Quinidine as a resistance modulator of epirubicin in advanced breast cancer: mature results of a placebo-controlled randomized trial.

PURPOSE: To evaluate the effect of quinidine, a putative modulator of P-glycoprotein-mediated drug resistance, on the response rate and toxicity profile of epirubicin in patients with advanced breast cancer. PATIENTS AND METHODS: Between 1989 and 1992, 223 eligible patients were randomized in double-blind fashion to receive epirubicin 100 mg/m2 by intravenous (i.v.) bolus and prednisolone 25 mg orally twice daily, along with either placebo or quinidine (250 mg) capsules, taken for 4 days before and 2 days after chemotherapy. Treatment was continued for a maximum of eight courses. RESULTS: Ten eligible patients did not complete the first cycle of treatment. Of the remaining patients, 106 in the placebo arm received 619 courses of treatment, and 107 in the quinidine arm received 612 courses. The median cumulative dose of epirubicin in both arms was 600 mg/m2. The median quinidine level (measured before epirubicin administration in 288 courses) was 5.5 mumol/L; at this concentration, the drug partially reverses anthracycline resistance in multidrug-resistant (MDR) breast carcinoma cells in vitro. There were no statistically significant differences in hematologic or gastrointestinal toxicity between the two arms. The response rate in the placebo arm was 44% (6% complete remission [CR], 38% partial remission [PR]), and in the quinidine arm was 43% (4% CR, 39% PR). Surviving patients have been monitored for a median time of 74 weeks, and there is no significant difference in the overall or progression-free survival between the two arms. The median survival times were 59 weeks for placebo and 47 weeks for quinidine patients. The estimated relative death rate (quinidine/placebo) was 1.2 (P = .247; 95% confidence interval [CI], 0.88 to 1.63). CONCLUSION: Quinidine at this dose does not significantly alter the toxicity profile, response rate, or survival after epirubicin chemotherapy in patients with advanced breast cancer. This may be due to ineffective modulation of P-glycoprotein by quinidine or the lack of expression of mdr-1 in a sufficient proportion of cells in these tumors, or alternative mechanisms underlying resistance to epirubicin.

Epirubicin at two dose levels with prednisolone as treatment for advanced breast cancer: the results of a randomized trial.

Two hundred eleven patients with advanced breast cancer were randomized to receive either epirubicin (E) 50 mg/m2 and prednisolone (LEP) or E 100 mg/m2 and prednisolone (HEP). The intended treatment consisted of 16 courses of LEP or eight courses of HEP given at 3-weekly intervals. Reasons for stopping treatment early included progressive disease, stable disease without symptomatic improvement, or severe toxicity deemed intolerable by either the patient or physician. Toxicity was recorded at 3-weekly and response at 9-weekly intervals using the World Health Organization (WHO) criteria of response and toxicity. Two hundred nine patients were eligible for analysis, 98% of whom have been followed for more than a year. One hundred four patients received LEP and 105 HEP. Significantly worse myelosuppression, alopecia, nausea and vomiting, and mucositis were seen in the high-dose arm (P less than or equal to .001). More patients in the LEP arm stopped treatment before the fourth course than in the HEP arm, and the commonest reason for stopping was progressive disease. A similar median number of courses was given in each arm. There was a significantly higher response in the HEP arm (HEP - complete response [CR] + partial response [PR] = 41%, LEP - CR + PR = 23%). Despite this, no statistically significant differences was seen in overall survival or progression-free interval. The median survival for HEP and LEP was 44 and 46 weeks, respectively.

No correlation between ras, c-myc and c-jun proto-oncogene expression and prognosis in advanced carcinoma of cervix.

55 patients suffering from stage III or IV carcinoma of cervix were treated with two pulses of neo-adjuvant chemotherapy prior to radical radiotherapy. 51% (26/51) had a partial response. The initial response to chemotherapy is associated with significantly better long-term survival. The 3-year survival of chemotherapy responders is 62% against 21% for non-responders (P = 0.009 log-rank test). To detect possible differences in oncogene expression in biopsy specimens taken from responding and non-responding patients, paraffin-fixed material was immunocytochemically stained for the expression of the protein products of ras, c-myc and c-jun proto-oncogenes. The frequency of oncogene expression was ras 80.4%, c-myc 45.1% and c-jun 39.2%. There was no statistically significant association between oncogene expression, time to local recurrence or development of metastases or survival.

The Scottish and Manchester randomised trial of neo-adjuvant chemotherapy for advanced cervical cancer.

