Single dose treatment of vaginal candidosis: Randomised comparison of amorolfine (50 mg and 100 mg) and clotrimazole (500 mg) in patients with vulvovaginal candidosis

A double blind randomised comparative study of single dose treatment with amorolfine vaginal tablets (50 mg and 100 mg) and clotrimazole 500 mg monodose vaginal tablets (open labelled) was undertaken in patients with vaginal candidosis. Vaginitis was demonstrated by both a positive culture and positive findings on microscopic examination of a vaginal smear as well as by the presence of clinical symptoms. 118 patients seen over a 6 month period were randomly allocated to receive one 50 mg vaginal tablet of amorolfine (regimen A, 40 patients), a 100 mg vaginal tablet of amorolfine (regimen B, 38 patients) or a 500 mg tablet of clotrimazole (regimen C, 40 patients). At the assessment one week after the end of therapy the proportion of cured patients was 90% in group A, 94.7% in group B and 92.5% in group C. 4 patients (10%) in group A, 2 (5.2%) in group B and 3 (7.5%) in group C did not respond to the treatment. There was a significant association between Candida glabrata and treatment failure (P less than 0.001) and C. glabrata and carrier state (P less than 0.01). At the assessment 4 weeks after the end of therapy the proportion of cured patients was 80% in group A, 84.2% in group B and 67.5% in group C with a relapse rate of 10% (group A), 10.5% (group B) and 25% (group C). C. glabrata was significantly associated with non-effective overall treatment (P less than 0.05). The relapse rate was significantly associated with positive culture results one week post therapy (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Low-dose aminoglutethimide (500 mg/day) and hydrocortisone (30 mg/day) in advanced cancer of breast

One hundred-twenty-seven advanced breast cancer patients who had been -for most of them- heavily pretreated with chemo- and/or hormone therapy received 500 mg aminoglutethimide and 30 mg hydrocortisone/day. The response rate was 20% (58% when stabilizations were included); the best responses were observed in skin and node metastases. The response rate in bone metastasis was 16%. The general condition of the patient (according to the Karnofsky index) was improved in 50% of the responders (including stabilizations) and in 23% of the non-responders. The survival of patients who were only stabilized was close to the survival of responders. The tolerability of this treatment was very good.     

A Comparative Trial of the Diagnostic Quality of Metrizamide 180 mg/ml and 280 mg/ml for Leg Phlebography

Metrizamide represents a significant advance in patient tolerance to ascending phlebography of the leg. The objection to its general introduction is its high cost. From a randomised, prospective, within patient study using metrizamide 280mg/ml for one leg and 180mg/ml for the other, it is concluded that a substantial reduction in cost can be made using the more dilute medium while maintaining full diagnostic quality.     

Fulvestrant 250mg versus Anastrozole 1 mg in the Treatment of Advanced Breast Cancer: a Meta-Analysis of Randomized Controlled Trials

Objective: Most patients with advanced breast cancer experience resistance to endocrine treatment andeventual disease progression. This meta-analysis was designed to compare the efficacy and tolerability offulvestrant 250mg with anastrozole 1mg in postmenopausal women with advanced breast cancer. Methods:Electronic literature databases (Cochrane Library, Medline, and Embase) were searched for randomizedcontrolled trials (RCTs) published prior to August 2013. Only RCTs that compared fulvestrant 250mg toanastrozole 1mg in postmenopausal women with advanced breast cancer were selected. The main outcomeswere time to treatment failure (TTF), time to progression (TTP), duration of response (DOR), clinical benefitrate, and tolerability. Results: Four RCTs covering 1,226 patients (fulvestrant, n=621; anastrozole, n=605)were included in the meta-analysis. Fulvestrant increased the DOR compared to anastrozole (HR =1.31, 95%confidence interval [CI] 1.13–1.51). There was no statistically significant difference between fulvestrant andanastrozole in terms of TTF (HR=1.02, 95%CI 0.89–1.17), complete response (RR=1.79, 95%CI, 0.93–3.43),and partial response (RR=0.91, 95%CI 0.69–1.21). As for safety, there was no statistical significance betweenthe two groups for common adverse events. Conclusion: Fulvestrant 250mg is as effective and well-toleratedas anastrozole 1mg treatment for advanced breast cancer in postmenopausal women whose disease progressedafter prior endocrine treatment. Thus, fulvestrant may serve as a reasonable alternative to anastrozole whenresistance is experienced in breast cancer cases.     

