Alcohol-related words are distracting to both alcohol abusers and non-abusers in the Stroop colour-naming task

A combination chemotherapy with continuous infusion of cisplatin (5 mg/body, day 1-5) and UFT (400-600 mg/body, day 1-5) was administered to thirteen patients for advanced non-small cell lung cancer. Myelosuppression and other toxicity were mild, and the quality of life of the patients was good. The response rate of thirteen patients was 23% (CR 0, PR 3). It was considered that chemotherapy using cisplatin (5 mg/body, day 1-5) and UFT (400-600 mg/body, day 1-5) was well tolerated and effective for the treatment of non-small cell lung cancer.     

Neo-adjuvant chemotherapy +/- immunotherapy with s.c. IL 2 in advanced squamous cell carcinoma of the head and neck: a pilot study

We carried out a pilot nonrandomized phase II study to compare the neo-adjuvant chemotherapic regimen with cisplatin, 5-FU and vinorelbine with the same combination plus s.c. IL 2 in advanced head and neck squamous cell carcinoma (HNSCC). The primary goals of the trial were to evaluate the feasibility and response rates of the two regimens. The study design consisted of a patient's assignment to either of the two following arms: Arm A: Cisplatin 80 mg/m2 i.v. on day 1; 5-FU 600 mg/m2 i.v. on days 2-5; and vinorelbine 20 mg/m2 i.v. on days 2 and 8, Arm B: the same chemotherapic regimen plus recombinant IL 2 (Proleukin, Eurocetus) 9 MIU s.c. daily from day 9 to 13 and from day 16 to 20 for every cycle. From March 1993 to November 1993 twenty three patients with Stage III-IV HNSCC were enrolled in the study. Patients could be evaluated for response to treatment if they had received at least 2 complete cycles of therapy. The overall response rate (ORR) was 63% in Arm A and 100% in Arm B. The differences for ORR and CR rates were statistically significant in favor of Arm B. The analysis for each of the three drugs included in the chemotherapy schedule shows that both the actually received average dose-intensity and the actually delivered average cumulative doses/patient were higher for Arm B (chemo-plus IL 2 therapy) (approximately 80% of programmed dose-intensity) than for Arm A (approximately 70% of programmed dose-intensity). Both the actually received average dose-intensity and the actually delivered average cumulative doses/patient for IL 2 were more than 80%. In both arms the most frequent side effects were myelosuppression, phlebitis and electrolyte disturbances. There were 2 toxic deaths, 1 in Arm A and 1 in Arm B, both for hematologic toxicity. Our "pilot" study suggests that the combination of cisplatin, 5-FU, vinorelbine plus IL 2 is a highly active, but rather toxic, neo-adjuvant treatment in advanced HNSCC with very high ORR and CR rates.     

Food and food additives hypersensitivity in adult asthmatics. III. Adverse reaction to sulfites in adult asthmatics

To improve the survival rate of patients with esophageal cancer, several protocols of a preoperative combination of chemotherapy and radiotherapy, known as chemoradiation therapy, have been developed, recently characterized by the combination of 5-fluorouracil (5-FU), cisplatin, and radiation. Although some of these combinations have been demonstrated to be effective, the optimal chemoradiation dose and schedule are not yet precisely established. Recent investigations have elucidated that the radiosensitizing effects of cisplatin are able to be achieved more effectively by the daily administration of cisplatin before each fraction of radiation. Based on these investigations, we report herein the case of a patient with esophageal cancer with direct invasion to the trachea, in whom a complete response was achieved by the continuous administration of 5-FU, 600 mg/m2 per day, from days 1-5 combined with the daily administration of low-dose cisplatin, 10 mg/m2 per day before each fraction of radiation, given as 2Gy each time, throughout the entire treatment period of 3 weeks beginning on day 1. The benefits of our preoperative chemoradiation therapy included no severe side effects, down-staging and resectability of the tumor, as well as a pathological complete response, which could prolong the survival time. Our experience of this case prompts us to recommend the concurrent daily preoperative chemoradiation therapy for patients with locally advanced esophageal cancer.     

