Protracted Infusion 5-fluorouracil Research Articles

Concurrent chemoradiotherapy with protracted infusion of 5-fluorouracil (5-FU) and cisplatin for locally advanced resectable esophageal cancer.

Neoadjuvant concurrent chemoradiotherapy (CCRT) has become the standard treatment for esophageal cancer (EC) in North America. The cisplatin/5-flurouracil (5-FU) combination has been the most commonly used regimen. For the last 15 years we incorporated a daily continuous infusion of 5-FU and 2 doses of cisplatin into our neoadjuvant CCRT for potentially resectable EC. Between July 1997 and June 2012, 129 patients with locally advanced EC (T3 or N1 and higher), received neoadjuvant CCRT with cisplatin 75 mg/m(2) on day 1 and day 29 and continuous infusion of 5-FU (225 mg/m(2)/day) on the days of radiation. The median age of patients was 63 years, 85% had adenocarcinoma, 29, 74 and 26 patients had stage II, III and IVa disease respectively, 110 patients had N1 disease based on the American Joint Committee on Cancer (AJCC) 6(th) edition, 118 patients experienced weight loss during treatment. All patients completed treatment. Treatment was well tolerated with 14% of patients having ≥ grade 3 toxicity and 18 patients requiring hospital admission. Sixty-four percent of patients had surgical resection following CCRT, with disease progression and patient refusal being the most common reasons for not proceeding with surgery. An R0 resection was achieved in 96% of patients. A pathological complete response (pCR) was achieved in 45% of patients. With a median follow up of 26 months (1.2-144 months), 48/129 patients recurred and 60/129 died of their disease. Our study has its limitation, however, and compared to the conventional chemotherapy regimens containing the cisplatin/5-FU doublet, our treatment strategy for locally advanced EC CCRT seems to be feasible and well tolerated.

Concurrent chemoradiotherapy with protracted infusion of 5-fluorouracil (5 FU) and cisplatin for locally advanced resectable esophageal cancer: A retrospective study.

119 Background: Neoadjuvant CCRT has become the standard treatment for esophageal cancer. Most clinicians use a conventional cisplatin/5 FU combination which is associated with moderate to severe toxicity. For the last 15 years we have used contiuous low-dose 5-FU combined with two doses of cisplatin. Methods: Between July 1997 and June 2012, 155 patients with locally advanced esophageal cancer (T3 or N1 and higher), received CCRT consistent of cisplatin 75 mg/m2 on day 1 and day 29 and continuous infusion of 5-FU (225 mg/m2/day) on the days of radiation. Results: Median age of patients was 63 year (30-76).Seventeen percent of pts were female and 85% had adenocarcinoma. (3, 34, 86 and 31 pts had stage I, II, III and IVa disease respectively. One hundred and twenty seven pts had N1 disease. Radiation dose (RT) ranged from 45-60 Gy (median 56Gy). Median weight loss was 6.5%. All patients completed treatment. 20% of patients had >=grade 3 toxicity, with 29 patients requiring hospital admission. 53% of patients had surgical resection between 37-149 days following CCRT (median 62 days). R0 resection was achieved in 96% of patients. A pathological complete response was achieved in 38 of 83 pts (45%) who underwent surgical resection. With a median follow up of 26 months (1.2 -144 months), 36% of pts recurred and total of 50% died. Conclusions: Compared to conventional chemotherapy regimen, our CCRT regimen for locally advanced esophageal cancer is well tolerated and associated with a high pathological response rate.

S0356: A Phase II Clinical and Prospective Molecular Trial With Oxaliplatin, Fluorouracil, and External-Beam Radiation Therapy Before Surgery for Patients With Esophageal Adenocarcinoma

Pathologic complete response (pCR) after neoadjuvant therapy for locally advanced esophageal adenocarcinoma is associated with improved survival. The Southwest Oncology Group designed a trimodality, phase II, single-arm trial with objectives of achieving a pCR rate of 40% with prospective exploratory analyses of intratumoral molecular markers postulated to affect response and survival. Patients with clinically staged II or III esophageal adenocarcinoma received oxaliplatin 85 mg/m(2) on days 1, 15, and 29; protracted-infusion fluorouracil (PI-FU) 180 mg/m(2)/d on days 8 through 43; and external-beam radiation therapy (EBRT) 5 days a week at 1.8 Gy/d for 25 fractions; surgery was performed 28 to 42 days after neoadjuvant therapy. Chemotherapy was planned after surgery. Tumors were analyzed for mRNA expression and polymorphisms in genes involved in drug metabolism and DNA repair. Ninety-three patients were evaluable. Two deaths (2.2%) were attributable to preoperative therapy, and two deaths (2.2%) were attributable to surgery. Grade 3 and 4 toxicities were recorded for 47.3% and 19.4% of patients, respectively. Seventy-nine patients (84.9%) underwent surgery; 67.7% of patients had R0 resections. Twenty-six patients (28.0%) had confirmed pCR (95% CI, 19.1% to 38.2%). At a median follow-up of 39.2 months, estimates of median and 3-year overall survival (OS) were 28.3 months and 45.1%, respectively. Intratumoral ERCC-1 gene expression was inversely related to progression-free survival and OS. Neoadjuvant oxaliplatin, PI-FU, and EBRT for esophageal adenocarcinoma is active and tolerable. Because the regimen failed to meet the primary end point, it does not define a new standard. However, future trials can be built on this platform to validate the role of ERCC-1 in determining the best systemic regimen for individual patients.

