Continuous Intravenous Infusion Of 5-fluorouracil Research Articles

A Multicenter Randomized Controlled Phase 3 Trial of Locoregional Radiotherapy in Combination with Chemotherapy in <i>de novo</i> Metastatic Nasopharyngeal Carcinoma

Background: The role of locoregional radiotherapy in de novo metastatic nasopharyngeal carcinoma (mNPC) patients is unclear. Methods: mNPC patients with biopsy-proven disease, who demonstrated complete or partial response (RECIST v1.1) following 3 cycles of cisplatin and 5-fluorouracil chemotherapy, were enrolled. Eligible patients were randomly assigned (1:1) to receive either chemotherapy plus radiotherapy or chemotherapy alone. The chemotherapy regimens were 5-fluorouracil continuous intravenous infusion at 5 gm/m2 over 120 h and 100 mg/m2 intravenous cisplatin on day 1, administered every 3 weeks for six cycles. Patients assigned to the chemotherapy plus radiotherapy group received intensity-modulated radiotherapy (IMRT) after chemotherapy. Primary endpoint of the study was overall survival (OS). Findings: 126 of 173 patients screened were eligible to the study, and randomized to chemotherapy plus radiotherapy (n = 63) or chemotherapy alone (n = 63). Median follow-up duration was 26.7 months (IQR 17.2-33.5). The study met its primary end-point of improved OS (stratified hazard ratio [HR] = 0.42; 95% confidence interval [CI], 0.23-0.77; P = 0.004) in favor of chemotherapy plus radiotherapy. PFS was also improved in the chemotherapy plus radiotherapy group compared to the chemotherapy alone group (stratified HR = 0.36; 95% CI 0.23-0.57). No significant differences in acute hematological or gastrointestinal toxicities were observed between the treatment arms. The frequency of acute ≥grade 3 dermatitis, mucositis, and xerostomia was 8.1%, 33.9%, and 6.5%, respectively, in the chemotherapy plus radiotherapy group. The frequency of late severe ≥grade 3 hearing loss and trismus was 5.2% and 3.4%, respectively, in the chemotherapy plus radiotherapy group. Interpretation: Radiotherapy added to chemotherapy significantly improved OS in chemotherapy-sensitive mNPC patients. Trial Registration: This trial was registered as NCT02111460. Funding Statement: Funding was provided by the Program of Sun Yat-Sen University for Clinical Research 5010 Program (No.201310), the National Natural Science Foundation of China (No.81572912, 81772895, 81874134), Guangdong Province Science and Technology Development Special Funds (Frontier and Key Technology Innovation Direction – Major Science and Technology Project) (No. 703040078088), Guangzhou Science and Technology Planning Project - Production and Research Collaborative Innovation Major Project (No. 201505012235268). MC is supported by the National Medical Research Council Singapore Clinician-Scientist Award - #NMRC/CSA/0027/2018 and the Duke-NUS Oncology Academic Program Proton Research Program. This research is also supported by the National Research Foundation Clinical Research Programme Grant (NRF-CRP17-2017-05). Declaration of Interests: The authors declare that they have no conflicts of interest. Ethics Approval Statement: The study protocol was approved by the ethics committee of the Sun Yat-sen University Cancer Center (SYSUCC). The trial was performed in accordance with the Declaration of Helsinki, and the results are reported according to the CONSORT statement. All participants provided written informed consent.

Definitive Chemoradiation Therapy With Docetaxel, Cisplatin, and 5-Fluorouracil (DCF-R) in Advanced Esophageal Cancer: A Phase 2 Trial (KDOG 0501-P2)

A previous phase 1 study suggested that definitive chemoradiation therapy with docetaxel, cisplatin, and 5-fluorouracil (DCF-R) is tolerable and active in patients with advanced esophageal cancer (AEC). This phase 2 study was designed to confirm the efficacy and toxicity of DCF-R in AEC. Patients with previously untreated thoracic AEC who had T4 tumors or M1 lymph node metastasis (M1 LYM), or both, received intravenous infusions of docetaxel (35 mg/m(2)) and cisplatin (40 mg/m(2)) on day 1 and a continuous intravenous infusion of 5-fluorouracil (400 mg/m(2)/day) on days 1 to 5, every 2 weeks, plus concurrent radiation. The total radiation dose was initially 61.2 Gy but was lowered to multiple-field irradiation with 50.4 Gy to decrease esophagitis and late toxicity. Consequently, the number of cycles of DCF administered during radiation therapy was reduced from 4 to 3. The primary endpoint was the clinical complete response (cCR) rate. Characteristics of the 42 subjects were: median age, 62 years; performance status, 0 in 14, 1 in 25, 2 in 3; TNM classification, T4M0 in 20, non-T4M1LYM in 12, T4M1LYM in 10; total scheduled radiation dose: 61.2 Gy in 12, 50.4 Gy in 30. The cCR rate was 52.4% (95% confidence interval [CI]: 37.3%-67.5%) overall, 33.3% in the 61.2-Gy group, and 60.0% in the 50.4-Gy group. The median progression-free survival was 11.1 months, and the median survival was 29.0 months with a survival rate of 43.9% at 3 years. Grade 3 or higher major toxicity consisted of leukopenia (71.4%), neutropenia (57.2%), anemia (16.7%), febrile neutropenia (38.1%), anorexia (31.0%), and esophagitis (28.6%). DCF-R frequently caused myelosuppression and esophagitis but was highly active and suggested to be a promising regimen in AEC. On the basis of efficacy and safety, a radiation dose of 50.4 Gy is recommended for further studies of DCF-R.