A novel zinc finger cDNA with a polymorphic pentanucleotide repeat (ATTTT)n maps on human chromosome 19p

PURPOSE: To evaluate the therapeutic effectiveness of a combined chemoradiotherapy program, followed by surgery in selected cases, in Stage III non-small cell lung cancer. METHODS AND MATERIALS: Between August 1988 and February 1990, 43 patients Staged IIIa-b (UICC 1987, 58% IIIb) have been treated with concomitant chemotherapy (cisplatin 15 mg/m2 and VP16 75 mg/m2, 5 days a week on week 1 and 5) and radiotherapy (40 Gy split course, 2 Gy/day on week 1, 2, 5, and 6), followed by attempted curative thoracotomy or more cycles of full dose chemotherapy with the same two drugs. RESULTS: Planned chemoradiotherapy has been given to 91% of patients; 13/43 patients have been operated, with 12 complete resections and three (7%) pathological complete responses. Toxicity was significant, with two postoperative deaths and two fatal radiation pneumonitis. Crude progression-free survival rate is 21% at 30 months, with nine patients (21%) alive and free from progression at follow-up times ranging from 31 to 49 months. Subset survival analysis showed a possibly greater therapeutic effect for non-squamous histology as compared to squamous carcinoma. CONCLUSION: These results are encouraging in a cohort of patients with quite advanced disease (58% Stage IIIb).     

Combination chemotherapy of continuous infusion 5-fluorouracil and daily low-dose cisplatin in advanced gastrointestinal and lung adenocarcinoma

Continuous intravenous infusion (c.v.i.) of 5-fluorouracil (5-FU) plus daily low-dose cisplatin (CDDP) was evaluated in 45 patients with advanced and recurrent unresected colorectal, lung, gastric and pancreatic adenocarcinoma. 5-FU was given at a dose of 320 mg/m2/day, c.v.i. for 4 weeks, and CDDP between 3.5 to 7 mg/m2/day, infused for one hour five times a week for 4 weeks. Patients received 1 to 3 cycles of treatment (average 1.5 cycle). Pancreatic cancer cases needed longer treatment periods (2.25 cycles). The response rate of colorectal cancer cases was 57.7% (15/26), pancreas cancer 40%, gastric cancer 62.5%, and lung cancer 66.7%. The overall response rate was 57.8%. No severe side effects occurred in any of these cases. These data indicate that this combination 5-FU + daily low-dose CDDP chemotherapy is effective in the treatment of advanced gastrointestinal and lung adenocarcinoma.     

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.     

Effect of gastrectomy on the pharmacokinetics of tegafur, uracil, and 5-fluorouracil after oral administration of a 1:4 tegafur and uracil combination

The effects of gastrectomy on the pharmacokinetics of UFT, a combined oral preparation of 1-(2-tetrahydrofuryl)-5-fluorouracil (tegafur) and uracil at a molar ratio of 1:4, were examined in 26 patients with macroscopic Stage I gastric cancer. In all, 200 mg UFT (in terms of tegafur) was given to 17 patients who underwent partial gastrectomy (9 cases of Billroth I reconstruction, 8 cases of Billroth II reconstruction) and to 9 patients who underwent total gastrectomy with modified Roux-en-Y reconstruction. Before the operation, the area under the curve (AUC) for tegafur, uracil, and 5-fluorouracil (5-FU) was 79.28 +/- 26.88, 4.41 +/- 1.78, and 0.51 +/- 0.20 micrograms h ml-1, respectively. Partial (Billroth I and II) and total gastrectomy did not alter the AUC of tegafur, and partial gastrectomy using the Billroth I and II methods decreased the AUCs of uracil and 5-FU during the first 2 weeks postoperation. However, plasma levels of uracil and 5-FU reverted to preoperative values at 3 months postsurgery. Our findings show that when UFT is prescribed for patients treated in the early postoperative period following partial gastrectomy for cancer, dose increases and the timing of administration should be given close attention.     

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.     

