Treatment of advanced colorectal cancer with folinic acid and 5-fluorouracil in combination with cisplatinum

51 patients with metastatic colorectal cancer (stage Dukes D) were treated with intravenous (i.v.) infusion on days 1, 3, 5, 8 and 16 with folinic acid (200 mg/m2) and 5-fluorouracil (600 mg/m2), and on days 1, 8 and 16 with cisplatinum (25 mg/m2 i.v.); cycles were repeated every 4 weeks. All 51 patients were evaluable for toxicity and response criteria. 26 patients had objective responses (3 complete responses, 5.9%; 23 partial responses, 45.1%), relative risk 51% (95% confidence intervals 36.7-65.0%). Response duration ranged from 4 to 28.0 months (median 16.8). Overall median survival of all patients included was 14.7 months (range 3.0-33.0). Toxicity of WHO grade III, requiring dose reduction, occurred in 9 (18%) patients. The regimen described here appears to be active, safe and well tolerated for treatment of patients with advanced colorectal cancer.     

Acute myocardial infarction in a patient during dobutamine stress echocardiography

Combined chemotherapy/radiotherapy treatments appear to yield better results in locally advanced non-small-cell lung cancer (NSCLC) than radiotherapy alone. The optimal induction chemotherapy regimen remains to be established. In the present study, chemotherapy with cisplatin and vinorelbine was used prior to radical radiotherapy in Stage III-B NSCLC. Thirty-three patients were entered prospectively into a Phase II study. Treatment consisted of three cycles of chemotherapy with cisplatin 100 mg/m2 on day 1 and vinorelbine 30 mg/m2 on days 1 and 8, followed by thoracic radiotherapy (60 Gy). Twenty-two percent of the 33 patients had grade 3-4 leukopenia, and there were six episodes (in 4 patients) of neutropenia-associated fever. Gastrointestinal toxicity was generally moderate. Peripheral neuropathy was present in 42% of the patients, although in most of them it was slight. The main radiotherapy toxicity was esophagitis grade I-II. Evaluation of response after the third chemotherapy course showed an objective response in 16 patients (48%), whereas in three patients (9%) the disease progressed during therapy. The median survival of the entire group was 13 months. Cisplatin plus vinorelbine followed by radiotherapy is an effective schedule for patients with locally advanced non-small-cell lung cancer.     

Phase II trial of cisplatin and gemcitabine in advanced squamous-cell carcinoma of the head and neck

BACKGROUND: To evaluate the toxicity profile and efficacy of cisplatin combined with gemcitabine in patients with irresectable locally recurrent or metastatic squamous cell carcinoma of the head and neck. PATIENTS AND METHODS: Gemcitabine was given at a dose of 800 mg/m2 on days 1, 8 and 15, plus cisplatin at a dose of 50 mg/m2 on days 1 and 8; every four weeks. RESULTS: Twenty-four patients with a median age of 59 years (range 42-74) were included. All patients were evaluable for toxicity and 22 patients were assessable for response. Eleven cases had advanced recurrent locoregional disease while 13 patients had metastatic disease. One CR (4.7%) and four PR (18%) were observed, for an overall response rate of 22.7% (95% CI: 8%-42%). The main toxicity was hematological: neutropenia grade 3-4 in 28% of the cycles and thrombocytopenia grade 3-4 in 16%. The most significant non-hematological toxicity was asthenia grade 2-3 in 24% of the cycles. CONCLUSIONS: This cisplatin plus gemcitabine combination schedule has a favourable toxicity profile with a discrete activity in patients with locally recurrent or metastatic squamous-cell carcinoma of the head and neck.     

