Protracted Venous Infusion 5-fluorouracil Research Articles

Impact of preoperative radiation dose escalation on pathologic outcomes and radiation toxicity in locally advanced rectal cancer (LARC): A matched-pair analysis.

e14036 Background: Compared with postoperative chemoradiotherapy (CRT), preoperative CRT has been shown to improve local control and reduce toxicity for LARC patients. However, the dose of preoperative RT in such regimens is empirically chosen based on experience with postoperative CRT regimens. We hypothesized that higher RT dose improves tumor downstaging without increasing toxicity. Methods: Between 1995 and 2003, LARC patients were treated with preoperative RT and concurrent protracted venous infusion 5-fluorouracil (5FU). 76 patients in the high dose (boost) CRT group (5FU + 52.5 Gy in five weeks, 1.8 Gy/morning and an additional 1.5 Gy/afternoon in the fifth week) were matched (based on type of surgery and clinical T/N stage) with 76 patients in the low dose CRT group (5FU + 45 Gy in five weeks, 1.8 Gy/day). Radiation toxicity, pathological complete response (pCR), and T downstaging were tabulated. Discrete and categorical variables were compared using McNemar’s chi-square test. Results: Both groups were balanced for patient gender, age, and matched parameters. There was a trend in increased grade I/II skin toxicity in the boost group (Table) but no difference in grade III toxicity. Rate of pCR did not differ between the boost and no boost groups (17.1% vs. 15.8%, p=0.83) but T downstaging was greater with RT boost (76.3% vs. 51.3%, p<0.001). Conclusions: CRT with radiation dose escalation in LARC improves T downstaging without significantly increasing toxicity. This approach could improve resectability of more advanced tumors, particularly within the distal rectum. Parameter Boost (n=76) No boost (n=76) P value Gender (M) 49 (64.5%) 50 (65.8%) 0.87 Age (years) 57.1 ± 13.0 55.9 ± 11.7 0.54 Procedure LAR: 19 (25.0%) Same N/A CAA: 36 (47.4%) APR: 21 (27.6%) Initial T stage T2: 2 (2.6%) Same N/A T3: 71 (93.4%) T4: 3 (4.0%) Same N/A Initial N stage N+: 34 (44.7%) Same N/A Grade I/II Skin 53/76 (69.7%) 34/63 (54.0%) 0.06 Radiation toxicity Nausea 21/76 (27.6%) 12/63 (19.0%) 0.24 Diarrhea 44/76 (57.9%) 41/63 (65.1%) 0.39 Pain 14/76 (18.4%) 8/63 (12.7%) 0.36 Abbreviations: APR, abdominoperineal resection; CAA, proctectomy with coloanal anastomosis; LAR, low anterior resection.

Predicting Grade 3 Acute Diarrhea During Radiation Therapy for Rectal Cancer Using a Cutoff-Dose Logistic Regression Normal Tissue Complication Probability Model

Understanding the dose-volume relationship of small bowel irradiation and severe acute diarrhea may help reduce the incidence of this side effect during adjuvant treatment for rectal cancer. Consecutive patients treated curatively for rectal cancer were reviewed, and the maximum grade of acute diarrhea was determined. The small bowel was outlined on the treatment planning CT scan, and a dose-volume histogram was calculated for the initial pelvic treatment (45 Gy). Logistic regression models were fitted for varying cutoff-dose levels from 5 to 45 Gy in 5-Gy increments. The model with the highest LogLikelihood was used to develop a cutoff-dose normal tissue complication probability (NTCP) model. There were a total of 152 patients (48% preoperative, 47% postoperative, 5% other), predominantly treated prone (95%) with a three-field technique (94%) and a protracted venous infusion of 5-fluorouracil (78%). Acute Grade 3 diarrhea occurred in 21%. The largest LogLikelihood was found for the cutoff-dose logistic regression model with 15 Gy as the cutoff-dose, although the models for 20 Gy and 25 Gy had similar significance. According to this model, highly significant correlations (p <0.001) between small bowel volumes receiving at least 15 Gy and toxicity exist in the considered patient population. Similar findings applied to both the preoperatively (p = 0.001) and postoperatively irradiated groups (p = 0.001). The incidence of Grade 3 diarrhea was significantly correlated with the volume of small bowel receiving at least 15 Gy using a cutoff-dose NTCP model.

