had been considered the standard therapy for patients with colorectal cancer. However, several studies have shown that oral therapy with UFT/L or capecitabine is as effective as intravenous (i.v.) therapy and in addition it is claimed that patients prefer oral to i.v. therapy as long as efficacy is not compromised. In a previous crossover study by Borner et al., it was shown that 26 out of 31 patients preferred oral therapy with UFT/L to i.v. FL (Mayo regimen) [Borner M, Schöffski P, de Wit R, et al. Patient preferences and pharmacokinetics of oral modulated UFT versus intravenous fluorouracil and leucovorin: a randomised crossover trial in advanced colorectal cancer. Eur J Cancer 2002;38:349-58]. The objective of the present study was to investigate patient preference between i.v. FL and oral capecitabine using the design described by Borner. The Nordic FL schedule is a bolus regimen with efficacy comparable to other i.v. regimens and at the same time a very tolerable and easy administered regimen. We randomised 60 patients with colorectal cancer (53 patients received adjuvant therapy and seven patients received palliative therapy) to start therapy with either oral capecitabine or Nordic bolus FL. After 6 weeks of therapy (two courses of capecitabine or three courses of Nordic FL) patients were crossed over to the other regimen. After having completed 12 weeks of therapy the patients (49 evaluable patients) were asked to choose one of the regimens for a further 12 weeks of therapy. Patients had more side-effect when treated with capecitabine and a total of 30 out of 49 (61%) preferred the Nordic FL regimen and 19 (39%) preferred capecitabine. We conclude that patients prefer the regimen with less toxicity and that it is of minor importance whether the medication is administrated orally at home or i.v. at the hospital.

Plasma levels of folates and thymidine in mice are about 10-fold higher than in humans and may influence the therapeutic efficacy of thymidylate synthase (TS) inhibitors, such as 5-fluorouracil (5FU) and the antifolates pemetrexed (MTA) and raltitrexed (RTX). Therefore, we tested their therapeutic efficacy in various murine tumor models, grown in mice on a normal and a folate-depleted diet, with high and low thymidine kinase (TK) levels. MTA and RTX were inactive against Colon-26-10 [doubling times gained by treatment; growth delay factor (GDF), 0.5 and 0.3, respectively], whereas 5FU was very active (GDF, >10; complete cures). Colon-26-10/F, grown in mice on a folate-depleted diet, was more sensitive to RTX and MTA (GDF, 2.1 and 1.3, respectively) but not to 5FU (GDF, 1.2); however, leucovorin reversed the effect leading to cures. Folate depletion did not reverse resistance of Colon-26A and Colon-26G (low TK) to MTA and RTX, whereas leucovorin only enhanced the 5FU effect in Colon-26A and Colon-26A/F. Folic acid at 15 mg/kg did not improve the therapeutic efficacy of MTA in folate-deficient mice. The folate-depleted diet decreased the reduced folates in Colon-26A/F and Colon-26-G/F tumors less (4-5-fold; P < 0.01) than in Colon-26-10/F tumors (8-fold; P < 0.001). Folate depletion increased TS levels 2-3-fold in all of the models and TK levels 6-fold (P < 0.01) in Colon-26G/F, explaining the lack of activity of MTA and RTX in Colon-26G/F. In contrast, TK-deficient FM3A/TK tumors were much more sensitive to RTX, MTA, and 5FU than parent FM3A tumors, which have comparable TS levels. The rate of thymidine phosphorylysis varied considerably in all of the tumors without a clear relation to antitumor activity. In conclusion, tumor folates may potentiate (5FU) or protect (antifolates). Murine tumor models should combine low folates and low thymidine rescue to optimize preclinical testing of antifolates.

UNASSIGNED

The prognostic value of BRAF and KRAS mutations in patients who have undergone resection for colon cancer and have been treated with combination leucovorin, fluorouracil, and oxaliplatin (FOLFOX)-based adjuvant chemotherapy is controversial, possibly owing to a lack of stratification on mismatch repair status.

UNASSIGNED

To examine the prognostic effect of BRAF and KRAS mutations in patients with stage III colon cancer treated with adjuvant FOLFOX with or without cetuximab.

