This report describes studies designed to evaluate possible inhibitory effects of diaminoantifolates on folate-dependent biosynthetic enzymes in intact L1210 leukemia cells. A novel approach is described which involves an assessment of the metabolism of and biosynthetic flux of the one-carbon moiety from (6S)5-formyltetrahydrofolate in folate-depleted cells. Pretreatment with methotrexate (10 microM), resulting in the formation of methotrexate polyglutamates, or continuous incubation with trimetrexate (1 microM) inhibited growth of folate-depleted L1210 cells in the presence of folic acid or 5-formyltetrahydrolate. In both control and drug-treated cells, double-labeled (6S)-5-[14C]formyl[3H]tetrahydrofolate was rapidly metabolized with the loss of the [14C]formyl group. Under all conditions, the predominant metabolite was 10-formyl[3H]tetrahydrofolate, detectable both intracellularly and extracellularly. In drug-treated cells, there was a remarkably small decrease in the level of 10-formyl[3H]tetrahydrofolate (approximately 30%) and a 10-fold rise in the level of [3H]dihydrofolate to less than 20% of the total folate pool. The incorporation of [14C]formyl group from 5-[14C]formyltetrahydrofolate into thymidylate, serine, and methionine was unaffected by the presence of 1 microM trimetrexate, consistent with the generation of sufficient 5,10-[14C]methylenetetrahydrofolate to drive these reactions. Similarly, the presence of methotrexate polyglutamates had no effect at the level of amino acid synthesis; however, carbon transfer into thymidylate was markedly inhibited. Even though 10-formyltetrahydrofolate was readily formed from 5-formyltetrahydrofolate in this model, the net incorporation of 14C from 5-[14C]formyltetrahydrofolate into purine nucleotides was inhibited by both methotrexate and trimetrexate treatments. Similar findings were obtained when [14C]glycine incorporation into purine nucleotides was monitored in cells incubated with unlabeled 5-formyltetrahydrofolate. Finally, in antifolate-treated cells incubated with unlabeled 5-formyl-tetrahydrofolate, transfer of 14C from [14C]formate or [14C]serine into biosynthetic products or incorporation of [3H]deoxyuridine into nucleic acids was potently inhibited. These results suggest that insufficient levels of tetrahydrofolate and 5, 10-methylenetetrahydrofolate were formed to drive these reactions despite the presence of high levels of 10-formyltetrahydrofolate.(ABSTRACT TRUNCATED AT 400 WORDS)

For several decades, 5-fluorouracil (5-FU) with or without leucovorin defined the standard of care for the treatment of metastatic colorectal cancer (CRC). The addition of other chemotherapy regimens to 5-FU has improved survival, but often at the expense of increased toxicity. Recent advances in our understanding of the molecular basis of CRC have led to the production of novel targeted agents, such as bevacizumab (Avastin). Bevacizumab is currently approved for the first-line treatment of metastatic CRC and is currently being tested in combination with standard therapies for a range of indications. Phase II/III trials have demonstrated that the addition of bevacizumab to 5-FU-based first-line chemotherapy improves survival, progression-free survival and response rate compared with chemotherapy alone. Combination therapy does not appear to exacerbate side effects known to be associated with the chemotherapy regimen. The most common side effects attributable to bevacizumab therapy include hypertension, proteinuria and bleeding. Although uncommon, gastrointestinal perforation and arterial thromobembolic events are the most serious side effects reported to date. Bevacizumab is currently being evaluated in combination with oxaliplatin (Eloxatin)-based therapies and preliminary data are encouraging. Ongoing trials of bevacizumab in combination with standard first-line chemotherapy regimens will evaluate bevacizumab's potential in a range of cancer types. .

Prior studies have suggested that pre-irradiation methotrexate (MTX)-based chemotherapy improves duration of response and survival in primary central nervous system lymphoma (PCNSL). To circumvent the potential emergence of drug resistance, we combined high-dose MTX with agents highly active against systemic lymphoma. Patients received three week cycles of CHOD (cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and vincristine 1.4 mg/m2 [2 mg maximum] on day 1; dexamethasone 10 mg/m2 days 1-5), and MTX (3.5 gm/m2) with leucovorin rescue on day 8 (or on recovery from the CHOD nadir). Whole brain irradiation (WBRT) was planned after at least three cycles. Eighteen patients were treated. Complete responses were seen in eleven patients, and partial responses in three. Four progressed during therapy, three succumbing to progressive disease and one subsequently responding to WBRT. Response duration was 37.5 months in those responding to therapy. The time to progression for all eighteen patients was 19.5 months. Medial survival was 25.5 months. Disease-free survival was 50% at 38 months in MCHOD responders. Grade 3 or 4 myelotoxicity was seen in 19 of 50 cycles. There were three instances of neutropenic fever, three of azotemia, two of deep vein thrombosis, and one each of community-acquired pneumonia, intracranial hemorrhage, superior vena cava syndrome, and hepatotoxicity. Late radiation-related toxicities were seen in two patients. Pre-irradiation MCHOD has activity against PCNSL, but appears to be no better than MTX monotherapy and has greater toxicity.