Epirubicin, Cisplatin and Protracted Venous Infusion 5-Fluorouracil Chemotherapy for Advanced Salivary Adenoid Cystic Carcinoma

Aims Adenoid cystic carcinoma (ACC) is a rare tumour that usually arises in the salivary glands. Initial management is surgery often combined with adjuvant radiotherapy. Chemotherapy is reserved for treatment of symptomatic recurrence. We evaluated the combination of epirubicin, cisplatin and protracted venous infusion 5-fluorouracil (ECF) in the management of ACC. Materials and methods Patients referred for treatment of advanced, symptomatic ACC were considered. The drugs given were epirubicin 50 mg/m 2 3-weekly, cisplatin 60 mg/m 2 3-weekly and protracted venous infusion 5-fluorouracil 200 mg/m 2/day. Results Eight patients (median age 46 years) received a median of five cycles of chemotherapy. All patients had had previous surgery, seven had had previous radiotherapy and one had had previous chemotherapy. One patient showed a partial response (duration 34 months) and five showed stable disease (median duration 13.6 months [6.8–15.9+ months]). Median survival was 27 months (3.5–62.3 months). Conclusions The activity of ECF in ACC of the head and neck seems to be similar to the combination of cisplatin and 5-fluorouracil and single-agent epirubicin.

78-Year-Old Man With Emesis and Jaundice

78-Year-Old Man With Emesis and Jaundice

A Phase II study of preoperative radiotherapy and concomitant weekly irinotecan in combination with protracted venous infusion 5-fluorouracil, for resectable locally advanced rectal cancer

The aim of this study was to evaluate the efficacy and tolerance of preoperative chemoradiotherapy (CRT) with irinotecan (CPT-11) and 5-fluorouracil (5-FU) in patients with resectable rectal cancer. Patients with resectable T3-T4 rectal cancer and Eastern Cooperative Oncology Group performance status <2 were included. CPT-11 (50 mg/m(2) weekly) and 5-FU (225 mg/m(2)/day continuous infusion, 5 days/week) were concurrently administered with radiation therapy (RT) (45 Gy, 1.8 Gy/day, 5 days/week), during 5 weeks. A total of 74 patients were enrolled: mean age, 59 years (20-74 years; SD, 11.7). Planned treatment was delivered to most patients (median relative dose intensity for both drugs was 100%). Grade 3/4 lymphocytopenia occurred in 35 patients (47%), neutropenia in 5 (7%), and anemia in 2 (3%). Main Grade 3 nonhematologic toxicities were diarrhea (14%), asthenia (9%), rectal mucositis (8%), and abdominal pain (8%). Of the 73 resected specimens, 13.7% (95% confidence interval [CI], 6.8-23.7) had a pathologic complete response and 49.3% (95% CI, 37.4-61.3) were downstaged. Additionally, 66.7% (95% CI, 51.1-80.0) of patients with ultrasound staged N1/N2 disease had no pathologic evidence of nodal involvement after CRT. This preoperative CRT schedule has been shown to be effective and feasible in a large population of patients with resectable rectal cancer.

Efficacy and tolerability of chemotherapy in elderly patients with advanced oesophago-gastric cancer: A pooled analysis of three clinical trials

The aim of this study was to determine the benefits of chemotherapy for oesophago-gastric cancer (OGC) in patients 70 years and above (⩾70) in comparison to younger patients. 1080 patients were enrolled into three randomised controlled trials assessing fluorouracil-based combination chemotherapy. Patients received either a platinum-containing regimen (ECF, MCF), PVI 5-FU (protracted venous infusion of 5-fluorouracil) ± mitomycin C (MMC), or FAMTX. Of the 1080 patients randomised, 257 (23.8%) were aged ⩾70 years. There were no significant differences in the incidence of grades 3/4 toxicity between the two cohorts. Objective and symptomatic response rates, failure-free and overall survival were not significantly different. In a multivariate analysis, independent prognostic factors for survival were performance status and locally advanced disease, not age. Patients ⩾70 years with OGC obtained similar benefits from palliative chemotherapy with respect to symptomatic response, tumour regression and survival, without increased toxicities.