UNASSIGNED

This study included patients with available tumor blocks of resected stage III colon adenocarcinoma who participated between December 2005 and November 2009 in the PETACC-8 phase III randomized trial.Mismatch repair, BRAF V600E, and KRAS exon 2 mutational status were determined on prospectively collected tumor blocks from 2559 patients enrolled in the PETACC-8 trial. The data were analyzed in April 2015.

UNASSIGNED

Patients were randomly assigned to receive 6 months of FOLFOX4 or FOLFOX4 plus cetuximab after surgical resection for stage III colon cancer.

UNASSIGNED

Associations between these biomarkers and disease-free survival (DFS) and overall survival (OS) were analyzed with Cox proportional hazards models. Multivariate models were adjusted for covariates (age, sex, tumor grade, T/N stage, tumor location, Eastern Cooperative Oncology Group performance status).

UNASSIGNED

Among the 2559 patients enrolled in the PETACC-8 trial (42.9% female; median [range] age, 60.0 [19.0-75.0] years), microsatellite instability (MSI) phenotype, KRAS, and BRAF V600E mutations were detected in, respectively, 9.9% (177 of 1791), 33.1% (588 of 1776), and 9.0% (148 of 1643) of cases. In multivariate analysis, MSI (hazard ratio [HR] for DFS: 1.10 [95% CI, 0.73-1.64], P = .67; HR for OS: 1.02 [95% CI, 0.61-1.69], P = .94) and BRAF V600E mutation (HR for DFS: 1.22 [95% CI, 0.81-1.85], P = .34; HR for OS: 1.13 [95% CI, 0.64-2.00], P = .66) were not prognostic, whereas KRAS mutation was significantly associated with shorter DFS (HR, 1.55 [95% CI, 1.23-1.95]; P < .001) and OS (HR, 1.56 [95% CI, 1.12-2.15]; P = .008). The subgroup analysis showed in patients with microsatellite-stable tumors that both KRAS (HR for DFS: 1.64 [95% CI, 1.29-2.08], P < .001; HR for OS: 1.71 [95% CI, 1.21-2.41], P = .002) and BRAF V600E mutation (HR for DFS: 1.74 [95% CI, 1.14-2.69], P = .01; HR for OS: 1.84 [95% CI, 1.01-3.36], P = .046) were independently associated with worse clinical outcomes. In patients with MSI tumors, KRAS status was not prognostic, whereas BRAF V600E mutation was associated with significantly longer DFS (HR, 0.23 [95% CI, 0.06-0.92]; P = .04) but not OS (HR, 0.19 [95% CI, 0.03-1.24]; P = .08).

UNASSIGNED

BRAF V600E and KRAS mutations were significantly associated with shorter DFS and OS in patients with microsatellite-stable tumors but not in patients with MSI tumors. Future trials in the adjuvant setting will have to take into account mismatch repair, BRAF, and KRAS status for stratification.

UNASSIGNED

EudraCT 2005-003463-23.

Seven patients with bone or soft tissue sarcomas but without metastatic CNS disease developed a chronic leukoencephalopathy after high-dose (8000-15,000 mg/m2) iv methotrexate (MTX) chemotherapy with leucovorin (LV) rescue. Approximately 12 MTX-LV treatments were administered over a 3-7 month period. None of the patients had cranial irradiation. The syndrome usually began several months after the initiation of chemotherapy with subtle personality changes followed by a progressive dementia, focal seizures, pseudobulbar palsy, spastic quadriparesis, and stupor. Computerized tomographic scans revealed diffuse white matter hypodensity in five patients and atropic changes in five patients. Serum MTX concentrations were elevated in four of six patients prior to several MTX-LV treatments, suggesting that MTX persisted in tissues for a long time. Abnormally high levels of MTX were detected in the cerebrospinal fluid of all four patients several days after an MTX-LV treatment, at a time when their encephalopathy was most severe. Pathologic brain material was obtained from three patients and revealed a spectrum of abnormalities. The syndrome observed in our patients clinically resembles the one described in children with acute lymphatic leukemia who received cranial irradiation and large cumulative amounts of low-dose (12-20 mg/m2) systemic MTX without LV.