BACKGROUND

The aim of the study was to evaluate the efficacy and tolerability of the combination of oxaliplatin, fluorouracil and leucovorin in patients with advanced esophagus cancer.

METHODS

Thirty-five patients with recurrent or metastatic esophageal adenocarcinoma or squamous cell carcinoma were enrolled. Up to one prior chemotherapy regimen was allowed. All patients had bi-dimensionally measurable disease. Patients received oxaliplatin 85 mg/m2 as a 2-h infusion on day 1. Leucovorin (500 mg/m2) followed by fluorouracil bolus (400 mg/m2) and 22-h continuous infusion fluorouracil (600 mg/m2) was administered on days 1 and 2. Granulocyte colony stimulating factor was not routinely administered unless the patient developed febrile neutropenia or prolonged neutropenia. Treatment was repeated every 14 days.

RESULTS

Of the thirty-five patients enrolled, all were evaluated for toxicity and 34 were evaluated for response. The overall response rate was 40% (95% confidence interval, 24% to 57%) with complete and partial response rates of 3% and 37%, respectively. The median response duration was 4.6 months, and the median overall survival was 7.1 months. One-year survival was 31%. The major toxicity noted was cumulative neutropenia, with 29% developing grade 4 toxicity. There was one treatment-related death secondary to neutropenic sepsis. The most common non-hematologic toxicity encountered with this regimen was cumulative peripheral neuropathy, with 26% experiencing grade 2 or 3 toxicity.

CONCLUSIONS

The combination of oxaliplatin, leucovorin, and fluorouracil shows significant anti-tumor activity and a favorable toxicity profile in patients with metastatic carcinoma of the esophagus.

Adjuvant chemotherapy with fluorouracil (FU) and levamisole or FU/leucovorin (LV) has been established as effective adjuvant treatment for patients with stage III colon cancer. Among several other promising treatment strategies in resected colon cancer, intraperitoneal anti-cancer drug administration with its appealing rationale of counteracting microscopic residual disease on peritoneal surfaces and occult metachronous liver metastases by achieving high intraportal drug concentrations has not yet undergone sufficient clinical evaluation. To determine whether a combination of this locoregional therapeutic concept with systemic intravenous administration of FU/LV would yield better results than conventional adjuvant chemoimmunotherapy with FU/levamisole, the present randomized study was initiated. A total of 241 patients with resected stage III or high-risk stage II (T4N0M0) colon cancer were randomly assigned to 'standard therapy' with FU and levamisole, given for a duration of 6 months, or to an investigational arm, consisting of LV 200 mg m(-2) plus FU 350 mg m(-2), both administered intravenously (days 1-4) and intraperitoneally (days 1 and 3) every 4 weeks for a total of six courses. In patients with stage II disease, no significant difference was noted between the two arms after a median follow-up time of 4 years (range 2.5-6 years). Among 196 eligible patients with stage III disease, however, a comparative analysis of the two treatment groups suggested both an improvement in disease-free survival (P = 0.0014) and a survival advantage (P = 0.0005), with an estimated 43% reduction in mortality rate (95% confidence interval 26-70%) in favour of the investigational arm. In agreement with its theoretical rationale, combined intraperitoneal and intravenous FU/LV was particularly effective in reducing locoregional tumour recurrences with or without liver or other organ site involvement (9 vs 25 patients in the FU/levamisole arm; P = 0.005). Treatment-associated side-effects were infrequent and generally mild in both arms, although a lower rate of severe (WHO grade 3) adverse reactions was noted in patients receiving locoregional plus intravenous chemotherapy (3% vs 12%; P = 0.01). The results of this trial suggest that combined intraperitoneal plus systemic intravenous chemotherapy with FU/LV is a promising adjuvant treatment strategy in patients with surgically resected stage III colon carcinoma.

OBJECTIVE

Diarrhea is a prominent feature of fluorouracil (5FU) gastrointestinal toxicity, especially when 5FU is combined with leucovorin (LV) or interferon (IFN). No treatment for this condition has been well defined, although drugs, such as diphenoxylate or loperamide, generally are used. The efficacy of octreotide in the treatment of 5FU-induced diarrhea recently has been reported. We performed a randomized trial that compared octreotide with loperamide, the drug most commonly used for therapy for this disorder.

METHODS

Forty-one patients with grade 2 (four to six stools per day) or grade 3 (seven to nine stools per day; National Cancer Institute toxicity criteria) diarrhea after chemotherapy with a 5FU-containing regimen for colorectal cancer in 28 cases, gastric cancer in six cases, pancreatic cancer in five cases, and breast cancer in two cases, were entered onto the study. Twenty-one patients received octreotide at a dosage of 0.1 mg subcutaneously twice per day for 3 days, and 20 patients received loperamide 4 mg orally initially and then 2 mg every 6 hours for 3 days. The two arms were comparable for age, sex, and primary tumor. Patients were evaluated for response each treatment day; all patients were assessable.