A Randomised Comparison Between 6 Months of Bolus Fluorouracil/Leucovorin and 12 Weeks of Protracted Venous Infusion Fluorouracil as Adjuvant Treatment in Colorectal Cancer

A Randomised Comparison Between 6 Months of Bolus Fluorouracil/Leucovorin and 12 Weeks of Protracted Venous Infusion Fluorouracil as Adjuvant Treatment in Colorectal Cancer

Randomized Comparison of Weekly Cisplatin or Protracted Venous Infusion of Fluorouracil in Combination With Pelvic Radiation in Advanced Cervix Cancer: A Gynecologic Oncology Group Study

Concurrent chemoradiotherapy is the standard of care for locally advanced cervix cancer; the optimal chemotherapy regimen is not yet defined. This trial was designed to compare the outcome of protracted venous infusion (PVI) fluorouracil (FU) with standard weekly cisplatin and concurrent radiation therapy (RT). Patients with stage IIB, IIIB, and IVA cervical cancer with clinically negative aortic nodes were eligible. Pelvic RT dose was 45 Gy with a parametrial boost to involved sides of 5.4 to 9 Gy, and high- or low-dose rate intracavitary brachytherapy. Standard therapy was weekly cisplatin 40 mg/m2, and experimental therapy was PVI FU 225 mg/m2/d for 5 d/wk for six cycles during RT. The study was closed prematurely when a planned interim futility analysis indicated that PVI FU/RT had a higher treatment failure rate (35% higher) and would, most likely, not result in an improvement in progression-free survival compared with weekly cisplatin/RT. The PVI FU/RT arm continues to show a higher risk of treatment failure (relative risk [RR] unadjusted, 1.29) and a higher mortality rate (RR unadjusted, 1.37). There was no difference in pelvic treatment failure between regimens, but there was an increase in the failure rate at distant sites in the PVI FU arm. In this study, PVI FU does not show improved outcome over weekly cisplatin. Future research should explore combinations of FU with cisplatin, new radiosensitizers, and active drugs combined with RT to reduce the high rate of pelvic and distant treatment failure still seen in advanced cervix cancer.

Chemoradiotherapy for Cervical Cancer: What Next?

