Treatment of persistent glaucoma secondary to periocular corticosteroids

PURPOSE: To describe two patients with uveitis who developed increased intraocular pressure that was unresponsive to maximum medical therapy eight and 13 months after periocular injection of triamcinolone acetonide. METHODS: Excised periocular tissue was analyzed for corticosteroid activity by gas chromatography and mass spectrometry. RESULTS: Excision of the periocular tissue, which contained visible triamcinolone acetonide, resulted in a normal intraocular pressure within 14 days in both patients. Analysis of the excised tissue disclosed residual corticosteroid in one of the two patients. CONCLUSION: Removal of periocular tissue containing injected corticosteroids may facilitate the management of patients developing increased intraocular pressure unresponsive to maximum medical therapy.     

Corticosteroid responsive tenosynovitis is a common pathway for limited joint mobility in the diabetic hand

OBJECTIVE: To test the hypothesis that diabetic tenosynovitis participates in the contractures of the syndrome of limited joint mobility (SLJM). METHODS: Adults with diabetes mellitus were referred for the evaluation of diabetic hand conditions. Patients with SLJM or diabetic trigger finger were studied after Dupuytren's contracture, hand neuropathy, carpal tunnel syndrome, and arthritis were excluded. A time series design was employed in which patients were observed for 3 mo to obtain a baseline, then the planar flexor tendon sheaths were injected with 10 mg of methylprednisolone acetate or 10 mg triamcinolone acetonide and were reassessed at 1, 3, and 12 mo. RESULTS: Response rates, defined by complete resolution of digital contractures and triggering after corticosteroid injection, were 94% (31/33), 76% 28/33), and 61% (17/29) at 1, 3, and 12 mo, respectively, which were all significantly different from preinjection (p < 0.001). Individual response rates for SLJM and trigger finger were similar. No appreciable differences between methylprednisolone acetate and triamcinolone acetonide were observed, although there was a trend for earlier recurrence with methylprednisolone. CONCLUSION: Corticosteroid injection is a safe and effective therapy that should be considered in patients with SLJM or diabetic trigger finger. The excellent response to injection indicates that diabetic tenosynovitis is a common pathway in diabetic hand conditions.     

In situ detection of AE2 anion-exchanger mRNA in the human liver

The aim of this study was to examine the effect of long-term treatment with glucocorticoids on the uterine response to oestradiol. Ovariectomized rats were treated with crystal triamcinolone acetonide (0.1 mg/100 g, i.m.) or saline (0.1 ml/100 g i.m.) for 29 days. Over this period five injections were administered, one per week. On the second day after the last triamcinolone injection, rats were treated with a single injection of oestradiol dipropionate (5 micrograms/100 g, s.c.) or vehicle (olive oil, 0.1 ml/100 g, s.c.). The effects of oestradiol in the uterus were determined by measuring mitotic index, bromodeoxyuridine (BrdU)-labelling index (BrdU was injected 2 h before the rats were killed; 2 mg/100 g, i.p.), and proliferating cell nuclear antigen (PCNA)-labelling index 24, 36 and 48 h after the injection of oestradiol or vehicle. Long-term treatment with glucocorticoids resulted in dissimilar changes in oestradiol-induced proliferation in epithelial and connective-tissue (stroma) components of the uterus. In luminal and glandular epithelia, there was an initial reduction in proliferation at 24 h, followed by an increase at 36 h and a further reduction at 48 h after the oestradiol injection. In stromal cells of the endometrium, triamcinolone treatment caused a large constant increase in oestradiol-induced proliferation throughout the experiment. The glucocorticoid treatment had no effect on the parameters without oestradiol administration.     