RESULTS

Diarrhea resolved in 19 patients in the octreotide arm (one within the first day; four within the second day; and 14 within the third day) versus only three (all after the third day of therapy) in the loperamide arm (P < .005). Median frequency of stools in the 3 days of therapy was four, three, and zero in the octreotide arm and five, five, and five in the loperamide arm. No side effects were observed in both arms. Ten patients on the loperamide arm and only one on the octreotide arm required hospitalization for parenteral replenishment of fluids and electrolytes.

CONCLUSIONS

Octreotide seems to be more effective than loperamide in control of diarrhea and elimination of the need for replenishment of fluids and electrolytes.

We explored the relationship between time to relapse and different exposure variables (serum methotrexate (S-MTX) 23, 36 and 42 h after start of administration, MTX elimination time and leucovorin (LV) dose) during high-dose MTX (HDM) treatment of 445 children with acute lymphoblastic leukemia. MTX was infused at 5 g/m2 (non-high risk) or 8 g/m2 (high risk) over 24 h, 2-9 times per patient. LV rescue dose was adjusted according to the S-MTX concentration. Time from end of the last HDM to relapse was analyzed by Cox regression analysis with the logarithms of S-MTX and LV dose as exposures. The combined results from all risk groups suggest that high LV dose is related to higher risk for relapse. Doubling of the LV dose increased the relapse risk by 22% (95% confidence interval 1-49%, P = 0.037). High LV doses correlated with high MTX levels at 23, 36 and 42 h and longer elimination time. The results suggest that high doses of LV increase the risk for relapse despite the fact that they were correlated with high MTX levels and longer MTX elimination time. The choice of MTX and LV doses may be regarded as an intricate balance between effect and counter-effect.

BACKGROUND

The aim of this study was to determine the maximum-tolerated dose (MTD) and the recommended dose of irinotecan and oxaliplatin with a fixed 5-fluorouracil (5-FU)/leucovorin (LV) regimen in patients with metastatic solid tumors.

METHODS

The trial was designed to evaluate escalating doses of oxaliplatin and irinotecan, starting at 60 mg/m2 and 90 mg/m2, respectively, given at day 1 with the full-dose LV5FU2 regimen, given on days 1 and 2 as follows: folinic acid 200 mg/m2 followed by 5-FU 400 mg/m2 bolus and 600 mg/m2 22 h continuous infusion, every 2 weeks. The second cohort of patients was treated at the recommended dose for oxaliplatin and irinotecan with the simplified LV5FU regimen: on day 1, a 2-h infusion of folinic acid (400 mg/m2), followed by a 10-min intravenous bolus of 5-FU (400 mg/m2), followed by a continuous infusion of 5-FU (2400 mg/m2) over 46 h.

RESULTS

Thirty-four patients were treated at the following dose levels (oxaliplatin/irinotecan mg/m2): 60/90, 60/120, 85/120, 85/150, 85/180, 85/200 and 85/220 and seven patients were treated at the recommended dose with the simplified LV5FU scheme. The MTD was reached at dose level 85/220 mg/m2 but the recommended dose chosen for the second step was 85/180 mg/m2 to keep a better compliance with the biweekly schedule. Main grade 3/4 toxicities per patient included the following: neutropenia in 78% (febrile episodes in 12%), diarrhea in 27%, nausea/vomiting in 24% and peripheral neuropathy in 37% (Lévi's scale). Antitumor activity was observed at almost all dose levels. Most objective responses were observed in digestive malignancies, since 10 out of 11 were obtained in five colorectal cancers, two pancreatic cancers, two cholangiocarcinoma and one gastric cancer.

CONCLUSIONS

The recommended dose for the triple association is 85/180 mg/m2 of oxaliplatin and irinotecan, respectively, with LV5FU2 or simplified LV5FU. The antitumor activity in gastrointestinal malignancies should be evaluated in phase II studies in different tumor types.

OBJECTIVE

We studied the pharmacokinetics of heated intraoperative intraperitoneal (i.p.) oxaliplatin (LOHP) solution and its safety profile in increasingly hypotonic solutions. This is the first clinical study of i.p. chemohyperthermia with hypotonic solutions.

METHODS

Patients with peritoneal carcinomatosis (PC) underwent complete cytoreductive surgery followed by intraoperative i.p. chemohyperthermia (IPCH) with successive dextrose solutions of 300, 200, 150 and 100 mosm/l. LOHP (460 mg/m(2)) was administered in 2 liters of solution/m(2) at an i.p. temperature of 42-44 degrees C for 30 min. IPCH was performed using an open procedure (skin pulled upwards) with a continuous closed circuit. Patients received intravenous leucovorin (20 mg/m(2)) and 5-fluorouracil (400 mg/m(2)) just before IPCH to maximize the effect of LOHP. i.p. plasma and tissue samples were analyzed by means of atomic absorption spectrophotometry. Sixteen consecutive patients with PC of either gastrointestinal or peritoneal origin were treated. The safety of the procedure was studied.