204 eligible patients were entered into a multicentre randomised trial of neo-adjuvant chemotherapy prior to radical radiotherapy. The aim of this study was to assess whether there was any survival advantage in patients undergoing chemotherapy and radiotherapy compared with those given radiotherapy alone. Patients were aged up to 70 years, performance status 0-1/2, with bulky stage IIb, stage III or stage IVa squamous or adenosquamous carcinoma. Three cycles of methotrexate 100 mg/m2 and cisplatin 50 mg/m2 were given at 2-weekly intervals before radical radiotherapy. 104 eligible patients received the combination treatment and 100 radiotherapy only. The two arms of the study were well balanced for tumour and patient characteristics. The response rate to chemotherapy was 49%, 33% of patients in the radiotherapy (XRT) alone arm and 45% of the combination arm were clinically free of tumour at the end of treatment. The median follow-up for surviving patients is 5.4 years (range: 11 months-8 years) and 84% have been followed-up for more than 4 years. 134 patients have died (68 XRT only, 66 combined arm). The median survival RT alone was 111 weeks (95% confidence interval (CI) 72-151 weeks), combination arm 125 weeks (95% CI 79-170 weeks). The estimated death ratio is 0.79 (P = 0.19, 95% CI 0.56-1.12). The estimated 3-year survival is 40% (95% CI 30-50%) RT only compared with 47% (95% CI 37-57%) in the combination arm. Acute and late toxicity of radiotherapy was not increased by the addition of chemotherapy.

Weekly large fraction radiotherapy and 5 fluorouracil as a palliative treatment for large bowel carcinoma: a pilot study.

Palliative radiotherapy for large bowel cancer is generally given in fraction sizes of 2-3 Gy. Theoretical considerations led us to believe that a larger fraction size would not lead to a decreased response rate and practical considerations led us to treat patients once a week. The results of a pilot study of 32 patients with large bowel cancer are presented. Patients were treated with a fraction size of 6 Gy given weekly and combined with 5 FU. The response rate of 58% and the median survival of 9 months seems comparable with other regimens, as does the rate of acute side effects. The late high dose effect of subcutaneous fibrosis was seen in 30% of the long term survivors; the implications of this are discussed. We draw the conclusion that this treatment is convenient and effective in terms of tumor response, but that the late high dose effects were more severe than expected and that these effects may be potentiated by 5 FU.

Clinical trials of nimodipine as a potential neuroprotector in ovarian cancer patients treated with cisplatin.

Our previous randomised trial in patients with advanced ovarian cancer indicated a significant response and survival advantage for those receiving high-dose (100 mg/m2) as compared with low-dose (50 mg/m2) cisplatin in combination with cyclophosphamide (750 mg/m2). However, this was accompanied by more toxicity; peripheral neuropathy was troublesome, with 32% of patients experiencing > or = WHO grade 2 at the cisplatin dose of 100 mg/m2. Nimodipine is a calcium-channel antagonist that has provided protection from cisplatin-induced neurotoxicity in a rat model system. We performed a pilot study in 50 patients that demonstrated the feasibility of co-administration of nimodipine in a chronic oral dosing schedule with cisplatin-based chemotherapy in an open-label non-randomised trial. This led us to initiate a double-blind, placebo-controlled, randomised trial in patients with ovarian cancer, which was prematurely discontinued because of problems with nausea and vomiting, leading to poor patient compliance, that were not predicted by the pilot study. These studies did not demonstrate a neuroprotective effect for nimodipine. The primary efficacy variable, i.e, the neurotoxicity score at the end of treatment, gave a significantly lower mean for placebo patients than for nimodipine patients. This report details our experience and discusses the reasons for premature termination of the randomised trial.

Carboplatin-based combination chemotherapy for advanced carcinoma of the cervix.

A combination of carboplatin, vincristine, methotrexate and bleomycin (COMB) was given to 29 patients with locally advanced, metastatic or recurrent cervical carcinoma. A total of 85 cycles of chemotherapy were given, with half of the patients receiving greater than 3 cycles. Both the response rate (32.1%) and the median duration of response (30 weeks) were relatively disappointing. Renal toxicity was minimal, but one-third of our patients experienced severe (WHO grades 3 and 4) nausea and vomiting. This combination showed little advantage over carboplatin used as a single agent.

A randomised trial of tamoxifen versus tamoxifen with aminoglutethimide in post-menopausal women with advanced breast cancer.

Sixty-six post-menopausal women with metastatic breast cancer were randomised to receive tamoxifen or tamoxifen with aminoglutethimide. The women in the tamoxifen group were virtually free of toxicity, whilst 45% of patients in the aminoglutethimide group had toxicity and 13% discontinued the drug because of this. Responses were seen in 19% of patients receiving tamoxifen alone and 23% of those receiving both drugs. There is no indication that the increased toxicity seen with the addition of aminoglutethimide to tamoxifen in this situation is justified by an increased response rate.

Late radiation side-effects in three patients undergoing parotid irradiation for benign disease.