局所進行食道癌に対するcisplatin単回投与, 5-fluorouracil 持続静注と放射線による術前複合療法

局所進行食道癌に対するcisplatin単回投与, 5-fluorouracil 持続静注と放射線による術前複合療法

An Updated Report on the Pathologic Complete Response and Survival Outcome of Southwest Oncology Group (SWOG S0536): A Phase II Trial of Oxaliplatin (oxp) Plus Protracted Infusion 5-Fluorouracil (PIFU) and External Beam Radiation (EBRT) Prior to Surgery(s) for Potentially Curable Esophageal Adenocarcinoma (EA) with Molecular Correlates

An Updated Report on the Pathologic Complete Response and Survival Outcome of Southwest Oncology Group (SWOG S0536): A Phase II Trial of Oxaliplatin (oxp) Plus Protracted Infusion 5-Fluorouracil (PIFU) and External Beam Radiation (EBRT) Prior to Surgery(s) for Potentially Curable Esophageal Adenocarcinoma (EA) with Molecular Correlates

Oxaliplatin (OXP) plus protracted infusion 5-fluorouracil (PIFU) and external beam radiation (EBRT) prior to surgery (S) for potentially curable esophageal adenocarcinoma (EA): A Southwest Oncology Group (SWOG) phase II trial with molecular correlates (S0356)

4513 Background: Although neoadjuvant combined modality therapy (NACMTX) has become a standard of care in the United States, median overall survival (OS) for patients (PTS) with EA has changed little over the past 25 years. Progression free survival (PFS) and OS after NACMTX depend on extent of primary tumor response. New regimens to increase pathologic complete response (pCR) are needed. Based on phase I data, SWOG designed a phase II trial (S0356) to test OXP with PI5FU and EBRT for PTS with EA. Objectives included pCR rate ≥ 25%, acceptable toxicity (TOX), PFS, OS and exploration of molecular parameters relevant to pCR. Methods: Eligibility: clinical stage II/III EA, ≥ 18 years, Zubrod PS ≤ 2, standard hematologic/non-hematologic values, and tumor < 2 cm into the gastric cardia. OXP 85 mg/m2 was given day (d) 1, 15 and 29; PI5FU 180 mg/m2/d was given d 8-d43. EBRT 180 cGy/d started d 8 x 25 fractions, 5 d/week to total dose 4500 cGy. S was planned 2–4 weeks after NACMTX, with a second cycle of OXP/ PI5FU after S. Central pathology review of surgical specimens was mandated. The trial used a 2-stage design; the trial was halted at 45 PTS to review pCR rate; it reopened to full accrual. Results: 98 PTS enrolled between 9/15/04 and 8/18/08. 6 PTS were ineligible; 2 PTS did not receive therapy (TX). 90 PTS, 84 men (93%), median age 61.7 years, were analyzed. 4 deaths (4.5%) were due to protocol TX; 2 due to NACMTX, 2 to S. 43% and 18% of PTS had grade 3/4 toxicity, respectively: 39% GI, 22% flu-like/fatigue, 17% pulmonary, 16% hematologic, 14% mucositis and 3% neurologic. 77 PTS (86%) underwent S. 30 PTS (33%) had pCR. 9 PTS (10%) had in-situ cancer or T1N0M0. <50% received postoperative CTX. Conclusions: OXP, PI5FU and EBRT for PTS with EA has produced the highest pCR rate reported to date for a cooperative group trial. Significant but manageable non-hematologic TOX was observed. S mortality is acceptable. Future trials built on this platform should plan to complete all TX before S. Tumor molecular profiles (analyses in progress) may predict benefit from this treatment. Data on PFS and OS will follow. [Table: see text]

A phase II trial of chemoradiation therapy with weekly oxaliplatin and protracted infusion of 5-fluorouracil for esophageal cancer

Chemoradiation therapy using regimens containing cisplatin and 5-fluorouracil are most commonly used for inoperable cancer of the esophagus. Cisplatin is relatively toxic and is not suitable for many patients. Little data exists using platinum analogues together with protracted infusion 5-fluorouracil and radiation therapy in the curative setting. Fourteen patients with localised oesophageal cancer suitable for curative chemoradiation therapy registered on the study. Chemotherapy consisted of 5-fluorouracil 225 mg/m(2) daily throughout radiation therapy, with oxaliplatin 60 mg/m(2) weekly. The radiation dose was 56 to 60 Gy in 28 to 30 fractions. The median age of the patients was 70.5 years. Therapy was associated with excessive grade 3 and 4 non-hematologic toxicity. There was one treatment related death. The median progression-free survival was 31.5 months and median overall survival 32.6 months. Six patients achieved a prolonged complete endoscopic and radiological response. Although weekly oxaliplatin in combination with infusional 5 fluorouracil produces durable remissions in esophageal cancer, the regimen used in this trial was not acceptable for routine use. Future protocols should incorporate lower chemotherapy doses.

