A randomized prospective clinical trial involved 259 cases of advanced recurrent Stage III and IV epidermoid cancers of the head and neck. The cases were randomized among three treatment programs evaluating two dose schedules and a combination treatment of methotrexate. The treatments consisted of: weekly methotrexate, biweekly methotrexate with leucovorin rescue (ML), and biweekly ML combined with cyclophosphamide and cytosine arabinoside (MLCC). Equivalent overall drug-related toxicity was produced with a 5% drug-related fatality rate. Methotrexate alone produced significantly more skin and mucosal toxicity, and the combination (MLCC) resulted in more hematologic toxicity than other treatments. Complete and partial objective responses were achieved in 26%, 24%, and 18% by each treatment. Methotrexate alone produced a median duration of response and 105 days compared with 42 and 49 days from the other treatments. Duration of response was significantly longer and survival was better in the methotrexate-alone group. Response was markedly stage dependent; 40% of Stage III patients achieved response, whereas only 17% of Stage IV patients responded. Presence of visceral metastases decreased response rates and the likelihood of response was particularly compromised by pulmonary metastatic spread; only seven of 54 such patients responded. Decreased survival was related to non-ambulatory performance status, disease-free intervals of less than one year and weight loss. Survival differences between Stage III and IV patients could not be shown. This study demonstrates the therapeutic superiority of weekly i.v. treatment with methotrexate but failed to support claims of an improved therapeutic index for high-dose methotrexate with leucovorin rescue. As the only randomized prospective clinical trial of chemotherapy in advanced head and neck cancer, this study reinforces the weekly i.v. schedule of methotrexate as the standard against which other drug schedules and drug combinations should be compared.

A Phase I study was performed to determine the maximum tolerated dose (MTD), toxicities, and pharmacokinetic profile of irinotecan (CPT-11) and its active metabolites when given on a once-every-3-week schedule. Thirty-four patients with advanced refractory solid malignancies were treated with CPT-11 (240-340 mg/m2) administered as a 90-min i.v. infusion every 3 weeks. Patients were divided into two groups: those with and those without prior abdominal/pelvic (AP) radiotherapy. Gastrointestinal toxicity (nausea, vomiting, and diarrhea) and hematological toxicity (leukopenia and neutropenia) were dose-limiting side effects. Other common toxicities included anorexia, asthenia, and acute cholinergic symptoms (abdominal cramps, diaphoresis, and lacrimation). For patients with no prior AP radiation therapy, the MTD was determined to be 320 mg/m2, whereas those with prior AP radiation therapy had a MTD of 290 mg/m2. Dose-proportional increases in the mean area under the concentration-time curves for CPT-11, SN-38, and SN-38G were not observed over the narrow dose range studied. Mean values of terminal phase half-life, clearance, terminal phase volume of distribution, and steady-state volume of distribution for CPT-11 were 12.4 +/- 1.8 h, 13.0 +/- 3.8 liters/h/m2, 234 +/- 83 liters/m2, and 123 +/- 38 liters/m2, respectively. The pharmacodynamic analyses indicated the strongest correlation to be between SN-38 area under the concentration-time curves and neutropenia (p = 0.60; P = 0.001). A total of five responses (one complete response and four partial responses) were observed in the cohort of 32 patients with previously treated metastatic colorectal carcinoma. In conclusion, gastrointestinal toxicity and hematological toxicity were the dose-limiting toxicities of CPT-11 when administered as a 90-min infusion every 3 weeks. In this trial, the recommended Phase II starting dose for patients with no prior AP radiation therapy was found to be 320 mg/m2; for patients with prior AP radiation, the recommended Phase II starting dose was 290 mg/m2. This once-every-3-week schedule has been incorporated into a Phase I trial of CPT-11 combined with 5-fluorouracil and leucovorin.

The benefit of adjuvant therapy, such as 5-fluorouracil (5-FU) combined with leucovorin, is a matter of debate for patients with Dukes' B colon cancer. Several approaches have been taken to address this issue. Initially, studies were conducted to assess treatment benefits in both Dukes' B and Dukes' C patients. These studies identified an overall benefit of adjuvant treatment and enrolled enough Dukes' C patients to determine a treatment benefit for adjuvant 5-FU/leucovorin in this subpopulation. However, the individual studies were insufficiently powered to detect a treatment benefit in Dukes' B patients. An analysis of four separate studies (National Surgical Adjuvant Breast and Bowel project) compared the benefit of adjuvant treatment in Dukes' B patients with that in Dukes' C patients and showed similar relative reductions in mortality and disease-free survival in Dukes' B and in Dukes' C patients. The Liver Infusion Meta-Analysis Group also reported similar relative benefits from a portal vein infusion of 5-FU-based chemotherapy in Dukes' B and Dukes' C patients. The International Multicenter Pooled Analysis of Colon Cancer Trials B2 study, which combined data from patients with Dukes' B colon cancer in five separate trials, failed to show a statistically significant benefit of adjuvant 5-FU/leucovorin compared with surgery alone. We review the advantages and limitations of different approaches to detect treatment benefits in patients with Dukes' B colon cancer, and we argue that there is a need for a meta-analysis of all adjuvant trials to reliably address this question.