Intramuscular high-dose triamcinolone acetonide in the treatment of severe chronic asthma

We describe our experience with administering intramuscular triamcinolone acetonide to 22 steroid-dependent patients with asthma. These patients represent the minority of those with asthma whose disease is characterized by frequent emergency department visits, hospital admissions, and long-term dependency on oral corticosteroid therapy. The participants were randomly assigned to 2 treatment groups, one group receiving 120 mg of intramuscular triamcinolone acetonide, the second receiving 360 mg as a series of three 120-mg daily doses. We determined relative efficacy by comparing peak expiratory flow rates and incidents of emergency department visits, hospital admissions, and ventilatory failure of the study and during the 12 months before enrollment. Peak expiratory flow rates improved significantly in both groups. The mean (+/- standard deviation [SD]) monthly percentage of predicted peak expiratory flow on the study was 88.6 +/- 3.7% and 91.2 +/- 3.9% compared with 63 +/- 15.1% and 64 +/- 14.5% at entry in patients receiving 120 and 360 mg, respectively (P < 0.02). Patients receiving 120 mg required 8 hospital stays and 8 emergency department visits compared with 27 hospital stays and 72 emergency department visits in the previous year (P < 0.05). Patients receiving 360 mg required 5 hospital stays and 5 emergency department visits compared with 33 hospital stays and 34 emergency department visits in the previous year (P < 0.05). The average monthly interval (+/- SD) between exacerbations was 2.7 +/- 2.3 and 7.8 +/- 3.5 for patients receiving 120 mg and 360 mg, respectively. A total of 25 intubations was required in the previous year and only 1 during the study. The incidence of cushingoid facies, weight gain, and hypertension was reduced in both groups (P < 0.05). Total steroid use was reduced in both groups (P < 0.02). A dose of 360 mg produced a longer exacerbation-free period than 120 mg (P < 0.02).     

The role of viscosupplementation with hylan G-F 20 (Synvisc) in the treatment of osteoarthritis of the knee: a Canadian multicenter trial comparing hylan G-F 20 alone, hylan G-F 20 with non-steroidal anti-inflammatory drugs (NSAIDs) and NSAIDs alone

To determine the safety and efficacy of viscosupplementation with hylan G-F 20, a cross-linked hyaluronan preparation, used either alone or in combination with continuous non-steroidal anti-inflammatory drug (NSAID) therapy, a randomized, controlled, multicenter clinical trial, assessed by a blinded assessor, was conducted in 102 patients with osteoarthritis (OA) of the knee. All patients were on continuous NSAID therapy for at least 30 days prior to entering the study. Patients were randomized into three parallel groups: (1) NSAID continuation plus three control arthrocenteses at weekly intervals; (2) NSAID discontinuation but with three weekly intra-articular injections of hylan G-F 20; and (3) NSAID continuation plus three injections, one every week, intra-articular injections of hylan G-F 20. Outcome measures of pain and joint function were evaluated by both the patients and an evaluator at baseline and weeks 1, 2, 3, 7 and 12, with a follow-up telephone evaluation at 26 weeks. At 12 weeks all groups showed statistically significant improvements from baseline, but did not differ from each other. A statistical test for the equivalence, the q-statistic, demonstrated that viscosupplementation with hylan G-F 20 was at least as good or better than continuous NSAID therapy for all outcome measurements except activity restriction. At 26 weeks both groups receiving hylan G-F 20 were significantly better than the group receiving NSAIDs alone. A transient local reaction was observed in three patients after hylan G-F 20 injection; only one patient withdrew from the study as a result and all recovered without any sequela. Hylan G-F 20 is a safe and effective treatment for OA of the knee and can be used either as a replacement for or an adjunct to NSAID therapy.     

Weight loss in the clinical setting: applications for cardiac rehabilitation

A 57-year-old man developed oligoarthritis of the right sacroiliac joint, knee and elbow in the wake of Clostridium difficile pseudomembranous colitis. He was HLA B27-positive and had a history of Reiter's syndrome. His joint manifestations resolved after a course of nonsteroidal antiinflammatory drug therapy and injection of the right knee with triamcinolone acetonide. Clostridium difficile should be recognized as a rare cause of reactive arthritis.     