Superselective intra-arterial chemoradiation therapy for functional laryngeal preservation in advanced squamous cell carcinoma of the glottic larynx

Conclusion: Superselective intra-arterial chemotherapy is a safe and useful treatment that preserves the vocal, swallowing, and feeding functions of the larynx in T3 cancer supplied by the superior laryngeal artery and T4a cancer not extending beyond the thyroid cartilage. Objective: To evaluate the outcomes of superselective intra-arterial chemotherapy for squamous cell carcinoma of the glottic larynx. Methods: Sixty-four patients with squamous cell carcinoma of the glottic larynx underwent treatment of the primary tumor using induction chemotherapy with two cycles of intra-arterial docetaxel and cisplatin, plus continuous intravenous infusion of 5-fluorouracil for 120 h starting on day 2; followed by two cycles of concurrent chemoradiation therapy. Residual neck lymph node metastases were treated by neck dissection. Results: The overall 5- and 10-year survival rates were 70.4% and 62.9%, respectively. The 5- and 10-year survival rates were 96.3% and 89.9%, respectively, in the 29 patients with T3 cancer, and 50.4% and 44.1%, respectively, in the 35 patients with T4a cancer. The overall 5- and 10-year laryngeal preservation rates were 71.0% and 60.6%, respectively. The 5- and 10-year laryngeal preservation rates were 92.5% and 87.4%, respectively, in patients with T3 cancer, and 48.6% and 35.6%, respectively in patients with T4a cancer. No irreversible adverse effects were reported.

Safety and preliminary results of perioperative chemotherapy and hyperthermic intraperitoneal chemotherapy (HIPEC) for high-risk gastric cancer patients

BackgroundGastric cancer relapse occurs in about 30% of the patients treated with gastrectomy and D2-lymphadenectomy, mainly as distant or peritoneal metastases. Hyperthermic intraperitoneal chemotherapy (HIPEC) has been associated with an improvement in survival and lower peritoneal recurrence, albeit with increased morbidity. The aim of this study is to report the preliminary results of the association of perioperative chemotherapy, radical surgery and HIPEC in high-risk gastric patients in a single institution.MethodsTreatment protocol was started in 2007 and included patients younger than 65 years old, with good performance status and gastric adenocarcinoma with serosa involvement and lymph node metastases, located in the body or antrum. Patients should receive three preoperative cycles of DCF (Docetaxel 75 mg/m2, Cisplatin 75 mg/m2 and continuous intravenous infusion of 5-Fluorouracil 750 mg/m2 for 5 days), followed by gastric resection with D2-lymphadenectomy, hyperthermic intraperitoneal chemotherapy with Mytomicin C 34 mg/m2 and three more postoperative cycles of DCF.ResultsTen patients were included between 2007 and 2011. Their median age was 47 years old and six were male. Nine were staged with cT4 cN + tumors and one as cT3 cN+. Nine patients completed all three preoperative chemotherapy cycles. Eight individuals were treated with a total gastrectomy and the other two had a distal gastrectomy, all having HIPEC. Postoperative morbidity was 50%, with no deaths. Regarding postoperative chemotherapy, only 5 patients completed three cycles. With a median follow-up of 25 months, three relapses were identified and 7 patients remain disease-free, two with more than 4 years of follow-up.ConclusionThe association of perioperative systemic and intraperitoneal chemotherapy plus radical surgery is a feasible multimodality treatment, with acceptable morbidity. With a longer follow-up and a larger group of patients, we hope to be able to determine if it also influences survival outcomes and patterns of recurrence.Mini-The association of perioperative chemotherapy, gastric resection and D2-lymphadenectomy and hyperthermic intraperitoneal chemotherapy proved to be associated with acceptable morbidity. For survival analysis, a longer follow-up is needed.

