The clinical rationale for S-phase radiosensitization in human tumors

Nonhypoxic cell radiosensitizers, principally the halogenated pyrimidines and hydroxyurea, have been studied in the laboratory and clinical setting for more than 30 years. Early clinical experience in the 1960s and 1970s with the thymidine analogs 5-bromodeoxyuridine (BUdR) and 5-iododeoxyuridine (IUdR) was disappointing because normal tissue toxicity eliminated any potential for therapeutic gain. Inadequate delivery systems for intravenous and intraarterial infusions also contributed to the decline of this strategy. More recently, laboratory investigations have revealed further information regarding the mechanism of IUdR/BUdR radiosensitization. This knowledge provided a rationale for the sequence and timing of drug and radiation exposure, which could be both effective and tolerable. Advancing technology also provided safer infusion devices, and a resurgence in clinical trials combining IUdR or BUdR and radiation resulted. Current laboratory studies are now providing data on tumor cell kinetics, which is being applied to ongoing clinical trials. Fluoropyrimidines, principally 5-fluorouracil (5-FU), were also used in early clinical trials and unlike IUdR/BUdR were found to have significant activity as single agents against a variety of tumor types. The clinical integration of 5-FU and radiation occurred more slowly, but recent trials have demonstrated a therapeutic gain. Improved rates of local control and survival with combined 5-FU and radiation versus radiation alone have now been demonstrated in patients with rectal, esophageal, and anal carcinomas. However, the mechanism of interaction between the fluoropyrimidines and radiation remains uncertain and continues to be investigated with the hope of improved clinical outcome. As the cellular pathways influenced by the halogenated pyrimidines have been defined, the potential for biochemical modulation of these agents has been recognized. Leucovorin, the most commonly applied modulator, has been shown to enhance the activity of 5-FU in patients with metastatic colorectal carcinoma. These studies serve as an example for current trials that use biochemical modulators of IUdR, BUdR, and 5-FU as radiosensitizers. Hydroxyurea, currently used in the treatment of chronic leukemia, has also been considered a radiosensitizer. As with IUdR/BUdR, the clinical trials have often been inconclusive and interest in this radiosensitizer has waned. A poor understanding of the mechanism of action and tumor cell/normal tissue kinetics may be responsible for the lack of overall success with this strategy. Current investigations of cell kinetics in humans and potential mechanisms of hydroxyurea action could provide information critical to future trials of hydroxyurea radiosensitization.     

A case report: multiple liver metastasis of gastric cancer responding to intraarterial infusion of MTX and 5-FU

In a 63-year-old male patient with gastric cancer having multiple liver metastases, the metastatic lesions responded well to postoperative staggered intraarterial infusion therapy with MTX and 5-FU. The intraarterial infusion therapy was administered once a week. A total of 5 courses of this therapy produced marked regression of liver metastases and remarkable necrosis. The effect was thus rated as PR. The patient is healthy and has been successfully rehabilitated. His dose is oral 5-FU (200 mg x 2).     

Primary chemoradiation therapy with fluorouracil and cisplatin for cancer of the anus: results in 35 consecutive patients