A correlation between osteopontin, E-cadherin, β-catenin, and cyclooxygenase 2 overexpression and poor clinicopathological features and prognosis has been previously suggested in gastric cancer. This translational study was aimed at assessing the correlation of these immunohistochemical biomarkers with outcome in patients with radically resected gastric cancer. We analyzed osteopontin, E-cadherin, β-catenin, and cyclooxygenase 2 expression by immunohistochemistry in 346 primary gastric tumor tissue samples from patients enrolled in the ITACA-S trial. This phase III study randomized patients with radically resected gastric cancer to receive adjuvant chemotherapy with either 5-fluorouracil and leucovorin or a sequential regimen of infusional 5-fluorouracil and leucovorin plus irinotecan followed by cisplatin and docetaxel. High expression of osteopontin was correlated with high histological grade, diffuse histotype, and peritoneal relapse, but not with TNM stage. Moreover, osteopontin overexpression was associated with higher risk of tumor recurrence and metastases, and was an independent prognostic factor for both relapse-free and overall survival of gastric cancer patients following adjuvant chemotherapy. Abnormal E-cadherin expression and abnormal β-catenin expression were correlated with more advanced disease stage, and as a consequence, with poor outcome. Our results suggest that osteopontin overexpression is a valuable independent predictor of tumor recurrence and survival in patients with radically resected gastric cancer.

OBJECTIVE

To investigate the tolerance and efficacy of a modified concurrent chemoradiation (CCRT) protocol for patients with invasive bladder cancer "unfit" for radical cystectomy.

METHODS

Twenty-three muscle-invasive bladder cancer patients who were unfit for or unwilling to receive radical cystectomy were enrolled in this study. All patients had transitional cell carcinoma of bladder, and distribution of stage was 14 (61%), 1 (4%), and 8 (35%) for T3a, T3b, and T4, respectively. This study included a relatively old-age population, with the median age being 75 and 70% of patients over 70 years old. Patients were treated with maximal transurethral resection of the bladder tumor followed by curative CCRT. The chemotherapy (C/T) regimen was comprised of cisplatin, 50 mg/m(2) intravenously (i.v.) on Day 1; 5-fluorouracil (5-FU), 500 mg/m(2)/day by continuous i.v. infusion on Days 1-3; and leucovorin, 50 mg/day by continuous i.v. infusion on Days 1-3. Chemotherapy course was repeated at 21-day intervals. The radiation dose was 44-45 Gy to whole pelvis and 60-61.2 Gy to bladder, with a daily fraction of 1.8-2 Gy. The completeness of the CCRT protocol was defined as patients receiving at least 55 Gy of radiotherapy to the whole bladder and at least three courses C/T.

RESULTS

Seventy-four percent of patients (17/23) completed the CCRT protocol. Radiation Therapy Oncology Group (RTOG) Grade 3 acute toxicities were observed in 4 patients, which included leucopenia, vomiting, genitourinary (GU) tract infection, and diarrhea. No treatment-related deaths occurred during the CCRT period. RTOG Grade 3 or more late complications were observed in 3 patients; one of them died of radiation cystitis superimposed with GU infection. Of the 18 patients whose response to CCRT was evaluated, a complete tumor response was documented in 16 patients (89%). With a median follow-up of 3 years, the 3-year overall survival (OS) and disease-free survival (DFS) for all patients was 69% and 65% respectively. Meanwhile, the 3-year overall and DFS rates for patients who completed CCRT vs. those who did not complete CCRT were 82% vs. 33% and 75% vs. 33%, respectively (p = 0.18 for OS and p = 0.04 for DFS).

CONCLUSIONS

Concurrent cisplatin, 5-FU, leucovorin, and radiotherapy for treatment of invasive bladder cancer is a feasible and promising treatment even for relatively old patients. Our results are comparable to those in recent studies by using combined modality treatment or neoadjuvant chemotherapy plus radical cystectomy. Consequently, this novel protocol warrants a prospective clinical trial and may be a safe, effective alternative to radical cystectomy.

OBJECTIVE

Downstaging rectal carcinoma by preoperative radiotherapy decreases local recurrence, and recent phase II studies suggest that, in the lower one-third lesions, sphincter-preserving surgery can be considered. The purpose of the current study was to assess the efficacy and the toxicity of endorectal high dose-rate brachytherapy as a preoperative downstaging treatment modality.

METHODS

Patients with newly diagnosed invasive rectal adenocarcinoma, T2 to very early T4, operable tumors were eligible. A dose of 26 Gy was given over four consecutive daily treatments of 6.5 Gy prescribed at the tumor radial margin using endorectal brachytherapy with high dose-rate delivery system. Surgery as planned initially was done four to eight weeks later to allow for tumor downstaging. Patients found to have pathologic positive nodes received postoperative external beam (45 Gy/25 fractions) to the pelvis and systemic 5-fluorouracil-leucovorin chemotherapy.