Cytarabine and cisplatin as salvage therapy in patients with metastatic colorectal cancer who failed 5-fluorouracil + folinic acid regimen. French Northern Oncology Group

The combination of CDDP and ARA-C has shown some clinical efficiency as first-line therapy in advanced colorectal cancer. Our study was aimed to evaluate the therapeutic activity of this combination in advanced colorectal cancer who failed 5-fluorouracil (FU) and folinic acid (LV) regimen. Seventeen patients with measureable metastatic colorectal cancer who failed 5FU-LV therapy as first line (n = 14) or second line treatment (n = 3), entered the study. Three patients who recurred during adjuvant treatment with 5FU and levamisol, were also included. Median age was 59.5 (40-69). Performance status was as follows: 0 (n = 5), 1 (n = 11), 2 (n = 3), 3 (n = 1). Site of metastases included liver (n = 16), lung (n = 7), abdomen (n = 2), pelvic recurrences (n = 2), cutaneous (n = 1). Seven patients had 2 metastatic sites and two 3. The treatment was given as follows: ARA-C 75 mg/m2/day, days 1-3, followed 1 hour later by CDDP 30 mg/m2/day, days 1-3, every 28 days. The median number of cycles was 3 (range: 1-6 cycles). All patients but one were evaluable for both response and toxicity. Of these patients, 50% experienced severe hematologic toxicity and nonhematologic toxicity mainly consisted of fatigue and/or vomiting. No objective response was observed, but there were 3 stabilizations and 16 progressive diseases. Median time to progression was 10 weeks. Thus, the CDDP/ARA-C regimen is not of clinical value as salvage therapy in advanced colorectal cancer because of its toxicity and its lack of efficiency.     

A pilot study on concurrent platinum chemotherapy and intracavitary brachytherapy for locally advanced cancer of the uterine cervix

This study aims to evaluate the feasibility, toxicity and efficacy of concurrent chemotherapy with platinum compounds and brachytherapy, for locally advanced carcinoma of the cervix (Stages IIA/B, IIIA). The hypothesis was that synchronous chemo-brachytherapy may be sufficient to cause down-staging of the tumour, to render it operable, and hopefully improve the prognosis. 36 women with locally advanced cervical cancer were treated with concomitant brachytherapy and chemotherapy before surgery and/or definitive external radiotherapy. All patients received two caesium-137 Selectron MDR applications, 1 week apart. The dose calculated to point A for each implant was 20-25 Gy. Chemotherapy consisting of continuous cisplatin infusion (50 mg m2) and of carboplatin (300 mg m-2) was given simultaneously with intracavitary irradiation during the first and second application, respectively. The combined therapy was followed when feasible by radical hysterectomy, pelvic lymphadenectomy and pelvic radiotherapy. Patients deemed ineligible for surgery because of poor response were given full dose external radiotherapy. 31/36 patients were treated by Wertheim hysterectomy of whom 10 had negative lymph nodes and resection margins. Definitive external radiotherapy was given in the remaining five patients. Overall, 83% were disease free at 2.8 years mean follow-up. The most frequent acute side-effects of chemobrachytherapy were nausea and vomiting. No renal toxicity was observed. Thrombocytopenia was seen in five patients and was responsible for delayed surgery in four patients. Concerning late effects, two patients developed grade 2 intestinal sequelae, two mild frequency and two vaginal stenosis. One rectovaginal and one vesicovaginal fistula developed in two patients; and a third patient had a fistula associated with tumour recurrence. Concurrent brachytherapy and chemotherapy with platinum compounds is well tolerated and effective in reducing tumour bulk before definitive local treatment (surgery or external radiotherapy), in patients with locally advanced carcinoma of the uterine cervix.     

Concomitant infusion cisplatin and hyperfractionated radiotherapy for locally advanced nasopharyngeal and paranasal sinus tumors