Epidermal Growth Factor Receptor is a Possible Predictor of Sensitivity to Chemoradiotherapy in the Primary Lesion of Esophageal Squamous Cell Carcinoma

Chemoradiotherapy (CRT) is currently performed for patients with esophageal squamous cell carcinoma (SCC). Some reports have revealed that patients who responded well to CRT had favorable outcomes, whereas poor responders conversely showed a worse prognosis. The aim of this study was to identify molecular markers predicting sensitivity to CRT. We reviewed 62 patients with T(3-4), N-any, and M-any esophageal SCC treated with definitive CRT. The regimen comprised protracted 5-fluorouracil infusion and a 2-h infusion of cisplatinum combined with radiation therapy (2 Gy/day) at a total radiation dose of 60 Gy. The expressions of epidermal growth factor receptor (EGFR), vascular endothelial growth factor, cyclin D1, and proliferating cell nuclear antigen were investigated immunohistochemically in biopsy specimens obtained before treatment from all 62 patients. The immunoreactivities were compared with responsiveness to CRT, as evaluated by endoscopy. The complete response rate of the primary tumor estimated by endoscopy was 62% (13/21) in patients in the EGFR-positive group. The difference in the CR rate between EGFR-positive and -negative groups was significant (p = 0.037). The immunoreactivities of the other molecular markers did not show a significant correlation with the responsiveness of the primary lesion to CRT. Multiple logistic regression analysis revealed that positive immunostaining for EGFR was significantly correlated with primary CR for CRT in esophageal SCC. Among 62 patients with esophageal SCC, differences in the responsiveness of primary lesions to CRT were correlated with EGFR immunoreactivity assessed in the biopsy specimens. These results suggest that EGFR may help to predict the response of primary sites to definitive CRT in esophageal SCC, although the results should be confirmed in a larger, more homogeneous series.

Capecitabine plus oxaliplatin (xelox) versus protracted 5-fluorouracil venous infusion plus oxaliplatin (pvifox) as first-line treatment in advanced colorectal cancer: A GOAM phase II randomised study (FOCA trial)

This phase II randomised trial compares oxaliplatin plus protracted infusion of 5-fluorouracil (pviFOX) or oxaliplatin plus capecitabine (XELOX) in the first-line treatment of advanced colorectal cancer (ACRC). Methods: From December 2001 to March 2005, 118 patients were randomised to arm A ( pviFOX: pvi5-FU by a central venous catheter 250 mg/m2/daily d1-21 + oxaliplatin 130 mg/m2 d1 q3w) (56 pts) or arm B (XELOX: capecitabine 1000 mg/m2 po bid d1-14 + oxaliplatin at the same schedule) (62 pts). Results: Patient characteristics were well-balanced between the two arms. Median number of complete cycles was six. The objective responses were: CR 1 (1.7%) and 3 (4.8%), PR 26 (46.4 %) and 24 (38.7%), SD 13 (23.2%) and 20 (32.3%), P 13(23.2%) and 10 (16.1%), not evaluable 3 (5.4%) and 5 (8.1 %) in arms A and B, respectively; the CR + PR rate was 48.2% (95% confidence limits 34.6%–61.9%) versus 43.5 % (31.0%–56.7%). Median TTP was 7 versus 9 months, respectively. About 50% of the patients with symptoms or low performance status at baseline experienced improvement without major differences between the two arms. G3–4 diarrhoea was observed in 14.0% versus 8.2%, G3 stomatitis in 3.7% versus 0, and G3 neurotoxicity in 18.5% versus 24.6% in arms A and B, respectively. Eight patients in arm A (14.8%) had venous line problems that obliged the temporary suspension (six cases) or stopping (two cases) of the 5-FU infusion. Conclusion: Both pviFOX and XELOX are effective and safe first-line treatments for patients with ACRC. By avoiding intravenous (i.v.) administration by a central catheter, XELOX is favoured in clinical practice.