RESULTS

Forty-nine patients entered the study. Tumors were in the lower one-third in 24 patients, middle one-third in 22, and upper one-third in 3. With preoperative endorectal ultrasound and magnetic resonance imaging, the clinical staging of the tumors was: 3 T2, 42 T3, 4 T4, and 16 N1-2. Acute toxicity related to brachytherapy was limited to a moderate proctitis (Radiation Therapy Oncology Group acute toxicity scoring system, Grade 2) in all patients, with two patients with tumors extending into the anal canal having Grade 3 dermatitis. Forty-seven patients underwent surgery. Two patients refused their operation based on a normal endoscopic rectal ultrasound after treatment. A complete clinical response was obtained in 32 of 47 (68 percent) patients with 32 percent pathologically pT0N0-1, and 36 percent had only residual microfoci of carcinoma. The surgical approaches did not yield more complications than expected.

CONCLUSIONS

Preoperative high dose-rate endorectal brachytherapy seems to be safe, because acute toxicity was mainly local, with moderate proctitis (Grade 2) and occasional dermatitis (Grade 3) for very low tumors. Finally, this modality, by providing high rate of tumor downstaging and downsizing especially for patients with lesions in the lower one-third of the rectum, represents a definite potential for sphincter-preserving surgery for investigation in future studies.

Adjuvant therapy with chemotherapy and/or radiation therapy in addition to surgery improves outcome for patients with high-risk carcinomas of the colon or rectum. For colon cancer, fluorouracil (5-FU) combined with leucovorin is a current standard of care that improves long-term survival. A recent European trial (MOSAIC) has documented significant improvement in 3-year disease-free survival when oxaliplatin (Eloxatin) was added to infusional 5-FU and leucovorin in the FOLFOX regimen. Two US cooperative group trials will evaluate the addition of antiangiogenesis therapy with bevacizumab (Avastin) to chemotherapy. A third trial will evaluate FOLFOX, irinotecan (Camptosar) combined with infusional 5-FU and leucovorin (FOLFIRI), and the sequential use of FOLFOX followed by FOLFIRI. In rectal cancer, postoperative 5-FU-based chemotherapy combined with irradiation can improve both local tumor control and survival. The German Rectal Cancer Group has recently reported that preoperative combined-modality therapy is less toxic and more effective in preventing local tumor relapse compared to similar treatment given postoperatively. A coordinated pair of cooperative group clinical trials will evaluate oral capecitabine (Xeloda) as a radiation enhancer in the preoperative setting, and the FOLFOX and FOLFIRI regimens compared to 5-FU and leucovorin following surgery. Predictive and prognostic molecular markers will be studied in these new adjuvant therapy clinical trials for both colon and rectal cancer with the goal of developing future regimens tailored to individual patients. There has been a recent and dramatic increase in the pace of drug development for colorectal cancer which holds promise to further improve curative therapy as part of a multidisciplinary approach in the surgical adjuvant setting.

With a resurgence of interest in leucovorin calcium (LV), many questions about its role in cancer chemotherapy are being asked again. How does it modulate 5-fluorouracil (5-FU) therapy? Can it potentiate the cytotoxicity of 5-FU more in malignant than in normal cells? Does it rescue tumor cells from high-dose methotrexate (MTX) more than it does normal cells? How should LV rescue be individualized to maximize the therapeutic index? When can LV be administered orally, and how can LV rescue be conducted at home? When is LV rescue necessary, and what toxicities occur when it is inadequate? Some answers to these questions are provided in this review.

OBJECTIVE

This Phase I study was designed to determine a safe combination dose of 5-fluorouracil (5-FU) and arsenic trioxide (ATO) to treat 5-FU-resistant relapsed/refractory colorectal cancer patients. We studied the effect of ATO in the downregulation of thymidylate synthase (TS) in peripheral blood mononuclear cells and in tumor biopsies.

METHODS

ATO was administered for 5 consecutive days during the first week and twice during weeks 2 to 3 and once on week 4. 5-FU/leucovorin (LV) was administered on days 8, 15, and 22. A modified accelerated titration design was used. 5-FU was dose escalated first followed by a planned dose increase for ATO.

RESULTS

No dose-limiting toxicities were seen in seven patients who received 0.15 mg/kg ATO; grade 3 toxicities were as follows: neutropenia 1, diarrhea 1, and bowel obstruction 1. In patients receiving 0.20 mg/kg ATO, grade 3 toxicities were QTc prolongation 1, fatigue 4, alkaline phosphatase elevation 2, diarrhea 2, and peripheral edema 1. TS gene expression in peripheral blood mononuclear cell decreased in all patients. Eight tumors were biopsied, four showed TS downregulation, three showed upregulations, and one did not change. Estimated median progression-free survival and overall survival were 3.1 and 13.9 months, respectively. In patients who showed TS increase or no change versus TS reduction, estimated median progression-free survival was 2.6 versus 7.9 months (P = 0.188) and overall survival was 8.6 versus 11.7 months (P = 0.44), respectively.

CONCLUSIONS

Thus, we determined 0.20 mg/kg ATO, 2,600 mg/m(2) 5-FU, and 500 mg/m(2) leucovorin (LV) to be the recommended phase II dose.

OBJECTIVE

To evaluate the efficacy and tolerability of the metastatic irinotecan plus oxaliplatin (MIROX) strategy (adjuvant FOLFOX-7 followed by FOLFIRI), in patients with resectable metastatic colorectal cancer.