RESULTS

Pharmacokinetics: The mean duration of the entire procedure was 7.7 +/- 2.6 h. Half the LOHP dose was absorbed within 30 min at all dose levels. Absorption was not higher with hypotonic solutions than with isotonic solutions. The area under the curve of LOHP in plasma did not increase with decreasing osmolarity of the i.p. solutions. Intratumoral LOHP penetration was high; it was similar to that at the peritoneal surface, and about 18 times higher than that in nonbathed tissues. LOHP penetration was not significantly increased by using hypotonic solutions.

RESULTS

There was a very high incidence of unexplained postoperative peritoneal bleeding (50%) and unusually severe thrombocytopenia in the 150 and 100 mosm/l groups.

CONCLUSIONS

Contrary to experimental studies, this clinical study showed no increase in tumoral or systemic penetration of LOHP with i.p. hypotonic solutions (200, 150 or 100 mosm/l) during IPCH. A high incidence of i.p. hemorrhage and thrombocytopenia was observed.

OBJECTIVE

To evaluate comparative outcome between adjuvant postoperative chemoradiotherapy (postoperative CRT) and lateral pelvic lymph node dissection (LPLD) following total mesorectal excision (TME) in rectal cancer patients.

BACKGROUND

Although TME results in lower rate of locoregional recurrence compared with conventional surgery, these 2 treatment modalities following TME have not adequately been appraised until the present trend of preoperative chemoradiotherapy.

METHODS

Between 1995 and 2000, patients with stage II and III rectal cancer underwent TME plus postoperative CRT (n = 309) or LPLD (n = 176). Patients in the postoperative CRT group received 8 cycles of 5-fluorouracil plus leucovorin and 45 Gy pelvic radiotherapy. Patients in the LPLD group underwent lateral lymph node dissection outside the pelvic plexus.

RESULTS

The 5-year overall and disease-free survival rates were 78.3% and 67.3% in the postoperative CRT group, respectively, and 73.9% and 68.6% in the LPLD group, respectively, without significant differences between these groups. Patients in the LPLD group with stage III lower rectal cancer had a locoregional recurrence rate 2.2-fold greater than those in the postoperative CRT group (16.7% vs. 7.5%, P = 0.044). Multivariate analysis showed that APR and advanced T-category (T4) were significantly associated with locoregional recurrence, whereas lymph node metastases, high preoperative serum carcinoembryonic antigen, and APR were significantly associated with shortening of disease-free survival.

CONCLUSIONS

Postoperative-CRT and LPLD following TME resulted in comparable survival rates, but the locoregional recurrence rate was higher in the LPLD group. These findings suggest that initial surgery is appropriate for rectal cancer patients who are candidates for low anterior resection without extensive local disease (T1-T3), regardless of lymph node status.

OBJECTIVE

To evaluate the role of early intensification with high-dose therapy (HDT) and autologous stem-cell transplantation (ASCT) as front-line chemotherapy for patients with high-risk, histologically aggressive non-Hodgkin's lymphoma (NHL).

METHODS

We planned a multicenter, randomized trial to compare a conventional chemotherapy regimen of methotrexate with leucovorin rescue, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin (MACOP-B; arm A) with an abbreviated regimen of MACOP-B (8 weeks) followed by HDT and ASCT (arm B) for intermediate-high-risk/high-risk patients (according to the age-adjusted International Prognostic Index). From September 1994 to April 1998, 150 patients with aggressive lymphoma were enrolled onto the trial. Seventy-five patients were randomly assigned to arm A and 75 patients were randomly assigned to arm B. In both arms, involved-field radiation therapy (36 Gy) was delivered to the site of bulky disease.

RESULTS

The rate of complete response was 68% in arm A and 76% in arm B (P = not significant [NS]). Three toxic deaths (4%) occurred in arm B and one (1%) occurred in arm A (P = NS). In arm B, 30 patients (40%) did not undergo HDT and ASCT. According to the intention-to-treat analysis at a median follow-up of 24 months, 5-year overall survival probability in arms A and B was 65% and 64% (P =.95), 5-year progression-free survival was 49% and 61% (P =.21), and 5-year relapse-free survival was 65% and 77% (P =.22), respectively.

CONCLUSIONS

Abbreviated chemotherapy followed by intensification with HDT-ASCT is not superior to conventional chemotherapy in patients with high-risk, aggressive NHL. Additional randomized trials will clarify whether HDT-ASCT as front-line therapy after a complete course of conventional chemotherapy improves survival in this group of patients.

OBJECTIVE

We compared health-related quality of life (HRQL), symptoms, and convenience of care (COC) in patients with stage II/III carcinoma of the colon who received either oral uracil/ftorafur (UFT) plus leucovorin (LV) or standard intravenous (IV) fluorouracil (FU) plus LV as adjuvant chemotherapy.