PURPOSE: This prospective phase II study was designed to test the activity and toxicity of a regimen of fluorouracil (5-FU) and cisplatin (CDDP) in combination with radiation therapy in the treatment of epidermoid cancer of the anal canal. PATIENTS AND METHODS: Thirty-five consecutive patients with untreated epidermoid cancer of the anal canal were candidates for chemoradiation therapy (CRT). Staging of cancer was as follows: T1, 26%; T2, 60%; T3, 14%; and N1, 2,3, 26%. No patient had distant metastases. The treatment protocol consisted of two to three cycles of chemotherapy starting on days 1 and 21 and concurrent radiotherapy at a daily dose of 1.8 Gy up to a total dose of 36 to 38 Gy in 4 weeks, delivered to the anal region, perineum, middle and lower pelvis, and inguinal and external iliac nodes. Radiotherapy was then delivered to the anoperineal region and metastatic inguinal nodes to a total dose of 18 to 24 Gy in 10 fractions. Chemotherapy consisted of 24-hour intravenous (IV) infusion of 5-FU 750 mg/m2 on days 1 to 4 and CDDP 100 mg/m2 by 60-minute IV infusion on day 1. RESULTS: All patients received two cycles of chemotherapy; the second was delayed in three patients because of leukopenia that was evident in 11 (31%). In eight patients, a third cycle was added. They all experienced nausea or vomiting; one patient showed signs of cardiotoxicity and one developed proctitis, dermatitis, and diarrhea (grade 3). Complete regression (CR) was assessed in 33 patients (94%); nine patients with metastatic lymph nodes also had CR. Two patients had a partial response (PR); both underwent abdominoperineal resection, which was not curative in one. Two patients (6%) had a local recurrence; in one, this was associated with hepatic metastases. One of these patients underwent surgery and is alive after about 4 years, while the other is undergoing chemotherapy. After a median follow-up duration of 37 months, 94% of patients are alive without evidence of disease and 86% are colostomy-free. CONCLUSION: This regimen is well tolerated; its toxicity does not exceed that observed with the combination of 5-FU and mitomycin (MMC). Compared with our previous experience based on the classic CRT (5-FU, MMC, and radiation), the objective response rate observed with this new combination was similar. However, the local recurrence rate, observed in patients treated with the new regimen, was lower (6% v 24%). According to more recent data from the literature, primary CRT is the elective indication in epidermoid cancer of the anus and replacement of MMC with CDDP seems an effective and logical evolution.     

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.     

Circadian chemotherapy in cancer patients

Continuous infusion of 5-FU at night was performed for four patients: three had liver metastasis (one with gastric cancer and two with rectal cancer) and one had local recurrence of rectal cancer. The chemotherapy schedule was 400 mg/m2/day 5-FU intraarterial or intravenous infusion from 6:00 p.m. to 6:00 a.m. for five days repeated every 3 weeks. There were one complete response, two partial responses and one with no change. It is expected that the chemotherapy of 5-FU at night will result in a high efficacy and lower toxicity.     

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.     

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.     

Evaluation of intra-arterial infusion chemotherapy for advanced gastric cancer

We evaluated the therapeutic efficacy of intraarterial infusion chemotherapy in advanced gastric cancer, its side effect and patient prognosis, in comparison with systemic infusion. Of 125 cases of advanced gastric cancer, 41 cases received intraarterial chemotherapy (A group) and the rest were given systemic infusion (S group). Protocols of chemotherapy were 5-FU + MTX in 49 cases, 5-FU + cisplatin in 62, and 5-FU + MMC in 14. Location of the disease was the peritoneum in 69 cases, nodes in 59, liver in 38, and other sites, 33. The response rate of A group was significantly higher than that of S group, at 31% and 13% respectively. Although 41% of cases showed side effects (> or = grade 2), there was no significant difference between the 2 groups. The median survival period and 1-year survival rate were 8.4 months and 35%, respectively, and there was no significant difference between the 2 groups. In cases with liver metastasis, the prognosis of A group was better than that of S group. The results suggest that intra-arterial infusion chemotherapy is an effective treatment for liver metastasis from gastric cancer.     