BACKGROUND

The aim of the study was to evaluate the efficacy and toxicity of neoadjuvant chemotherapy with intravenous (i.v.) cisplatin and fluorouracil (5-FU), surgery and postoperative intraperitoneal (i.p.) floxuridine (FUdR) and leucovorin (LV) in patients with locally advanced gastric cancer.

METHODS

Preoperative staging was confirmed by laparoscopy (LAP). Two cycles of i.v. cisplatin (20 mg/m(2)/day, rapid infusion) and 5-FU (1000 mg/m(2), continuous 24-h infusion), given on days 1-5 and 29-34, were followed by a radical gastrectomy and a D2 lymphadenectomy. Patients having R0 resections were to receive three cycles of i.p. FUdR (1000 mg/m(2)) and LV (240 mg/m(2)), given on days 1-3, 15-17 and 29-31. Intraperitoneal chemotherapy was begun 5-10 days from surgery.

RESULTS

Thirty-eight patients were treated. Both preoperative and postoperative chemotherapy were well tolerated. T stage downstaging (pretreatment LAP versus surgical pathological stage) was seen in 23% of patients. The R0 resection rate was 84%. Neither an increase in postoperative morbidity nor operative mortality was noted. With a median follow-up of 43.0 months, 15 patients (39.5%) are still alive (median survival 30.3 months). Good pathologic response, seen in five patients (15%), was associated with better survival (P = 0.053). Peritoneal and hepatic failures were found in 22% and 9% of patients, respectively. Quality of life seemed to be preserved.

CONCLUSIONS

Neoadjuvant cisplatin/5-FU followed by postoperative i.p. FUdR/LV can be safely delivered to patients undergoing radical gastrectomy and D2 lymphadenectomy. The R0 resection and the survival rates are encouraging. An association between pathologic response and patient outcome was suggested.

Colorectal, gastric and pancreatic cancers are major health problems worldwide. Although surgery is a curative option in 50% of patients with colorectal cancer, it is much less effective in gastric cancer (< 20% of patients) and virtually ineffective in pancreatic cancer. These three cancer types also respond poorly to chemotherapy. CPT-11 (irinotecan), a novel cytotoxic drug, is now available in many countries as a single agent for second-line therapy in metastatic colorectal cancer. The response rate in the pivotal European study of metastatic colorectal cancer patients was 14%, with a median duration of response of 8.5 months. There was also a high rate of disease stabilisation (44%), with a median duration of 4.8 months. Median survival time was 10.4 months. The dose-limiting toxicities (DLT) for CPT-11 are delayed diarrhoea and neutropenia, both of which are schedule dependent and non-cumulative. These encouraging data in second-line therapy support the further study of CPT-11 as first-line therapy for colorectal cancer in combination with other agents. Four Japanese trials of CPT-11 as first- and/or second-line single-agent therapy for advanced gastric cancer report response rates of 18-43%. The median durations for response and survival time in the late phase II trial were 2.3 months and 5.8 months, respectively. These results are in the range of those reported for sequential high-dose methotrexate and 5-fluorouracil (5-FU)/doxorubicin (FAMTX), etoposide/leucovorin/5-FU (ELF) or cisplatin/5-FU therapy in gastric cancer. Data are currently available from five phase II studies of CPT-11 in advanced pancreatic cancer: four Japanese and one European. The response rates ranged from 9 to 19%. The median duration of survival for all treated patients in the European study was 5.2 months. CPT-11 in combination with 5-FU is currently being investigated in Japan, the U.S.A. and Europe in patients with gastrointestinal tumours. CPT-11 is also being evaluated in combination with each of the following agents: oxaliplatin, docetaxel, raltitrexed, etoposide and mitomycin C. Japanese studies of CPT-11 plus cisplatin in patients with gastric cancer have produced response rates of 48-59%. These encouraging data highlight the potential for CPT-11 in combination therapy for gastrointestinal tumours.

BACKGROUND

UFT is a fixed-ratio combination of uracil and Ftorafur, a prodrug that is absorbed orally and metabolized in vivo to 5-fluorouracil (5-FU). Uracil potentiates 5-FU through interference with its catabolism. The combination of UFT and leucovorin in patients with advanced incurable colorectal cancer, to evaluate preliminary activity and toxicity in this patient population.

METHODS

Twenty-one patients were treated. Twenty patients were evaluable for toxicity and response. Patients received UFT 350 mg/m2/day divided every 8 hours. Patients took a 5 mg tablet of leucovorin every 8 hours, concurrent with each UFT dose. Treatment was continued for 28 consecutive days, followed by a 7-day rest.