METHODS

We measured HRQL with the Functional Assessment of Cancer Therapy-Colorectal (FACT-C) questionnaire, Short Form-36 Vitality Scale (SF-36), and a Quality of Life Rating Scale (QLRS) at baseline, once during chemotherapy, and at 1 year. We used the Symptom Distress Scale (SDS) and treatment-specific Symptom Checklist (SCL) to assess symptoms and a modified Burden of Care form to assess COC at baseline, on day 1 of each treatment cycle, and at 1 year. Repeated measures analyses controlling for demographic variables and baseline scores were used for statistical comparisons.

RESULTS

The study accrued 1,608 patients, 803 to the FU arm and 805 to the UFT arm. There were no differences between the arms in overall FACT-C scores, FACT-C scores within the subscales of colon-specific, physical, emotional, social, and functional health, or QLRS scores. Patients taking UFT reported substantially higher COC. Statistically significant but small differences were observed for SF-36, favoring FU, and for SDS and SCL, both favoring UFT.

CONCLUSIONS

Patients perceive adjuvant treatment with UFT + LV as more convenient than standard IV treatment with FU + LV. Both regimens are well tolerated and do not differ in their impact on HRQL.

OBJECTIVE

To evaluate clinical characteristics and survival outcomes among patients with locally advanced or metastatic colorectal cancer who achieve a complete response (CR) to systemic treatment either alone or with multimodality approach.

METHODS

Data were collected retrospectively from CRC patients enrolled onto the phase III trial N9741, a National Cancer Institute-funded and Gastrointestinal Cancer Intergroup-sponsored study coordinated by the North Central Cancer Treatment Group. Patients were randomly assigned to combinations of oxaliplatin, fluorouracil (FU)/leucovorin (LV) and irinotecan. The three treatment arms consist of IFL (irinotecan + FU/LV), FOLFOX4 (oxaliplatin + FU/LV), and IROX (irinotecan + oxaliplatin). Median follow-up was 42.6 months.

RESULTS

Sixty-two (4%) of 1,508 patients had a CR to chemotherapy alone, and an additional 32 (2%) had a CR after multimodality treatment. Factors associated with achieving CR with systemic chemotherapy alone included FOLFOX4 treatment, patients with assessable disease, or a single site of metastasis. Continuing protocol treatment beyond two cycles after documentation of CR was not associated with improved survival. The rate of curative intent resection was significantly higher for patients treated with oxaliplatin-containing regimens (P = .02). Median survival was similar between patients with CR after chemotherapy alone (44.3 months) or after multimodality approach (47.4 months; P = .81).

CONCLUSIONS

FOLFOX4 was more likely to produce a CR than were IFL or IROX. Oxaliplatin regimens were more likely to result in successful surgical resections. Patients who have CR to systemic chemotherapy alone can achieve impressive survival outcomes similar to those seen among patients who attained a CR status after multimodality treatment.

Irinotecan, a water-soluble, semisynthetic derivative of camptothecin, is a key component of first- and second-line treatment regimens for metastatic colorectal cancer (CRC). In the first-line treatment of metastatic CRC, the results of two prospective, multicenter phase III trials have shown that the combination of irinotecan with bolus or infusional 5-fluorouracil (5FU)/leucovorin (LV) can significantly prolong survival compared with 5FU/LV alone, with a manageable side effects profile. In addition, irinotecan-based regimens, with or without oxaliplatin, may improve resectability of metastases and further increase patient survival. Studies of irinotecan in the first-line setting in combination with newer agents, such as bevacizumab, have shown impressive overall survival. In the second-line setting, irinotecan has demonstrated efficacy superior to that of best supportive care. Initial studies of irinotecan plus bolus 5FU/LV, and the preliminary results from trials of irinotecan plus infusional 5FU/LV in the adjuvant setting, have been disappointing; however, for the largest trial, the Pan-European Trial in Adjuvant Colon Cancer, results with sufficient follow-up are pending. Irinotecan has an acceptable tolerability profile and is not associated with cumulative toxicities in patients with metastatic CRC; regimens containing irinotecan extend treatment duration and improve survival. New regimens and adjunctive therapies are being explored to reduce the incidence of common complications of irinotecan treatment, such as diarrhea and neutropenia.