Toxicity of doxorubicin and cyclophosphamide (60 mg/600 mg/m2) in adjuvant chemotherapy for breast cancer

We evaluated the toxicity of 4 cycles of doxorubicin (60 mg/m2) and cyclophosphamide (600 mg/m2) every 3 weeks (AC 60/600) in adjuvant chemotherapy for breast cancer. Between 1994 and 2003, 62 patients received 6 cycles of doxorubicin (40 mg/m2) and cyclophosphamide (500 mg/m2) every 3 weeks (AC 40/500), and 106 patients received AC 60/600 as adjuvant chemotherapy for breast cancer. The performance status of all patients was 0 or 1. Toxicity was determined using the National Cancer Institute Common Toxicity Criteria (NCI-CTC) ver. 2. Grade 3/4 neutropenia was frequent in AC 60/600 (6.5% vs 24.3%, p < 0.001). However, febrile neutropenia was not significant in either group (1.6% vs 3.8%, p = 0.39). There was also no statistical difference in the toxicity greater than grade 3 of anemia, nausea, vomiting, fatigue, diarrhea and cardiotoxicity. There was no treatment-related death in both groups. The number of patients who completed chemotherapy was higher in those receiving AC 60/600 than in those receiving AC 40/500 (91.9% vs 99.1%, p = 0.026). AC 60/600 is tolerated and feasible in adjuvant chemotherapy of breast cancer in Japanese patients from the viewpoint of toxicities.     

Differences in adverse events between 250 mg daily gefitinib and 150 mg daily erlotinib in Japanese patients with non-small cell lung cancer

Purpose

The maximum tolerated dose (MTD) of erlotinib (150 mg) is the approved daily dose. In contrast, the approved daily dose of gefitinib (250 mg) is only one-third of its MTD. Significantly different adverse events have been associated with gefitinib and erlotinib.

Experimental design

A retrospective investigation examining the adverse events and tolerances of 250 mg daily gefitinib and 150 mg daily erlotinib in Japanese patients with non-small cell lung cancer (NSCLC) was performed. Adverse events were assessed according to Common Terminology Criteria for Adverse Events version 3.0. To determine tolerance for each agent, failure was defined as dose reduction or discontinuation of the drug due to adverse events, and early failure as dose reduction or discontinuation due to adverse events before the first evaluation of response.

Results

More adverse events including skin disorders, diarrhea, oral mucositis, asthenic conditions, anorexia, nausea, vomiting, and gastrointestinal bleeding were observed in the erlotinib group. Liver function test abnormalities and pneumonitis did not differ between the two groups. Based on multivariate analysis, failure, early failure, and discontinuation due to adverse events were independently associated with erlotinib use.

Conclusion

Our data show that 150 mg daily erlotinib was associated with more toxicity and less tolerability than 250 mg daily gefitinib.     

Safety Implications of Switching Pembrolizumab Dosage From 200 mg Every 3 Weeks to 400 mg Every 6 Weeks in Patients With Advanced NSCLC

IntroductionAdministration of 400 mg pembrolizumab every 6 weeks (400 mg Q6W) has been approved on the basis of the results of simulated pharmacokinetic modeling and exposure–response analyses. Nevertheless, the safety of switching dosage from 200 mg every 3 weeks (Q3W) to 400 mg Q6W during treatment remains unclear.MethodsThis study involved patients (N = 45) with advanced NSCLC, in whom the pembrolizumab dosage was switched from 200 mg Q3W to 400 mg Q6W between August 2020 and November 2021 in our institute.ResultsAt the time of switching, the median age of the patients was 71 (range: 32–84) years, and 32 patients (71.1 %) were males. The median number of cycles of 200 mg Q3W before switching was six (range: 1–31). After switching, new or worsening immune-related adverse events (irAEs) occurred in 17 of the 45 patients (37.8%) within three cycles. The irAEs were pneumonitis in 11 patients (24.4%), diarrhea in three patients (6.7%), renal dysfunction in two patients (4.4%), adrenal dysfunction in two patients (4.4%), a skin rash in one patient (2.2%), fulminant type 1 diabetes mellitus in one patient (2.2%).ConclusionsThe switching of pembrolizumab dosage from 200 mg Q3W to 400 mg Q6W resulted in the occurrence of new or worsening irAEs, in particular, pneumonitis, in the early cycles even in patients who had received stable treatment with 200 mg Q3W.     