Preoperative chemoradiotherapy with capecitabine versus protracted infusion 5-fluorouracil for rectal cancer: A matched-pair analysis

To retrospectively compare the acute toxicity, pathologic response, relapse rates, and survival in rectal cancer patients treated with preoperative radiotherapy (RT) and either concurrent capecitabine or concurrent protracted infusion 5-fluorouracil (5-FU). Between June 2001 and February 2004, 89 patients with nonmetastatic rectal adenocarcinoma were treated with preoperative RT and concurrent capecitabine, followed by mesorectal excision. These patients were individually matched by clinical T and N stage (as determined by endoscopic ultrasound and CT scans) with 89 control patients treated with preoperative RT and concurrent protracted infusion 5-FU between September 1997 and August 2002. In each group, 5 patients (6%) had Grade 3-4 toxicity during chemoradiotherapy. The pathologic complete response rate was 21% with capecitabine and 12% with protracted infusion 5-FU (p = 0.19). Of the 89 patients in the capecitabine group and 89 in the 5-FU group, 46 (52%) and 55 (62%), respectively, had downstaging of the T stage after chemoradiotherapy (p = 0.20). The estimated 3-year local control (p = 0.15), distant control (p = 0.86), and overall survival (p = 0.12) rate was 94.4%, 86.3%, and 89.8% for patients treated with capecitabine and 98.6%, 86.6%, and 96.4% for patients treated with protracted infusion 5-FU, respectively. Preoperative concurrent capecitabine and concurrent protracted infusion 5-FU were both well tolerated, with similar, low rates of Grade 3-4 acute toxicity. No significant differences were seen in the pathologic response, local and distant recurrence, or overall survival among patients treated with preoperative RT and concurrent capecitabine compared with those treated with RT and concurrent protracted infusion 5-FU.

Late toxicity in complete response cases after definitive chemoradiotherapy for esophageal squamous cell carcinoma

We retrospectively investigated long-term toxicity after concurrent chemoradiotherapy (CRT) for patients with esophageal squamous cell carcinoma (ESCC). Concurrent chemoradiotherapy was performed in 110 patients with T1 to T4 disease containing M1 lymph node (LYM) disease. Chemotherapy consisted of protracted infusion of 5-fluorouracil 400 mg/m(2) per 24 h on days 1 to 5 and 8 to 12, combined with 2-h infusion of cisplatin 40 mg/m(2) on days 1 and 8. Radiation treatment of the mediastinum at a dose of 30 Gy in 15 fractions was administered concomitantly with chemotherapy. A course schedule with a 3-week treatment and a 2-week break was applied twice, with a total radiation dose of 60 Gy. For the assessment of toxicity, the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer late radiation morbidity scoring schema was adopted. A total of 81 patients were recruited in patients with stage I to IVA. Of 34 patients with complete response, 1 patient died as a result of acute myocardial infarction. Grade 2, 3, and 4 late toxicities occurred with the following incidences: pericarditis in 3 patients, 1 patient, and 2 patients, respectively; heart failure in 0, 0, and 3 patients; pleural effusion in 2, 3, and 0 patients; and radiation pneumonitis in 0, 0, and 1 patient, respectively. Definitive chemoradiotherapy for ESCC is effective with substantial toxicities. Further investigation is warranted to minimize the normal tissue toxicities.

Just When You Thought the Fluorouracil Debate Was Over: S-1 and Gastric Cancer

Despite a decline in incidence in the United States and Western Europe, gastric cancer is common worldwide and remains the second leading cause of cancer-related death. In a shift in the epidemiology of gastric cancer, adenocarcinomas of the esophagus and gastroesophageal junction are increasing at a dramatic rate in the United States and Western Europe, and represent an even more virulent disease entity. The pattern of more distal gastric cancer elsewhere in the world may be a function of rates of infection by Helicobacter pylori, dietary practices, and potential dietary deficiency in micronutrients such as selenium and vitamin C. The predominance of adenocarcinoma of the esophagus and gastroesophageal junction in the West may reflect population trends in obesity and tobacco abuse, and paradoxically, a decrease in Helicobacter infection that may increase the risk of esophageal reflux disease. Because of the absence of effective screening, patients with gastric cancer in the United States usually present with symptomatic and either locally advanced or metastatic disease. High rates of recurrence after surgery have engendered decades of clinical trials evaluating the use of adjuvant chemotherapy, with or without radiation. Fortunately, recent clinical trials have made advances with the validation of the use of systemic chemotherapy to improve survival. Intergroup trial 116 showed that postoperative bolus fluorouracil (FU), leucovorin, and radiation therapy improved survival compared with surgery alone, despite the relative inactivity for FU and leucovorin in metastatic disease. Although postoperative adjuvant chemotherapy alone has failed to affect survival in gastric cancer, preand postoperative chemotherapy with epirubicin, cisplatin, and protracted-infusion FU (ECF) without the use of radiation, as recently reported in the MAGIC trial from the United Kingdom, significantly improved survival compared with surgery alone. The improvement in survival in recent adjuvant trials, however, is marginal, and the key to further progress is the identification of more active systemic agents in gastric cancer. The evaluation of a novel combination chemotherapy regimen, S-1 and cisplatin, is the focus of the phase I trial reported by Ajani et al in the current issue of the Journal of Clinical Oncology. This trial raises important issues about the pace of progress of chemotherapy development in gastric cancer, including the role of oral agents as a replacement for intravenous drugs. The trial also, for better or for worse, rekindles the time-worn debate of how best to administer fluoropyrimidines as part of combination chemotherapy. Conventional chemotherapy used in the treatment of gastric cancer has limited effectiveness and significant toxicity, depending on the dose and schedule of agents used. If we are searching for direction in gastric cancer drug development, colorectal cancer should clearly serve as a model. Progress has been made in colorectal cancer in the identification of new chemotherapy agents, optimal dosing and scheduling of agents, and the incorporation of targeted therapies. Colorectal cancer trials have firmly established that, in comparison with bolus FU, the use of continuous-infusion FU administered as a biweekly 48-hour infusion results in superior antitumor efficacy, longer patient survival, and improved therapy tolerance. The debate about the optimal schedule of FU has largely been replaced by discussion of the best sequencing of available therapies and the addition of targeted agents. The substitution of oral agents for continuous-infusion FU is a topic of more secondary interest given the accumulating data from phase III trials that show equivalence, but not necessarily superiority, of oral drugs. Whereas response, survival, and toxicity benefits have all been accomplished in colorectal cancer trials, such advances have eluded gastric cancer investigators. In gastric cancer, there has been a seeming reluctance to incorporate lessons learned from the trial experience in colorectal cancer. There is continued acceptance of the combination of a 5-day infusion of FU in combination with every 3to 4-week dosing of relatively high doses of cisplatin. The toxicity and limited efficacy of this regimen was underscored in a phase III JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 23 NUMBER 28 OCTOBER 1 2005