Bevacizumab, a humanized monoclonal antibody used to treat recurrent and metastatic colorectal cancer, targets the vascular endothelial growth factor (VEGF) molecule. It is hypothesized that bevacizumab works by both depriving tumors of the neovascularity they require to grow, and by improving local delivery of chemotherapy through alterations of tumor vasculature permeability and Starling forces. Complications of bevacizumab treatment include bowel ischemia and perforation, but to date, these complications have only rarely been described as occurring at the site of presumably healed anastomoses following surgery. We report two cases of delayed, "spontaneous" low anterior colorectal anastomotic dehiscence and one right colon anastomotic colocutaneous fistula associated with bevacizumab therapy. After seeing three patients with complications arising from apparently healed low anterior colorectal or right colon anastomoses following initiation of bevacizumab therapy for treatment of metastatic colorectal cancer, we reviewed the experience of The Cancer Institute of New Jersey (CINJ) with use of bevacizumab in approximately 50 patients between April 2004 and December 2006. The three index cases had been treated surgically at CINJ but received chemotherapy elsewhere. None of the 50 patients receiving bevacizumab at CINJ who had previous colon or rectal anastomoses were identified as having this complication. The medical records of the three index cases were reviewed and analyzed. Additionally, a Medline search was performed to identify other reports documenting similar cases. Two reports of related cases were found in the literature. In two of our index cases who underwent low anterior anastomoses, the patients had received preoperative pelvic irradiation before their initial low anterior resection. In one of the two cases, the initial resection was complicated by an anastomotic leak requiring proximal diversion and then subsequent stoma takedown. In both cases, the dehiscence occurred more than 1 year after anastomosis, and became evident 1-10 months following initiation of bevacizumab treatment. In the third index case, a colocutaneous fistula arising from the anastomotic site presented 5 months following right colon resection and 3 months after starting adjuvant systemic therapy with FOLFOX (5-fluorouracil (5-FU), leucovorin, and oxaliplatin) and bevacizumab. Delayed colorectal anastomotic complications may occur in association with bevacizumab therapy. Contributing factors may include anastomotic leak at the time of the original operation and history of anastomotic irradiation. Clinicians treating patients who receive bevacizumab following colectomy for colorectal cancer should be aware of this possible life-threatening complication. These findings may also be relevant to the design of trials of the use of bevacizumab for the postoperative adjuvant treatment of patients with colorectal cancer.

Tumor markers such as carcinoembryonic antigen (CEA) and CA19-9 were analyzed as response indicators and prognostic factors in advanced colorectal carcinoma. Eighty-five patients participated in a phase II chemotherapy study from October 1984 to July 1990. A three-drug schedule was administered including low dose epirubicin and sequential methotrexate 5-fluorouracil, followed by leucovorin rescue. Serum specimens for CEA and CA19-9 were obtained prior to the initiation of chemotherapy, and subsequently at 4-6 weeks' intervals. In univariate analysis Karnofsky, the site of the primary tumor, the extent of metastases, the presence of abdominal or liver metastases, serum CEA (cut-off of 20 micrograms/l), and CA19-9 levels correlated with survival. In stepwise multivariate analysis an elevated CA19-9 level, a poor Karnofsky, and the presence of liver metastases were independent adverse prognostic factors. Tumors originating from the left colon had a better prognosis than the others. This was related to a higher response rate in this patient group. Serum CA19-9 level was the most significant prognostic factor whether it was entered as a continuous or as a dichotomized variable into the model. The median survival of patients with a normal CA19-9 level was 30.0 months (lower 95% confidence interval: 16.4 months; upper limit was not calculable), and with an elevated CA19-9 value 10.3 months (8.0-12.6 months, 95% confidence interval). Five of 85 patients had a complete response and 20 a partial response, the overall response rate being 29%. When compared with tumor shrinkage, "CEA response" and "CA19-9 response" had a sensitivity of 84% and 88% and specificity of 77% and 67%, respectively. In conclusion, serum CEA value seems to be the best tumor marker for response prediction, while CA19-9 level is one of the best available prognostic indicators in advanced colorectal carcinoma.

Colon cancer is the fourth most common cancer worldwide. The role of systemic adjuvant chemotherapy in colorectal cancer patients with lymph node involvement has been established in a large number of clinical trials. However, its role in stage II colorectal cancer is less well established. 5-Fluorouracil has been the mainstay of therapy for the last four decades. With the development of novel chemotherapy and biological agents, we have entered into a new era for the treatment of colorectal cancer. The combination of adjuvant 5-fluorouracil, leucovorin, and oxaliplatin has been shown to significantly improve disease-free survival and is now considered the standard of care for completely resected colon cancer in healthy patients. For rectal cancer patients with locally advanced tumors, neoadjuvant chemoradiation followed by adjuvant chemotherapy after surgery is the mainstay of treatment. The availability of oral chemotherapy agents has helped with the ease of administration and avoidance of indwelling catheters. A number of national clinical trials are under way to determine the role of targeted agents in combination with chemotherapy. The goal is to develop a regimen that would improve survival without excessive toxicity while maintaining quality of life. Patients should be encouraged to participate in clinical trials whenever feasible. Despite the advances, many patients will develop recurrent disease. It is of utmost importance to develop molecular markers that could predict which patients are at high risk for disease recurrence. Clinical trials are under way to address this issue. Thus, it will be advantageous to be able to tailor therapy individually, according to the risk of recurrence.