Current perspectives on pyridoxine-dependent seizures

An advanced gastric cancer patient with T3N1M0 successfully underwent a curatively total gastrectomy combined with distal pancreatectomy and lymphnode dissection following ELF-P combined chemotherapy. The patient received two courses of etoposide (75 mg/m2, Day 1-5, i.v.), leucovorin (30 mg/body, Day 2-5, i.v.), 5-FU (500 mg/m2, Day 2-5, i.v.) and CDDP (60 mg/m2, Day 1, i.v.). A partial response for the primary lesion and lymphnode metastasis was obtained, and a successful curative resection of the stomach was performed. No drug adverse responses occurred. The effect of ELF-P chemotherapy was confirmed with grade 1b by histopathological examinations. Neoadjuvant chemotherapy with ELF-P may be useful as an inductive approach for advanced gastric cancer.     

Effects of 6alpha-methylprednisolone acetate on an equine osteochondral fragment exercise model

OBJECTIVE: To determine effects of intra-articularly administered 6alpha-methylprednisolone acetate (MPA) in exercised horses with carpal osteochondral fragmentation. ANIMALS: 18 horses: 3 groups of 6 each. PROCEDURE: An osteochondral (chip) fragment was created in 1 randomly chosen middle carpal joint of each horse. Polyionic fluid (PF) was injected into both middle carpal joints of horses in the control group. In horses of the MPA-control group, MPA was injected into the middle carpal joint without an osteochondral fragment; a similar volume of PF was injected into the contralateral middle carpal joint. In the MPA-treated group of horses, 100 mg of MPA was injected into the middle carpal joint containing the osteochondral fragment; a similar volume of PF was injected into the contralateral joint. Injections were administered on postsurgical days 14 and 28, and horses were exercised on a high-speed treadmill for 8 weeks, starting on postsurgical day 15. RESULTS: Clinical improvement in degree of lameness was not associated with MPA administration. Joints that contained an osteochondral fragment and were treated with MPA had lower prostaglandin E2 concentration in synovial fluid, and lower scores for intimal hyperplasia and vascularity in synovial membrane, compared with PF-treated joints. However, articular cartilage erosion and morphologic lesions suggested possible deleterious effect of intra-articular MPA administration. CONCLUSIONS: Some beneficial effects of MPA administration on synovial fluid and synovial membrane were identified; however, the deleterious findings contrast with those associated with triamcinolone acetonide used in a similar model, but agree with other results of MPA administration in normal and abnormal joints.     

Intrasynovial injection of steroids uses and abuses

Intra-articular injection of steroids is a valuable method of treatment, but selection of the appropriate clinical setting is required to obtain maximal benefits and to minimize the complications. All intra-articular injections must be performed under strict aseptic technique. The rheumatoid patient with one or two joints that resist systemic therapy and the patient with an occasional osteoarthritic joint with an acute inflammation are amenable to this treatment. The patient who has acute attacks of tendinitis, pseudogout, or bursitis will obtain significant benefits. Selected patients with traumatic and acute gouty arthritis also may benefit. Repetitive injections appear to be contra-indicated as they may create an environment conducive to joint destruction.     

Development of problem-solving abilities in the neonatal Peking duck.

294 Peking ducklings, aged 1–24 days posthatch, were tested in 3 experiments involving 3 different problem-solving situations: a delayed response task, spatial habit reversal learning, and a detour problem. In the delayed response task, the length of the delay did not improve significantly with increasing age, averaging 1.6 sec on Day 1 and 2.8 sec on Day 14. In the habit reversal learning, Ss were tested longitudinally beginning on Days 1, 2, 3, and 4. In each group, errors decreased rapidly and progressively with successive reversals, with this steady improvement resembling that found in adult birds and mammals. In the detour problem, groups of Ss were tested longitudinally, beginning on Days 1–6. In groups started at each age, learning was rapid, with criterion usually met within the 1st 1 or 2 days of testing. Even when testing began on Day 1, the Ss typically solved the problem on the 1st or 2nd day of testing, requiring a mean of 10.78 trials to criterion. Results suggest that the neonatal Peking duckling is well equipped to deal with its environment and is capable of a high level of adaptive modification in response to externally imposed stimulus contingencies. (24 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