Serpentine supravenous streaks induced by 5-fluorouracil

To the Editor: Hrushesky1Hrushesky W.J. Unusual pigmentary changes associated with 5-fluorouracil therapy.Cutis. 1980; 26: 181-182PubMed Google Scholar was the first to report hyperpigmentation of the skin immediately overlying veins used for multiple 5-fluorouracil (5-FU) infusions and used the term “serpentine supravenous fluorouracil hyperpigmentation” for this entity.A 30-year-old male developed asymptomatic serpiginous hyperpigmentation characteristically overlying the right cephalic, basilic, median cubital veins, and median vein of forearm (Fig 1) after receiving 2 cycles of adjuvant 5-FU as continuous intravenous infusion for rectal adenocarcinoma. There was no clinical evidence of thrombophlebitis, and these veins were still patent. The histopathology of the involved skin showed an increase in the epidermal melanin content and melanin incontinence into the dermis (Fig 2). The patient received a third cycle of 5-FU that did not worsen the pigmentation.Fig 2Photomicrograph showing increased epidermal melanin content and melanin incontinence into the dermis. (Hematoxylin-eosin stain; original magnification: ×100.)View Large Image Figure ViewerDownload (PPT)The exact mechanism of this phenomenon is unknown, but it has been postulated that these cytotoxic agents cause endothelial injury. The agent then leaches from the vessel to the overlying epidermal melanocytes and interferes in melanosome packaging with the keratinocytes,2O'Daugherty D. Hyperpigmentation after cancer chemotherapy.Lancet. 1975; 2: 365Abstract Scopus (6) Google Scholar thereby resulting in hyperpigmentation of that skin.This is an isolated occurrence of 5-FU–induced serpentine supravenous streaks; in the absence of other dermatologic, hematologic, or gastrointestinal side effects, this is an extremely rare phenomenon. There is no specific treatment3Perlin E. Ahlgern J.D. Pigmentary effects from protracted infusion of 5-fluorouracil.Int J Dermatol. 1991; 30: 43-44Crossref PubMed Scopus (18) Google Scholar for the pigmentary streaks induced by 5-FU. In time, the pigmentation disappears and may not warrant discontinuation of the drug. To the Editor: Hrushesky1Hrushesky W.J. Unusual pigmentary changes associated with 5-fluorouracil therapy.Cutis. 1980; 26: 181-182PubMed Google Scholar was the first to report hyperpigmentation of the skin immediately overlying veins used for multiple 5-fluorouracil (5-FU) infusions and used the term “serpentine supravenous fluorouracil hyperpigmentation” for this entity. A 30-year-old male developed asymptomatic serpiginous hyperpigmentation characteristically overlying the right cephalic, basilic, median cubital veins, and median vein of forearm (Fig 1) after receiving 2 cycles of adjuvant 5-FU as continuous intravenous infusion for rectal adenocarcinoma. There was no clinical evidence of thrombophlebitis, and these veins were still patent. The histopathology of the involved skin showed an increase in the epidermal melanin content and melanin incontinence into the dermis (Fig 2). The patient received a third cycle of 5-FU that did not worsen the pigmentation. The exact mechanism of this phenomenon is unknown, but it has been postulated that these cytotoxic agents cause endothelial injury. The agent then leaches from the vessel to the overlying epidermal melanocytes and interferes in melanosome packaging with the keratinocytes,2O'Daugherty D. Hyperpigmentation after cancer chemotherapy.Lancet. 1975; 2: 365Abstract Scopus (6) Google Scholar thereby resulting in hyperpigmentation of that skin. This is an isolated occurrence of 5-FU–induced serpentine supravenous streaks; in the absence of other dermatologic, hematologic, or gastrointestinal side effects, this is an extremely rare phenomenon. There is no specific treatment3Perlin E. Ahlgern J.D. Pigmentary effects from protracted infusion of 5-fluorouracil.Int J Dermatol. 1991; 30: 43-44Crossref PubMed Scopus (18) Google Scholar for the pigmentary streaks induced by 5-FU. In time, the pigmentation disappears and may not warrant discontinuation of the drug.