Outcome of patients with advanced gastro-intestinal stromal tumours crossing over to a daily imatinib dose of 800 mg after progression on 400 mg

In the EORTC-ISG-AGITG trial 946 patients with advanced gastro-intestinal stromal tumours (GIST) were randomised to receive 400 or 800 mg of imatinib daily. An increase in progression free survival (PFS) was demonstrated for patients randomised to the high-dose arm. Patients randomised to low-dose could cross-over to high-dose upon progression. We evaluated the feasibility, safety and efficacy of this policy. Of the 241 patients available for follow-up, 133 patients (55%) crossed over to high-dose imatinib according to the protocol. Of these patients, 92% had not had a prior dose reduction. The cumulative incidence of subsequent dose reductions after cross-over was 17% after six months with 51% discontinuing therapy without requiring a dose reduction. The extent of anaemia and fatigue increased significantly after cross-over, whilst neutropenia was less severe than during low-dose treatment. Objective responses after cross-over included three patients (2%) with a partial response and 36 (27%) with stable disease. The median PFS after cross-over was 81 days, although 18.1% of patients were still alive and progression free one year after cross-over. We conclude that a cross-over to high-dose imatinib is feasible and safe in GIST patients who progress on low-dose therapy.     

A comparison of two doses of tamoxifen in patients with advanced breast cancer: 20 mg/day versus 40 mg/day

In order to establish the optimal dose of Tamoxifen in the treatment of advanced breast cancer, a randomized trial comparing 40 mg/day to 20 mg/day was conducted. Thirty-four patients were entered in the study, and the results were as follows: 1) The response rates of 40 mg/day and 20 mg/day were 35.3% and 23.5%, respectively, without any significant difference between them. 2) The response rate in relation to metastatic sites were also similar at the two dose levels. 3) There was no significant difference in the median duration of response, either. 4) Among nine patients, one PR and three NC case were observed with subsequent increase of the dosage to 40 mg/day after 20 mg/day. The conclusion from this study was that 20 mg/day of Tamoxifen was suitable as an initial dosage for the treatment of advanced breast cancer. But, in certain cases who failed to respond, a dose-escalation to 40 mg/day appeared to be effective.     

Thiotepa 10 mg/kg Treatment Regimen Is Superior to Thiotepa 5 mg/kg in TBF Conditioning in Patients Undergoing Allogeneic Stem-Cell Transplantation

Introduction

The optimal intensity of myeloablation with a reduced-toxicity conditioning regimen to decrease relapse rate after allogeneic stem-cell transplantation without increasing transplant-related mortality (TRM) has not been well established.

A pilot randomised comparison of dexamethasone 96 mg vs 16 mg per day for malignant spinal-cord compression treated by radiotherapy: TROG 01.05 Superdex study

AimTo test the viability of a full-scale randomised comparison of two steroid doses given with radiotherapy for malignant spinal-cord compression (MSCC), to test internet randomisation and to compare different functional outcome measures.Materials and methodsA log of screened patients at eight recruiting centres was maintained. Patients were randomised via the Superdex website to either 96 mg or 16 mg daily of dexamethasone. Radiotherapy treatment was 30 Gy in 10 fractions. Outcomes assessed used ambulation, Barthel Index ambulation, Functional Independence Measure (FIM) ambulation and Functional Improvement Score (FIS) at 1 month.ResultsOne hundred and thirty-one patients were screened. Ninety-three (71%) were ineligible, 65% of these were because duration of prior steroid use was greater than 12 h, failure to meet strict definition of magnetic resonance imaging, defined MSCC, multi-level disease or previous spinal-cord compression treatment. Twenty of the 38 eligible patients were randomised, including seven outside standard office hours. There was a high rate of serious adverse events (n = 9), but only one was considered likely to be related to study medication. At baseline, 75% were ambulant, 70% had FIM ambulation scores greater than 5 and 50% had Barthel Index ambulation scores greater than 2. At day 28, including all randomised patients (by scoring four dead patients as non-ambulant), ambulation scores by the various definitions were 60%, 45% and 40%, respectively. For the 16 patients evaluable at day 28, the mean FIS was −1.4. Median survival was 69 days and 1-year survival 13%.ConclusionWeb randomisation was successful; however, the high ineligibility rate precludes a full-scale dexamethasone dose trial in Australia. Choice of measure of ambulation has potentially significant effects on outcomes and implications for the design of any future MSCC trials. Referral delays are of concern.     