In this issue, Lanciano et al report the results of the Gynecologic Oncology Group’s most recent randomized study of concurrent chemoradiotherapy for cervical cancer (GOG-165). This trial, which compared the results of radiation therapy delivered concurrently with either weekly cisplatin or protracted venous infusion of fluorouracil (FU), was closed well before the planned accrual goal of 416 patients and 150 events because a scheduled interim analysis suggested that patients treated with FU were not likely to have a better outcome than those treated with the control regimen of radiation and weekly cisplatin. Although this negative study does not represent a major advance in the treatment of patients with cervical cancer, it does highlight many of the issues and challenges faced by investigators who seek to improve cervical cancer treatment in the modern era. GOG-165 is best understood in its historical context. The trial was designed and opened in 1997. In that year, the GOG published abstracts describing encouraging preliminary results from GOG trials of cisplatin-based concurrent chemoradiotherapy. However, the inclusion of hydroxyurea in the control arms of these trials and other perceived weaknesses, including problems with the quality of radiation therapy, prevented clinicians from reaching an early consensus about the trials’ importance. Therefore, in an effort to consolidate earlier findings, GOG-165 was designed. The study initially was planned with three arms: a control arm of modern radiation therapy alone, a second arm intended to confirm the value of adding weekly cisplatin, and a third, experimental arm that consisted of treatment with radiation and protracted venous infusion FU. This third arm drew on extensive data demonstrating the value of FU-based chemoradiotherapy in patients with gastrointestinal neoplasms and was intended to follow-up on an inconclusive but encouraging Canadian study of concurrent radiation and protracted venous infusion FU in patients with cervical cancer. However, in 1999, just 18 months after GOG-165 was opened, the near-simultaneous publication of results from five prospective randomized trials, all of which demonstrated significant improvements in local control and survival with cisplatin-based chemoradiotherapy, led to a National Cancer Institute alert establishing chemoradiotherapy as a standard treatment for patients with locoregionally advanced cervical cancer. At that point, the GOG felt compelled to drop the radiationonly control arm of GOG-165 but continued to accrue patients to the two concurrent chemoradiotherapy arms. The results of GOG-165 suggest that radiation plus protracted venous infusion FU was not a better treatment than radiation plus weekly cisplatin, but it does not prove that FU is ineffective as a radiation sensitizer in patients with cervical cancer. More importantly, the study does not answer the potentially more interesting question of whether FU can enhance the beneficial effects of adding cisplatin to radiation therapy. In fact, although randomized trials have demonstrated the benefit of concurrent cisplatin and of concurrent cisplatin with FU, no trial has yet compared the two regimens directly. Although the GOG regimen of radiation plus weekly cisplatin tends to be favored by gynecologic oncologists in the United States, data from the seven randomized trials suggest that radiation plus a combination of cisplatin and FU might be more effective. Of four randomized trials that included radiation therapy plus weekly cisplatin, only one, reported by Keys et al in 1999, demonstrated a benefit for radiation therapy plus cisplatin over radiation therapy alone. In that study, patients with bulky stage IB cancers were randomly assigned to prehysterectomy radiation therapy or chemoradiotherapy. Two other trials—the current trial and the GOG three-arm trial published in 1999—did not have a control arm of radiation therapy only; instead, they included chemotherapy of uncertain value in the noncisplatin-containing JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 23 NUMBER 33 NOVEMBER 2

Capecitabine and mitomycin C as third-line therapy for patients with metastatic colorectal cancer resistant to fluorouracil and irinotecan

Protracted venous infusion 5-fluorouracil (5FU) combined with mitomycin C (MMC) has demonstrated significant activity against metastatic colorectal cancer. Owing to potential synergy based upon upregulation of thymidine phosphorylase by MMC, the combination of capecitabine and MMC may improve outcomes in irinotecan-refractory disease. Eligible patients with progressive disease during or within 6 months of second-line chemotherapy were treated with capecitabine (1250 mg m−2 twice daily) days 1–14 every 3 weeks and MMC (7 mg m−2 IV bolus) once every 6 weeks. A total of 36 patients were recruited, with a median age of 64 years (range 40–77), and 23 patients (78%) were performance status 0–1. The objective response rate was 15.2%. In all, 48.5% of patients had stable disease. Median failure-free survival was 5.4 months (95% CI 4.6–6.2). Median overall survival was 9.3 months (95% CI: 6.9–11.7). Grade 3 toxicities were palmar-plantar erythema 16.7%, vomiting 8.3%, diarrhoea 2.8%, anaemia 8.3%, and neutropenia 2.8%. No patients developed haemolytic uraemic syndrome. Symptomatic improvement occurred for pain, bowel symptoms, and dyspnoea. Capecitabine in combination with MMC is an effective regimen for metastatic colorectal cancer resistant to 5FU and irinotecan with an acceptable toxicity profile and a convenient administration schedule.