PURPOSE: This is a prospective study to improve the therapeutic ratio in the treatment of patients with locally advanced nasopharyngeal and paranasal sinus tumors by using split-course concomitant infusion cisplatin chemotherapy and hyperfractionated radiotherapy. METHODS AND MATERIALS: From 1983 to 1993, 21 patients with locally advanced nasopharyngeal and paranasal sinus tumors (T3 and T4, or recurrent tumors involving the facial bones and/or the base of the skull) were treated with a regimen of split-course hyperfractioned radiotherapy (1.2 Gy/fraction/bid) and concomitant infusion cisplatin (5-10 mg/m2/24 h). The therapy was given in three separate 2-week sessions with 1 to 2 week breaks between sessions. Seventeen of 21 patients were treated with curative intent with cumulative radiation doses ranging from 64.8 to 70.8 Gy. Four patients were treated with palliative intent to a total dose of less than 60 Gy or to a limited field due to previous irradiation. RESULTS: Sixteen of 17 patients (94%) treated curatively achieved a complete response. Of the 16 patients who achieved complete response, 7 patients (50%) were alive at the time of analysis (36 to 126 months). One patient was alive at 4 years with no evidence of disease, and died in 10 years at the age of 80 of unknown cause. Two patients died of local recurrence at 21 and 45 months and one patient died of a cerebrovascular accident at 12 months with disease status unknown. Five patients died of distant metastases. The one patient who had a partial response died in 25 months with local disease and metastases to the bone and lung. Four patients that were previously irradiated received a reduced total dose or treated to a limited irradiation field. All had near complete responses, but died within a year of treatment, with the exception of one patient who died at 23 months. Acute reactions included intense erythema of the mucosa in all patients. Five of 21 (23%) developed punctate mucositis and 3 of 21 (14%) developed confluent mucositis. Hematologically, one patient developed neutropenia (1800 WBC/mm3) and one developed thrombocytopenia (38,000/mm3). A rising creatinine was observed in three patients (2.0, 1.7, 1.7) all of whom were treated with the higher 10 mg/m2/day dose of infusional cisplatin. In all three of these cases, the creatinine slowly returned to normal over a 6-month period. Hormonal evaluations were performed in three patients and all were within normal ranges. There was no evidence of neck fibrosis or trismus. One patient with gross recurrent disease of the orbit developed blindness of the involved eye due to corneal opacification. The orbital area had been reirradiated in this patient. CONCLUSIONS: Concomitant infusion cisplatinum with hyperfractionated radiation improved tumor control, but did not increase normal tissue injury. Acute reactions were minimized by splitting the treatment with a 1- to 2-week break after each 2 weeks of radiation treatment. Late complications were not increased by using a hyperfractionated radiation regimen. The local failure rate was only 18% (3 of 17 patients), but the distant failure rate was 35% (6 patients). Further investigation is needed to prove if adjuvant chemotherapy after concomitant chemoradiation improves survival by decreasing the distant failure in such advanced cases.     

Interleukin 2 and interferon alpha-2a do not improve anti-tumour activity of 5-fluorouracil in advanced colorectal cancer

Treatment using a combination of 5-fluorouracil (5-FU), interferon-alpha (IFN alpha-2a) and interleukin 2 (IL-2) has been shown to mediate disease regression in selected patients with advanced colorectal cancer. This phase II study was designed to evaluate the anti-tumour activity and toxicity of the combination of IL-2, IFN alpha-2a and 5-FU in patients with advanced colorectal cancer. Forty-four patients with metastatic colorectal cancer were treated, predominantly on an outpatient basis, with subcutaneous IFN alpha-2a and IL-2 three times per week followed by once a week bolus intravenous 5-FU injections. There were six (14%) partial responses among the 43 evaluable patients [95% confidence interval (CI) 5-28%]. Twenty-four patients had stable disease (56%) and 13 patients (30%) showed progressive disease. The median time to progressive disease in 43 patients was 19 weeks (range 2-72 weeks) and in responders 34 weeks (range 24-30 weeks). The median overall survival was 47 weeks (range 2-85 weeks) and in responders 60 weeks (range 35-71 weeks). Treatment-related toxic effects included fatigue, nausea and vomiting. Granulocytopenia was the main reason for the dose reductions or treatment interruptions in 32 out of 44 patients. One patient died of toxicity due to renal failure. Serial assessments of immunophenotyping and cytolytic activities of peripheral blood lymphocytes did not show changes in the numbers of circulating natural killer (NK) cells or in the levels of NK and lymphokine-activated killer (LAK) cytolytic activities. This regimen of IL-2 and IFN alpha-2a with 5-FU has only modest anti-tumour activity in advanced colorectal cancer.     