Phase I and pharmacologic study of intermittent twice-daily oral therapy with capecitabine in patients with advanced and/or metastatic cancer

PURPOSE: Capecitabine is an orally administered fluoropyrimidine carbamate selectively activated to fluorouracil (5-FU) in tumors. It passes through the intestinal mucosal membrane intact and is subsequently activated by a cascade of three enzymes that results in the preferential release of 5-FU at the tumor site. PATIENTS AND METHODS: In this phase I study, capecitabine was administered twice daily as outpatient therapy, each cycle administered for 2 weeks followed by 1 week of rest. Thirty-four patients with solid tumors, all of whom except three patients were pretreated, were treated at dose levels from 502 to 3,514 mg/m2 daily. RESULTS: The median treatment duration was four cycles (85 days; range, 14 to 833+ days). Two patients continue on treatment at 686 and 833+ days. Capecitabine 3,000 mg/m2 daily was not tolerable, with dose-limiting toxicities of diarrhea with hypotension, abdominal pain, and leukopenia. Palmar-plantar erythrodysesthesia (PPE) became evident at higher dose levels after prolonged treatment. Evidence of objective tumor response was reported in four patients at 2,510 mg/m2 daily and greater (one complete response [CR] and three partial responses [PRs]) with subjective minor tumor responses in a further seven patients. Pharmacokinetic studies showed rapid gastrointestinal absorption of capecitabine, followed by extensive conversion into 5'-deoxy-5-fluorouridine (5'-DFUR), with only low systemic 5-FU levels. CONCLUSION: Capecitabine is a tolerable oral outpatient therapy that shows promising clinical activity in a variety of cancers. The recommended phase II dose is 2,510 mg/m2 daily administered by this intermittent schedule.     

A case of left main bronchus obstruction due to recurrent esophageal cancer successfully treated by Nd-YAG laser followed by radiotherapy, low-dose CDDP and continuous infusion of 5-FU

A 63-year-old female patient with obstruction of left main bronchus due to recurrent esophageal cancer was treated by emergency Nd-YAG laser therapy under bronchoscopy. Severe dyspnea subsided dramatically and she was the given radiotherapy with a total dose of 50 Gy (2 Gy/f and 25 f/5 wks). Concurrent chemotherapy was performed at the 3rd week of radiation therapy. In this chemotherapy of CDDP plus 5-FU, CDDP (10 mg/day) was given for 5 days by intravenous and 5-FU (500 mg/day) for 5 days by continuous infusion the same week. By this treatment, a partial response (PR) was obtained, and the patient returned to normal life. But after 4 months, she had a recurrent lesion at the same place, and underwent only palliative laser therapy. Nd-YAG laser therapy for obstructive lesion of trachea due to recurrent cancer is the most useful one, but some subsequent treatment is required.     

Treatment of a habitual smoker using nicotine gum: a case report

39 untreated patients with local cancer of the bladder without distal metastases were included in the trial to assess efficacy of combined drug plus radiation treatment, its toxicity and chances to preserve the bladder. The examination comprised tumor biopsy, ultrasonography, computed tomography, excretory urography and routine laboratory tests. The patients received one or two courses of intraarterial chemotherapy, radiation (50 Gy) and two doses of cysplatinum in a dose 70 mg/m2 before and after radiation. A complete response was achieved in 66.6%, partial in 12.8%, stabilization in 10.3% and progression in 10.3% of patients. One-year survival was reported in 89.7%, recurrence-free survival with functioning bladder being 66.7%. Side effects were mild and did not demand the treatment discontinuation.     

Anticancer activity and toxicity of S-1, an oral combination of tegafur and two biochemical modulators, compared with continuous i.v. infusion of 5-fluorouracil