Systemic combination therapy of intravenous continuous 5-fluorouracil and subcutaneous pegylated interferon alfa-2a for advanced hepatocellular carcinoma

In Japan, sorafenib is now the first-line therapy for individuals with advanced hepatocellular carcinoma (HCC), but no other treatment is available for such patients. The aim of this study was to assess the efficacy and safety of combination therapy with systemic continuous intravenous infusion of 5-fluorouracil (5-FU) and subcutaneous peginterferon alfa-2a, which was used before sorafenib was introduced to Japan. Two hundred and twenty-three HCC patients, who were not amenable to curative surgery, percutaneous ablation, or transarterial chemoembolization (TACE), and for whom intraarterial chemotherapy was not indicated because of the presence of extrahepatic metastasis or stenosis of the common hepatic artery, received peginterferon alfa-2a (90 μg subcutaneously on days 1, 8, 15, and 22) and 5-FU (500 mg/day intravenously given continuously on days 1-5 and 8-12). We assessed their response to treatment and survival, and treatment safety. The response rate was 9.4 % (including six patients with complete response) and the disease-control rate was 32.7 %. The median time to progression was 2.0 months. The overall median survival time was 6.5 months (Child-Pugh class A: 9.2 months vs. Child-Pugh class B: 2.8 months). In a multivariate analysis, Eastern Cooperative Oncology Group (ECOG) performance status >0, Child-Pugh class B, and the presence of macroscopic vascular invasion were independent predictors of poor prognosis. The major grade 3-4 adverse events were leucopenia (13.9 %) and thrombocytopenia (5.8 %). No treatment-related deaths occurred. This combination therapy was well tolerated and showed promising efficacy. Further studies are needed to establish the usefulness of this treatment.

Effect of coefficient of viscosity and ambient temperature on the flow rate of drug solutions in infusion pumps

Context: FOLFOX6 and FOLFIRI regimens are often selected as the first- or second-line treatment for advanced or recurrent colorectal cancer. Patients are now able to undergo at-home treatment by using a portable disposable infusion pump (SUREFUSER®A) for continuous intravenous infusion of 5-fluorouracil (5-FU). The duration of continuous 5-FU infusion is normally set at an average of 46 h, but large variations in the duration of infusion are observed.Objective and methods: The relationship between the total volume of the drug solution in SUREFUSER®A and the duration of infusion was analyzed by regression analysis. In addition, multiple regression analysis of the total volume of the drug solution, dummy variables for temperature, and duration of infusion was carried out.Results: The duration of infusion was affected by the coefficient of viscosity of the drug solution and the ambient temperature.Conclusion: The composition of the drug solutions and the ambient temperature must be considered to ensure correct duration of continuous infusion.

Retrospective analysis of treatment outcomes after postoperative chemoradiotherapy in advanced gastric cancer

PurposeTo evaluate retrospectively the survival outcome, patterns of failure, and complications in patients treated with postoperative chemoradiotherapy (CRT) in advanced gastric cancer.Materials and MethodsBetween January 2000 and December 2006, 80 patients with advanced gastric cancer who received postoperative concurrent CRT were included. Pathological staging was IB-II in 9%, IIIA in 38%, IIIB in 33%, and IV in 21%. Radiotherapy consisted of 45 Gy of radiation. Concurrent chemotherapy consisted of a continuous intravenous infusion of 5-fluorouracil and leucovorin on the first 4 days and last 3 days of radiotherapy.ResultsThe median follow-up period was 48 months (range, 3 to 83 months). The 5-year overall survival, disease-free survival, and locoregional recurrence-free survivals were 62%, 59%, and 80%, respectively. In the multivariate analysis, significant factors for disease-free survival were T stage (hazard ratio [HR], 0.278; p = 0.038), lymph node dissection extent (HR, 0.201; p = 0.002), and maintenance oral chemotherapy (HR, 2.964; p = 0.004). Locoregional recurrence and distant metastasis occurred in 5 (6%) and 18 (23%) patients, respectively. Mixed failure occurred in 10 (16%) patients. Grade 3 leukopenia and thrombocytopenia were observed in 4 (5%) and one (1%) patient, respectively. Grade 3 nausea and vomiting developed in 8 (10%) patients. Intestinal obstruction developed in one (1%).ConclusionThe survival outcome of the postoperative CRT in advanced gastric cancer was similar to those reported previously. Our postoperative CRT regimen seems to be a safe and effective method, reducing locoregional failure without severe treatment toxicity in advanced gastric cancer patients.