5-Fluorouracil, folinic acid, etoposide and cisplatin chemotherapy for locally advanced or metastatic carcinoma of the oesophagus

38 patients with advanced oesophageal carcinoma were treated with intravenous (i.v.) folinic acid (300 mg/m2), 5-fluorouracil (500 mg/m2), etoposide (100 mg/m2), and cisplatin (30 mg/m2) (FLEP), on days 1, 2 and 3, every 22-28 days. 26 patients had locally advanced disease (LAD) and 12 had metastatic disease (M1). Oesophagectomy was planned for patients with LAD in case of tumour regression after chemotherapy, while patients with M1 disease received chemotherapy only. The overall remission rate was 45% (17/38) including four clinical and two pathologically confirmed complete remissions. 16 patients underwent oesophagectomy, 12 after response to FLEP, and 4 after FLEP and subsequent irradiation +/- 5-fluorouracil/mitomycin. Toxicity was mainly haematological, with WHO grade 3 and 4 leukocytopenia in 50% and thrombocytopenia in 31% of the patients. Two treatment-related deaths were observed; one due to chemotherapy and one postoperatively. Median survival time of LAD patients was 13 months, and actuarial 2-year survival was 31%. Patients with complete tumour resection after FLEP had a median survival time of 18 months and a 2-year survival rate of 42%. Median survival of M1 patients was 6 months. FLEP is an active combination for oesophageal cancer, especially when used preoperatively in LAD.     

Weekly paclitaxel and cisplatin with concurrent radiotherapy in locally advanced non-small-cell lung cancer: a phase I study

PURPOSE: Both cisplatin (CDDP) and paclitaxel have shown good antitumor activity in non-small-cell lung cancer (NSCLC) patients and are able to potentiate the antitumor effects of radiation therapy (RT). This study aimed to determine the maximum-tolerated doses (MTDs) of CDDP and paclitaxel (escalated alternately) when given concurrently with RT and to define the nature of the dose-limiting toxicity (DLT). PATIENTS AND METHODS: Chemotherapy-naive patients with locally advanced NSCLC received six weekly administrations of a CDDP-paclitaxel combination with concurrent local RT. The starting doses of CDDP and paclitaxel were 30 mg/m2/wk and 35 mg/m2/wk, respectively. RT was initially given at the dose of 1.2 Gy twice daily for 5 days per week for 5 weeks (total dose, 60 Gy) and at a single daily dose of 2 Gy for 5 days per week for 6 weeks in the last two cohorts of patients. The drug doses were escalated alternately until DLT occurred in more than one third of the patients in a given cohort. RESULTS: Overall, 25 patients were recruited through five different cohorts. All were assessable for toxicity. Esophagitis was the main toxicity and occurred in 16 of 25 patients (64%) and was grade 3 or 4 in five of them. At step 3 (CDDP 35 mg/m2/wk and paclitaxel 45 mg/m2/wk), two of five patients had to discontinue treatment because of severe esophagitis and one of these died of complications related to grade 4 esophagitis. However, keeping the same doses of chemotherapy and replacing hyperfractionation with a standard single-day fraction, weekly doses of CDDP and paclitaxel of 35 mg/m2 and 45 mg/m2 could be safely administered. Neutropenia was by far the most relevant hematologic toxicity and occurred in 33 of 141 weekly delivered courses, but it was of grade 4 in only four courses. Substantial pulmonary or neurologic toxicity was not observed in this study. Two complete responses (CRs) and 13 partial responses (PRs) were observed, for a 60% overall response rate (95% confidence interval [CI], 39% to 79%). The median survival time was 16 months, with a 66% 1-year survival probability. CONCLUSION: CDDP 35 mg/m2/wk and paclitaxel 45 mg/m2/wk can be safely administered with concurrent standard RT. The use of hyperfractionation is associated with a more frequent occurrence of severe esophagitis and requires a reduction of the CDDP dose to 30 mg/m2/ wk. Only future randomized trials will elucidate which of these two approaches (standard or hyperfractionated RT) is the better option to improve the outcome of patients with locally advanced NSCLC.     