METHODS

Forty-seven patients with resectable metastases of colorectal cancer were prospectively enrolled onto this study. Treatment consisted of six cycles of leucovorin 400 mg/m(2), oxaliplatin 130 mg/m(2) in a 120-minute infusion, and fluorouracil (FU) 2,400 mg/m(2) in a 46-hour infusion, every 2 weeks (FOLFOX-7), followed by six cycles of leucovorin 400 mg/m(2), irinotecan 180 mg/m(2) in a 90-minute infusion, bolus FU 400 mg/m(2), and FU 2,400 mg/m(2) as a 46-hour infusion, every 2 weeks (FOLFIRI). Surgery was performed before chemotherapy in 25 patients and after six cycles of FOLFOX-7 in 22 patients (six cycles of FOLFIRI were administered after surgery).

RESULTS

All but one of the patients underwent curative surgery. Two patients refused postoperative chemotherapy. Tolerability was generally good. The main toxicities were grade 3 to 4 neutropenia (13%) and thrombocytopenia (11%); no febrile neutropenia or bleeding occurred, and there were no deaths caused by toxicity. Two pathologically confirmed complete responses and 15 partial responses were obtained with FOLFOX-7 in the 22 patients who received this regimen before surgery (overall response rate, 77%; 95% CI, 68 to 86). The median disease-free survival time was 21 months; the median overall survival has not yet been reached. The 2-year overall and disease-free survival rates were 89% and 47%, respectively.

CONCLUSIONS

The MIROX strategy is feasible and well tolerated by patients with resectable metastatic colorectal cancer. Progression-free and overall survival rates are promising, with a median of 38 months of follow-up. This strategy currently is being compared with the leucovorin and FU regimen in a phase III trial.

OBJECTIVE

Patients who undergo resection of liver metastases from colorectal cancer have an average 2-year survival of 65%. With hepatic arterial infusion (HAI) plus systemic fluorouracil and leucovorin, 2-year survival increased to 86%. For further improvement in both local and systemic control, combinations of new systemic drugs with HAI are being explored. The purpose of this study was to determine the maximum-tolerated dose (MTD) of systemic irinotecan (CPT-11) and HAI floxuridine (FUDR) plus dexamethasone (DEX) as combination adjuvant therapy after liver resection.

METHODS

Ninety-six patients who underwent complete resection of liver metastases from colorectal cancer were treated with six monthly cycles of HAI FUDR plus DEX for 14 days of each 4-week cycle plus escalating doses of systemic CPT-11. The primary end points of the phase I/II study were the MTD and efficacy of this regimen.

RESULTS

The MTD for combined systemic CPT-11 and HAI FUDR was CPT-11 at 200 mg/m2 every other week and FUDR at 0.12 mg/kg x pump volume / pump flow rate. The dose-limiting toxicities were diarrhea and neutropenia. With a median follow-up time of 26 months, the 2-year survival rate is 89%. All of the 27 patients who were treated at the MTD are alive.

CONCLUSIONS

In patients who undergo resection of liver metastases from colorectal cancer, adding systemic CPT-11 to HAI therapy in an adjuvant regimen is feasible. This regimen seems to have comparable activity to fluorouracil and leucovorin, but further studies are needed to assess whether it improves local control or decreases extrahepatic recurrences.

There are several treatment options for patients with metastatic colorectal cancer (mCRC), including those with disease that has progressed after treatment with chemotherapy. Bevacizumab-containing regimens show good efficacy in patients with previously treated disease. Compared with infused 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX-4), overall survival and progression-free survival are significantly longer with FOLFOX-4 in combination with bevacizumab as second-line treatment in patients with advanced or mCRC. In addition, the response rates and time to progression are greater with the combination of bevacizumab, cetuximab, and irinotecan in patients with irinotecan-refractory mCRC compared with cetuximab and irinotecan therapy. This combination is well tolerated, with no additive toxicities reported. The role of bevacizumab in the treatment of patients with disease refractory to 5-fluorouracil, irinotecan, and oxaliplatin is less clear, owing to inconclusive results in a multicenter study in this population. More research is necessary to determine the efficacy of combinations with bevacizumab in the third- and later-line settings. However, bevacizumab clearly provides significant clinical benefits in previously treated patients with mCRC. On the basis of these benefits and in addition to its approval in the first-line setting, bevacizumab in combination with intravenous 5-fluorouracil-based chemotherapy recently received US Food and Drug Administration approval for the second-line treatment of patients with mCRC.