High pathological response rate in locally advanced esophageal cancer after neoadjuvant combined modality therapy: dose finding of a weekly chemotherapy schedule with protracted venous infusion of 5-fluorouracil and dose escalation of cisplatin, docetaxel and concurrent radiotherapy

Background: This phase I study was aimed at defining the toxicity profile and pathological response rate of a neoadjuvant schedule including weekly docetaxel and cisplatin, protracted venous infusion (PVI) of 5-FU and concomitant radiotherapy (RT) in locally advanced esophageal cancer.Patients and methods: The schedule consisted of a first phase of chemotherapy alone and a second phase of concurrent chemoradiation. Initial doses were: docetaxel and cisplatin 20mg/m2 on days 1, 8, 15, 29, 36 and 43 plus 5-FU 150mg/m2 PVI on days 1–21 and 29–49; RT (40 Gy) started on day 29. In the following steps the doses were escalated up to docetaxel 35mg/m2 and cisplatin 25mg/m2 on days 1, 8, 15, 29, 36, 43, 50 and 57 plus 5-FU 180mg/m2 PVI on days 1–21 and 150mg/m2 PVI on days 29–63 concurrently with RT 50 Gy.Results: Forty-seven patients were enrolled and 46 completed the planned treatment. During the concomitant phase, grade 3–4 hematological toxicities occurred in three patients (6.5%) (or 3/174 cycles) and non-hematological toxicities in six patients (13%) (or 7/179 cycles). A pathological downstaging was obtained in 59.6% of the cases (28/47): complete remission (pCR) in 14 patients, near pCR (residual microfoci on the primary pN0) in eight patients, pT2 pN0 in three patients and partial response on the primary with positive lymph nodes in three patients. Six (13%) and 13 (28%) patients were considered stable and non-responders, respectively. In the last dose level, eight pCR and four near-pCR were obtained out of 15 patients. The maximum tolerable dose was not formally defined because dose escalation was stopped at the last dose level.Conclusion: This schedule represents a feasible treatment and the high pathological response rate is extremely encouraging; the doses found in the last dose-level are the basis for an ongoing phase II study at our institution.

Longitudinal quality of life and quality adjusted survival in a randomised controlled trial comparing six months of bolus fluorouracil/leucovorin vs. twelve weeks of protracted venous infusion fluorouracil as adjuvant chemotherapy for colorectal cancer

Longitudinal quality of life (QOL) assessment is infrequently made in adjuvant therapy for colorectal cancer (CRC). This analysis aims to assess QOL and quality adjusted survival (QAS) in patients receiving adjuvant 5-FU for stage II and III CRC. We performed a multicentre study in which 801 patients were randomised to 6 months of bolus 5-FU/leucovorin (LV n = 404) or 12 weeks of protracted venous infusion (PVI) 5-FU ( n = 397). There were significant differences in the deterioration of QOL scores at week 2 with bolus 5-FU/LV compared to PVI 5-FU ( P < 0.001), coinciding with toxicity peak during the first cycle. Following week 12, global QOL recovered to baseline when PVI 5-FU was stopped but this was delayed with bolus 5-FU/LV until completion at week 24. QOL scores significantly improved in both arms during follow-up ( P < 0.001) and reached a plateau by year 1 without incremental improvement between years 2 and 5. There was a trend towards better QAS with PVI 5-FU. Twelve weeks of adjuvant PVI 5-FU was associated with significantly better QOL during treatment and faster time to recovery compared to 6 months of bolus 5-FU/LV.

A randomised comparison between 6 months of bolus fluorouracil/leucovorin and 12 weeks of protracted venous infusion fluorouracil as adjuvant treatment in colorectal cancer