S-1 is an oral combined form of 1 M tegafur [a prodrug of 5-fluorouracil (5-FU)], 0.4 M 5-chloro-2,4-dihydroxypyridine (a reversible inhibitor of dihydropyrimidine dehydrogenase) and 1 M potassium oxonate (an inhibitor of orotate phosphoribosyltransferase). S-1 has been shown to exert a potent antitumor effect with low gastrointestinal toxicity in experimental tumor models. We have therefore compared the antitumor effect of oral S-1 with that of continuous infusion of 5-FU in rats bearing transplants of human and murine tumors. Almost complete inhibition of the tumor growth was obtained on 7 day schedules in Yoshida sarcoma-bearing rats by consecutive administration of 30 mg/kg/day of oral S-1 and 40 mg/kg/day infusion of 5-FU. However, a significant difference between the incidence of toxicities of S-1 and 5-FU, including body weight loss and diarrhea, was noted. The rats given the 5-FU infusion had marked weight loss and severe diarrhea, while those given oral S-1 had neither. Although about 50% inhibition of the tumor growth was attained with 15 mg/kg/day of oral S-1 and 30 mg/kg/day infusion of 5-FU in nude rats with xenografted human colon cancer (KM12C), the rate of body weight loss in the 5-FU-treated group was distinctly higher than in the S-1-treated group. The ratio of the 5-fluoronucleotide concentrations in gastrointestinal tissue to that in the tumor was lower in the S-1-treated rats than in the 5-FU-treated rats. In conclusion, the results suggest that oral S-1 might be more effective in the treatment of cancer patients than continuous infusion of 5-FU, from the standpoint of antitumor potency and toxicity.     

Mixed mesodermal tumor of the ovary. Description of a case with a small primary neoplastic mass. Anatomo-clinical and histogenetic considerations]

Forty-one patients with locally advanced hypopharyngeal carcinomas were followed for at least 3 years (median, 60 months) after simultaneous radiochemotherapy. Conventionally fractionated radiotherapy was administered as 5 x 2 Gy/week to a total dose of 30 Gy within 3 weeks. From the fourth week an accelerated hyperfractionated schedule was used as 2 x 1.4 Gy/day five days weekly given exclusively to the first order target volume of macroscopic tumor (adding up to a total dose of 72 Gy in six weeks). The second and third order target volumes received conventional fractionation only to 60 Gy and 50 Gy, respectively. The moderate acceleration of the concomitant boost scheme in the second half was counterbalanced during the first week by the introduction of a 5-fluorouracil bolus of 350 mg/M2 with 200 mg/M2 folinic acid and a subsequent continuous infusion using the same dose each 24 h for 5 days. Additionally, a Mitomycin-C bolus of 10 mg/M2 was infused at the fifth day and on the first day of the sixth week. Six weeks after treatment the patients were restaged. In cases with residual carcinoma salvage surgery was performed (11 patients). Late effects of therapy were analyzed according to the Lent-Soma index and life quality according to the European Organisation for Research and Treatment of Cancer-Module. Late effects of treatment were tolerable and were controlled locally. The 3-year-survival rate was 39%, with a local-regional recurrence-free control rate of 71%. Fifty-two percent of all cases of death were caused by distant metastases, secondary carcinomas or other diseases not related to tumor recurrence. The poor prognosis of hypopharyngeal carcinomas despite acceptable local tumor control may be due to specific biological factors present in affected patients.     

A case of stage IV (N4) esophageal cancer successfully treated with concurrent chemoradiotherapy

A 71-year-old man with inoperable intrathoracic esophageal cancer was treated by concurrent chemoradiation. A dose of 48 Gy (neck) and 60.6 Gy (mediastinum) and four courses of 5-FU (500 mg/day)-CDDP (50 mg/week) were delivered. The esophageal tumor and metastatic lymph nodes of the neck showed a complete response (CR) to the treatment, whereas paraaortic lymph nodes evidenced no change (NC). The patient is doing well without symptoms at 13 months after treatment. The chemoradiotherapy produced effective improvement and quality of life in this patient.     