The human reduced folate carrier (hRFC) facilitates membrane transport of folates and antifolates. hRFC is characterized by 12 transmembrane domains (TMDs). To identify residues or domains involved in folate binding, we used substituted cysteine (Cys) accessibility methods (SCAM) with sodium (2-sulfonatoethyl)methanethiosulfonate (MTSES). We previously showed that residues in TMD11 of hRFC were involved in substrate binding, whereas those in TMD12 were not (Hou, Z., Stapels, S. E., Haska, C. L., and Matherly, L. H. (2005) J. Biol. Chem. 280, 36206-36213). In this study, 232 Cys-substituted mutants spanning TMDs 1-10 and conserved stretches within the TMD6-7 (residues 204-217) and TMD10-11 connecting loop domains were transiently expressed in hRFC-null HeLa cells. All Cys-substituted mutants showed moderate to high levels of expression on Western blots, and only nine mutants including R133C, I134C, A135C, Y136C, S138C, G163C, Y281C, R373C, and S313C were inactive for methotrexate transport. MTSES did not inhibit transport by any of the mutants in TMDs 1, 3, 6, and 9 or for positions 204-217. Whereas most of the mutants in TMDs 2, 4, 5, 7, 8, and 10, and in the TMD10-11 connecting loop were insensitive to MTSES, this reagent inhibited methotrexate transport (25-75%) by 26 mutants in these TMDs. For 13 of these (Y126C, S137C, V160C, S168C, W274C, S278C, V284C, V288C, A311C, T314C, Y376C, Q377C, and V380C), inhibition was prevented by leucovorin, another hRFC substrate. Combined with our previous findings, these results implicate amino acids in TMDs 4, 5, 7, 8, 10, and 11, but not in TMDs 1, 2, 3, 6, 9, or 12, as important structural or functional components of the putative hydrophilic cavity for binding of anionic folate substrates.

BACKGROUND

We conducted an open-label, pilot phase II trial to evaluate the efficacy and safety of FOLFOXIRI plus cetuximab as first-line treatment of patients with metastatic colorectal cancer (mCRC).

METHODS

Thirty patients with KRAS wild-type mCRC, <70 years and with performance status 0-1 were included in the trial.

RESULTS

Complete and partial responses were observed in 4 (13.3%) and 17 (56.7%) patients, respectively (overall response rate (ORR)=70%; 95% confidence interval (CI): 53.6%-86.4%); 8 patients (26.7%) had stable disease and 1 had progressive disease. The median time to tumour progression was 10.2 months (95% CI: 7.1-13.4) and the overall median survival time was 30.3 months (95% CI: 18.8-41.9). Secondary R0 resection was performed in 11 (37%) patients. Grade 3 or 4 diarrhoea and neutropenia were observed in 16 (53%) and 7 (23.3%) patients, respectively, and febrile neutropenia observed in 2 (6.6%) patients. Neurotoxicity grade 2 or 3 was reported in 7 (23.3%) and in 2 (6.7%) patients, respectively, and grade 3 rush was reported in 1 patient.

CONCLUSIONS

The FOLFOXIRI/cetuximab combination presented increased activity in terms of response rate and R0 secondary liver metastases resection, and merits further investigation, especially in patients with initially unresectable disease confined to the liver.

We performed a phase I study with the thrombospondin-1-mimetic angiogenesis inhibitor ABT-510 combined with 5-fluorouracil and leucovorin (5-FU/LV) to determine safety profile and assess pharmacokinetic interactions. Patients with advanced solid malignancies received LV 20 mg/m(2) followed by 5-FU 425 mg/m(2) both administered intravenously in 15 min daily for 5 days every 4 weeks. ABT-510 was administered subcutaneously twice daily continuously from day 2 onwards. Blood and urine samples for pharmacokinetic analyses were collected at days 1, 5 and 22. Twelve patients received a total of 45 cycles of 5-FU/LV combined with ABT-510. ABT-510 dose levels studied were 50 and 100 mg. The combination was well tolerated, with a toxicity profile comparable to that of 5-FU/LV alone. At the dose levels studied no significant pharmacokinetic interactions were observed. These data indicate that ABT-510 administered twice daily subcutaneously can be safely combined with 5-FU/LV administered daily for 5 days, every 4 weeks.

BACKGROUND

Patients older than 75 years of age are usually excluded from metastatic colorectal cancer randomized studies. The OPTIMOX1 study evaluated FOLFOX7, a simplified (s) leucovorin (LV) and 5-fluorouracil (5FU) regimen (sLV5FU2) with high-dose oxaliplatin, in a new oxaliplatin stop-and-go strategy. An exploratory cohort of patients aged 76 to 80 years was included in the study.

METHODS

In all, 620 previously untreated patients were randomized between FOLFOX4 until progression (arm A), or FOLFOX7 for 6 cycles, maintenance without oxaliplatin for 12 cycles, and reintroduction of FOLFOX7 (arm B).

RESULTS

A total of 37 patients aged 76 to 80 years were included, 20 in arm A and 17 in arm B. The overall response rate (ORR) was 59.4%, comparable to younger patients (59%). Median progression-free survival (PFS) was 9.0 months and median overall survival (OS) was 20.7 months. These results did not differ from that in younger patients < or =75 years in the OPTIMOX1 study with PFS 9.0 months (P = .63) and OS 20.2 months (P = .57). They experienced slightly more grade 3 of 4 toxicity than younger patients: 65% versus 48% (P = .06), mainly with more neutropenia (41% vs 24%, P = .03) and neurotoxicity (22% vs 11%, P = .06). Tolerability, however, was manageable and no toxic death occurred in this elderly population.