First-line treatment of advanced nonsmall cell lung carcinoma with docetaxel and vinorelbine

BACKGROUND: Docetaxel and vinorelbine are active agents in the treatment of nonsmall cell lung carcinoma (NSCLC). The efficacy and toxicity of this combination was evaluated in a Phase II study in patients with advanced NSCLC. METHODS: Forty-six chemotherapy-naive patients (44 men and 2 women with a median age of 64 years) with NSCLC (11 with Stage IIIB and 35 with Stage IV disease) were entered into the study; the World Health Organization (WHO) performance status was 0, 1, and 2 in 32, 11, and 3 patients, respectively. Patients received vinorelbine (25 mg/m2) on Day 1 and docetaxel (100 mg/m2) on Day 2 in cycles repeated every 3 weeks. Granulocyte-colony stimulating factor was given to all patients from Day 3 to Day 10. RESULTS: One hundred and seventy-seven courses of chemotherapy were administered. Adverse events included WHO Grade 4 neutropenia (15 patients), Grade 3/4 thrombocytopenia (3 patients), Grade 3 anemia (2 patients), Grade 2 and 3 neurotoxicity (7 patients and 1 patient, respectively), and Grade 3 fatigue (2 patients). Twenty patients (43%) required hospitalization: 11 (24%) for neutropenic fever (2 deaths from sepsis), and 9 (20%) for nonneutropenic pulmonary infections (2 deaths from cardiopulmonary insufficiency). The median overall survival was 5 months and the 1-year survival was 24%. Four complete responses (9.8%) and 11 partial responses (26.8%) (overall response rate of 36.6%; 95% confidence interval, 21.8-51.3%) were documented in 41 evaluable patients (intent-to-treat: 32.6%). Stable and progressive disease occurred in 13 patients each (31.7%). The median duration of response was 5 months and the median time to progression was 3 months (6 months for the responders). CONCLUSIONS: This schedule of docetaxel and vinorelbine combination is effective but its relatively high incidence of complicated neutropenia precludes its general use in patients with advanced NSCLC.     

Mitomycin C, vinblastine, and carboplatin regimen in patients with nonsmall cell lung cancer. A phase II trial