Feasibility of chemoradiation therapy with protracted infusion of5-fluorouracil for esophageal cancer patients not suitable for cisplatin

Chemoradiation therapy is the standard treatment for esophageal cancer in patients not fit for surgery. The regimen most commonly used includes cisplatin and 5-fluorouracil. Little data exists regarding alternative chemotherapy regimens in patients not suitable for cisplatin. We report on a regimen using protracted infusion 5-fluorouracil alone for both curative and palliative indications. Twenty-two patients with localized esophageal cancer suitable for curative chemoradiation therapy and 24 patients suitable for palliative therapy were enrolled. Chemotherapy consisted of 5-fluorouracil 225 mg/m(2) daily throughout the radiation therapy. The radiation dose was 56 to 60 Gy in 28 to 30 fractions (curative patients) and 30 to 35 Gy in 15 fractions (palliative patients). The median age of the patients was 75 years. The regimen was tolerable. Significant grade 3 toxicities experienced were esophagitis (11%) and venous catheter toxicity (9%). The median survival was 17 months for curative patients and 9 months for palliative patients. The complete response rate was 86% endoscopically and 45% radiologically for curative patients. Relief of dysphagia was experienced in 67% of palliative patients. Quality of life was satisfactory in both groups. This study showed that continuous-infusion 5-fluorouracil given concurrently with radiation therapy is a useful alternative to platinum-based chemoradiation therapy in patients with esophageal carcinoma.

Chemoradiotherapy for Locally Advanced Pancreatic Carcinoma in Elderly Patients

Objectives: Chemoradiotherapy, which is one of the standard treatments for locally advanced pancreatic carcinoma, is considered a high-risk procedure in elderly patients. This study investigated the outcome and tolerability of this treatment in elderly patients. Methods: We reviewed our database from November 1993 to March 2003 and retrospectively examined the clinical data of patients with histologically confirmed exocrine pancreatic carcinomas that were nonresectable but confined to the pancreatic region, who were treated with protracted 5-fluorouracil infusion (200 mg/m²/day) and concurrent radiotherapy (50.4 Gy in 28 fractions over 5.5 weeks). We evaluated the outcome of patients ≧70 years and those <70 years. Results: There were 19 patients ≧70 and 39 patients <70. On pretreatment evaluation, the elderly patients showed lower serum albumin levels, lower transaminase levels, better ECOG performance status, more frequent body weight loss and less frequent abdominal and/or back pain with the administration of morphine than the younger patients. There were no significant differences in the frequency of severe toxicity. Neither the response rate nor the incidence of treatment discontinuation differed significantly between the two groups. The median survival time was longer in the elderly patients than in the younger patients (11.3 vs. 9.5 months, p = 0.04). Conclusions: With careful patient selection, chemoradiotherapy can be one of the treatment options for locally advanced pancreatic carcinoma in elderly patients.

Phase II study of hyperfractionated radiotherapy with protracted 5-fluorouracil infusion in patients with locally advanced pancreatic cancer

4111 Background: As shown in our previous phase I study (Oncology 2004, 67:215–221), hyperfractionated radiation therapy (HFRT) with concurrent administration of protracted 5-fluorouracil (5-FU) infusion appears to be feasible and effective in locally advanced pancreatic cancer (LAPC). The present phase II study was conducted to assess the efficacy and toxicity of HFRT with protracted 5-FU infusion in patients (pts) with LAPC. Methods: Eligibility criteria included locally advanced unresectable pancreatic cancer, histological or cytological confirmation of adenocarcinoma, 20–74 years of age, Karnofsky performance status of ≥70, and no prior chemotherapy or radiotherapy. All pts received two fractions of 1.2 Gy each per day for 5 days a week over 5.3 weeks (total dose, 64.8 Gy) and protracted 5-FU infusion (200 mg/m2/day) during the course of radiation therapy. After this therapy, patients received gemcitabine (1000 mg/m2 weekly x 3 every 4 weeks) for at least 4 courses. Results: Thirty-nine of 40 enrolled pts were assessable for efficacy and toxicity. Of the 39 pts, 35 (90%) pts completed the scheduled course of treatment. Although no complete response was seen, a partial response was obtained in 16 (41%) pts and 18 (47%) pts showed stable disease according to RECIST criteria. At the time of analysis, although 20 pts developed distant metastasis, local progression has not been observed. The median time to progression was 7.8 months, and the median overall survival was 13.2 months with 1-year survival rates of 56%. The most common grade 3–4 toxicities observed during radiation therapy were anorexia (59%), nausea (21%), gastric or duodenal ulcer (13%), and fatigue (13%). Hematological toxicity was mild and transient. With regard to late complications, one patient developed treatment-resistant gastric ulcer. Conclusions: HFRT with protracted 5FU infusion showed good local control and survival with an acceptable toxicity profile in pts with LAPC. No significant financial relationships to disclose.