Tumor Hypoxia Detected by Positron Emission Tomography with 60Cu-ATSM as a Predictor of Response and Survival in Patients Undergoing Neoadjuvant Chemoradiotherapy for Rectal Carcinoma: A Pilot Study

The response of rectal cancers to neoadjuvant chemoradiotherapy is variable. Tumor hypoxia reduces the effectiveness of both radiation therapy and chemotherapy and is a well-known risk factor for tumor radioresistence. We hypothesized that imaging with the novel hypoxia-detecting agent, (60)Cu-diacetyl-bis (N(4)-methylthiosemicarbazone) ((60)Cu-ATSM), previously validated in cervical and lung cancers, would predict the response of rectal cancers to neoadjuvant chemoradiotherapy and prognosis. Patients with locally invasive (T2-4) primary or node-positive rectal cancer located <12 cm from the anal verge were recruited for this pilot study. Pretreatment tumor size and stage were determined by endorectal ultrasonography, CT, and magnetic resonance imaging. Eleven patients also underwent clinical positron emission tomography with (18)F-fluorodeoxyglucose at the discretion of the treating clinician. The primary tumor was imaged by positron emission tomography with (60)Cu-ATSM, and accumulation of the tracer was measured semiquantitatively by determining the tumor-to-muscle activity ratio. Neoadjuvant chemoradiotherapy was then administered (within 2 weeks of (60)Cu-ATSM-positron emission tomography) and consisted of 45 Gy given in 25 fractions to the pelvis with continuous intravenous infusion of 5-fluorouracil (225 mg/m(2)/day). Proctectomy was performed six to eight weeks after neoadjuvant chemoradiotherapy and the tumor submitted to pathology for size measurement and staging. Tumor-to-muscle activity ratios were compared with tumor (18)F-fluorodeoxyglucose uptake, tumor response to neoadjuvant chemoradiotherapy, and with patient survival. Nineteen patients were enrolled in the study, two of whom were excluded from final analysis (1 death during neoadjuvant chemoradiotherapy and 1 tumor perforation during neoadjuvant chemoradiotherapy requiring emergent surgery). Of the 17 remaining patients, 14 had a reduction in tumor size and 13 were downstaged. The median tumor-to-muscle activity ratio of 2.6 discriminated those with worse prognosis from those with better prognosis. Both overall and progression-free survivals were worse with hypoxic tumors (tumor-to-muscle activity ratio >2.6) than with nonhypoxic tumors (tumor-to-muscle activity ratio <or=2.6; both P < 0.05). In addition, 2 of the 3 tumors with no change in size had tumor-to-muscle activity ratios >2.6 (positive predictive value 66 percent), whereas 6 of 14 with decreased size had tumor-to-muscle activity ratios >2.6 (negative predictive value 57 percent). Three of the 4 tumors not downstaged had tumor-to-muscle activity ratios >2.6 (positive predictive value 75 percent), whereas 5 of 13 downstaged tumors had tumor-to-muscle activity ratios >2.6 (negative predictive value 62 percent). The mean tumor-to-muscle activity ratio for downstaged tumors (2.2) was significantly lower than that of nondownstaged tumors (3.3) (P = 0.03). The difference in mean tumor-to-muscle activity ratio between downsized (2.3) and nondownsized (2.9) tumors did not reach statistical significance (P = 0.36). Tumor (18)F-fluorodeoxyglucose uptake (n = 11) did not correlate with (60)Cu-ATSM uptake (r = 0.4; P = 0.9) and there was no significant difference in mean tumor (18)F-fluorodeoxyglucose uptake between patients with hypoxic tumors and those with normoxic tumors (P = 0.3). The results of this small pilot study suggest that (60)Cu-ATSM-PET may be predictive of survival and, possibly, tumor response to neoadjuvant chemoradiotherapy in patients with rectal cancer. A larger Phase II study is warranted to validate these results.

Phase II study of combination therapy with S-1 and irinotecan in patients with advanced colorectal cancer

BackgroundA 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. Patients and methodsForty 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 m2), 50 mg (BSA ≥ 1.25 to < 1.50 m2), or 60 mg (BSA ≥ 1.50 m2). Irinotecan (150 mg/m2) was administered by intravenous infusion on day 1. ResultsA 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%. ConclusionsCombined 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.

Responders benefit from neoadjuvant radiochemotherapy in esophageal squamous cell carcinoma: results of a prospective phase-II trial

Background. We present the results of a prospective phase-II-study of neoadjuvant combined radiochemotherapy followed by surgical resection in patients with histological proven locally advanced squamous cell carcinoma of the esophagus located at or above the level of the tracheal bifurcation. Methodology. Between February 1995 and March 2000 a total of 76 patients with esophageal squamous cell carcinoma (uT3/4N0/+-categories) received simultaneous combined neoadjuvant radiochemotherapy consisting of a continuous intravenous infusion of 5-fluorouracil (300 mg/m2/day) 7 day per week concurrently with conventional fractioned external beam radiation therapy (2 Gy/day), five fractions per week up to a total dose of 30 Gy. Results. Radiochemotherapy related acute severe toxicity rate (CTC-grade-III) occurred in 34 patients, two patients died. Sixty-four patients underwent surgery with a complete resection in 48 patients. Three patients died during a 90-day post-operative course. The histopathological workup revealed no viable residual tumour cells in eight patients (ypCR) and according to the modified criteria of Mandard in 26 patients a histopathological response. Twenty-two of these patients underwent a R0-resection. The median follow-up time was 5.4 years with an overall median survival time of 20.6 months. The median survival in the 26 responders was 32.3 months versus 19.5 months in 38 non-responders (p=0.03). Conclusions. Patients with locally advanced squamous cell carcinoma of the esophagus, who respond to preoperative neoadjuvant combined radiochemotherapy, seem to have more benefit from subsequent resection than non-responding patients.