Effect of anordrin on the development of mouse preimplantation embryos in vitro

The aim of this study was to establish the feasibility, evaluate the response rate, and assess the impact on local control and survival in locally advanced (bulky nodal) squamous cell carcinoma of the head and neck (SCCHN) patients treated with neoadjuvant chemotherapy consisting of cisplatin followed by continuous infusion of vindesine and fluorouracil with intermittent i.v. folinic acid. Eligibility criteria included histologically proven SCCHN, previously untreated locally advanced stage III-IV with measurable or evaluable disease, no distant metastases, an Eastern Cooperative Oncology Group (ECOG) performance status of less than 2, patient age of at least 18 years, and adequate bone marrow, hepatic, and renal functions. The protocol consisted of three cycles (day 1, day 21, day 42) of Cisplatin (CDDP) 100 mg/m2/day i.v. on day 1 immediately followed by 4 days (96 h) of continuous infusion of vindesine 0.8 mg/m2/day and 5-fluorouracil (5-FU) 600-700 mg/m2/day with folinic acid 150 mg/m2 i.v. every 6 h x 16 doses before locoregional treatment with radiotherapy preceded by radical surgery when appropriate. Twenty-nine patients were enrolled in this study, and 28 were evaluable for activity; an objective response rate of 55% (four complete responses, 12 partial responses) was achieved. Leukopenia and mucositis were the most frequent and severe toxicities. The addition of vindesine did not improve the activity of the CDDP-FU-folinic acid combination, but this may be partly because of the particularly poor prognosis of the present patient population, with 75% of stage IV bulky nodal disease (N2c-N3).     

A prospective randomized evaluation of a compound of tegafur and uracil as an adjuvant chemotherapy for hepatocellular carcinoma treated with transcatheter arterial chemoembolization

A prospective randomized trial was conducted to evaluate the efficacy of long-term oral administration of low-dose tegafur combined with uracil as an adjuvant chemotherapy, following transcatheter arterial embolization (TAE) in 40 patients with hepatocellular carcinoma (HCC). Forty eligible patients were randomized into two groups: 20 with TAE plus UFT (a compound of tegafur 200 mg and uracil 448 mg per day) and 20 with TAE alone. A good necrosis rate or decrease in size of more than 70% of the original tumor mass was attained in 10 by TAE plus UFT arm and in 12 by TAE arm alone. As for the "responded" patients, there was no significant difference in the time from tumor response to tumor regrowth between the two groups. The appearance rate of ascites and/or encephalopathy in patients with chemotherapy was slightly higher than that in control patients. The median survival time was 22.7 months for TAE plus UFT arm and 28.2 months for TAE arm alone. There was no significant difference in the cumulative survival curves. In conclusion, these results indicated no substantial benefit for this chemotherapy regimen, as an adjuvant therapy for patients with HCC during repeated TAE.     

Hyperfractionated irradiation with or without concurrent chemotherapy for locally advanced head and neck cancer

BACKGROUND: Radiotherapy is often the primary treatment for advanced head and neck cancer, but the rates of locoregional recurrence are high and survival is poor. We investigated whether hyperfractionated irradiation plus concurrent chemotherapy (combined treatment) is superior to hyperfractionated irradiation alone. METHODS: Patients with advanced head and neck cancer who were treated only with hyperfractionated irradiation received 125 cGy twice daily, for a total of 7500 cGy. Patients in the combined-treatment group received 125 cGy twice daily, for a total of 7000 cGy, and five days of treatment with 12 mg of cisplatin per square meter of body-surface area per day and 600 mg of fluorouracil per square meter per day during weeks 1 and 6 of irradiation. Two cycles of cisplatin and fluorouracil were given to most patients after the completion of radiotherapy. RESULTS: Of 122 patients who underwent randomization, 116 were included in the analysis. Most patients in both treatment groups had unresectable disease. The median follow-up was 41 months (range, 19 to 86). At three years the rate of overall survival was 55 percent in the combined-therapy group and 34 percent in the hyperfractionation group (P=0.07). The relapse-free survival rate was higher in the combined-treatment group (61 percent vs. 41 percent, P=0.08). The rate of locoregional control of disease at three years was 70 percent in the combined-treatment group and 44 percent in the hyperfractionation group (P=0.01). Confluent mucositis developed in 77 percent and 75 percent of the two groups, respectively. Severe complications occurred in three patients in the hyperfractionation group and five patients in the combined-treatment group. CONCLUSIONS: Combined treatment for advanced head and neck cancer is more efficacious and not more toxic than hyperfractionated irradiation alone.     