CONCLUSIONS

The efficacy of FOLFOX-based treatment was maintained in patients >75 years with both FOLFOX regimens. The oxaliplatin stop-and-go management strategy performed well in this population.

Leucovorin potentiates the cytotoxicity of fluorouracil (5-FU) in experimental tumor systems and appears to enhance the effectiveness of 5-FU in patients with colon cancer. Twenty-two eligible patients (18 previously untreated) with advanced pancreatic adenocarcinoma were treated in a phase II trial of leucovorin 500 mg/m2/d for 6 days by continuous intravenous infusion with 5-FU 370 mg/m2/d by rapid intravenous injection on 5 consecutive days, beginning 24 hours after initiation of leucovorin infusion. Among the 20 assessable patients, there were no complete or partial regressions, although there was one minor response lasting 4 months. Three patients had stable disease for 5, 20, and 21 months, respectively. Median survival was 10 weeks. Toxicity was predominantly mucosal; stomatitis grade 2 or worse was seen in five patients, and diarrhea grade 2 or worse was seen in four. Hospitalization for toxicity was necessary in four previously untreated patients and three previously treated patients. The median WBC nadir was 4.6 (range, 1.4 to 9.6) x 10(3)/microL, and the median platelet nadir was 147.0 (range, 69.0 to 240.0) x 10(3)/microL. This combination of leucovorin and 5-FU did not demonstrate meaningful therapeutic activity in patients with adenocarcinoma of the pancreas and was associated with moderate to severe toxicity. It should not be considered a standard treatment for patients with this disease.

BACKGROUND

Platinum and 5-fluorouracil (5-FU)-based regimens have been used the most frequently in palliative chemotherapy for gastric cancer. The present study evaluated the prognostic significance of Bax, excision repair cross-complementation group 1 (ERCC1), and thymidylate synthase (TS) in advanced gastric cancer patients treated with 5-FU, leucovorin, and oxaliplatin (FOLFOX) palliative chemotherapy.

METHODS

Seventy-two patients with metastatic or recurrent gastric cancer were treated with FOLFOX regimen. Pretreatment tumor biopsy specimens were analyzed for Bax, ERCC1, and TS expression by immunohistochemistry.

RESULTS

High expression of Bax, ERCC1, and TS was observed in 31 (43%), 33 (46%), and 35 (49%) patients, respectively. The median overall survival (OS) of patients was 12 months. Low expression of Bax was associated with poor OS (median, 9 months vs. 18 months; 2-year, 10% vs. 48%; p=0.0005) in univariate analysis, while expression of ERCC1 and TS was not correlated with patient outcome. In multivariate analysis, low expression of Bax was a significant independent predictor of poor OS (p=0.028). Low expression of Bax was significantly associated with poor survival of patients with metastatic or recurrent gastric cancer treated with FOLFOX chemotherapy.

CONCLUSIONS

Immunohistochemical staining for Bax with pretreatment biopsy specimen may be useful in selecting FOLFOX regimen as a treatment option for advanced gastric cancer patients.

BACKGROUND

Levamisole combined with 5-fluorouracil (5-FU) was previously shown to significantly reduce tumor relapses and improve patient survival when given postoperatively in patients with resected stage III colon cancer. Laboratory investigations subsequently documented a direct dose-dependent enhancement of 5-FU cytotoxicity with increasing concentrations of levamisole against human cancer cell lines. A clinical trial was designed to test the value of levamisole given at its maximum tolerated dose in combination with 5-FU-based chemotherapy.

METHODS

Eight hundred seventy-eight patients who had undergone complete surgical resection of high-risk stage II/III colon cancer were stratified by known prognostic factors and randomized to receive 1 of 2 treatment regimens: standard-dose levamisole combined with 5-FU and leucovorin; or high-dose levamisole combined with the same chemotherapy. Serum neopterin was monitored in a cohort of patients to evaluate immune function.

RESULTS

Severe vomiting and neurologic side effects required reduction in the dose of levamisole that could be safely administered on the high-dose levamisole regimen. There were no significant differences in disease-free survival, overall survival, or levels of serum neopterin between the treatment regimens.

CONCLUSIONS

It was not possible to improve the efficacy of surgical adjuvant chemotherapy for patients with high-risk colon cancer by giving levamisole at its maximum tolerated dose in combination with 5-FU and leucovorin. High rates of severe gastrointestinal and neurologic side effects were observed with the high-dose levamisole regimen.

BACKGROUND

Because only approximately 50% of gastric carcinomas are resectable for cure, the authors hypothesized that effective systemic preoperative (neoadjuvant) chemotherapy, aimed at decreasing the size and extent of the primary tumor and eradicating distant microscopic disease, may increase the rate of resectability and have a greater impact on survival than postoperative (adjuvant) treatment alone. In addition, because the peritoneal cavity is the most common site of first recurrence after successful gastric cancer resection, intraperitoneal (IP) chemotherapy seemed a logical choice for postoperative (adjuvant) treatment.