BACKGROUND: The mitomycin C, vinblastine, and cisplatin (MVP) combination is one of the most frequently used in the palliative setting, but it produces considerable toxicity. Carboplatin and cisplatin have different patterns of toxicity. The goal of this study was to evaluate a combination similar to MVP, using carboplatin instead of cisplatin to render it more feasible in an outpatient setting. METHODS: Inclusion criteria for this study included: inoperable patients or patients relapsing after previous surgery, with nonsmall cell lung carcinoma (NSCLC), a performance status (PS) > 50%, and no previous chemotherapy. The chemotherapy regimen included carboplatin, 300 mg/m2 on Day 1; mitomycin, 8 mg/m2 on Day 1; and vinblastine, 4 mg/m2 on Days 1, 8, and 15 (on Day 15 vinblastine was delivered only in the first cycle) (MVC) every 3 weeks for at least 3 cycles. RESULTS: From August 1991 until August 1994, 70 patients entered the trial. All were evaluable for toxicity and response. The median age was 62 years (range, 40-73 years). The male/female ratio was 60:10 (86%:14%); the ratio of Stage III to Stage IV disease was 26:44 (37%:63%); and the ratio of PS > 70 to < or = 70 was 49:21. A total of 296 cycles (median, 4 [range, 1-6 cycles] per patient) were delivered, 280 of 296 (95%) in an outpatient setting with only 4 patients requiring hospitalization for treatment delivery. Overall response rate (RR) was 38.6% (95% confidence interval [CI], 27-51%) (1 complete response, 1.5%; 26 partial responses, 37.1%). Median duration of response was 9.8 months (range, 2-27 months). In Stage III patients the RR was 42% and in Stage IV patients it was 34%. Overall median survival was 9.5 months (95% CI, 6.8-15.3 months). Survival at 1 year was 39% (standard error [SE] 3.6%) and was 11% at 2 years (SE 3.6%). In Stage III patients median survival was 13 months and the 1-year survival rate was 54% (SE 10%); Stage IV patients had a median survival of 7.4 months and a 1-year survival rate of 28% (SE 7%). Delivered dose intensity was: carboplatin, 71%; vinblastine, 60%; and mitomycin C, 77% of the planned dose intensity. The back calculation of carboplatin area under the curve (AUC) with Calvert's formula and with the Cockcroft-Gault glomerular filtration rate estimation, showed a median AUC value of 4 (range, 2-8). Using the more precise Chatelut formula, AUC was again 4 (range, 2-7). Hematologic toxicity was the major side effect; Grades 3 and 4 leukopenia were observed in 34% and 6% of patients, respectively, and Grades 3 and 4 thrombocytopenia in 25% and 4% of patients, respectively. Grade 2 infection occurred in 10% of patients, with only 1 case of sepsis; severe constipation and Grade 2 alopecia occurred in only 1 patient; and no case of higher than Grade 1 nephrotoxicity was observed. No pulmonary toxicity was observed. Compliance with treatment was good with only one patient refusal after the first cycle. CONCLUSIONS: Chemotherapy for advanced NSCLS is still controversial, because effectiveness in terms of RR and symptom control must be weighed against treatment toxicity and costs. From our study it appears that MVC is easy to deliver in an outpatient setting, and has good patient compliance, low toxicity profile, and promising RR and response duration. The substitution of carboplatin for cisplatin in regimens for advanced NSCLC should be considered.     

A sudden death case from retropharyngeal abscess

Sixty metastatic and recurrent breast cancer patients who had been given cyclophosphamide, methotrexate and fluorouracil (CMF) therapy previously and were treated at the Oncology Departments of Cukurova and Ege University Medical Schools between March 1992-94, were randomized into 2 groups for the chemotherapy program. The 30 patients in the 1st group were given etoposide: 200 mg x day x 5 days orally every 3 weeks. The 30 patients of the 2nd group were given fluorouracil: 500 mg x m2, doxorubicin: 5O mg/m2, cyclophosphamide: 500 mg/m2 intravenously every 3 weeks. The response rates were 21/30 in group 1 and 17/30 in group 2. The median duration of responses was 11 months (8-21) in the 1st and 9 months (4-18) in the 2nd group. Severe myelotoxicity was observed in 2 of the patients in the 1st group and in 5 of the patients in the 2nd group.     

Phase II trial of 5-fluorouracil, interferon-alpha and continuous infusion interleukin-2 for patients with metastatic renal cell carcinoma

BACKGROUND: This study was designed to evaluate the efficacy and toxicity of the combination of 5-fluorouracil, interferon-alpha, and interleukin-2 for patients with metastatic renal cell carcinoma. METHODS: Previously untreated patients with a Zubrod performance status of < or =2; adequate cardiac, pulmonary, and renal function; and absence of brain metastases were eligible. One course of therapy was 28 days. 5-fluorouracil was administered at a dose of 600 mg/m2/day as a continuous infusions on Days 1-5. Interleukin-2 also was administered as a continuous infusion on Days 1-5 at a dose of 2 million Roche U/m2/day. Interferon-alpha was given as a daily subcutaneous injection of 4 million U/m2/day. RESULTS: Fifty-five patients were enrolled in the trial and 52 were evaluable for response. All patients experienced fever and flu-like symptoms. Grade 3 or 4 nonhematologic toxic effects included hypertension (48%), dermatitis (12%), stomatitis (11%), and altered mental status (9%). There was one toxic death. Four complete responses and 12 partial responses were observed for a total response rate of 31% (95% confidence interval, 18-46%). The survival of responding patients was significantly better than that of nonresponding patients. The improvement in survival was even more significant when comparing patients with at least stable disease with those who progressed through treatment. CONCLUSIONS: The three-drug combination described in this study demonstrates activity. However, it appears to be more toxic than other regimens with similar response rates and cannot be recommended for standard practice. Changing the interleukin-2 route to subcutaneous administration may permit more continuous administration with less toxic effects.     