In vitro percutaneous penetration through hairless rat skin: influence of temperature, vehicle and penetration enhancers

From February 1995 through October 1996, 25 patients with metastatic colorectal cancer showing a clinical resistance to 5-fluorouracil (5-FU) entered this study. Thirteen received oxaliplatin alone and 12 received it in combination with 5-FU. Oxaliplatin was administered at 130 mg/m2 over a 2-hour infusion every 3 weeks, alone or added either to 5-FU as a continuous infusion at 200 mg/m2 to 300 mg/m2 (six patients) or to a 5-FU bolus, 375 mg/m2, plus leucovorin, 100 mg/m2, daily for 5 days every 3 weeks (6 patients). Eighty-six of 98 administered cycles were evaluable for toxicity (47 for oxaliplatin plus 5-FU and 39 for oxaliplatin alone). Hematologic toxicity was mild, occurring as grade 2 leukopenia in 23% of the cycles of 5-FU and oxaliplatin and in 5% of the cycles of oxaliplatin alone. The most common toxicity was neurologic (grade 1 to 2 in 60%-6% of the cycles of the combination, respectively, and 68%-10% of oxaliplatin given alone) as hand-foot paresthesia or hypersensitivity to cold. No grade 4 toxicity was reported and only three patients in the 5-FU group developed grade 3 diarrhea. Grade 2 nausea and vomiting occurred in 33% of the cycles when both drugs were given and in 15% when oxaliplatin was administered alone. The combination of oxaliplatin and 5-FU induced four partial remissions (33%; 95% confidence interval, 6%-60%), whereas eight patients of the whole group had stable disease. No response occurred when oxaliplatin was administered as a single agent. The results of this study confirm the antitumor activity of oxaliplatin when added to 5-FU in patients who have metastatic colorectal cancer previously refractory to 5-FU. The possible therapeutic synergy with 5-FU was not accompanied by increased toxicity.     

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.     

America: where kids are getting killed

Two cases of liver metastasis from colon cancer were treated by percutaneous ethanol (PEI) and acetic acid (PAI) injection for the recurrent lesion after surgery. Case 1 was a 60-year-old female who received sigmoidectomy with partial hepatectomy, and intraarterial 5-FU infusion was done after surgery. One year later, recurrence of liver tumor was detected, and PEI and PAI were performed for the metastatic lesions of the liver. Tumor regression and histopathological examination revealed coagulative necrosis. The patient died of lung metastasis 2 years and 10 months after treatment. Case 2 was a 58-year-old-male with ascending colon cancer and liver metastasis, who received surgery, and chemotherapy with intraarterial 5-FU infusion was continued. Four months later, recurrence of liver metastasis with elevation of serum CEA was noted. The patient received PEI three times and CEA decreased. Re-operation of hepatectomy revealed complete necrosis at the site of PEI. The patient has been alive for 1 year and 6 months with a new recurrence in the liver and is receiving repeated PEI therapy. PEI and PAI seem to be useful for the treatment of unresectable liver metastasis.     

Simultaneous radiochemotherapy versus radiotherapy alone in advanced head and neck cancer: a randomized multicenter study

PURPOSE: A prospective randomized multicenter trial was performed to evaluate the contribution of simultaneously administered chemotherapy (CT) and radiotherapy (RT) in previously untreated patients with unresectable stage III/IV head and neck cancer. PATIENTS AND METHODS: Patients with locoregionally advanced head and neck cancer were treated either with RT alone (arm A) or simultaneous RT plus CT (RCT; arm B). RT was identical in both arms and administered in three courses with 13 fractions of 1.8 Gy each twice daily. During one course, from day 3 to 11, 23.4 Gy was delivered. In arm B, cisplatin (CDDP) 60 mg/m2, fluorouracil (5-FU) 350 mg/m2 by intravenous (i.v.) bolus, and leucovorin (LV) 50 mg/m2 by i.v. bolus were given on day 2, and 5-FU 350 mg/m2/24 hour by continuous infusion and LV 100 mg/m2/24 hours by continuous infusion were given from day 2 to 5. Treatment was repeated on days 22 and 44; a total RT dose of 70.2 Gy was administered. Treatment breaks were scheduled from days 12 to 21 and days 34 to 43. RESULTS: From 1989 to 1993, 298 patients were enrolled and 270 patients were assessable. Acute mucositis grade 3 or 4 was more frequent in arm B (38%) than in arm A (16%) (P < .001). Total treatment time was significantly longer in arm B than in arm A (P < .001) due to prolonged breaks. According to hematologic toxicity, scheduled drug doses were given in 74% of patients for the second course and 46% for the third course. The 3-year overall survival rate was 24% in arm A and 48% in arm B (P < .0003). The 3-year locoregional control rate was 17% in arm A and 36% in arm B (P < .004). Both arms showed similar distant failure patterns (arm A, 13 of 140; arm B, 12 of 130). Serious late side effects were not significantly different between treatment arms (arm A, 6.4%; arm B, 10%; not significant). CONCLUSION: Concomitant CT offered improved disease control and survival in advanced head and neck cancer patients. Due to increased acute toxicity, more supportive care is demanded when CT is given simultaneously. Increased total treatment time does not exert a negative impact on outcome in this combined modality regimen.     