Tissue preparation for immunocytochemistry

The results in 9 patients with unresectable recurrent squamous cell cancer of the head and neck who were treated with aggressive concurrent chemoradiotherapy are reported. Treatment consisted of one or two courses of chemotherapy with 5-fluorouracil 1000 mg/m2/day and cisplatin 20 mg/m2/day, both given as 4-day continuous intravenous infusions, concurrent with radiation therapy. Salvage radiation doses between 30 and 70 Gy were administered. Seven patients had previously undergone an attempt at curative surgery, and 7 had been treated with radiation doses between 52 and 72 Gy. The recurrent disease was locally confined in 3, locoregional in 5, and locoregional with metastases in 1 of the 9 patients. Treatment toxicity was significant and included mucositis, nausea/vomiting, and granulocytopenia, but there were no toxic deaths. Complete tumor clearance was possible in 6 of these 9 patients, and 5 patients remain disease-free at 41+, 43+, 45+, 47+, and 50+ months. Of these 5 patients, 4 had previously been treated with both surgery and radiation, while 1 had only undergone surgery. We conclude that aggressive chemotherapy and concurrent (re)irradiation can be given to patients with unresectable, recurrent, squamous cell cancer of the head and neck. Treatment is tolerable, and disease-free long-term survival is possible. Careful patient selection, however, is required.     

Treatment of advanced gastric cancer with oral etoposide, leucovorin and tegafur: experience with an oral modification of the etoposide, leucovorin and 5-fluorouracil (ELF) regimen

Recent data have suggested enhanced therapeutic activity with prolonged administration of both etoposide as well as fluoropyrimidines in the treatment of gastrointestinal malignancies. Based on this rationale, we investigated the clinical effectiveness and tolerance of an oral modification of the widely applied etoposide, leucovorin and 5-fluorouracil (ELF) regimen in patients with advanced gastric cancer. 32 patients with advanced gastric cancer were treated with oral etoposide (100 mg), leucovorin (3 x 100 mg), and tegafur (3 x 200 mg) over 14-21 days for a maximum of six cycles. Objective response was seen in only 5 patients (16%), stable disease was documented in 7 (22%), while the remaining patients progressed during therapy. The median time to progression was 2.8 months (range 0.7-12 months) and median overall survival was 6 months (range 1-18+ months). Due to grade 3 nausea/emesis, 8 patients discontinued treatment prematurely, while 12 patients experienced anorexia and progressive weight loss. Haematological toxicity was modest, with 4 patients developing asymptomatic grade 3-4 granulocytopenia. We conclude that this oral combination regimen cannot be recommended for the treatment of advanced gastric cancer.     

Phase II study of vinorelbine (Navelbine) in previously treated small cell lung cancer patients. EORTC Lung Cancer Cooperative Group

26 previously treated patients with progressive recurrent small cell lung cancer (SCLC) were given vinorelbine (Navelbine), 30 mg/m2 weekly. All patients had responded to first-line chemotherapy and were off therapy for at least 3 months. Partial response was observed in 4 out of 25 eligible patients (16%; 95% confidence interval 4-36%), stable disease in 7 patients and progression in 12 patients. The limiting toxicity was a non-cumulative leucopenia (80%, 32% WHO grade 3-4). Reaction at the site of injection was observed in 5 patients, causing treatment discontinuation in 2 cases. Other non-haematological toxicities were moderate. These results suggest acceptable toxicity and some antitumour activity of vinorelbine in pretreated SCLC patients.     