Calcitonin inhibits production of immunoglobulins, rheumatoid factor and interleukin-1 by mononuclear cells from patients with rheumatoid arthritis

OBJECTIVES: Elcatonin (eCT), an eel calcitonin derivative, is shown to considerably improve the clinical signs and symptoms, as well as laboratory data, in patients with rheumatoid arthritis (RA). The therapeutic efficacy of eCT, however, is reduced by preceding and/or concomitant use of corticosteroid. Thus the effects of eCT on the production of immunoglobulins, IgMRF and interleukin-1 (IL-1) by mononuclear cells (MNCs)/monocytes were studied, and compared among patients with RA that received three kinds of treatment and also normal volunteers (NV). METHODS: Ten patients with RA had been treated with a non-steroidal anti-inflammatory drug only (NSAID group), 11 with oral prednisolone (PSL group), and eight with intramuscular eCT (eCT group). MNCs/monocytes from these patients, and also 10 from the NV group, were collected and cultured. IgG, IgA, IgM, IgMRF, IL-1 alpha and IL-1 beta in the supernatants were measured by enzyme-linked immunosorbent assay (ELISA). In the NSAID, PSL and NV groups, eCT was added to the culture medium, and the effects of eCT on production of these substances were studied. RESULTS: Baseline production of IgM, IL-1 alpha and IL-1 beta by MNCs/monocytes in the eCT and NV groups was significantly lower than that in the NSAID group. Furthermore, addition of eCT to the culture medium significantly inhibited the productions of IgG, IgMRF, IL-1 alpha and IL-1 beta by MNCs/monocytes in the NSAID group, whereas production of neither IgG, IgA, IgM, IgMRF nor IL-1 by MNCs/monocytes in the PSL and NV groups was affected by eCT. CONCLUSION: eCT may regulate immune responses through MNC/monocyte function in patients with RA. The present results support our proposal that eCT is an effective agent for the treatment of RA.     

Intraarticular corticosteroid injection in the management of children with chronic arthritis

OBJECTIVE: Intraarticular (IA) corticosteroid injection is a common therapeutic approach in the management of adult rheumatoid arthritis. This study examined the safety and efficacy of IA corticosteroid injection in 71 patients with juvenile arthritis who were being seen at the Sheba Medical Center during the years 1991-1996. METHODS: Sixty-one patients fulfilled the American College of Rheumatology revised criteria for the diagnosis of juvenile rheumatoid arthritis (JRA), 6 patients had reactive arthritis, and 4 patients had various other arthritic conditions. The mean +/- SD age was 9.4 +/- 5.6 years (range 0.5-18 years); 47 were female (mean age 8.1 +/- 5.5 years) and 24 were male (mean age 10.8 +/- 5.4 years). A total of 300 joints were injected with triamcinolone hexacetonide. The most common sites of injection were the knees (124 injections), ankles (71 injections), wrists (46 injections), shoulders (10 injections), and elbows (7 injections). Children under the age of 6 (n = 17), or older children who received more than 4 joint injections at one time (n = 10) were sedated with either ketamine HCI or propofol. All other children received their joint injections under local anesthesia. RESULTS: Full remission of the joint inflammation lasting >6 months following injection was achieved in 246 of the 300 injections (82.0%). In 54 (18.0%) of the injected joints, the inflammation recurred within 6 months of injection. In patients with pauciarticular arthritis, 115 of 141 injections (81.6%) resulted in full remission. Discontinuation of all oral medications was accomplished in 43 patients (60.6%) of the total group of 71 patients and in 32 of the 43 patients with pauciarticular disease (74.4%). Correction of joint contraction was achieved in 42 children (55 joints). In all 11 patients with Baker's cyst and in 12 patients with tenosynovitis, complete remission was achieved following injection. No infection or other serious complications occurred in any of the patients following the procedure. CONCLUSION: IA corticosteroid joint injection in children with juvenile arthritis is a safe and effective mode of therapy. It may be the only therapy needed in patients with pauciarticular JRA, obviating the need for prolonged oral medications, and is effective in correcting joint contractions and deformities.     