This randomised phase II study evaluates the safety and efficacy profile of uracil/tegafur/leucovorin combined with irinotecan (TEGAFIRI) or with oxaliplatin (TEGAFOX). One hundred and forty-three patients with measurable, non-resectable metastatic colorectal cancer were randomised in a multicentre study to receive TEGAFIRI (UFT 250 mg m(-2) day days 1-14, LV 90 mg day days 1-14, irinotecan 240 mg m(-2) day 1; q21) or TEGAFOX (UFT 250 mg m(-2) day days 1-14, LV 90 mg day days 1-14, oxaliplatin 120 mg m(-2) day 1; q21). Among 143 randomised patients, 141 were analysed (68 received TEGAFIRI and 73 TEGAFOX). The main characteristics of the two arms were well balanced. The most common grade 3-4 treatment-related adverse events were neutropenia (13% of cases with TEGAFIRI; 1% in the TEGAFOX group). Diarrhoea was prevalent in the TEGAFIRI arm (16%) vs TEGAFOX (4%). Six complete remission (CR) and 19 partial remission (PR) were recorded in the TEGAFIRI arm (odds ratio (OR): 41.7; 95% confidence limit (CL), 29.1-55.1%), and six CR and 22 PR were recorded in the TEGAFOX group, (OR: 38.9; 95% CL, 27.6-51.1). At a median time follow-up of 17 months (intequartile (IQ) range 12-23), a median survival probability of 20 and 19 months was obtained in the TEGAFIRI and TEGAFOX groups, respectively. Median time to progression was 8 months for both groups. TEGAFIRI and TEGAFOX are both effective and tolerable first-line therapies in MCRC patients. The employment of UFT/LV given in doublet combination is interesting and the presented data appear comparable to equivalent infusion regimens described in the literature. The safety profile of the two combinations also allows an evaluation with other biological agents such as monoclonal antibodies.

Although immunotherapy has shown promising results in the treatment of cancer, clinical studies assessing immunologic approaches in patients with advanced cancer will seldom be conducted in the absence of conventional treatment strategies such as chemotherapy. Here we investigate the combination of chemotherapy with CpG oligonucleotide and dendritic cell-based immunotherapy in the C26 mouse model of colon carcinoma. The coinjection of antigen-pulsed, mature dendritic cells and CpG oligonucleotides together with a peritumoral injection of CpG oligonucleotides elicits a CD8 T-cell response resulting in tumor rejection and long-term protection in the C26 model. Tumor-bearing mice were treated weekly for 4 weeks by this immunotherapy protocol, by 5-fluorouracil plus leucovorin or irinotecan, or by the combination of immunotherapy and chemotherapy. We observed that immunotherapy was more effective in reducing tumor growth and increasing survival than 5-fluorouracil or irinotecan. Immunotherapy was well tolerated, whereas therapeutic doses of 5-fluorouracil or irinotecan were associated with dose-limiting toxicity. Furthermore, the efficacy of immunotherapy combined with either 5-fluorouracil or irinotecan was similar to that of immunotherapy alone. Addition of immunotherapy to either 5-fluorouracil or irinotecan treatment strongly decreased the toxicity of chemotherapy. Immunotherapy both with and without chemotherapy generated a memory immune response, leading to tumor rejection in mice rechallenged with C26 tumor cells up to several months after treatment. In summary, immunotherapy with a combination of dendritic cells and CpG oligonucleotides is superior to chemotherapy in the C26 tumor model. This immunotherapy protocol can be combined with current chemotherapy agents with no loss in therapeutic activity.

The purpose of this study was to evaluate the maximum tolerated dose (MTD) and recommended dose of oxaliplatin given synchronously with 5-fluorouracil (5FU), leucovorin (LV) and preoperative pelvic radiation for primary unresectable, locally advanced, rectal cancer. Preoperative pelvic radiotherapy using a three- or four-field technique and megavoltage photons comprised 45 Gy given in 25 fractions, 1.8 Gy per fraction, and delivered with escalating doses of oxaliplatin in combination with low-dose LV and 5FU. Chemotherapy was given synchronously with radiotherapy in weeks 1 and 5. Escalating doses of oxaliplatin (85, 130 and 150 mg m(-2)) were given on days 2 and 30, followed by low-dose LV (20 mg m(-2)) and 5FU (350 mg m(-2)), both given on days 1-5 and 29-33. Surgery was performed 6-10 weeks later. The MTD was determined as the dose causing more than a third of patients to have a dose-limiting toxicity (DLT). Once the MTD was reached, a further 14 patients were treated at the dose level below the MTD. In all, 32 patients received oxaliplatin at the three dose levels, median age 60 years (range 31-79), 24 males and eight females. The MTD was reached at 150 mg m(-2) when four out of six patients experienced DLT. Dose-limiting grade 3 or 4 diarrhoea was reported in two out of six patients at 85 mg m(-2), 5 out of 20 at 130 mg m(-2) and four out of 6 at 150 mg m(-2). Grade 3 neuropathy was reported at 130 mg m(-2) (1 out of 20) and at 150 mg m(-2) (two out of six), and serious haematological toxicity was minimal; one grade 3 anaemia at 150 mg m(-2). In all, 28 out of 32 patients completed all treatments as planned; three had radiotherapy interrupted and three a chemotherapy dose reduction. Four patients did not proceed to surgery due to the presence of metastatic disease (two), unfitness (one) or patient refusal (one). Also, 28 patients underwent surgical resection. Histopathology demonstrated histopathological complete response (pCR) 2 out of 27 (7%), Tmic 3 out of 27 (11%), pCR+Tmic 5 out of 27 (19%), pT0-2 6 out of 27 (22%) and histologically confirmed clear circumferential resection margins in 22 out of 27 (81%). Dose-limiting toxicity with oxaliplatin is 150 mg m(-2) given days 2 and 30 when added to the described 5FU LV and 45 Gy radiation preoperatively. The acceptable toxicity and compliance at 130 mg m(-2) recommend testing this dose in future phase II studies. The tumour downstaging and complete resection rates are encouragingly high for this very locally advanced group.