RESULTS

Five major objective responses (one complete and four partial) were observed. Toxicity was mild, with no dose-limiting myelosuppression. Four patients experienced grade 3 diarrhea or higher, and two patients experienced dose-limiting mucositis.

CONCLUSIONS

UFT and low dose leucovorin is a well tolerated, orally administered regimen with activity in colorectal cancer. A randomized comparison of this regimen with conventional parenteral regimens is warranted.

Chemotherapy agents available for the treatment of stage II and stage III colon cancer have changed substantially since the 1992 National Institutes of Health consensus report recommended that all stage III patients routinely receive adjuvant treatment with 5-fluorouracil/levamisole. Subsequent trials demonstrated superiority of 5-fluorouracil/leucovorin over 5-fluorouracil/levamisole in the adjuvant setting, and the recent addition of oxaliplatin to this regimen has further improved disease-free survival. While stage III colon cancer patients are routinely treated, the use of adjuvant chemotherapy in patients with stage II disease is still a subject of debate. Many trials that are assessing the potential role of biologics in the adjuvant setting will soon be completed. However, identifying molecular prognostic markers that accurately select patients with stage II or III cancers who are at risk of recurrence would be essential to select and individualize therapy.

We have shown previously (J. A. Houghton et al., Proc. Natl. Acad. Sci. USA, 94: 8144-8149, 1997) that thymineless death in thymidylate synthase-deficient (TS-) colon carcinoma cells is mediated via Fas/FasL interactions after deoxythymidine (dThd) deprivation, and that Fas-dependent sensitivity of human colon carcinoma cell lines may be dependent upon the level of Fas expressed. The objective of this study was to elucidate whether a Fas-dependent component exists in 5-fluorouracil (FUra)/leucovorin (LV)-induced cytotoxicity of colon carcinoma cells, and whether this may be potentiated by IFN-gamma-induced elevation in Fas expression, using the HT29 cell line as a model. The cytotoxic activity of FUra/LV was inhibited by dThd in HT29 cells and also, in part, by NOK-1+NOK-2 MoAbs that prevent Fas/FasL interactions. FUra/LV-induced cytotoxicity was significantly potentiated by IFN-gamma, reversed by exposure to NOK-1+NOK-2 antibodies, and correlated with a 4-fold induction of Fas expression in the presence of IFN-gamma and significant elevation in expression of FasL. Using five additional human colon carcinoma cell lines, FUra/LV-induced cytotoxicity was dThd-dependent in GC3/c1, VRC5/c1, and Caco2 but not in HCT8 or HCT116 cells. Like HT29 cells, this cytotoxicity was potentiated by IFN-gamma in GC3/c1 and VRC5/c1 but not in Caco2, which fails to express Fas, nor in HCT8 and HCT116, in which no dThd-dependent FUra-induced cytotoxicity was demonstrated. Data suggest that a Fas-dependent component, potentiated by IFN-gamma, exists in FUra/LV-induced cytotoxicity but requires FUra/LV-induced DNA damage for IFN-gamma-induced potentiation to occur.

Prior studies from these laboratories demonstrated 3.2-fold potentiation of 5-fluorouracil (FUra) cytotoxicity by recombinant human interferon-alpha 2a (rIFN-alpha 2a) in GC3/cl colon adenocarcinoma cells that was significantly enhanced to 14-fold when FUra was combined with rIFN-alpha 2a + a mixture of the diasteroisomers of the biologically active (6S) and inactive (6R) leucovorin or 5-formyl-H4PteGlu (LV), events that were reversible by thymidine (dThd). In GC3/clTS-c3/c3 cells, deficient in thymidylate synthase, rIFN-alpha 2a cytotoxicity was not influenced by the concentration of dThd, indicating no direct effect at the level of dThd-less stress. Direct assays of thymidylate synthase indicated no significant difference between FUra-induced accumulation of total thymidylate synthase or free or unbound thymidylate synthase in cells receiving FUra + modulators. In addition, the cytotoxic activity of CB3717, a specific quinazoline-based inhibitor of thymidylate synthase, was not potentiated by rIFN-alpha 2a. These studies suggested that thymidylate synthase was not the primary target site for rIFN-alpha 2a activity. Since data indicated that a 5-fluoropyrimidine was required in the interaction among FUra, LV, and rIFN-alpha 2a, attention was focused at the level of DNA. Both DNA single-strand breaks (SSBs) and DNA double-strand breaks (DSBs) induced by FUra were significantly elevated by rIFN-alpha 2a and LV administered as single modulators and were influenced by the concentrations of both FUra and rIFN-alpha 2a. However; when FUra was combined with LV, rIFN-alpha 2a further potentiated the frequency of DNA SSBs, and data correlated with the relative cytotoxic activity of FUra-LV-rIFN-alpha 2a combinations. No effect on CB3717-induced DNA SSBs or DSBs by rIFN-alpha 2a was demonstrated. Drug exposure for 48 h was required to detect measurable differences in DNA SSB frequency among FUra-LV-rIFN-alpha 2a treatment groups and correlated with decreased clonogenic survival under these conditions. Continuous exposure to FUra (72 h) allowed shorter exposures to LV and/or rIFN-alpha 2a (48 h) to maintain maximal cytotoxicity. Shorter exposure times for FUra during continuous exposure to the modulators were less cytotoxic. Data suggest that the primary locus of the interaction among FUra, LV, and rIFN-alpha 2a lies at the level of DNA. rIFN-alpha 2a may exert its effects via enhancement of FUra base excision or incorporation into DNA, events that subsequently become influenced by thymidylate synthase inhibition and dThd-less stress and are further potentiated by LV.(ABSTRACT TRUNCATED AT 400 WORDS)