Multivariate analyses of the hominid ulna from Klasies River mouth

BACKGROUND: The combination of 5-fluorouracil (5-FU) and cisplatin has shown great activity in many different types of tumour with an in vitro synergistic effect between 5-FU and cisplatin. A phase II study of 5-FU plus cisplatin was performed in 25 previously untreated patients with inoperable locally advanced or metastatic biliary tract carcinoma. PATIENTS AND METHODS: Twenty-five patients, 10 of them men and 15 women with a median age of 58, were entered into the study. The chemotherapy regimen consisted of 5-FU: 1 g/m2/day in continuous intravenous (i.v.) infusion for five consecutive days, and cisplatin: 100 mg/m2/day on day 2 in a one-hour infusion with standard hyperhydration. Twenty-two patients had metastatic tumours and three had locally advanced disease. RESULTS: Of the 25 patients entered into the study, 24 were evaluable for response and 25 for toxicity. Nausea and vomiting was the main toxic side effect in 19 patients. Severe, WHO grade 3-4 thrombocytopenia or neutropenia were observed in three and seven patients, respectively. There were no toxic deaths. Of 25 patients, six had partial remissions (overall response 24%, 95% confidence interval 7%-41%). For three patients, tumour reduction permitted local radiotherapy and one of these patients with initially advanced disease is still alive six years after the beginning of treatment. CONCLUSIONS: This study, one of the largest phase II trials performed in this disease, shows interesting activity of the combination of 5-FU and cisplatin in advanced biliary tract carcinoma.     

An EORTC-ECSG phase II study of vinorelbine in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck

BACKGROUND: Vinorelbine is an active drug in the treatment of lung and breast cancers and has a favorable toxicity profile. Many clinical trials have demonstrated its antitumor activity in other tumor types including squamous cell carcinoma of the head and neck (SCCHN). We investigated the efficacy and tolerability of vinorelbine in patients with recurrent and/or metastatic SCCHN, previously untreated by chemotherapy. PATIENTS AND METHODS: Seventy-one patients with locoregional recurrent and/or metastatic SCCHN were treated with vinorelbine at a dose of 30 mg/m2/week i.v. by short-duration infusion on an out-patient basis. Doses were adjusted according to tolerance. RESULTS: Two complete and seven partial responses were observed among 56 evaluable patients, yielding a response rate of 16% (95% confidence interval (CI): 8%-28%). The overall response rate of all eligible patients (63) was 14%. The responses were seen in recurrent tumors, lymph nodes and in lung metastases, and their median duration was 19 weeks (12-63). The main toxicity, severe and reversible neutropenia (grade 3-4) occurred in 53% of the 69 evaluable (for toxicity) patients. Twelve patients developed severe bronchopulmonary infections, which caused two early deaths. Constipation was observed in 31 patients (45%). Other gastrointestinal toxicities, asthenia, acute pain syndrome and peripheral sensory neuropathy, were mild to moderate. The median number of treatments was seven cycles and the median relative dose intensity of vinorelbine was 85% (25.5 mg/m2/week). CONCLUSIONS: Vinorelbine is an active drug, with acceptable toxicity, in recurrent and/or metastatic SCCHN, at the dose and schedule administered in the present study. Further evaluation in association with other agents and/or radiotherapy is warranted.     

A miniature analytical instrument for nucleic acids based on micromachined silicon reaction chambers

BACKGROUND: The authors studied rapidly alternating chemotherapy and radiotherapy as the initial treatment for patients with muscle-invasive transitional cell carcinomas of the urinary bladder whose advanced age and lack of strength precluded cystectomy. METHODS: Twenty-one patients with T2 (28%) or T3 (72%) NXM0 carcinomas were treated by transurethral resection followed by chemoradiotherapy. Their median age was 73 years. The chemotherapy (consisting of methotrexate, vinblastine, doxorubicin, and cisplatin) was given during Weeks 1, 4 and 7. Radiotherapy (1.8-2 Gray [Gy] twice a day, to a total dose of 18-20 Gy per week) was given during Weeks 2, 5 and 8, for a final dose of 40 Gy to the pelvis plus 14-20 Gy boost to the affected bladder. RESULTS: There was 1 treatment-related death (5% of patients), but otherwise the acute toxicity was relatively mild. Cystoscopy 1 month after chemoradiotherapy did not reveal invasive cancer in any patient. Subsequent cystoscopies detected recurrent invasive cancer in 3 patients after 30, 44, and 82 months, respectively. The observed survival rate after 5 years was 37%, the cause specific survival rate was 63%, the metastasis free rate was 71%, and the local control rate was 80%. Eighty-four percent of patients had normal bladder function. CONCLUSIONS: Transurethral resection plus chemoradiotherapy was successful in preserving bladder function in the majority of the patients. The survival and progression free rates compared favorably with what has been reported recently after radical cystectomy and chemotherapy, and they add to the growing body of evidence that chemoradiotherapy might be a safe, effective alternative to cystectomy for many patients with muscle-invasive carcinoma of the urinary bladder.     