Phase II trial of paclitaxel, ifosfamide, and cisplatin in patients with recurrent head and neck squamous cell carcinoma

PURPOSE: To assess the activity and toxicity profile of combined taxol (paclitaxel), ifosfamide, and platinum (cisplatin) (TIP) in patients with recurrent or metastatic squamous cell carcinoma (SCC) of the head and neck. PATIENTS AND METHODS: Recurrent or metastatic head and neck SCC patients received paclitaxel 175 mg/m2 in a 3-hour infusion on day 1; ifosfamide 1,000 mg/m2 in a 2-hour infusion on days 1 through 3; mesna 600 mg/m2 on days 1 through 3; and cisplatin 60 mg/m2 on day 1, repeated every 3 to 4 weeks. All were premedicated with dexamethasone, diphenhydramine, and cimetidine. Prophylactic hematopoietic growth factors were not permitted. RESULTS: Fifty-two patients were assessable for response and toxicity; 53 for survival (local-regional recurrence alone in 57% and distant metastasis with or without local-regional recurrence in 43%). Overall response rate was 58% (30 of 52) of patients; complete response rate was 17% (nine of 52) of patients, with six complete responses that continued for a median 15.7+ months. Median follow-up of all patients was 17.7 months. Median survival was 8.8 months (95% confidence interval [CI] 8.1 to 17.5 months). Toxicity was relatively well tolerated and caused no deaths. The most frequent moderate-to-severe toxicity (90% of patients) was transient grades 3 to 4 neutropenia; neutropenic fever occurred in 27%. Grade 3 peripheral neuropathy occurred in three patients, none had grade 4. Grade 3 mucositis occurred in only one patient, none had grade 4. CONCLUSION: TIP had major activity in this setting, with a 58% objective response rate, 17% complete response rate, durable complete responses (six of nine persisting), and relatively well-tolerated toxicity, with no toxic deaths. The activity of TIP, a novel taxol-cisplatin-based regimen, in recurrent or metastatic head and neck SCC should be confirmed in a phase III trial.     

Final report of a phase II study of chemotherapy with bleomycin, epirubicin, and cisplatin for locally advanced and metastatic/recurrent undifferentiated carcinoma of the nasopharyngeal type

PURPOSE: This article presents an assessment of the combination of bleomycin, epirubicin, and cisplatin as induction chemotherapy before radiotherapy in the treatment of undifferentiated carcinoma of the nasopharyngeal type in patients with recurrent/metastatic disease (group A), and in previously untreated patients with locoregionally advanced disease (UICC-AJCC 87, N2-3, M0) (group B) in terms of toxicity, antitumoral activity, and therapeutic efficacy. PATIENTS AND METHODS: From January 1987 to September 1990, 111 consecutive patients with histologically proven UCNT were treated with six cycles of intravenous cisplatin (100 mg/m2 day 1) epirubicin (80 mg/m2 day 1), and bleomycin (15 mg bolus day 1), followed by 16 mg/m2/day continuous infusion for 5 days, repeated every 21 days for three cycles. Three further cycles without bleomycin were given to 44 patients in group A. In group B (67 patients), only three cycles of the same protocol were given, with a slightly lower dose of epirubicin (70 mg/m2), followed by conventional radiotherapy (70 Gy/7 weeks). RESULTS: Of 44 patients entered in group A, 38 were evaluable for response. We observed 9 (20%) complete responses and 11 (25%) partial responses, for a 45% overall response rate. In 12 patients not previously given chemotherapy, there were 4 complete responses, compared to 5 complete responses in 32 patients previously treated with chemotherapy. Four patients are alive with no evidence of disease after 53+, 60+, 61+, and 72+ months. In group B the overall response rate to chemotherapy was 98% with 42 complete (62%) and 24 partial responses (36%). Three months after the end of radiotherapy, the overall complete response rate was 94% (63 patients). After a median follow-up time of 77 months (range, 53-94), the 4-year overall survival and disease-free survival rates for this group are 66% and 60%, respectively. The median disease-free survival has not been reached at 90 months. CONCLUSION: The results of the BEC combination trial are very encouraging in metastatic and recurrrent UCNT, with durable remissions in this poor-prognosis population. The results in patients with locally advanced disease have motivated prospective phase III testing of the neoadjuvant chemotherapy approach to evaluate its impact on locoregionally advanced disease (> or =N2MO UICC-AJCC 87).     