We have sought to examine the response to immunosuppressive therapeutic intervention in inclusion body myositis (IBM) in a retrospective review of prior responses to therapy and in an open, randomized crossover trial. We collected information on the response to prior therapy on 25 patients, and for prospective therapy on 11 of these patients. All met criteria for a definite idiopathic inflammatory myopathy and had biopsy-proven IBM. Clinical and laboratory results were assessed by interviews of patients and by chart review in the retrospective trial. Manual muscle strength was assessed by a single trained observer; the patients' activities of daily living were assessed by questionnaire; and serum tests of muscle-associated enzymes were measured in the prospective trial. In the retrospective review, prednisone appeared to have been of some, albeit modest, clinical benefit in 10 of 25 (40%) patients. Other therapies, primarily azathioprine and methotrexate, also appeared to have halted the progression of weakness in 8 of 35 trials (23%). In the prospective study, combination therapy of oral azathioprine and methotrexate and a biweekly infusion of high-dose intravenous methotrexate with leucovorin rescue were given for 3 to 6 months in an open, crossover design. Both the oral and the intravenous regimens were clinically effective in some patients. There was clinical improvement in 3 trials, stabilization in 11 trials, and worsening in 5 trials, out of a total of 19 completed (22 intended) trials. The presence of active inflammation at entry into the prospective therapeutic protocol, either directly observed on muscle biopsy or indirectly indicated by serum creatine kinase level, may have been associated with clinical improvement. A complete laboratory response with normalization of creatine kinase and other muscle-associated enzymes did not, however, significantly predict clinical responsiveness in the prospective trial. In this first report, to our knowledge, of a prospective trial of immunosuppressive therapy for this disease, stabilization and even slight improvement of strength and functional abilities appeared to be achieved in some patients. We believe that prednisone and other immunosuppressive therapies were of modest benefit in about half of patients with inclusion body myositis, especially those with some evidence of active inflammation. Stabilization of an otherwise inexorably deteriorating course appears, therefore, to be an attainable goal in some patients with IBM.

A human acute lymphoblastic T-cell line, MOLT-3, was fed with Roswell Park Memorial Institute Medium 1640-10% fetal bovine serum-antibiotics, containing increasing concentrations of methotrexate (MTX). After 10 months of feeding, the cells became resistant to 10(-7) M MTX; resistance was not reversed when the cells were placed in the original MTX-free medium. At 10(-7) M MTX, the concentration which produced complete inhibition of the parent MOLT-3 cell growth, the resistant cells were not inhibited at all. On a 50% inhibitory concentration basis, the resistant cells were approximately 30-fold more resistant to MTX. The parent MOLT-3 and the resistant line had the same doubling time of approximately 36 hr. There were no differences in light microscopic morphology. MOLT-3 produced loose colonies on 0.5% agar enriched with fetal bovine serum, whereas the colonies of the resistant line were tightly packed. The development of resistance was accompanied by a 4- to 5-fold decrease in [3H]MTX transport (MOLT-3/MTXt). Kinetic analysis of MTX uptake showed that the resistant subline did not have an altered Km for MTX (6.6 microM) but had a decreased Vmax of about 20% of the parent cell line. These data suggest that either the number of folate transport sites or the turnover rate of these sites has been reduced in the MTX-resistant cell line. Dihydrofolate reductase was only minimally elevated in the resistant cell line. The MTX-resistant cell line was cross-resistant to dichloromethotrexate. The sensitivity of the resistant line to the substituted 2,4-diaminoquinazoline and pyrimidine compounds, 2,4-diamino-5-methyl-6-[(3',4',5'-trimethoxyanilino) methyl] quinazoline (JB-11) and 2,4-diamino-5-(3',4'-dichlorophenyl)-6-methylpyrimidine, increased more than 3-fold. While leucovorin equally reversed the MTX effects on the parent and resistant cells, leucovorin reversal of 2,4-diamino-5-methyl-6-[(3',4',5'-trimethoxyanilino) methyl] quinazoline and 2,4-diamino-5-(3',4'-dichlorophenyl)-6-methylpyrimidine effects was limited only to the parent cell line. 2,4-diamino-5-methyl-6-[(3',4',5'-trimethoxyanilino) methyl] quinazoline or 2,4-diamino-5-(3',4'-dichlorophenyl)-6-methylpyrimidine plus leucovorin might prove to be unique in treating patients with acute lymphoblastic leukemia when the leukemic cells develop transport resistance to MTX.