OBJECTIVE

Treatment options for advanced or metastatic gastric cancer (A/MGC) are limited and inclusion of novel substances is necessary. Few studies have confirmed the activity and tolerability of the combination of oxaliplatin (OXA) and 5-fluorouracil (5-FU) modulated with leucovorin (LV) administrated to patients with A/MGC. The goal of current study was to evaluate the efficacy and toxicity of Folfox-4 regimen in patients with A/MGC.

METHODS

Fifty-six patients were treated with Folfox-4 regimen. Treatment was continued until disease progression, unacceptable toxicity or until a patient chose to discontinue treatment. Responses to treatment and toxicity were recorded according to the WHO criteria and NCI toxicity criteria.

RESULTS

All patients were assessable for toxicity and response. Patients (71.4% male, 28.6% female) had a median age of 65 years (range, 28-78). All patients had histologically confirmed metastatic (89.3%) or advanced (10.7%) gastric cancer. Response was evaluated every 6 weeks; 1 complete (1.8%) and 23 (41.1%) partial remission were observed (overall response rate 42.9%). Twenty patients (35.7%) showed stable disease and 12 (21.4%) had a progressive disease. Median overall survival, time to progression and follow up were 10 months, 6 months, and 11.5 months, respectively. WHO grade 3 or 4 hematologic toxicities included leucopenia, neutropenia, thrombocytopenia, and anemia. No patient experienced neutropenic fever. Other grade 3/4 toxicities included nausea, vomiting, diarrhea, stomatitis, and anorexia. Three patients (5.3%) experienced grade 3 peripheral neuropathy. No treatment-related deaths were recorded.

CONCLUSIONS

Folfox-4 regimen is active and well tolerated in patients with advanced/metastatic gastric cancer.

OBJECTIVE

To determine whether high-dose infusional fluorouracil (FU) is effectively modulated by leucovorin (LV), interferon (IFN) alpha-2b, or both when given to patients with metastatic colorectal cancer.

METHODS

Patients (n = 236) with progressive, measurable disease were randomized to three groups and received FU 2,600 mg/m2 as a 24-hour continuous infusion (CI) weekly for 6 weeks with 2 weeks rest (FU24h) and LV 500 mg/m2 as a 2-hour infusion before FU or IFN 3 x 10(6) U subcutaneously 3 times weekly or both. Treatment continued until progressive disease or unacceptable toxicity was observed. Pairs of treatment arms were analyzed sequentially to detect equivalence or a 25% difference in response rates.

RESULTS

The rate of objective remission in patients who received FU24h/LV (44%; 40 of 91) was significantly higher than in patients who received FU24h/IFN (18%; 16 of 90; P < .05). The response rates of patients who received FU24h/LV versus FU24h/LV/IFN (27%; 13 of 49) were statistically equivalent. Significant differences were observed for time to tumor progression (TTP) (FU24h/LV, 7.1 months; FU24h/IFN, 3.9 months; FU24h/LV/IFN, 6.3 months; global P value < .009) and survival (16.6 months, 12.7 months, 19.6 months, respectively; global P value < .04). Unpredictable and life-threatening toxicity in the FU24h/LV/IFN arm required dose reduction of FU to 2,000 mg/m2/day and early stoppage of this arm. Toxicity was manageable in patients who received both FU24h/LV (grade 3 to 4 diarrhea, 21%) and FU24h/IFN (grade 3 to 4 diarrhea, 15%).

CONCLUSIONS

Response rate, TTP, and overall survival were superior for LV-containing regimens compared with IFN modulation alone. The addition of IFN to high-dose infusional FU plus LV offers no advantage and may increase toxicity. The regimen of high-dose infusional FU24h/LV warrants further evaluation in patients with metastatic colorectal cancer.

In advanced gastric cancer, we investigated feasibility and activity of sequential chemotherapy with docetaxel after an intensive weekly regimen consisting of cisplatin, epidoxorubicin, fluorouracil, leucovorin (PELF) plus filgrastim. Chemotherapy-naive patients with relapsed or metastatic gastric cancer received 8 weekly administrations of chemotherapy with cisplatin 40 mg/m(2), fluorouracil 500 mg/m(2), epidoxorubicin 35 mg/m(2), 6S-stereoisomer of leucovorin 250 mg/m(2) and glutathione 1.5 g/m(2). On the other days filgrastim 5 microg kg(-1) was administered by subcutaneous injection. Subsequently, patients with partial response or stable disease received 3 cycles of docetaxel 100 mg/m(2) every 3 weeks. 40 patients have been enrolled and they are evaluable for response and toxicity. After the PELF regimen, 3 patients achieved complete response, 13 patients showed partial response, 21 patients had stable disease and 3 patients progressed (40% response rate; 95% CI 25% to 55%). After docetaxel, 9 out 34 patients improved the outcome (26.5%); 7 patients with stable disease achieved partial response and 2 patients with partial response achieved complete response. The overall response rate in the 40 patients was 57.5% (95% CI, 42.5% to 72.5%). The PELF regimen did not cause any grade IV toxicity, the most frequent grade III acute side-effects were thrombocytopenia and vomiting which occurred in the 10% of 320 PELF cycles. Docetaxel caused grade III-IV neutropenia and thrombocytopenia in the 10% and the 19% of cycles respectively. Fatigue was a frequent side-effect during both PELF and docetaxel chemotherapy. The sequential application of docetaxel after PELF chemotherapy gained major objective responses with manageable toxicity. This strategy is worth of further investigation in the setting of palliative or neoadjuvant chemotherapy.