We report three patients in whom standard radiation therapy was given and serious late radiation damage was seen. The first patient suffered recurrent parotiditis and a parotid fistula. He was treated initially with 20 Gy in ten fractions via a 300 kV field. Further irradiation was required 1 year later and 40 Gy was given in 2 Gy fractions by an oblique anterior and posterior wedged photon pair. Ten years later he developed localized temporal bone necrosis. The second patient, with pleomorphic salivary adenoma, developed localized temporal bone necrosis 6 years after 60 Gy had been given using standard fractionation and technique. The third patient received 55 Gy in 25 fractions for a pleomorphic salivary adenoma and after 3 years developed temporal bone necrosis. Sixteen years later the same patient developed cerebellar and brainstem necrosis. All patients developed chronic persistent infection during or shortly after the radiation therapy, which increased local tissue sensitivity to late radiation damage. As a result, severe bone, cerebellar and brainstem necrosis was observed at doses that are normally considered safe. We therefore strongly recommend that any infection in a proposed irradiated area should be treated aggressively, with surgical debridement if necessary, before radiotherapy is administered, or that infection developing during or after irradiation is treated promptly.

A linear quadratic analysis of gynaecological brachytherapy.

Four hundred and fourteen patients were treated by radical radiotherapy alone for cervical carcinoma at the Western Infirmary and the Royal Beatson Memorial Hospital between April 1982 and December 1987. All patients received external beam radiotherapy in addition to brachytherapy, using either manually inserted caesium (n = 107) or the Selectron afterloading machine (n = 307). Three mean Selectron dose rates were used: 0.91 Gy/h, 1.195 Gy/h and 1.74 Gy/h. During this period of time, the cumulative radiation effect formula was used to calculate an overall brachytherapy dose reduction to compensate for the increase in point 'A' dose rate. We have compared the local control rates and the incidence of late effects seen in these patients with theoretical parameters calculated using the linear quadratic (LQ) model. This model predicts a small rise in late effects as the dose rate increases, which is also seen in clinical practice; it also predicts a reduction in local control, partially offset by the addition of external beam radiotherapy, which would be most marked for early stage disease. There was a small fall in local control associated with Selectron treatment, but of a smaller size than predicted by the LQ model.

A comparison of remote afterloading and manually inserted caesium in the treatment of carcinoma of cervix.

Between 1982 and 1985, 240 patients with carcinoma of cervix were treated by radical radiotherapy, 140 using the selectron at the Royal Beatson Memorial Hospital (RBMH) and 100 with conventional caesium at the Western Infirmary. To allow for the increased dose rate to point A (1.2-1.4 Gy/h) during selectron treatment the overall intracavity dose was reduced by a mean value of 25%. Local recurrence rates were similar: 15% (selectron) against 14% (conventional). Three-year survival with local control was somewhat worse in the selectron group (77% against 81%) mainly because of an increased frequency of metastatic disease with local control (19.3% against 12.0%. The use of remote afterloading has not increased late morbidity (15.7% selectron, 15.0% conventional). The introduction of the selectron has brought about a marked reduction in staff radiation exposure. At the RBMH the mean recorded dose to nurses fell from 19 mSv in 1981 to 2.4 mSv in 1985.

Oestrogen and progesterone receptors in carcinoma of the cervix.

Oestrogen (ER) and progesterone (PR) receptors have been measured in 102 cervical carcinomas. With positive levels defined as concentrations exceeding 20 fmol/mg protein for cytoplasmic receptor and/or 200 fmol/mg DNA for nuclear receptor, 24% of tumours were dual receptor positive and 51% were dual receptor negative. The majority of adenocarcinomas (81%: 13/16) expressed ER (P less than 0.001) though only 54% (7/13) of these tumours co-expressed PR. There was a significant correlation between tumours positive for ER and those arising in premenopausal women (P = 0.011), with good or moderate differentiation (P = 0.027) and of smaller size (P = 0.025). Median follow-up is 19 months. Apart from advanced stage, tumour bulk (greater than 5 cm) was the only parameter associated with inferior progression-free survival, and most larger tumours were of advanced stage. No prognostic significance could be detected for receptor status.

Combination chemotherapy with carboplatin, capecitabine and epirubicin (ECarboX) as second- or third-line treatment in patients with relapsed ovarian cancer: a phase I/II trial.