Weekly high-dose methotrexate with leucovorin rescue and vincristine (HDMTX) and doxorubicin was administered as adjuvant postoperative therapy to 46 patients with a diagnosis of conventional high-grade nonmetastatic osteosarcoma of an extremity between July 1976 and December 1981. The primary lesions were managed by wide or radical amputation (26 patients) or by limb-sparing resection in 20 selected patients. The margins of the resections were retrospectively classified as marginal in three, wide in 16, and radical in one. The 5-year relapse-free survival (RFS) for all patients is 59% (95% confidence interval [CI], 43%, 74%) and overall survival is 78% (95% CI, 65%, 91%). The RFS for patients initially having a limb resection procedure is 55% (95% CI, 32%, 77%) compared with 62% (95% CI, 43%, 81%) for those initially having amputations (P = .52). Using multivariate analysis, the only significant prognostic variables that predicted RFS of greater than or equal to 3 years, were the presence of moderate to marked lymphocytic infiltration of the primary tumor (P less than .002), primary site outside of the proximal humerus (P less than .005), and the absence of a predominance of osteoblastic pattern in the primary tumor (P less than .03).

BACKGROUND

This study determined the optimally tolerated regimen (OTR) of oral lapatinib administered in combination with infusional 5-fluorouracil (5-FU), leucovorin and irinotecan (FOLFIRI) and assessed the safety, tolerability and pharmacokinetics of the combination.

METHODS

Twenty-five patients were enrolled; 12 patients were treated at three dose levels to determine OTR; then 13 patients were treated at OTR to evaluate the pharmacokinetics of the combination.

RESULTS

The 2-weekly OTR comprised lapatinib 1250 mg/day with irinotecan 108 mg/m(2) (day 1) and leucovorin 200 mg/m(2), 5-FU bolus 240 mg/m(2) and 5-FU infusion 360 mg/m(2) (days 1 and 2); doses of 5-FU and irinotecan represent a 40% reduction in dose compared to conventional FOLFIRI. Dose-limiting toxicities were grade 3 diarrhoea and grade 4 neutropenia. Co-administration of lapatinib increased the area under the plasma concentration-time curve of SN-38, the active metabolite of irinotecan, by an average of 41%; no other pharmacokinetic interactions were observed. Of 19 patients evaluable for disease response assessment, four patients had partial response and nine patients had stable disease.

CONCLUSIONS

The combination of lapatinib and FOLFIRI is safe and demonstrates clinical activity; the documented PK interaction can effectively be compensated by lowering the doses of 5-FU and irinotecan. This regime may be further tested in a phase II trial.

Bevacizumab is a humanised monoclonal antibody that inhibits vascular endothelial growth factor (VEGF), the key mediator of tumour angiogenesis, and has been shown to improve survival when given with chemotherapy to patients with metastatic colorectal cancer. In a pivotal Phase III clinical trial, 813 subjects were treated with irinotecan, 5-fluorouracil (5-FU) and leucovorin and randomised to receive placebo or bevacizumab. Median survival for the group receiving bevacizumab was increased by 30%, from 15.6 to 20.3 months (p < or = 001). Other Phase II and III studies in colorectal cancer have demonstrated a benefit when bevacizumab is added to regimens of 5-FU and leucovorin, and 5-FU, leucovorin and oxaliplatin. The toxicity associated with bevacizumab is generally mild, consisting of manageable hypertension, clinically insignificant proteinuria and mild mucosal bleeding. Infrequent severe toxicities have been reported, consisting of arterial thrombosis and gastrointestinal perforations (1.5%). Bevacizumab represents the first angiogenesis modulator that has a proven benefit in cancer therapy.

BACKGROUND

Intergroup Trial N9741 evaluated 5-fluorouracil (5-FU)/leucovorin (LV) administered in conjunction with either irinotecan or oxaliplatin in the first-line treatment of advanced colorectal carcinoma (CRC). The current report describes two treatment arms that were withdrawn from the protocol due to unexpected treatment-related toxicities and a high mortality rate. The complications observed in these arms highlight the importance of aggressive and immediate supportive care in the management of digestive toxicity.