A comparison of two doses of tamoxifen (Nolvadex) in postmenopausal women with advanced breast cancer: 10 mg bd versus 20 mg bd

The reactivation of U.V.-irradiated adenovirus 2 in HeLa cells is enhanced 8-9 fold if the cells are given a brief hyperthermic shock before infection. Maximum reactivation is achieved by heating for 10 min at 45.5 degrees C and with a delay of 36 h between heating and infection. The induction process requires protein synthesis only during the 3 h period immediately following heating; cycloheximide does not prevent the expression of enhanced reactivation if added to the cells after this time. Heat-enhanced reactivation exhibits properties similar in some respects to radiation-enhanced reactivation and indicates an increased capacity of the heated cells to tolerate DNA damage.     

Overdose with 6400 mg of imatinib: is it safe?

Imatinib mesylate (STI-571), a potent and selective tyrosinekinase inhibitor against BCR/ABL, is now considered as goldstandard treatment of CML. The drug is generally well tolerated.A suicidal attempt with 6400 mg of Imatinib by a young CML patientwithout any substantial side-effects is reported. This alsohighlights 6400 mg of imatinib is not lethal.     

Letrozole, a new oral aromatase inhibitor: Randomised trial comparing 2.5 mg daily, 0.5 mg daily and aminoglutethimide in postmenopausal women with advanced breast cancer

Background: The study compares letrozole and aminoglutethimide (AG), astandard therapy for postmenopausal women with advanced breast cancer,previously treated with anti-oestrogens.Patients and methods: 555 women were randomly assigned letrozole 2.5 mgonce daily (n = 185), letrozole 0.5 mg once daily (n = 192) oraminoglutethimide 250 mg twice daily with corticosteroid support (n = 178)in an open-label, multicentre trial. The primary endpoint was objectiveresponse rate (ORR), with time events as secondary. ORR was analysed ninemonths after enrolment of the last patient, while survival was analysed 15months after the last patient was enrolled. We report the results of theseanalyses plus an extended period of observation (covering a total durationof approximately 45 months) to determine the duration of response andclinical benefit.Results: Overall objective response rates (complete + partial) of19.5%, 16.7% and 12.4% were seen for letrozole 2.5 mg,0.5 mg and AG respectively. Median duration of response and stable diseasewas longest for letrozole 2.5 mg (21 months) compared with letrozole 0.5 mg(18 months) and AG (14 months). Letrozole 2.5 mg was superior to AG in timeto progression, time to treatment failure and overall survival.Treatment-related adverse events occurred in fewer patients on letrozole(33%) than on AG (46%). Transient nausea was the most frequentevent with letrozole (7% on 0.5 mg, 10% on 2.5 mg, 10%on AG), rash with AG (11%, 1% on 0.5 mg, 3% on 2.5 mgletrozole).Conclusions: Letrozole 2.5 mg offers longer disease control thanaminoglutethimide and letrozole 0.5 mg in the treatment of postmenopausalwomen with advanced breast cancer, previously treated with anti-oestrogens.     

Benefit‐risk assessment of nivolumab 240 mg flat dose relative to 3 mg/kg Q2W regimen in Japanese patients with advanced cancers

Nivolumab 3 mg/kg every 2 weeks (Q2W) has been approved in Japan for various cancers; however, use of a flat dose is expected to simplify dosing and administration. A quantitative clinical pharmacology approach was used to assess the benefit‐risk profile of nivolumab 240 mg Q2W relative to the approved dose of nivolumab 3 mg/kg Q2W in Japanese patients. Three exposure‐response safety analyses were performed for adverse events that led to discontinuation/death, were grade 3 or higher, and were immune‐mediated and grade 2 or higher for Japanese patients diagnosed with one of multiple tumor types. Exposure‐response analyses of efficacy were evaluated for overall survival and objective response rate. Exposures of nivolumab 240 mg Q2W were 37% higher than those of nivolumab 3 mg/kg Q2W in Japanese patients across the tumor types analyzed. Predicted safety profiles at the two doses differed by less than 2% across tumor types for adverse events leading to discontinuation/death, adverse events of grade 3 or higher, or immune‐mediated adverse events of grade 2 or higher. In addition, the predicted 1‐year and 2‐year overall survival rates, the mean overall survival and the objective response rates were comparable between the doses regardless of the tumor type analyzed. Overall, these results demonstrated that the benefit‐risk of nivolumab 240 mg Q2W was comparable to that of the previously approved 3 mg/kg Q2W dosing regimen, and was the basis for the approval of the 240 mg Q2W as an alternative dosing regimen for treatment in Japanese patients across multiple tumor types.