We performed a multicentre randomised trial to compare the efficacy and toxicity of 12 weeks of protracted venous infusion (PVI) 5-fluorouracil (5-FU) against the standard bolus monthly regimen of 5-FU/leucovorin (LV) given for 6 months as adjuvant treatment in colorectal cancer (CRC). Patients with curatively resected stage II and III CRC were randomly assigned to 5-FU/LV [5-FU 425 mg/m(2) intravenously (i.v.) and LV 20 mg/m(2) i.v. bolus days 1-5 every 28 days for 6 months] or to PVI 5-FU (300 mg/m(2)/day for 12 weeks). Between 1993 and 2003, 801 eligible patients were randomised to 5-FU/LV (n=404) or PVI 5-FU (n=397). With a median follow-up of 5.3 years, 231 relapses and 220 deaths have been observed. Five-year relapse-free survival (RFS) was 66.7% [95% confidence interval (CI) 61.6% to 71.3%] and 73.3% (95% CI 68.4% to 77.6%) with bolus 5-FU/LV and PVI 5-FU, respectively [hazard ratio (HR) 0.8; 95% CI 0.62-1.04; P=0.10]. Five-year overall survival (OS) was 71.5% (95% CI 66.4% to 75.9%) and 75.7% (95% CI 70.8% to 79.9%) with bolus 5-FU/LV and PVI 5-FU, respectively (HR 0.79; 95% CI 0.61-1.03; P=0.083). There was a significant survival advantage for patients starting adjuvant chemotherapy within 8 weeks (P=0.044). Significantly less diarrhoea, stomatitis, nausea and vomiting, alopecia, lethargy, and neutropenia (all with P <0.0001) were seen with PVI 5-FU. There was no OS difference between the two arms, although PVI 5-FU was associated with a trend towards better RFS and OS compared with bolus 5-FU/LV, as well as significantly less toxicity. Based on our results, the probability of 12 weeks of PVI 5-FU being inferior to 6 months of bolus 5-FU/LV is extremely low (P <0.005), and therefore shorter duration of adjuvant treatment should be explored further.

Epirubicin, Cisplatin, and Raltitrexed in Patients With Advanced Gastric and Hepatobiliary Carcinoma

The combination of epirubicin, cisplatin, and protracted venous-infusion 5-fluorouracil is the standard treatment of advanced gastric carcinoma in many European countries, and it is also an active regimen in hepatobiliary tumors. Raltitrexed is a specific inhibitor of thymidylate synthase with clinical activity in gastrointestinal malignancies. The aim of the study was to evaluate the clinical activity and toxicity of the combination of epirubicin, cisplatin, and raltitrexed in patients with advanced gastric and hepatobiliary tumors. Twenty consecutive patients with gastric carcinoma, 7 with biliary-tract carcinoma, and 5 patients with hepatocarcinoma were treated with epirubicin (60 mg/m2), cisplatin (60 mg/m2) on day 1, and raltitrexed (1 mg/m2) on days 1 and 8, every 3 weeks. The median age was 63 years (range, 28-76). Eight patients had locally advanced disease and 24 had metastatic tumors. Seven of the 18 evaluable patients (39%) with gastric carcinoma and 2 of the 5 patients with hepatocarcinoma have a partial response; 1 minimal response and 4 stabilization of disease were documented in the 7 patients with biliary-tract carcinoma. The median time to progression of the entire group was 6.8 months, and the median survival was 9.0 months. The toxicity was mild and no toxic death occurred. The combination of epirubicin, cisplatin, and raltitrexed, using this schedule, is tolerable and has clinical activity in gastric and hepatobiliary tumors.

Evidence-based oncology mitomycin C provides little additional benefit in the treatment of carcinoma of unknown primary site: Abstracted from: Assersohn L, Norman AR, Cunningham D et al. A randomised study of protracted venous infusion of 5-fluorouracil (5-FU) with or without bolus mitomycin C (MMC) in patients with carcinoma of unknown primary. European Journal of Cancer 2003; 39: 1121–1128

People with carcinoma of unknown primary site (CUP) comprise a heterogeneous group, in whom aetiologies and prognoses are varied. Optimal chemotherapy must have activity against a range of tumour types.

Plasma concentrations of 5-fluorouracil and F-beta-alanine following oral administration of S-1, a dihydropyrimidine dehydrogenase inhibitory fluoropyrimidine, as compared with protracted venous infusion of 5-fluorouracil.