METHODS

In Trial N9741, patients were randomly assigned to receive one of the following six regimens: 1) irinotecan plus bolus 5-FU/LV (Arm A); 2) sequential irinotecan plus bolus 5-FU/LV (Arm B); 3) bolus 5-FU/LV only (Mayo Clinic regimen; Arm D); 4) oxaliplatin plus bolus 5-FU/LV (Arm E); 5) oxaliplatin plus infusional 5-FU/LV (Arm F); or 6) oxaliplatin plus irinotecan (Arm G). In the current study, the authors investigated treatment-related toxicity in patients who received either of the two combination regimens containing daily bolus 5-FU (i.e., patients in Arm B or Arm E).

RESULTS

Sixty-one and 47 patients were enrolled in Arm B and Arm E, respectively. Diarrhea and neutropenia were the most common toxicities in both groups. Five patients in Arm B (8.2%) and 4 patients in Arm E (8.5%) died within 60 days of study entry. All fatal toxicities occurred within 15 days of treatment administration, and all deaths were associated with the simultaneous occurrence of multiple symptoms, which were dominated by Grade>> or = 3 diarrhea.

CONCLUSIONS

Combination regimens containing daily bolus 5-FU/LV and oxaliplatin or irinotecan can be associated with severe gastrointestinal toxicity and high mortality rates. Therefore, the authors recommend the use of more tolerable infusional 5-FU-based regimens in the treatment of metastatic CRC.

Patients with locally advanced pancreatic adenocarcinoma who receive conventional therapy with radiation with 5-fluorouracil (5-FU) have median survivals ranging from 8 to 12 months. Here we report our experience with a four-drug chemotherapeutic regimen that resulted in sufficient downstaging of tumor in some patients to justify surgical reexploration and resection. From April 1991 through April 1994, 38 patients received 5-FU as a continuous infusion (200 mg/m2/day), calcium leucovorin weekly by intravenous bolus injection (30 mg/m2), mitomycin-C every 6 weeks (10 mg/m2 intravenously), and dipyridamole daily orally (75 mg) for locally advanced unresected pancreatic cancer. All of these patients were evaluable for response, toxicity, and survival. There were 14 partial responses and one complete response--a 39% response rate. The median survival for all patients was 15.5 months; the 1-year survival rate from time of initial diagnosis was 70%. Six of 15 responding patients had sufficient tumor regression to meet clinical criteria for resectability and reexploration, four of whom underwent a curative resection. The median survival of these six patients was 28 months from the time of original diagnosis. The 1-year survival was 83%, with one patient still alive and free of disease at 53 months. We believe this unique experience from a single institution justifies a prospective multi-institutional trial to evaluate the efficacy of this approach in a larger number of patients.

OBJECTIVE

To provide an overview of recent clinical trials with monoclonal antibodies targeting epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) in head and neck cancer (HNC) and in other tumors. To discuss future therapeutic strategies.

RESULTS

Cetuximab, a chimeric monoclonal antibody targeting EGFR, has induced improved locoregional control and survival in combination with radiotherapy in a phase III study in locally advanced inoperable HNC. The recent Bowel Oncology with Cetuximab Antibody (BOND) study has shown that the combination of irinotecan and cetuximab yields a better response rate and a longer time to progression with respect to cetuximab monotherapy in irinotecan-refractory metastatic colorectal cancer, pointing to both a cetuximab single-agent activity and a cetuximab potential for reversal of irinotecan resistance. Non-small cell lung cancer and pancreatic cancer represent further areas for cetuximab development. Bevacizumab is a humanized monoclonal antibody that targets VEGF. It is the first antiangiogenic drug to have induced a survival advantage in cancer therapy, within a randomized trial of irinotecan, 5-fluorouracil, leucovorin (IFL) combined with bevacizumab or placebo in metastatic colorectal cancer. The use of bevacizumab in HNC is supported by preclinical evidence of an angiogenic loop; a few clinical trials are exploring the feasibility and the therapeutic potential of a combination of bevacizumab and EGFR-targeted drugs.

CONCLUSIONS

Monoclonal antibodies targeting EGFR and VEGF represent exciting therapeutic strategies that should be further evaluated both in combination with drugs acting on the same target at a different level and in combination with other antisignaling agents acting on different pathways.

Considerable progress has been made in improving disease-free survival in stage III colon cancer with the use of adjuvant chemotherapy. In recent years, it has been shown that infusional 5-fluorouracil regimens maintain the efficacy and reduce toxicity associated with bolus 5-fluorouracil, that improved tolerability can be achieved with use of the oral fluoropyrimidine capecitabine, and that improved efficacy can be achieved by combining 5-fluorouracil/leucovorin with other cytotoxic agents (eg, oxaliplatin and irinotecan). Studies are ongoing to identify optimal adjuvant regimens in stage II or III disease and to identify the potential benefits of adding bevacizumab or cetuximab to adjuvant therapy.