METHODS

Fifty-nine patients with invasive primary gastric adenocarcinoma who were deemed resectable for cure entered a clinical trial that called for 2 cycles of protracted infusion 5-fluorouracil with weekly leucovorin and cisplatin chemotherapy followed by surgery. Approximately 3-4 weeks after potentially curative surgery, patients were scheduled to receive two cycles of IP 5-fluoro-2'deoxyuridine and cisplatin.

RESULTS

Of the 59 patients studied, 58 (98%) received both cycles of systemic chemotherapy. Fifty-six patients (95%) underwent surgery: 40 patients (71%) had resections intended to cure for Stage 0-IIIB disease, 15 patients (27%) had palliative surgery for Stage IV gastric carcinoma, and one patient died intraoperatively without being staged. Two patients refused surgery, and the remaining patient died of progressive disease prior to surgery. Thirty-one of the 40 patients who underwent curative surgery completed both cycles of postoperative IP therapy; 4 patients received only 1 cycle. Three patients (5%) died secondary to treatment complications. There were two operative deaths, and one patient died of peritonitis associated with Grade 4 granulocytopenia. Nine of the 40 patients (23%) whose carcinomas were resected for cure had recurrent carcinoma. With a median follow-up period now exceeding 45 months, the calculated median survival for the 59 patients entered into the trial is >4 years.

CONCLUSIONS

This program of preoperative systemic and postoperative IP chemotherapy has been found to be safe and appears to decrease gastric carcinoma recurrence rates and increase survival compared with historic controls.

BACKGROUND

A combination of irinotecan with continuous intravenous infusions of 5-fluorouracil (5-FU) and leucovorin (LV) is often used to treat advanced colorectal cancer. However, recent concerns about safety and convenience have prompted the development of new oral fluoropyrimidine derivatives and improved regimens. This phase II study evaluated the efficacy and safety of the oral fluoropyrimidine S-1 plus irinotecan in patients with previously untreated advanced or recurrent colorectal cancer.

METHODS

Forty eligible patients with histologically confirmed colorectal adenocarcinoma received this treatment. S-1 was administered orally on days 1 to 14 of a 21-day cycle. Patients were assigned on the basis of body surface area (BSA) to receive one of the following oral doses twice daily: 40 mg (BSA < 1.25 m(2)), 50 mg (BSA>> or = 1.25 to < 1.50 m(2)), or 60 mg (BSA>> or = 1.50 m(2)). Irinotecan (150 mg/m(2)) was administered by intravenous infusion on day 1.

RESULTS

A total of 327 courses of treatment were administered to 40 patients. Five patients had complete responses, and 20 had partial responses. The overall response rate was 62.5% (95% confidential interval, 47.5%-77.5%). Median progression-free survival was 8.0 months (95% confidential interval, 5.2-11.4 months). The rates of grade 3 or 4 toxicity were as follows: neutropenia, 15%; anemia, 7.5%; anorexia, 12.5%; and diarrhea, 7.5%.

CONCLUSIONS

Combined treatment with S-1 and irinotecan is an effective, well tolerated, and convenient regimen in patients with advanced colorectal cancer. Our findings suggest that combined treatment with S-1 and irinotecan is a promising regimen, offering benefits in terms of safety and survival as compared with conventional regimens in patients with advanced colorectal cancer.

BACKGROUND

The purpose of this study was to report the pharmacokinetics (PK) and tolerance profile of intraoperative intraperitoneal chemo-hyperthermia (IPCH) with oxaliplatin and irinotecan.

METHODS

Thirty-nine patients with peritoneal carcinomatosis (PC) of either gastrointestinal or peritoneal origin underwent complete cytoreductive surgery followed by IPCH with a stable dose of oxaliplatin (460 mg/m(2)), plus one among seven escalating doses of irinotecan (from 300 to 700 mg/m(2)). IPCH was carried out with the abdomen open, for 30 min at 43 degrees C, with 2 l/m(2) of a 5% dextrose instillation in a closed continuous circuit. Patients received intravenous leucovorin (20 mg/m(2)) and 5-fluorouracil (400 mg/m(2)) just before IPCH to maximize the effect of oxaliplatin and irinotecan.

RESULTS

Irinotecan concentration in tumoral tissue increased until 400 mg/m(2) and then remained stable despite dose escalations. It was 16-23 times higher than in non-bathed tissues. Increasing doses of intraperitoneal irinotecan did not modify the PK of intraperitoneal oxaliplatin, and the drug concentration ratio was 17.8 higher in tumoral tissue (bathed) than in non-bathed tissues. The hospital mortality rate was 2.5% and the non-hematological complication rate was 25%. However, grade 3-4 hematological toxicity rate was 58%.

CONCLUSIONS

Intraperitoneal heated oxaliplatin (460 mg/m(2)) plus irinotecan (400 mg/m(2)) presented an advantageous PK profile and was tolerated by patients, despite a high hematological toxicity rate.