Cardiovascular disease prevention in eastern Europe

A phase II trial was conducted to evaluate the efficacy and toxicity of a modulation of 5-fluorouracil (5-FU) by methotrexate (MTX) (with leucovorin (LV) rescue) as first-line chemotherapy in patients with locally advanced (inoperable) or metastatic gastric carcinoma. From July 1993 through August 1996, 36 patients with advanced gastric carcinoma received a regimen that consisted of: MTX 200 mg/m2 diluted in 250 ml normal saline by intravenous infusion over 20 minutes at hour 0; 5-FU 1,200 mg/m2 intravenous push injection at hour 20. Beginning 24 hours after MTX administration all patients received LV 15 mg/m2 intramuscularly every 6 hours for six doses. Cycles were repeated every 15 days. One patient was not assessable for response. Objective regression was observed in 15 of 37 patients (43%; 95% confidence interval, 26%-60%). One patient (3%) achieved complete response and 14 (40%) achieved partial response. No change was recorded in 14 patients (40%) and progressive disease was noted in six patients (17%). The median time to treatment failure was 7 months and the median survival was 12 months. Toxicity was within acceptable limits but one therapy-related death resulting from severe leukopenia occurred. The dose-limiting toxicity was mucositis. Five episodes of grade 3 or 4 stomatitis were observed and caused dosage modifications of MTX and 5-FU. Biochemical modulation of 5-FU by MTX appears as an attractive modality in patients with advanced gastric cancer. Further investigation both in experimental and clinical fields is needed to clearly define its role and to design the best modulatory strategy.     

Locally advanced primary colorectal cancer: intraoperative electron and external beam irradiation +/- 5-FU

PURPOSE: For locally advanced primary colorectal cancer, our institution has combined intraoperative electron irradiation (IOERT) with external beam irradiation (EBRT) +/- 5-fluorouracil (5-FU) and surgical resection. Disease control and survival were compared with the current IOERT and prior non-IOERT regimens. METHODS AND MATERIALS: From April 1981 through August 1995, 61 patients received an IOERT dose of 10-20 Gy, usually combined with 45-55 Gy of fractionated EBRT; 56 had minimum follow-up of 18 months. The amount of residual disease remaining at IOERT after exploration and maximal resection in the 56 patients was gross in 16, < or = microscopic in 39, and unresected in 1. RESULTS: Survival (SR) and disease control were analyzed as a function of potential prognostic factors. Factors that achieved statistical significance for improved overall survival included treatment sequence of preop EBRT + 5-FU (vs. postoperative EBRT + 5-FU, p = 0.003) and < or = microscopic residual disease after maximal resection (vs. gross residual, p = 0.005). Those that appeared to favorably impact disease-free survival included EBRT + 5-FU (vs. EBRT alone, p = 0.01), < or = microscopic residual (vs. gross, p = 0.0014), and colon site of primary (vs. rectum, p = 0.009). Failures within an irradiation field have occurred in 4 of 16 patients (25%) who presented with gross residual after partial resection vs. 2 of 39 (5%) with < or = microscopic residual after gross total resection (p = 0.01). The significant prognostic factors for a decrease in distant metastases were the same as for disease-free SR with respective p-values of 0.013 (EBRT + 5-FU), 0.008 (microscopic residual), and 0.03 (colon primary). The current data suggests a relationship between IOERT dose and incidence of Grade 2 or 3 neuropathy (< or = 12.5 Gy--1 of 29 or 3%, > or = 15 Gy--6 of 26 or 23%, p = 0.03). CONCLUSIONS: Both overall survival and disease control appear to be improved with the addition of IOERT to standard treatment. More routine use of systemic therapy is indicated as a component of IOERT containing treatment regimens because the incidence of distant metastases was 50% of patients at risk.     