Responders benefit from neoadjuvant radiochemotherapy in esophageal squamous cell carcinoma: results of a prospective phase-II trial

Background. We present the results of a prospective phase-II-study of neoadjuvant combined radiochemotherapy followed by surgical resection in patients with histological proven locally advanced squamous cell carcinoma of the esophagus located at or above the level of the tracheal bifurcation. Methodology. Between February 1995 and March 2000 a total of 76 patients with esophageal squamous cell carcinoma (uT3/4N0/+-categories) received simultaneous combined neoadjuvant radiochemotherapy consisting of a continuous intravenous infusion of 5-fluorouracil (300 mg/m 2/day) 7 day per week concurrently with conventional fractioned external beam radiation therapy (2 Gy/day), five fractions per week up to a total dose of 30 Gy. Results. Radiochemotherapy related acute severe toxicity rate (CTC-grade-III) occurred in 34 patients, two patients died. Sixty-four patients underwent surgery with a complete resection in 48 patients. Three patients died during a 90-day post-operative course. The histopathological workup revealed no viable residual tumour cells in eight patients (ypCR) and according to the modified criteria of Mandard in 26 patients a histopathological response. Twenty-two of these patients underwent a R0-resection. The median follow-up time was 5.4 years with an overall median survival time of 20.6 months. The median survival in the 26 responders was 32.3 months versus 19.5 months in 38 non-responders ( p=0.03). Conclusions. Patients with locally advanced squamous cell carcinoma of the esophagus, who respond to preoperative neoadjuvant combined radiochemotherapy, seem to have more benefit from subsequent resection than non-responding patients.

Usefulness of Preoperative Chemoradiation in Locally Advanced Cervical Carcinoma

This study investigated response rate, toxicity, and influence on intra- and postoperative complications of neoadjuvant concurrent chemoradiation in locally advanced (Figo IB2–IIIB) cervical carcinomas. Twenty-eight patients (median age 46.5 years, age range 29–73 years), diagnosed as having squamous cell carcinomas (n = 21), adenocarcinomas (n = 6), and undifferentiated carcinoma (n = 1), entered this study. The chemoradiation protocol included external radiotherapy to the pelvis (39.6 Gy), intra-arterial or intravenous infusion of cisplatin (70 mg/m² on days 1 and 22), and 24-hour continuous intravenous infusion of 5-fluorouracil (700 mg/m² on days 1–4 and 22–25). Two weeks after the end of chemoradiotherapy, the patients underwent restaging followed by suitable operation including pelvic lymphadenectomy. The median follow-up period in the surviving patients was 13.1 months. The response rate for chemoradiation was 93% (26/28). The 2-year disease free survival was 85.2%. Grade 3–4 neutropenia was observed in 14 patients (50%), 4 patients (14%) showed grade 3 anemia, and 5 patients (17.8%) showed grade 3–4 thrombocytopenia. Nineteen patients (67.8%) could undergo surgery after concurrent chemoradiation. Pathological examination revealed a complete response (pT0) in 7 patients, and 5 patients showed only microscopic residual disease (pTmic). In 4 patients, there were intraoperative complications: vesical lesions in 2 (10%) and small intestine lesions in 2 (10%). Neoadjuvant therapy with concurrent chemoradiation for locally advanced cervical carcinoma is effective, safe, and useful for increasing operability rates as well as decreasing intra- and postoperative complications. Therefore, neoadjuvant concurrent chemoradiation should be considered for treatment in patients with locally advanced cervical carcinomas who could not undergo primary operation.

Intraoperative presacral electron boost following preoperative chemoradiation in T 3–4N x rectal cancer: initial local effects and clinical outcome analysis