Phase II randomized trial on protracted 5-fluorouracil infusion plus oxaliplatin (FOX) versus capecitabine plus oxaliplatin (XELOX) as first-line treatment in advanced colorectal cancer (ACRC): Preliminary results of the Italian FOCA Study

3617 Background: FOX regimen has shown to be safe and active in pretreated ACRC pts. Capecitabine (CAPE), an oral fluoropyrimidine, has been explored as an alternative to infusional 5-fluorouracil (5FU) in oxaliplatin (OXA) containing regimen (XELOX). The aim of this phase II randomized trial was to compare the efficacy and safety of FOX and XELOX as first line therapy in ACRC pts. Methods: From December 2001 to December 2004, 100 eligible untreated pts with ACRC have been randomized to arm A (FOX) (5-fluorouracil protracted infusion iv 250 mg/m2 d1–21 + oxaliplatin 130 mg/m2 iv d1, q3w) or arm B (XELOX) (capecitabine 1000 mg/m2 po bid d1–14, q3w + oxaliplatin 130 mg/m2 iv d1,q3w). Fourty-eight pts were randomized to arm A and 52 to arm B. Results: Baseline pt characteristics were well balanced between the two arms: M/F 52/48, median age 66.8 years (41–79); median KPS 90 (70–100); colon 71%, rectum 29%; primary tumor resection 80.9%; adjuvant chemotherapy 24%; metastatic sites: liver 77% (only liver 43%), lung 35%, lymph nodes 21%. Median number cycles was: 5 (1–10) in arm A and 6 (1–10) in arm B. Median dose intensity was: 5FU 100% (13–100) and OXA 100% (82–100) in arm A; CAPE 100% (16–100) and OXA 100% (60–100) in arm B. At the moment 75 pts were evaluable for response and 93 pts for toxicity. The objective responses were: arm A CR 3%, PR 48.5%, SD 27.3%, PD 21.2%; arm B CR 7.1%, PR 38.1%, SD 33.3%, PD 21.4%; RR 51.5% vs 45.2%. In arm A and B median TTP was 6 vs 9 months. Survival data are immature (58% of pts are still alive). Surgical resection of liver metastases after chemotherapy was performed in 4.1% pts in arm A vs 9.6% pts in arm B. Only 1 pt showed grade 4 toxicity (NCI-CTC2) (diarrhea) in arm A. Grade 3 treatment-related toxicity in arm A and B was: neutropenia 2.4% vs 0; thrombocytopenia 2.4% vs 2.4%; stomatitis 4.8% vs 0; diarrhea 14.3% vs 3.9%; hypertransaminasemia 0 vs 2%; hyperbilirubinemia 2.3% vs 2.1%; neurotoxicity 15.0% vs 20.4%. Conclusions: Our preliminary results suggest that FOX and XELOX, as administered in this trial, show high activity as first line treatment. Toxicity is low and similar in the two arms. No significant financial relationships to disclose.

Oxaliplatin (OX) and leucovorin (L) combined with protracted-infusion fluorouracil (F) and radiation (XRT) in locally advanced esophageal cancer (LAEC): A multicentric phase II study