A phase II study of DaunoXome in advanced urothelial transitional cell carcinoma

Liposomal encapsulation of anthracyclines is claimed to reduce toxicity and to improve pharmacokinetics. Therefore, 15 patients with locally advanced or metastatic transitional cell cancer (TCC) of the urinary tract were entered into a phase II study assessing the response rate (WHO criteria) and toxicity of DaunoXome 100 mg/m2 given as a 1 h infusion every third week. During treatment, 6 patients remained stable and 8 had progressive disease. 1 patient died of pulmonary embolism after the first cycle and was not evaluable for response. No patient developed grade 4 myelotoxicity. Grade 3 leucopenia was seen in 5 patients and grade 1 thrombocytopenia in 1 patient, with no treatment-related changes of biochemical liver and kidney function tests. 4 patients complained of angina pectoris-like chest pain during the initial phase of the first or second infusion. The event was associated with a decrease in systolic blood pressure by 20-30 mm in 1 patient leading to permanent treatment discontinuation. In the other 3 and all subsequent patients, intramuscular application of 100 mg hydrocortisone 1 h prior to DaunoXome infusion prevented similar hypotensive reactions. In this study, intravenous (i.v.) DaunoXome 100 mg/m2 every third week showed no anticancer activity in advanced TCC.     

Anosognosia and procedural learning in Alzheimer''s disease

Biochemical modulation of 5-fluorouracil (5-FU) by folinic acid (FA) increases the response rate in patients with metastatic colorectal cancer compared to 5-FU alone. Phase II trials also demonstrated increased efficacy when interferon was added to 5-FU. In two consecutive trials, 76 patients were treated on days 1-5 with FA 200 mg/m2 plus interferon 5 x 10(6) U/m2 and 5-FU 350 mg/m2 as intravenous bolus injection (n = 33, regimen A) or 5-FU 500 mg/m2 as 2-hour infusion (n = 43, regimen B), repeated every 3 weeks with individual 5-FU dose escalation in steps of 50 (regimen A) or 100 mg/m2 (regimen B). In regimen A 5-FU dose reduction to 300 mg/m2 due to toxicity was necessary in 49% of the patients; in regimen B a 5-FU dose of 600 mg/m2 or above was tolerated by 70% of the patients. Dose-limiting toxicity was severe mucositis and/or diarrhea. Objective responses were observed in 5 of 33 patients (15%) in regimen A (3-28%, 95% confidence interval) and 7 of 41 patients (17%) in regimen B (5-29%, 95% confidence interval). Median time to progression was 4.7 and 4.8 months, and median survival 9.9 and 11.4 months for regimens A and B, respectively. Prolonged 5-FU administration over 2 h allows the administration of a higher 5-FU dose compared to bolus injection with no apparent improvement in antineoplastic efficacy. The addition of interferon to the combination of 5-FU plus FA in this dose and schedule does not seem to improve the response rate but appears to increase treatment toxicity.     