Background and purpose: To analyze early results of a single institution experience using adjuvant intraoperative electron radiation therapy (IOERT) presacral boost in locally advanced rectal cancer following preoperative chemoradiation. Materials and methods: In a 63 month period (March 1995–June 2000), 100 consecutive T 3–4N x rectal cancer patients were treated with preoperative chemoradiation (45–50 Gy plus oral Tegafur or 5-Fluorouracil continuous intravenous infusion), radical surgery and IOERT presacral boost (mean dose, 12.5 Gy; range, 10–15 Gy). Adjuvant chemotherapy (5-FU–leucovorin: 4–6 cycles) was given to 52 patients. The median age was 63 years, and 39 patients were ≥70 years old (65 males). Clinical staging was performed with computed tomography (94%) and/or endorectal ultrasound (71%) categorizing 90 cT 3, 10 cT 4, 20 cN x, and 36 cN +. Abdomino-perineal resection was performed in 41 cases. Results: The IOERT cancellation rate was 6%. With a median follow-up of 23 months in IOERT treated patients, three developed pelvic recurrence: one anastomotic and one in the posterior vaginal wall (simultaneously with distant metastatic disease); and one presacral (in-field IOERT) as the only site of initial failure. Distant metastasis has been observed in 14 patients (exceptionally in pT 0–1 downstaged patients: 1/20; 5%). Overall treatment tolerances, including neoadjuvant and surgical segments, were acceptable. The actuarial 4-year estimations of local control, disease-free and overall survival are 94, 75 and 65%, respectively. Conclusions: IOERT electron boost to the presacral region is feasible to integrate systematically in the intensive combined treatment of locally advanced rectal cancer, including neoadjuvant chemoradiation segment. Topography of pelvic recurrences identified 2/3 relapses located in non-IOERT boosted anatomic intrapelvic sites: posterior vaginal wall and anastomotic suture. Presacral recurrence in locally advanced rectal cancer seems to be of low incidence, in a non-subspecialized academic surgical practice coordinated with a multidisciplinary oncology evaluation context, if an IOERT boost is included as a component of treatment together with preoperative chemoradiation.

Radiotherapy combined with simultaneous chemotherapy with mitomycin-C and 5-fluorouracil for inoperable head and neck cancer.

The feasibility and effectiveness of a combined chemoradiotherapy treatment modality for locally advanced head and neck cancer was tested in a phase II trial. From March 1995 to June 1998, 35 patients with advanced squamous cell carcinoma of the head and neck were treated with a continuous intravenous infusion of 5-fluorouracil (600 mg m-2 24 h-1 for Days 1 to 5 (120 h)) and mitomycin-C (10 mg m-2 intravenously) on Day 5 during the first week of radiotherapy and on Day 36. 31 patients had stage IV disease; 4 patients had stage III; and 1 patient had stage II. Patient ages ranged from 42-69 years (median 56.7 years). The tumours involved were as follows: oral cavity (n = 11); oropharynx (n = 14); hypopharynx/larynx (n = 10). Radiotherapy was delivered to a total dose of 70 Gy with conventional fractionation (2 Gy per fraction, five times a week). Chemotherapy was well tolerated and all patients received the intended dose. Mild nausea occurred in five patients. After a mean follow-up of 21 months (range 10-44 months), 8 (23%) patients remain alive. A complete response was seen in 28 (80%) patients. When a recurrence appeared, it was within the first year after treatment. 1- and 2-year overall survival rates were 46% and 23%, respectively. Grade 3 mucositis occurred in 17% of patients. Grade 1-2 thrombopaenia occurred in 3 (9%) patients, grade > 2 leukopaenia in 4 (11%) patients, and grade > or = 2 anaemia in 3 (9%) patients. We observed a treatment interruption of maximum 1 week for six patients owing to mucositis. Febrile neutropaenia or aplasia were not observed. The concomitant use of 5-fluorouracil, mitomycin-C and radiotherapy in locally advanced head and neck carcinoma is well tolerated in this group of patients. This protocol showed good locoregional response with a very low toxicity profile.

Intraarterial chemotherapy as neoadjuvant treatment of oral cancer

Neoadjuvant chemotherapy in patients with primary squamous cell carcinomas of the oral cavity should lead to high remission rates whilst having low morbidity. Efficacy can also be enhanced by treating small tumour stages. As part of a multi-modality therapy of all stages of primary oral cavity carcinoma, 103 patients were treated with neoadjuvant intraarterial (i.a.) chemotherapy. After regimen A with 100 mg/m2i.a. cisplatin followed by 5 day continuous intravenous infusion of 5-fluorouracil (1 g/m2per day) in 36 patients, an i.a. high pressure chemo-perfusion with a dose of 150 mg/m2cisplatin was used with simultaneous intravenous infusion of 9 g/m2sodium thiosulfate (regimen B, 67 patients). Subsequent treatment comprised radical surgery and simultaneous radiochemotherapy with docetaxel. Partial and complete remissions were found in 80.6% (regimen A) and 67.2% (regimen B) of cases, tumour growth was inhibited in 11.1% and 31.3%. Very low toxicity could be shown especially in regimen B. 66.7% and 74.6% of patients could be operated on radically. Survival rate was 61.1% (regimen A, 22.7 months of mean observation time) and 79.1% (regimen B, 8.4 months). Patients with high-grade remissions seemed to have a survival advantage. Neoadjuvant i.a. chemotherapy with cisplatin, especially in its high dose variant, is a practical therapeutic tool for the treatment of all stages of primary oral cavity carcinoma.