Platinum-based combination chemotherapy has been proven to be superior to single-agent platinum in the treatment of relapsed ovarian cancer after a treatment-free interval of more than 6 months. A response rate of 41% was previously reported by our group using a combination of epirubicin, cisplatin and 5-FU in patients who relapsed within 12 months, we therefore assessed a similar, but more convenient combination of epirubicin, carboplatin and capecitabine in this phase-I/II trial. In total, 18 patients with recurrent epithelial ovarian carcinoma, who had not received more than two lines of chemotherapy and the treatment-free interval exceeded 6 months were treated with carboplatin AUC5, epirubicin 50 mg m(-2) and capecitabine at several dose levels on continuous 21 day cycles and 14 of 21 day cycles. Patients were assessed for toxicity and by CT and CA-125 for response. The overall response rate was 61.1%, with three complete and eight partial responses. Grade 3/4 haematological toxicity was seen in 10 out of 18 patients and caused dose reductions and treatment delays. The combination of epirubicin, carboplatin and capecitabine showed good activity but caused excessive toxicity. A phase-II trial using carboplatin and capecitabine is underway.

The incidence of persistent functioning endometrial tissue following successful radiotherapy for cervical carcinoma.

Sixty-three patients under the age of 50 years who were long-term survivors following radiotherapy for cervical cancer and had been placed on hormone replacement therapy (HRT) were identified. The median age at treatment was 37 years and the mean delay from treatment to the initiation of HRT was over 15 months. Fifteen of the 63 patients had experienced vaginal bleeding attributable to the effects of HRT on persisting endometrial tissue. The significance of this is discussed.

Safety and efficacy of the combination of trastuzumab with docetaxel for HER2-positive women with advanced breast cancer. A review of the existing clinical trials and results of the expanded access programme in the UK.

Trastuzumab is a humanised monoclonal antibody against the extracellular domain of HER2 (human epidermal growth factor receptor-2) that is overexpressed in about 25% of human breast cancers. It has shown clinical benefit in HER2-positive breast cancer cases when used alone or in combination with chemotherapy. Trastuzumab increases the response rate to chemotherapy and prolongs survival when used in combination with taxanes. In this article, we review the clinical trials where trastuzumab has been administered together with docetaxel, and we present the results of the trastuzumab expanded access programme (EAP) in the UK. Combination of trastuzumab with docetaxel results in similar response rates and time-to-progression with the trastuzumab/paclitaxel combinations. The toxicity of the combination and the risk of heart failure are low. The clinical data for the docetaxel/trastuzumab combination indicate a favourable profile from both the efficacy and the safety point of view and confirm the feasibility and safety of trastuzumab administration both as monotherapy and in combination with docetaxel.

Carcinoma of the penis: a review of 42 cases.

A retrospective survey was made of 42 cases of carcinoma of the penis presenting over 14 years. Cases for attempted cure of the primary lesion were treated by either radiotherapy or surgery. It is recommended that radiotherapy should be the primary treatment as it is non-mutilative, allows secondary surgical salvage where necessary and has no greater occurrence of post-treatment lymph node metastases than surgery.

Combination chemotherapy prior to radical radiotherapy for stage III and IV carcinoma of the cervix.

Twenty-three patients with Stage III and seven patients with Stage IVa carcinoma of cervix were treated with two pulses of cisplatin, vincristine and bleomycin combination chemotherapy prior to radical radiotherapy. Seventeen of the 30 patients (57%) had a partial response to chemotherapy; 25 had a complete response following radiotherapy. Currently, 16 patients are tumour-free 6 to 31 months after treatment, eight are dead and six are alive, with tumour. The actuarial survival at 30 months is 66%. Acute and late effects of radiation upon normal tissue have not been increased. Pelvic tumour was eliminated in 21 of the 30 patients (70%). The high local control rate may be due to the initial tumour shrinkage after chemotherapy.

Paradoxical response of malignant melanoma to methotrexate in vivo and in vitro.

Methotrexate (MTX) shows consistent cytotoxicity for melanoma cells in vitro but it is ineffective in clinical use at equivalent concentrations in vivo. This apparent paradox has been investigated by cell culture techniques and results quantified by cell number. In an in vitro model of high dose MTX therapy followed by leucovorin rescue (HD-MTX-LCR) there was survival of both melanoma and choriocarcinoma cell lines but not of an acute lymphocytic leukaemia cell line. The 70H metabolite of MTX was identified by HPLC in plasma samples of melanoma patients treated by HD-MTX-LCR, in which MTX concentrations approximately 10(-5) M were maintained for 24 h. However, metabolism per se is unlikely to account for the lack of response to MTX clinically. In vitro 70H MTX (10(-7) - 10(-6) M) was two orders of magnitude less cytotoxic for melanoma than MTX (10(-9) - 10(-8) M). The cellular accumulation of [3H]-MTX, using a rapid gradient centrifuge technique for separation of melanoma cells from medium, was reduced in the presence of 70H-MTX. The results suggest that reduced cellular uptake of MTX combined with biochemical rescue of tumour cells may partially explain the paradoxical lack of clinical response of melanoma to the drug.