A Phase I dose escalation trial of continuous infusion paclitaxel to augment high dose cyclophosphamide and thiotepa plus stem cell rescue for the treatment of patients with advanced breast carcinoma

BACKGROUND: Paclitaxel, an effective chemotherapeutic agent in the management of breast carcinoma, may have activity in women whose disease has recurred after high dose chemotherapy. With this is mind the authors explored the addition of a 120-hour continuous infusion of paclitaxel to a previously reported regimen comprised of high dose cyclophosphamide and thiotepa. METHODS: Thirty-one women with advanced breast carcinoma (30 patients with Stage IV disease and 1 patient with Stage IIIB disease) underwent harvest and cryopreservation of bone marrow and/or peripheral blood progenitor cells. High dose cyclophosphamide (2.5 g/m2) and thiotepa (225 mg/m2) were administered intravenously on Days -7, -5, and -3. Paclitaxel was administered as a 120-hour continuous infusion starting on Day -7. RESULTS: Three patients were treated at the initial cohort dose of 50 mg/m2 (over 120 hours), 6 patients at 100 mg/m2, 6 patients at 125 mg/m2, 6 patients at 150 mg/m2, 6 patients at 180 mg/m2, and 4 patients at 210 mg/m2. All patients completed the treatment protocol as planned with no associated transplant-related deaths. Mucositis as evidenced by either stomatitis or noninfectious diarrhea was experienced by all patients and was determined to be the dose-limiting toxicity at the 210 mg/m2 dose level. One patient with dose-limiting mucositis required intubation for airway protection and also experienced Grade 3 (according to the Cancer and Leukemia Group B common toxicity grading scale) pulmonary and neurologic toxicity. Only one Grade 3 toxicity was encountered below the maximum tolerated dose in a patient who developed diffuse alveolar hemorrhage at a dose of 125 mg/m2. No allergic reactions or clinical evidence of peripheral neuropathies were encountered. Cardiac, hepatic, and renal toxicities were minimal. Response rates in this previously treated patient population were difficult to assess in light of the high incidence of bone metastases; an overall response rate of 24% was obtained. CONCLUSIONS: Paclitaxel at a dose of 180 mg/m2 as a 120-hour continuous infusion may be added safely to high dose cyclophosphamide and thiotepa with autologous stem cell rescue. Further studies are ongoing to evaluate the efficacy and further define the toxicity of this recommended Phase II dose.     

Limited sampling model for the area under the concentration versus time curve of irinotecan and its application to a multicentric phase II trial

We previously established a limited sampling model (LSM) for the area under the concentration versus time curve (AUC) of irinotecan (CPT-11). Using this LSM, we performed a pharmacokinetic-pharmacodynamic analysis of CPT-11 in a multicentric Phase II study for non-small cell lung cancer. Ten institutes participated in this study, 36 patients were registered, and 30 patients were evaluable for the pharmacokinetic-pharmacodynamic analysis. CPT-11 and etoposide were administered daily for three consecutive days, both at a dose of 60 mg/m2. Blood samples were obtained 4 and 8 h after infusion on days 1 and 3. When using the LSM, there is a significant possible source of error in the timing of these selected points. In this study, however, the sample timing error was small. Mean timing errors were 1.0-4.0 min at each point. The estimated CPT-11 AUCs were: Day 1 Day 2 Day 1 + 3 Mean +/- SD (mg.h/liter) 3.76+/-0.68 4.10+/-0.86 7.86+/-1.43 Range 2.01-5.03 2. 29-5.72 4.30-10.68 Max/min 2.50 2.45 2.48 High interpatient variability was observed in the AUC. The CPT-11 AUC correlated positively with the grade of emesis (P = 0.003) and the percent decreases in WBC count (P = 0.001) and absolute neutrophil count (P =0.0006), but it did not correlate with the grade of diarrhea or response. We concluded that the LSM was useful in estimating individual pharmacokinetic parameters in multicentric trials.