Treatment of renal cell carcinoma with 5-fluorouracil and alfa-interferon

Objectives Renal cell carcinoma is relatively resistant to both chemotherapy and immunotherapy. Response, survival, duration of response, and toxicity of treatment were evaluated in patients with advanced renal cell carcinoma receiving a continuous intravenous infusion of 5-fluorouracil (5-FU) and low dose subcutaneous alfa-2b-interferon. Methods Between 1989 and 1994, 21 patients with advanced renal cell carcinoma underwent treatment with continuous intravenous infusion of 5-FU, 200 mg/m 2/day, and subcutaneous injections of recombinant interferon alfa-2b (IFN- α), 1 x 10 6 U/day. Results Objective response was observed in 9 patients (43%). Complete response occurred in 4 patients (19%): 2 with lung, 1 with bone, and 1 with liver metastasis. Partial response occurred in 5 patients (24%). Three of 4 complete responders remain alive without recurrence. Mean survival rate was 195 weeks among complete responders, 184 weeks among partial responders, and 88 weeks among nonresponders. The overall mean duration of response was 101 weeks. Responders developed progression of disease a mean of 62 weeks after the initial response to therapy. Mild dose-dependent toxicity was related to 5-FU infusion. Nearly all toxicities subsided with the temporary cessation of 5-FU infusion and/or decreasing the dose of the infusion. Few if any of the toxicities appear to be directly related to the low dose interferon injections. Conclusions Although this study is based on a small sample size, we believe that the encouraging complete and partial responses, apparent prolongation of survival, and manageable toxicity of this combination therapy warrant further investigation with larger randomized trials.

Mechanism-based improvement in the therapeutic selectivity of 5-FU prodrug alone and under conditions of metabolic modulation.

To compare the antitumor activity of Tegafur (150 mg/kg/day) with continuous intravenous infusion of 5-fluorouracil (5-FU) (12.5 mg/kg/day) and with oral UFT (60 mg/kg/day) with and without low- or high-dose leucovorin (50 or 200 mg/kg/day), rats with advanced colon cancer were treated with Tegafur or UFT 3 times daily for 28 days and 5-FU by continuous intravenous infusion for 28 days. UFT alone had a complete remission (CR) rate of 38%, whereas Tegafur and 5-FU produced no CRs. When high-dose leucovorin was added, the CR rate for UFT increased to 75%; Tegafur plus high-dose leucovorin resulted in only a partial remission rate of 50%, with no CRs; low-dose leucovorin was not as effective as the high dose. Hence, UFT clearly offers significant therapeutic advantages over Tegafur and protracted infusion of 5-FU. High-dose leucovorin is essential for significant modulation of drug action in this tumor.

Low-dose continuous intravenous infusion of 5-fluorouracil for metastatic breast cancer

Third-line chemotherapies for advanced breast cancer are difficult to tailor to the individual patient because of reduced tolerance and significant toxicity. Treatment with a continuous intravenous infusion of low-dose 5-fluorouracil (FU-LDCI) is generally well tolerated and thus, a reasonable option for heavily pretreated patients. From 1989 to 1995, 106 consecutive patients with advanced breast cancer were treated with FU-LDCI. 5-Fluorouracil was given at an initial daily dose of 250 mg/m2 administered continuously with the aid of an elastomer, non-electronic pump through a permanent central venous line for 21 days followed by a 7-day rest. The median age was 56 years (range, 30-82), the median ECOG Performance Status was 1 (range 0-4) and the median number of metastatic sites was 2 (range 1-4). Sixty-one percent of the patients had previously received more than 2 chemotherapy regimens which in 81% included adriamycin, and in 90% 5-fluorouracil. Eighty patients were evaluable for objective response: 17 of them had partial responses (21%, 95% CI: 14%-31%) and 23 stable disease (29%, 95% CI: 20%-40%). One-hundred five patients were evaluable for subjective response, with 46 reporting improvement (44%, 95% CI: 35%-54%). Previous treatments with either 5-fluorouracil or adriamycin did not predict response to FU-LDCI. Median time to progression for patients with a partial response or stable disease was 259 days (range 82-737). The overall survival for the populations as a whole was 274 days (range 13-2264), and the median dose received was 1904 mg/week (range 753-4329). The main toxic effects were grades I and II mucositis, and nausea and vomiting (observed in 31% and 28%, respectively). Grade III toxicities were uncommon: mucositis in 3%, nausea and vomiting in 3%, anemia, thrombocytopenia and hepatitis in 2%, and skin toxicity (hand-foot syndrome) in 1%. Catheter-related thrombosis was observed in 2% of the patients, and there were no pump failures. A questionnaire concerning the impact of the treatment upon quality of life was completed by all of the 13 patients who were alive at the time of evaluation of the results, and all of them rated FU-LDCI as easy to tolerate. The monthly cost of FU-LDCI (US$1,051.00 in Switzerland) was lower than the cost of weekly low-dose adriamycin (US$1,483.00 in Switzerland), a treatment which is often used as a palliative regimen in similar circumstances. FU-LDCI is a useful, cost-effective third-line treatment for patients with metastatic breast cancer who need palliation with cytotoxic drugs.