A phase II trial of 5-fluorouracil (5-FU) [250-450 mg/m2/day x 5 days as an intravenous (IV) bolus] combined with calcium leucovorin (500 mg/m2/day x 5 1/2 days by continuous IV infusion) administered on a 28-day schedule was performed in 15 patients with advanced hepatocellular carcinoma. The median age was 58 years; performance status ranged from 50 to 100%. Of 15 evaluable patients, 1 (7%) had a partial response lasting 2.4 months; 8 (53%) had stable disease with a median duration of 5.7 months; and 6 (40%) had progressive disease with a median time to progression of 2.7 months. Median survival was 3.8 months. Treatment with 5-FU and calcium leucovorin was moderately well tolerated; 9% of the treatment courses were complicated by grade 3 or 4 hematological toxicity, and 10% of the courses were complicated by grade 3 or 4 gastrointestinal toxicity. Despite the efficacy of the combination of 5-FU and leucovorin in advanced colorectal cancer, our results document the general resistance of hepatocellular carcinoma to modulated 5-FU.

OBJECTIVE

The aim of this phase II study was to determine the efficacy and tolerability of the bimonthly, pharmacokinetically intensified LV5FU2 regimen in the treatment of metastatic colorectal cancers.

METHODS

A total of 53 patients (23% second-line; 25 male/28 female; mean age 67 years; WHO performance status 0 in 38, 1 in 10 and 2 in 5) were treated in cycle 1 with the standard LV5FU2 regimen (leucovorin 200 mg/m2 per day followed by a 5-FU bolus 400 mg/m2 per day and a 22-h 5-FU continuous infusion 600 mg/m2 per day for two consecutive days every 2 weeks), and the AUC in mg.h/l.m2 was calculated. For cycle 2, according to a predefined schedule depending on the cycle-1 AUC value, in the absence of grade 3 toxicity, the 5-FU infusion dose was increased by 150% for AUC < or =5, by 100% for AUC >5-10, by 50% for AUC >10-15, and by 25% for AUC >15-20. 5-FU plasma concentrations were determined using high-performance liquid chromatography. A Bayesian methodology was used to assess individual pharmacokinetic parameters using the NONMEM computer program.

RESULTS

Among the 53 eligible patients, 87% (per-protocol population) received an increased dose in cycle 2 and 72% received the same dose. The median relative dose intensity was 1.28 (range 0.5-1.54) compared with the non-adapted theoretical total 5-FU dose. The objective response rate was 37% (95% CI 23-50%) in the intention-to-treat population and 47% (95% CI 29-65%) in the first-line per-protocol population. The median response duration was 10.4 months. The median progression-free survival (PFS) and overall survival (OS) were, respectively, 7 and 18.6 months. PFS and OS in first-line per-protocol patients were, respectively, 9.2 and 20 months. No deaths were attributed to toxicity of 5-FU despite the high doses administered. Of the 53 patients, 19% experienced gastrointestinal and 30% haematological grade 3/4 toxicities. Hand-foot syndrome was common but mild (grade 3 in one patient).

CONCLUSIONS

This strategy could be compared in a phase III trial with the standard LV5FU2 regimen.

OBJECTIVE

To explore genes of the killer-cell immunoglobulin-like receptor (KIR) and of the HLA ligand and their relationship with the outcome of metastatic colorectal cancer (mCRC) patients treated with first-line 5-fluorouracil, leucovorin, and irinotecan (FOLFIRI).

METHODS

A total of 224 mCRC patients were screened for KIR/HLA typing. The determination of the KIR/HLA combinations was based upon the gene content and variants. Genetic associations with complete response (CR), time to progression (TTP) and overall survival (OS) were evaluated by calculating odds and hazard ratios. Multivariate modeling with prognostic covariates was also performed.

RESULTS

For CR, the presence of KIR2DL5A, 2DS5, 2DS1, 3DS1, and KIR3DS1/HLA-Bw4-I80 was associated with increased CR rates, with median ORs ranging from 2.1 to 4.3, while the absence of KIR2DS4 and 3DL1 was associated with increased CR rates (OR 3.1). After univariate analysis, patients that underwent resective surgery of tumor, absence of KIR2DS5, and presence of KIR3DL1/HLA-Bw4-I80 showed a significant better OS (HR 1.5 to 2.8). Multivariate analysis identified as parameters independently related to OS the type of treatment (surgery; HR 2.0) and KIR3DL1/HLA-Bw4-I80 genotype (HR for T-I80 2.7 and for no functional KIR/HLA interaction 1.8). For TTP, no association with KIR/HLA genes was observed.

CONCLUSIONS

This study, for the first time, evidences that the genotyping for KIR-HLA pairs are found predictive markers associated with complete response and improves overall survival prediction of FOLFIRI treatment response in metastatic colorectal cancer. These results suggest a role of the KIR/HLA system in patient outcome, and guide new research on the immunogenetics of mCRC through mechanistic studies and clinical validation.