The addition of leucovorin (LV) to 5-fluorouracil (5-FU) in advanced colorectal cancer has shown improved tumour response rates in many trials, but the optimal LV/5-FU regimen has yet to be determined. Seven studies carried out over the last 12 years to evaluate the safety and efficacy of various LV/5-FU regimens are reviewed. The initial bimonthly high-dose LV/5-FU regimen consisted of high-dose LV as a 2-h infusion followed by 5-FU as an intravenous (i.v.) bolus plus a 22-h continuous infusion (CI), repeated for two consecutive days every 2 weeks. A randomised comparison of this bimonthly high-dose LV/5-FU regimen and the NCCTG-Mayo Clinic regimen (LV [20 mg/m2/day] followed by 5-FU bolus [425 mg/m2/day] daily x 5, every 4 weeks) showed that the bimonthly high-dose LV/5-FU regimen was superior to the NCCTG-Mayo Clinic regimen in response rate and progression-free survival, but showed no difference in overall survival. In addition, toxicity was less with the bimonthly high-dose LV/5-FU regimen. These promising results led to a phase II trial of a simplified bimonthly high-dose LV/5-FU regimen consisting of LV (500 mg/m2/day) and a 48-h CI of 5-FU (1.5-2 g/m2/day) which has been administered alone or in combination. In summary, GERCOD-sponsored studies have further demonstrated that high doses of both LV and 5-FU given as a CI can improve response rates still more with acceptable toxicity. Further studies are focused on the effectiveness of combination with oxaliplatin or CPT-11 in metastatic disease and the use of high-dose LV/5-FU regimens for colorectal cancer in the adjuvant setting.

BACKGROUND

To determine the prognostic role of selected microRNA (miRNA) polymorphisms in advanced gastric cancer (AGC).

METHODS

Six hundred and seventy-four AGC patients received 5-fluorouracil (F), leucovorin (L), oxaliplatin (O) or FL + cisplatin (P) or additional docetaxel (T) to FLO (FLOT) within four clinical trials. Polymorphisms of mir-26a1 (rs7372209), mir-27a (rs895819), mir-100 (rs1834306), mir-146a (rs2910164), mir-196-a2 (rs11614913), mir-219-1 (rs107822) and mir-423 (rs6505162) were genotyped. Variable selection for the final multivariate model (n = 487) was based on univariate and multivariate Cox-regression analyses with a cut-off P-value of ≤ 20%.

RESULTS

Genetic factors significantly associated with overall survival (OS) were rs7372209 (mir-26a1) variant genotypes (hazard ratio, HR 1.307 [95% confidence interval (CI) 1.031-1.656], P = 0.0272), rs895819 (mir-27a) variant genotypes (HR 1.304 [95% CI 1.031-1.650], P = 0.0270) and rs11614913 (mir-196a2) variant genotypes (HR 0.791 [95% CI 0.625-1.000], P = 0.0497). Clinical factors with significant impact on OS were Eastern Cooperative Oncology Group (ECOG) 2 performance status (HR 1.880 [95% CI 1.254-2.820], P = 0.0023), curative surgery of advanced disease (HR 0.235 [95% CI 0.123-0.449], P < 0.0001) and addition of docetaxel in locally AGC patients (HR 0.348 [95% CI 0.145-0.838], P = 0.0301). Combined analyses revealed an improved OS in patients without any unfavourable genotype of 18 months compared with 14, 12 and 10 months in patients with 1, 2 and 3 unfavourable genotypes, respectively (P = 0.0257).

CONCLUSIONS

These data suggest a significant impact of selected miRNA polymorphisms on prognosis in AGC.

BACKGROUND

Venous ports are mandatory for chemotherapy in cancer patients because prolonged infusions are required. The aim of this study was to assess the safety of peripheral arm ports for chemotherapy in patients with colorectal cancer.

METHODS

A peripheral venous access port was placed in the upper arm in 113 consecutive patients with metastatic colorectal cancer (MCRC). All patients received modified FOLFOX (5-fluorouracil [5-FU]/l-leucovorin [LV]/oxaliplatin [L-OHP]) 6 or FOLFIRI (5-FU/LV/irinotecan hydrochloride [CPT-11]) regimens at least once via the venous access port. All patients were followed up at least once every 2 weeks.

RESULTS

Puncture of the basilic veins was successfully completed under real-time sonographic guidance or radiographic guidance in all patients. The median operative time was 30 min. The cumulative follow-up period was 29 886 catheter days (range, 9-560 days; mean, 264 days). No procedural complications, such as pneumothorax, hemothorax, arterial puncture, or cardiovascular problems, occurred in our series. A total of nine patients (8.0%) had complications. Port-site infection occurred in six patients (5.3%; 0.20 infections per 1000 catheter-days). One patient (0.9%) had an episode of ultrasound-documented deep vein thrombosis in the ipsilateral upper extremity (0.03/1000 catheter-days). Dislocation or migration of the catheter tip occurred in two patients (0.07/1000 catheter-days). A second port was placed in six patients (5.3%) after removal of the fi rst port.