Preoperative Infusional Chemoradiation, Selective Intraoperative Radiation, and Resection for Locally Advanced Pelvic Recurrence of Colorectal Adenocarcinoma

The results of preoperative infusional chemoradiation, resection, and selective intraoperative radiation (IORT) boost in 43 previously nonirradiated patients with locally advanced pelvic recurrence of colorectal adenocarcinoma are described. After surgery alone 10% to 30% of patients with carcinoma of the distal colon and rectum will develop isolated pelvic recurrence. In most cases, the disease is locally advanced and not amenable to curative resection. Preoperative infusional chemoradiation has been shown to increase resectability and decrease local recurrence in primary locally advanced colorectal cancer. Based on this experience, we initiated a multimodality treatment protocol to treat patients with pelvic recurrence of colorectal adenocarcinoma. Forty-three consecutive patients with histologically proven pelvic recurrence of colorectal adenocarcinoma were enrolled on a multimodality treatment protocol. The treatment plan consisted of 5 weeks of concurrent pelvic external beam radiotherapy (45 Gy) with continuous intravenous infusion of 5-fluorouracil and/or cisplatin. This was followed by surgery that included IORT boost (10-20 Gy) for 21 patients and brachytherapy for 4 patients. Forty patients (93%) underwent operation and 33 (77%) underwent resection with curative intent. There were 29 (88%) margin-negative resections. Fifteen patients (48%) underwent sphincter-preserving operations. There were no treatment-related deaths. Twenty-two patients experience perioperative complications. Median follow-up for the 43 patients was 26 months. The local recurrence rate was 36%. Median survival for the patients who underwent resection was 34 months, and actuarial 5-year disease-free and overall survival were 37% and 58%, respectively. Tumor cytoreduction by preoperative chemoradiation can increase resectability and enable sphincter-preserving surgery in patients with locally advanced pelvic recurrence of colorectal cancer.

Concomitant chemoradiotherapy, neutron boost, and adjuvant chemotherapy for anaplastic astrocytoma and glioblastoma multiforme.

The survival rate for patients with malignant gliomas is poor. We describe the results of a prospective study using concomitant chemoradiotherapy, neutron boost, and adjuvant chemotherapy for patients with malignant gliomas. Forty-two patients with anaplastic astrocytoma (AA) and glioblastoma multiforme (GBM) were treated with postoperative photon radiation 45 Gy/25 fraction (fxs) with concomitant continuous intravenous infusion of 5-fluorouracil at 300 mg/m2/day x 5 days and hydroxyurea 0.5 g orally every 12 hr for 6 days for 5 consecutive weeks, followed by a neutron boost of 450 N cGy/6 fxs delivered twice weekly. Adjuvant chemotherapy with procarbazine, CCNU, and vincristine (PCV) was given up to 1 year or until tumor progression. Thirty-four patients (81%) had GBM and 8 patients (19%) had AA. Sixteen patients (38%) were ineligible for the neutron boost because of large tumors or poor performance status and instead received a photon boost with concomitant chemotherapy for a total dose of 60-65 Gy to the tumor. The overall median survival is 68 weeks at a median follow-up of 203 weeks (range 166-302 weeks for the 11 patients remaining alive); 7/8 patients with AA are alive, 2 of these with progressive disease. For AA the median survival is not reached at a median follow-up of 203 weeks (range 166-302 weeks for the 7 patients alive with AA). Time to tumor progression for the 1 dead patient with AA was 35 weeks and the other 2 patients failed at 171 weeks and 179 weeks following treatment. The median survival for the 34 patients with GBM was 62 weeks; 4/34 patients with GBM are alive at 285, 238, 216, and 206 weeks. Multivariate survival analysis in the 34 patients with GBM revealed age and Karnofsky performance status as important prognostic factors. Extent of surgery and neutrons did not affect survival. Concomitant chemoradiotherapy was well tolerated by all patients. The only toxicities observed were mucositis < or = grade II in 3 patients (7%) and mild myelosuppression in 1 patient (2.4%). Adjuvant PCV was well tolerated. Continuous concomitant chemoradiotherapy was well tolerated by all patients with acceptable side effects. The survival rate for the patients with GBM suggests no significant impact on the prognosis for these patients. Patients with AA did well; however, the patient numbers are small.