BACKGROUND

Although surgical resection is the only curative therapeutic option for recurrent or metachronous pancreatic carcinomas, most such cancers are beyond surgical curability. We herein report on two rare cases of remnant pancreatectomy used to treat recurrent or metachronous pancreatic carcinomas.

METHODS

CASE#1 A 65-year-old male developed weight loss and diabetes mellitus 83 months after a pylorus-preserving pancreaticoduodenectomy followed by two years of adjuvant chemotherapy (5-fluorouracil plus leucovorin plus mitomycin C) for a pancreatic carcinoma in the head of the pancreas (stage IA). An abdominal CT scan revealed a 3 cm tumor in the remnant pancreas which appeared as a 'hot' nodule on FDG-PET. A remnant distal pancreatectomy was performed and a pancreatic carcinoma similar in profile to the primary lesion (stage IIB) was confirmed pathologically. CASE#2 A 67-year-old male showed increased CA 19-9 levels 25 months after a distal pancreatectomy for a pancreatic carcinoma in the body of the pancreas (stage IA). An abdominal CT scan revealed a cystic lesion in the cut end of the pancreas which appeared as a 'hot' nodule on FDG-PET. A remnant proximal pancreatectomy with duodenectomy was performed and a metachronous pancreatic carcinoma (stage III) was confirmed pathologically.

CONCLUSIONS

Remnant pancreatectomy can be considered a treatment option for recurrent or metachronous pancreatic carcinomas. FDG-PET can play a key role in detecting remnant pancreatic carcinomas.

Purpose After curative resection of gastric or gastroesophageal junction adenocarcinoma, Intergroup Trial 0116 (Phase III trial of postoperative adjuvant radiochemotherapy for high risk gastric and gastroesophageal junction adenocarcinoma: Demonstrated superior survival for patients who received postoperative chemoradiotherapy with bolus fluorouracil (FU) and leucovorin (LV) compared with surgery alone. CALGB 80101 (Alliance; Phase III Intergroup Trial of Adjuvant Chemoradiation After Resection of Gastric or Gastroesophageal Adenocarcinoma) assessed whether a postoperative chemoradiotherapy regimen that replaced FU plus LV with a potentially more active systemic therapy could further improve overall survival. Patients and Methods Between April 2002 and May 2009, 546 patients who had undergone a curative resection of stage IB through IV (M0) gastric or gastroesophageal junction adenocarcinoma were randomly assigned to receive either postoperative FU plus LV before and after combined FU and radiotherapy (FU plus LV arm) or postoperative epirubicin, cisplatin, and infusional FU (ECF) before and after combined FU and radiotherapy (ECF arm). Results With a median follow-up duration of 6.5 years, 5-year overall survival rates were 44% in the FU plus LV arm and 44% in the ECF arm ( Plogrank = .69; multivariable hazard ratio, 0.98; 95% CI, 0.78 to 1.24 comparing ECF with FU plus LV). Five-year disease-free survival rates were 39% in the FU plus LV arm and 37% in the ECF arm ( Plogrank = .94; multivariable hazard ratio, 0.96; 95% CI, 0.77 to 1.20). In post hoc analyses, the effect of treatment seemed to be similar across all examined patient subgroups. Conclusion After a curative resection of gastric or gastroesophageal junction adenocarcinoma, postoperative chemoradiotherapy using a multiagent regimen of ECF before and after radiotherapy does not improve survival compared with standard FU and LV before and after radiotherapy.

Options for first-line chemotherapy in patients with metastatic colorectal carcinoma have broadened considerably with the introduction of irinotecan and oxaliplatin. Furthermore, the oral fluoropyrimidine capecitabine has demonstrated efficacy in Phase III trials and recently was approved for first-line treatment in Europe and the United States. Capecitabine yielded similar median times to disease progression and median survival rates compared with bolus 5-fluorouracil (5-FU)/leucovorin (LV) (Mayo Clinic/North Central Cancer Treatment Group regimen), with superior and similar response rates, respectively. However, its role as a first-line, single-agent substitute for intermittent infusional 5-FU/LV remains to be defined. The addition of irinotecan or oxaliplatin to 5-FU/LV resulted in improved response rates and progression-free survival in large, randomized trials; moreover, irinotecan-containing regimens resulted in improved overall survival. Prevalent regimens of irinotecan/5-FU/LV and oxaliplatin/5-FU/LV have been compared in two randomized Phase III trials. One study demonstrated the statistical superiority of oxaliplatin/infusional 5-FU/LV over irinotecan/bolus 5-FU/LV in terms of response, time to disease progression, and median survival; however, those advantages may have been attributable to infusional administration or to major differences in second-line therapy. A randomized Phase III study comparing irinotecan and oxaliplatin in combination with the same infusional 5-FU/LV regimens and crossover in case of disease progression showed equivalent efficacy for both schedules in the first-line setting, but the irinotecan combination proved beneficial in terms of safety. New molecular targeted agents, such as angiogenesis-modulating compounds (e.g., bevacizumab) and epidermal growth factor receptor inhibitors (e.g., cetuximab), are under clinical investigation. This review updates current systemic frontline treatments and future perspectives for patients with advanced colorectal carcinoma.