The pharmacokinetics and pharmacodynamics of oral S-1, a dihydropyrimidine dehydrogenase (DPD) inhibitory fluoropyrimidine, were compared with those of protracted venous infusion (PVI) of 5-fluorouracil (5-FU). In all, 10 patients with gastric cancer received PVI of 5-FU at a dose of 250 mg m−2 day−1 for 5 days. After a washout period of 9 days, the patients received two divided doses daily for 28 days. S-1 was administered orally at about 0900 and 1900 hours. The daily dose of S-1 in terms of tegafur was 80 mg day−1 in patients with a body surface area (BSA) of <1.25 m2, 100 mg day−1 in those with a BSA of ⩾1.25 m2 to <1.5 m2, and 120 mg day−1 in those with a BSA of ⩾1.5 m2. Plasma concentrations of 5-FU and F-β-alanine (FBAL) were measured for pharmacokinetic analysis, and the plasma uracil concentration was monitored as a surrogate marker of DPD inhibition (pharmacodynamic analysis) in the same patients on days 1–5 of PVI of 5-FU and on days 1–5 of oral S-1. The area under the curve (AUC0–10 h) of 5-FU on day 5 was 728±113 ng h ml−1 for PVI of 5-FU and 1364±374 ng h ml−1 for S-1. The median 5-FU PVI : S-1 ratio of the AUC0–10 h of 5-FU was 1.9. The AUC0–10 h of FBAL on day 5 of PVI of 5-FU was 9465±3225 ng h ml−1, AUC0–10 h, as compared with 1725±605 ng h ml−1 on day 5 of S-1 treatment. The AUC0–10 h of uracil on day 5 was 252±60 ng h ml−1 with PVI of 5-FU and 12 582±3060 ng h ml−1 with S-1. The AUC0–10 h of FBAL was markedly lower and plasma uracil concentrations were significantly higher for S-1 than for PVI of 5-FU, clearly demonstrating the effect of DPD inhibition.

Radiotherapy and oral capecitabine in the preoperative treatment of patients with rectal cancer: rationale, preliminary results and perspectives.

Preoperative radiotherapy alone or combined with chemotherapy increases the chances of tumor down-staging and down-sizing and facilitates sphincter-sparing surgical procedures, thereby improving survival and quality of life. Though several innovative agents are being investigated in combination with radiotherapy, 5-fluorouracil in continuous infusion remains the common schedule used in the preoperative chemoradiation setting. However, the protracted venous infusion of 5-fluorouracil requires specialized pumps and long-term venous access, which makes patients susceptible to infections or thrombosis. To overcome the 5-fluorouracil infusion-related problems, oral 5-fluorouracil precursors and inhibitors of 5-fluorouracil degradation have been developed and explored. These include oral fluoropyrimidines such as tegafur (ftorafur), uracil plus tegafur (UFT), S-1, eniluracil and the oral carbamate capecitabine. Phase I trials have demonstrated the feasibility of the capecitabine-radiotherapy combination with respect to the bolus or infusion 5-fluorouracil-radiation approach and have defined the optimal dose of capecitabine during radiotherapy (825 mg/m2/day through a bid administration). Severe hand-foot syndrome occurred in 7-15% of patients, representing the most commonly observed toxicity. It is noteworthy that severe diarrhea with capecitabine during radiotherapy was not common. Leukopenia frequently occurred but was mild and reversible. Phase II trials, although limited in number, have evidenced a high probability of pathological complete response (up to 31%) with capecitabine and radiation, with an increased probability of sphincter-sparing surgical procedures. Although it is too early to assess whether oral capecitabine will be able to replace iv 5-fluorouracil in combination with preoperative radiotherapy, the NSABP will address this question in a large randomized trial. Finally, phase I-II trials evaluating escalating doses of capecitabine associated with oxaliplatin or irinotecan with radiotherapy are being carried out to assess the maximum-dose tolerance and efficacy in the preoperative setting. It is likely that these new chemoradiation associations might increase rectal cancer clearance, hopefully without increasing toxicity.