Agreement between face-to-face and telephone-administered mood ratings in patients with rapid cycling bipolar disorder

BACKGROUND AND PURPOSE: Clinical trials have demonstrated that high dose radiation therapy and daily cisplatin (CDDP) could increase local control and survival in carcinoma from various sites. The present phase I-II study has combined high dose radiation therapy and daily CDDP at escalating dosages. METHODS: From August 1994 to December 1995, 23 patients with non-resectable carcinoma of the pancreas were enrolled in a phase I-II multicentric, pilot study to test the toxicity and the effectiveness of high dose radiotherapy and daily cisplatin (CDDP) at escalating dosages. A dose of 6 mg/sqm/day of CDDP was selected for the phase II step since no grade IV toxicity occurred in any patient in the phase I step. RESULTS: Toxicity was considered fairly acceptable. At the time of analysis, the 23 patients who entered the study had clear evidence of evolutive disease either locally or distantly in the liver. It is suggested that high dose radiotherapy (60 Gy continuously) and daily CDDP have little effect on local control of the tumor and survival, and only a moderate effect on pain. CONCLUSIONS: In unresectable, apparently non-metastatic cancers of the pancreas, there is an urgent need for new agents or new combinations of agents to be tested.     

The relationship between AIDS dementia complex and the presence of macrophage tropic and non-syncytium inducing isolates of human immunodeficiency virus type 1 in the cerebrospinal fluid

CPT-11 is a camptothecin derivative with a broad spectrum of antitumor activity, both in vitro and in vivo. Like camptothecin, CPT-11 is a selective DNA topoisomerase I inhibitor. Phase I trials were conducted in Europe to determine the dose and schedule for phase II trials. These phase I trials assessed the toxicity of CPT-11 in 235 patients and tested three administration schedules: a single infusion once every 3 weeks; a weekly infusion for 3 out of 4 weeks; and a daily infusion for 3 consecutive days every 3 weeks. The maximum tolerated dose (MTD) was 115 mg/m2 in the daily schedule and 145 mg/m2 in the weekly schedule. When the drug was administered once every 3 weeks, diarrhea became the dose-limiting toxicity at doses above 350 mg/m2. This schedule offered the highest dose intensity and the best tolerability profile, and was the most convenient for outpatient treatment. Finally, using this schedule, concomitant administration of high-dose loperamide allowed the dose of CPT-11 to be increased to 750 mg/m2. An ongoing phase I trial is investigating the combination of CPT-11 and 5-fluorouracil (5-FU) in various solid tumors. Although the MTD has not yet been reached, preliminary results show no pharmacokinetic interaction between the two drugs, contrary to a previous Japanese study. Based on the results of the three phase I trials, CPT-11 350 mg/m2 as an intravenous infusion over 30 minutes once every 3 weeks was recommended for phase II trials, which started in Europe in 1992. To date, CPT-11 has shown remarkable efficacy in colorectal cancer, even in patients resistant to 5-FU. Interesting results have also been obtained in pancreatic, cervical and lung cancers. Future trials will explore the place of CPT-11 in combination with other cytotoxic agents or radiotherapy.