CONCLUSIONS

Peripheral arm ports can be maintained with excellent short-and long-term outcomes. Peripheral arm ports are considered to be a good alternative to central venous ports implanted in the chest in patients with MCRC.

OBJECTIVE

To determine whether the immunohistochemical expression of proliferation-associated antigens (proliferating cell nuclear antigen, MIB1) and the nuclear p53 reactivity in addition to total tumor volume, nodal CT density and T and N category are predictive for overall survival and locoregional tumor control in patients with squamous cell carcinoma of the head and neck region.

METHODS

Between October 1989 and September 1993, 87 patients with biopsy proven head and neck cancer were randomly allocated to receive radiation alone or simultaneous radiation and chemotherapy as part of a multicenter trial with a total of 298 randomized patients. There were only inoperable lesions in UICC (1992) stage III (8%) and IV (92%). Radiotherapy was delivered with 180 cGy twice daily up to a total dose of 7020 cGy in 51 days. Three cycles of 2340 cGy each were separated by a rest period of 11 days. Chemotherapy consisted of cis-DDP, 5-fluorouracil and leucovorin and was repeated on days 22 and 44. Routinely-processed paraffin-embedded sections were stained using monoclonal antibodies for detection of proliferation-associated antigens (MIB1 and PCNA) and p53 oncoprotein to determine the labeling index (LI). In addition, the total tumor volume and the percentage of necrosis were measured using CT data. The median follow-up was 3.9 years (range 1.9-5.0 years).

RESULTS

The overall survival and locoregional control for all 87 patients were 34 and 39% at 3 years, respectively. The addition of chemotherapy resulted in a better overall survival (27 versus 47%, P = 0.03) but did not influence locoregional control (31 versus 47%, P = 0.08). In univariate analysis, nodal CT density (P < 0.0001), total tumor volume (P < 0.0001), age (P = 0.001) and the MIB1-LI (P = 0.04) had a significant impact on overall survival. However, in the final Cox model only the nodal CT density (P = 0.0003) and age (P = 0.05) were independent prognostic factors for survival and only the nodal CT density (P = 0.0006) was an independent prognostic factor for locoregional control. The expression of the p53 oncoprotein was not found to have a clear predictive value.

CONCLUSIONS

Nodal CT density, total tumor volume and age will remain the relevant prognostic factors in stage III/IV head and neck cancer.

A 60-year-old woman was treated postoperatively for carcinoma of the gall bladder with a split course of radiotherapy. The tumour dose (TD) was 61.2 Gy in 34 fractions delivered by an anterior and two lateral wedge fields with 60Co; the Dmax was 70% of TD for the anterior field and 150% of the TD at the thin edge of the wedges. She also underwent 5-FU and leucovorin chemotherapy. No skin reaction was seen during radiotherapy or in 1 year of follow-up. A year after radiotherapy she was treated for hypercholesterolaemia by simvastatin. Within 2-3 days a severe skin and subcutaneous reaction developed in the lateral radiation fields but not in the anterior field. To our knowledge, recall of skin radiation reaction after simvastatin therapy has not been previously reported.

BACKGROUND

5-Fluorouracil (5-FU) is administered based on standard body surface area (BSA) dosing. BSA administration results in highly variable exposure, measured as the area under the concentration-time curve (AUC). An immunoassay (OnDose®; Myriad Genetic Laboratories, Inc., Salt Lake City, UT) that measures plasma 5-FU concentration and reports an AUC in mg · h/L has been developed to optimize therapy using pharmacokinetic (PK) dosing. The results of an analysis to model the 5-FU AUC-dose relationship are presented.

METHODS

A set of 589 sequential patients from a clinical database receiving 5-FU, leucovorin, and oxaliplatin (the FOLFOX6 regimen) for colorectal cancer (CRC) treatment was analyzed. A subset including only patients who had at least two consecutive cycles tested, received 1,600-3,600 mg/m2 of continuous infusion 5-FU during the initial test cycle, and had a blood sample collected after ≥18 hours, was used to conduct regression modeling of the change in AUC versus change in dose.

RESULTS

A simple regression model with R(2) = 0.51 developed over n = 307 cycle-pair observations characterizes the AUC-Dose relationship as: change in AUC = 0.02063 * dose change. The model suggests that dose changes in the range of 145-727 mg/m2 would be sufficient to adjust the AUC to a potential therapeutic threshold of >20 mg · h/L for most patients.

CONCLUSIONS

5-FU is an ideal candidate for PK dose optimization. Because individual factors other than dose change may also affect the change in AUC, longitudinal PK monitoring in all cycles and dose adjustment to ensure AUC in the desired range of 20-30 mg · h/L are recommended.