A randomised study of protracted venous infusion of 5-fluorouracil (5-FU) with or without bolus mitomycin C (MMC) in patients with carcinoma of unknown primary

No standard regimen has been identified for patients with a carcinoma of unknown primary (CUP). This study compared protracted venous infusion 5-fluorouracil (PVI 5-FU) with or without mitomycin C (MMC) in patients with CUP in a multicentre, prospectively randomised study. 88 patients were randomised to PVI 5-FU (300 mg/m2/day for a maximum of 24 weeks) ±MMC (7 mg/m2 6 weekly for four courses). The overall response rate was 11.6% for PVI 5-FU alone compared with 20.0% for PVI 5-FU plus MMC (P=0.29). Median failure-free survival (FFS) was 4.1 months for PVI 5-FU and 3.6 months for PVI 5-FU plus MMC (P=0.78) with an equivalent overall survival (OS) (6.6 versus 4.7 months, P=0.60). Symptomatic benefit was observed in most patients in each arm. PVI 5-FU is a well tolerated outpatient treatment regimen for patients with CUP, although the addition of MMC provides little extra benefit. PVI 5-FU may be a potential reference regimen in randomised trials with newer chemotherapy agents in patients with CUP.

Adjuvant radiation therapy of patients with rectal cancer.

The standard in rectal cancer has been to add adjuvant radiation therapy to surgery in patients with stage II and III disease. Total mesorectal excision has led to lower local recurrence rates, and, if properly performed, may make adjuvant radiation unnecessary for certain stage II and III patients, such as T3 N0 patients with proximal lesions. There is also debate about the best method of delivering adjuvant radiotherapy. Preoperative radiotherapy at low dose per fraction with concurrent chemotherapy offers the advantages of maximizing sphincter preservation and greater tolerability. However, this will occasionally result in treating patients who are overstaged by ultrasound and may lead to greater postoperative morbidity and mortality than postoperative radiation. Preoperative radiotherapy has stronger data to support a survival advantage when added to surgery than postoperative radiation. Two randomized, phase III European studies may answer the question of which radiation technique is best for the near future. Protracted venous infusion of 5-fluorouracil (5-FU) is the standard method of radiosensitization. However, studies are ongoing using concurrent oxaliplatin, irinotecan, and oral 5-FU prodrugs. For now, we recommend that stage II and III rectal cancer patients receive protracted venous infusion 5-FU concurrent with preoperative radiation.

Phase II trial of preoperative 3D conformal radiotherapy, protracted venous infusion 5-fluorouracil, and weekly CPT-11, followed by surgery for ultrasound-staged T3 rectal cancer

Purpose : CPT-11 sensitizes tumor cells to radiation and in combination therapy with 5-fluorouracil (5-FU) results in enhanced cytotoxicity to metastatic colorectal cancer. We report the results from a Phase II trial of preoperative radiotherapy (RT), CPT-11, and 5-FU for patients with ultrasound-staged T3 rectal cancer. Methods and Materials : Between April 1999 and August 2001, 32 patients (21 men, 11 women; median age 52 years, range 40–74) with biopsy-proven adenocarcinoma of the rectum were enrolled in the study. All patients underwent endorectal ultrasonography for staging (uT3N0 = 19; uT3N1 = 13; uT2N1 = 1). RT was prescribed to the draining lymph nodes (45 Gy in 1.8-Gy daily fractions) and tumor (50.4 Gy in 1.8-Gy daily fractions). Patients also received concurrent CPT-11 (50 mg/m 2, Days 1, 8, 15, and 22) and 5-FU (200 mg/m 2 daily, 7 d/wk, Days 1–33). Surgical resection was performed 6–10 weeks after completing chemoradiotherapy. Results : Acute toxicity was frequently observed, and 18 patients (56%) required either a chemotherapy dose reduction or RT interruption of >3 days. One patient withdrew because of diarrhea and abdominal cramping (Grade III) after 10 days of treatment. Although no Grade IV toxicity was observed, Grade III diarrhea ( n = 9, 28%), mucositis ( n = 7, 21%), rectal sores ( n = 7, 21%), abdominal cramping ( n = 3, 9%) were noted. Of the 32 patients who underwent surgery, 12 had a complete pathologic response. Of the 32 patients, the disease of 23 (71%) was downstaged. The average length of hospitalization was between 5 and 12 days, with 1 patient staying 33 days. All patients were followed for disease-free survival. Conclusion : Although associated with frequent acute toxicity, the regimen is associated with significant tumor “downstaging.” Additional patients and longer follow-up are necessary to define the role of this regimen fully.