Phase I and pharmacokinetic study of oral UFT, a combination of the 5-fluorouracil prodrug tegafur and uracil

UFT is an oral preparation combining the 5-fluorouracil (FU) prodrug tegafur (FT) and uracil (U) in a 1:4 ratio, which is commercially available in Japan for the treatment of breast and gastrointestinal cancers. We sought to determine the tolerance of daily oral UFT and to relate this tolerance to the pharmacokinetics of FT and/or the derived FU, while exploring the possibility of circadian FU kinetics contributing to the results. A 28-day schedule followed by 2 weeks rest was began at the initial level of 300 mg/m2/day administered either at 8 a.m. or at 6 p.m. At the following level, 400 mg/m2/day patients were randomly assigned to a split-dose administration or to the above single, timed dose administration. Intolerance to single dosing was clearly demonstrated, and only the split dosing was advanced to 500 mg/m2/day. When this level proved too toxic, 400 mg/m2 was studied further on a 7 a.m., 3 p.m., and 11 p.m. (every 8 h) schedule. Pharmacology was determined on selected patients. In the single dose administration, areas under the curves of FU were higher following p.m. dosing, although substantial interpatient variation was present. Toxicities (diarrhea and neutropenia) were more severe in patients receiving the drug in single daily doses. We conclude that the kinetics of FT are saturable, with disproportionate increases in area under the curve (and toxicities) as dose levels are increased. With divided dosing, tolerance improves. UFT at a dose of 400 mg/m2/day administered as three divided doses (every 8 h) is suitable for Phase II studies, although toxicity requiring cessation of drug administration prior to completion of 28-day cycles will occur in some patients.     

Serum creatine kinase in fasciocutaneous and musculocutaneous flap surgery

BACKGROUND: Stage III and IV squamous cell cancers of the head and neck are often unresectable at presentation and are associated with poor disease-free and overall survival rates. A phase II study using concurrent cisplatin and radiotherapy in advanced head and neck cancer indicated impressive local-regional control and survival with organ preservation. METHODS: A multicentered phase II study was undertaken consisting of 1.8 Gy fraction radiotherapy for 2 weeks followed by 1.2 Gy BID hyperfractionation to 46.8 Gy. Continuous infusion cisplatin 20 mg/m2 was given on days 1 through 4 and 22 through 25. Biopsy of the primary tumor was done at this point, and patients with clinical and pathologic complete response continued with hyperfractionated radiotherapy to 75.6 Gy plus simultaneous carboplatin 25 mg/m2 BID for 12 consecutive days. Residual disease at 46.8 Gy required curative surgery. RESULTS: Seventy-four patients entered the study, and 73 completed their treatment. Twenty were stage III and 54 were stage IV. Fifty patients had involved regional lymph nodes. Treatment was well tolerated with only one grade IV hematologic toxicity. At 46.8 Gy, biopsy revealed a complete response in 75% of the primary sites and 47% of the nodes. Only 12 patients required resection of the primary lesion. At 4 years (median follow-up is 26 months), 29 patients have recurred. CONCLUSIONS: Accelerated hyperfractionated radiotherapy with concurrent chemotherapy in stage III and IV head and neck cancer yields excellent local-regional control with organ preservation. This protocol is intensive, and some patients have distant failures.     