4071 Background: to evaluate activity and feasibility of FOXL concomitant with XRT in patients (pts) with unresectable LAEC. Methods: pts with histologically proven LAEC, unresectable for T or N extension, not previously treated, were enrolled. FOXL therapy consisted of OX 60 mg/m2 infused over 2h on days 1, 8, 15, 29, 36, 43, 50, 57, followed by L 20 mg/m2 over 1h, and F 200 mg/m2 for 24 hours on days 1–22 and 29–64. XRT, 1.8 Gy in 25 fractions (frs), started on day 29. Downstaged pts underwent either surgical operation (SO) or received brachiterapy (XBRT) 15 Gy in 3 frs. Primary end-point was 1-year PFS. We here report the feasibility, ORR, % of R0 resections, and pCRs in the first 45 pts, out of 52 currently enrolled, since they had sufficient time to complete the planned treatment (PT). Results: 45 pts were enrolled from November 2002 to July 2004, median age 58 (range: 40–73), male:female 36:9, ECOG PS 0/1: 12/33, scc/ad: 38/7; cervical/thoracic/distal: 2/29/14, dysphagia Grade (G) 2/3/4: 15/10/6. Stage at presentation was as follows: T2N1 (2), T3N1 (30) T4 (9) M1a (4). Thirty-two (71%) pts have received the eight planned wks of FOXL; 9 pts interrupted therapy due to toxicity and 2 for PD. 44 pts started XRT and 40 (83%) completed the whole PT. Major toxicity included: leukopenia G3–4: 9% neutropenia G3–4: 13%, anemia G3–4: 4%, thrombocytopenia G3–4: 7%, DVT G3: 7% (always catheter related), mucositis G3–4: 13% diarrhea G3–4: 16%, neuropathy G3: 2%. Three pts died prematurely: 2 for toxicity and 1 for a massive esophageal bleeding. We recorded 22 PRs and 4 CRs (ORR: 65%). SO was attempted in 27 (60%) pts and was radical in 22 (81% of resected, 51% of treated). pCR was recorded in 6 (22% of operated on) pts. Three pts with negative post-treatment endoscopy and biopsy refused surgery. There were two postoperative deaths: one due to myocardial failure and one to ARDS. Conclusions: After 8 weeks of FOXL and concurrent XRT, a radical resection in more than 50% of initially unresectable LAEC pts, with modest toxicity, was possible. With these findings confirmed after a longer follow-up, a phase III comparison to cisplatin-containing chemoradiotherapy should be considered. No significant financial relationships to disclose.

Phase I Study of Hyperfractionated Radiation Therapy with Protracted 5-Fluorouracil Infusion in Patients with Locally Advanced Pancreatic Cancer

Objective: This study investigated the maximum-tolerated dose of hyperfractionated radiation therapy with protracted 5-fluorouracil (5-FU) infusion in patients with locally advanced, unresectable pancreatic cancer. Methods: Five cohorts of patients were scheduled to receive escalating doses of hyperfractionated radiation therapy (range, 45.6–64.8 Gy). All patients received two fractions of 1.2 Gy each (separated by 6 h) per day for 5 days a week, and received protracted 5-FU infusion (200 mg/m²/day) during the radiation course. The maximum-tolerated dose was defined as one dose level below the dose at which more than one third of 3–6 patients experienced dose-limiting toxicity. Results: Twenty-nine patients were enrolled in this study. The most common toxicities were nausea/vomiting and anorexia. Although 1 patient developed bleeding from a gastric ulcer 3 months after the completion of chemoradiotherapy, the maximum-tolerated dose was not reached even at the highest dose level (level 5, 64.8 Gy). The median survival time was 12.2 months and the 1-year survival rate was 55.0%. Conclusion: The toxicity associated with our regimen was tolerable up to dose level 5 (64.8 Gy). We are currently conducting a phase II study of this hyperfractionated radiation therapy with protracted 5-FU infusion at a dose of 64.8 Gy.

Continuous fixed dose schedule for capecitabine

3633 Background: Capecitabine is an oral fluoropyrimidine commonly used in a cycling 21 day schedule with 14 days on and 7 days off with a daily dose of 2000 to 2500 mg/m2. The major limiting toxicities with this dose and schedule are diarrhea and hand/foot syndrome. A daily “fixed dose” not based on m2 and with a continuous uninterrupted non cycling schedule offers the potential for continuous exposure emulating the parenteral low dose protracted 5-fluorouracil infusion and the potential for less toxicity. Methods: Fifty consecutive patients receiving fixed dose (2000 mg/day) continuous (non cycling) dosing of capecitabine were retrospectively reviewed to determine feasibility, patterns of toxicity and tolerability of this dose schedule. Diagnosis included colon cancer, 26 patients; other GI cancers, 6 patients; GU tumors, 8 patients; and breast cancer, 7 patients. Nineteen of 50 patients received the fixed daily capecitabine dosing as a single agent and 31 patients received capecitabine as part of a multi-modality therapy with radiation or combination chemotherapy regimen. Results: Duration of continuous dosing therapy was 2 weeks to 6 months, median 3 months. None of the 19 patients receiving capecitabine alone developed gastrointestinal or cutaneous toxicity; median duration of therapy 4 months. Seven of the remaining 31 patients (22%) experienced a grade 2 or 3 toxicity; hand/foot syndrome in four, (all grade 2); diarrhea in three patients, grade 2 (2); grade 3 (1). The dose intensity of the continuous fixed dose schedule was 8750 mg/m2/week compared to 11,666 mg/m2/week for the standard dose and schedule. Conclusions: Capecitabine administered as a continuous daily fixed dose has a low toxicity profile in comparison to the cycling 14 days on, 7 days off dose schedule at 2500 or even 2000 mg/m2/day particularly with regard to gastrointestinal and cutaneous toxicity. The dose intensity of the non cycling continuous regimen provides up to 94% of the dose intensity of the intermittent cycling regimen. No significant financial relationships to disclose.