Hereditary deficiency of vitamin K-dependent coagulation factors with skeletal abnormalities

Thirteen patients with localized unresectable pancreas carcinoma were treated with a combination of accelerated radiotherapy and 5-fluorouracil. Radiotherapy consisted in 3 fractions of 1.1 Gy per day during 3 weeks up to a total dose of 45-50 Gy. 5-Fluorouracil was administered as continuous infusion in a dosis of 25 mg/kg/24 h the first and the third week concomitantly to radiotherapy. Grade 3 mucositis, diarrhoea and nausea/vomiting were observed in 15% of the patients. Eleven patients completed the treatment without modifications and in two patients the dose of 5-fluorouracil was reduced to 75% during the third week of treatment. Radiotherapy was always administered as planned. Median survival was 36 weeks.     

Concurrent chemoradiation therapy with oral etoposide and cisplatin for locally advanced inoperable non-small-cell lung cancer: radiation therapy oncology group protocol 91-06

PURPOSE: Patients with locally advanced inoperable non-small-cell lung cancer (NSCLC) have a poor clinical outcome. We conducted a prospective study to evaluate the merit of chemotherapy administered concurrently with hyperfractionated thoracic radiation therapy. PATIENTS AND METHODS: Seventy-nine patients with inoperable NSCLC were enrolled onto a multicenter phase II trial of concurrent chemoradiation therapy. Treatment consisted of two cycles of oral etoposide 100 mg/d (50 mg/d if body-surface area [BSA] < 1.70 m2), intravenous cisplatin 50 mg/m2 on days 1 and 8, and hyperfractionated radiation therapy 5 days per week (1.2 Gy twice daily > 6 hours apart; total 69.6 Gy). RESULTS: Seventy-six assessable patients with a Karnofsky performance status > or = 60 and adequate organ function who had received no prior therapy were evaluated for clinical outcome and toxic effects. After a minimum follow-up duration of 21 months, the 1- and 2-year survival rates and the median survival duration were 67%, 35%, and 18.9 months overall; they were 70%, 42%, and 21.1 months for patients with weight loss of < or = 5%. Toxicity was significant; 57% developed grade 4 hematologic toxicity, 53% grade 3 or 4 esophagitis, and 25% grade 3 or 4 lung toxicity. However, only 6.6% of patients had grade 4 or lethal nonhematologic toxicity, which included three treatment-related deaths (two of pneumonitis and one of renal failure). CONCLUSION: Concurrent chemoradiation therapy with oral etoposide and cisplatin plus hyperfractionated radiation therapy is feasible. The survival outcome from this regimen compares favorably with that of other chemoradiation trials and even of multimodality trials that have included surgery.     

Up-to-date approach to the treatment of rectal cancer

During the last 15 years 2404 radical operations of various types were carried out for cancer of the rectum. The rate of postoperative complications made up 28.3% and mortality--2.9%. The tendency to increase of locally spread forms of cancer up to 96.2% with metastases to regional lymph nodes up to--52.3% was detected. The use of adequate chemotherapy, updated suturing devices and new variants of radical operations, combined and extended ones in particular havw much contributed to carrying out radical interventions with complete restoration of bowel continuity in 70% of patients. 5 year survival rate of patients after sphincter saving plastics and restorative procedures made up 60.2-65.3%, after extirpations with colostomy--54.2%. Promising results of improvement the indices of 5 year survival were obtained when preoperative irradiation in regime of multifractioning SOD 45-55 Gy was used together with administration of 5-fluorouracil (5-7.5 g).