Accelerated hyperfractionated radiation therapy and concurrent 5-fluorouracil/cisplatin chemotherapy for locoregional squamous cell carcinoma of the thoracic esophagus: a phase II study

PURPOSE: To improve the poor prognosis of patients with locoregional esophageal squamous cell cancer, we used concurrent accelerated hyperfractionated radiation therapy (ACC HFX RT) and chemotherapy (CHT). MATERIAL AND METHODS: Between January 1988 and June 1993, 28 patients were treated with ACC HFX RT with 1.5 Gy twice daily, to a total dose of 54 Gy concurrently with 5-fluorouracil (5-FU) (300 mg/m2, days 1-5) and cisplatin (CDDP) (10 mg/m2, days 1-5), both given during weeks 1 and 4 of the ACC HFX RT course. Following the ACC HFX RT/CHT, two additional courses of 5-FU (500 mg/m2, days 1-5) and CDDP (20 mg/m2, days 1-5) were both given during weeks 7 and 10. The median age and Eastern Cooperative Oncology Group performance status were 62 and 1, respectively. The American Joint Committee on Cancer (AJCC) stage was I in 12 patients, II in 10, and III in 6. RESULTS: The median survival time was 26 months, and the 5-year survival rate was 29%. The rates at 5 years for freedom from relapse, locoregional recurrence, and distant metastasis were 29%, 61%, and 45%, respectively. Univariate analysis revealed that performance status, stage, weight loss, tumor length, and tumor location influenced survival, while age and sex did not. The most frequent acute high-grade (3 or 4) toxicities were esophagitis and leukopenia, seen in 50% and 39% of patients, respectively. Late high-grade toxicity was infrequent. There were no treatment-related deaths. CONCLUSION: The results of this study compare favorably with those of previous studies, albeit of relatively high incidence of acute high-grade toxicity. Further studies are warranted to compare its efficacy with other approaches.     

Concurrent cisplatin, prolonged oral etoposide, and vincristine plus chest and brain irradiation for limited small cell lung cancer: a phase II study of the Southwest Oncology Group (SWOG-9229)

PURPOSE: The primary objectives of the study were to evaluate the efficacy and safety of prolonged oral (PO) etoposide as part of cisplatin-based chemotherapy plus concurrent chest/brain irradiation induction, followed by CAV consolidation, in the treatment of patients with limited-stage small cell lung cancer (SCLC-LD) within a cooperative group setting. METHODS AND MATERIALS: Fifty-six eligible patients with SCLC-LD received three 28-day cycles of cisplatin 50 mg/m2 i.v. (days 1, 8; 29, 36; and 57, 64), PO etoposide 50 mg/m2 (days 1-14, 29-42, and 57-70), and vincristine 2 mg i.v. (days 1, 29, and 57). Thoracic irradiation (TRT) was administered at 1.8 Gy in 25 daily fractions to a total dose of 45 Gy via an AP:PA arrangement, to begin concomitantly with induction chemotherapy. Prophylactic cranial irradiation (PCI) was started on day 15 of induction therapy. Fifteen daily fractions of 2.0 Gy were administered to the entire brain to a total dose of 30 Gy to finish at approximately the same time as TRT. Two 21-day cycles of consolidation cyclophosphamide 750 mg/m2 i.v., doxorubicin 50 mg/m2 i.v., and vincristine 2 mg i.v. (all on days 1 and 22), were given beginning on day 106 or week 16, from the start of induction therapy. RESULTS: Among 56 eligible patients, 93% had SWOG performance status 0-1. All had adequate organ function and had not received prior therapy. The overall confirmed response rate was 46%, including 16% complete responders and 30% partial responders. After a minimum follow-up duration of 17 months, the Kaplan-Meier median progression-free (PFS) and overall survival (OS) were 10 and 15 months, respectively. Two-year survival is 28%. Only 28 of 56 patients (50%) completed chemotherapy per protocol, while 52 of 56 patients (93%) completed radiation per protocol. Eleven patients (20%) discontinued secondary to toxicity and two patients died from treatment. The major toxicity was hematologic. The two deaths were secondary to infection. Of the nonhematologic toxicities, there were 10 cases of pulmonary fibrosis (including one Grade 3) and six cases of pneumonitis (including one Grade 3). CONCLUSION: Concomitant chemoradiation with oral etoposide as part of a platinum-based chemotherapy and TRT induction regimen is toxic. The CR rate is not better than our prior best group-wide experience. The progression-free and overall survival are similar to published trials utilizing short-course i.v. etoposide. As in chemotherapy for extensive-stage SCLC, there is no apparent advantage to prolonged exposure to etoposide, and toxicity resulted in an inferior therapeutic index compared to programs with shortened exposure.     

Concurrent radiotherapy and chemotherapy with protracted continuous infusion of 5-fluorouracil in inoperable esophageal squamous cell carcinoma

PURPOSE: The feasibility of a concurrent chemoradiotherapeutic protocol for patients with inoperable esophageal squamous cell carcinoma was tested. METHODS AND MATERIALS: Concurrent chemoradiotherapy using protracted low-dose continuous infusions of five-fluorouracil (5-FU; 250-300 mg/m2/24 h) and standard external beam irradiation was given to 28 patients with inoperable esophageal squamous cell carcinoma between November 1991 and June 1993. RESULTS: For 25 patients receiving a total dose of > or = 60 Gy and concurrent 5-FU infusion for more than 5 weeks, the complete response rate was 52%. Local progression-free rate in this chemoradiotherapy group was significantly higher than the historical controls treated by radiotherapy alone (p < 0.05). A multivariate analysis revealed the treatment scheme (concomitant chemoradiotherapy vs. radiotherapy alone) to be a significant factor in local control (p < 0.01). Swallowing pain (39%), anorexia (39%), and nausea (32%) were the most frequent early reactions. Serious late radiation complications have not been observed. CONCLUSION: The concurrent chemoradiotherapy using protracted low-dose continuous infusion of 5-FU and standard radiotherapy is an effective and safe method to obtain a local control in inoperable esophageal squamous cell carcinoma.     

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.     

Drug abuse in Japan

OBJECTIVE: Cis-platinum and 13-cis-retinoic acid have received much attention in the treatment of head and neck squamous cell cancer. Even though they have different mechanisms of action, little information is available on their interaction. This paper reviews experimental evidence for retinoic acid-cis-platinum synergy and presents toxicity data from patients with stage IV head and neck squamous cell cancer participating in a phase I trial combining 13-cis-retinoic acid and cis-platinum. METHODS: Patients were given 13-cis-retinoic acid orally daily for 7 days before and daily during high-dose (150 mg/m2 per week for 4 weeks) intraarterial cis-platinum treatment with concurrent radiation. Toxicity was scored with use of the cancer and leukemia group B scale. RESULTS: In the phase I clinical trial, 15 patients were treated to determine a maximum tolerated dosage for 13-cis-retinoic acid of 20 mg/day. Grade 4 hematologic toxicity was dose limiting in 3 of 8 patients treated with 40 mg/day and in 1 patient treated with 60 mg/day. There were no deaths caused by toxicity; 12 of the 15 patients received all four weekly doses and the remaining 3 received three doses. Of 10 patients with fully evaluable data, all achieved a complete response at the primary site and 9 had a complete response in the neck. One patient had persistent neck disease after chemoradiation, and this tumor was removed with neck dissection. CONCLUSIONS: 13-Cis-retinoic acid and cis-platinum are strongly synergistic against head and neck squamous cell cancer in vitro. Pretreatment with retinoic acid results in stronger synergy than concurrent drug exposure alone. Preliminary clinical experience with combined retinoic acid and cis-platinum in a design that parallels the in vitro study indicates that toxicity is acceptable with 13-cis-retinoic acid dosages of 20 mg/day in a high-dose-intensity intraarterial chemoradiation regimen.