Casodex--mechanisms of action and opportunities for usage.
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Androgen Antagonists↗
Biomedical subjects
G Blackledge
Publications and source records attributed to G Blackledge.
Single agent high-dose cisplatin (200 mg m-2) treatment in ovarian carcinoma.
Twenty patients with epithelial ovarian carcinoma were treated with high-dose cisplatin 200mg m-2. Patients were to receive three cycles at 21 day intervals. Treatment was stopped if severe myelosuppression or any neurotoxicity occurred. Overall, eight (40%) of patients responded with a complete response in five (25%). Four of 16 (25%) previously treated patients responded. The median duration of response was 44 weeks (range 6-130). In patients previously treated there was a significant association (P < 0.002) between response and a remission free interval of 52 weeks or more from primary chemotherapy. Toxicity was assessable in 18 patients. Alopecia and nausea/vomiting were common. Myelosuppression was recorded in nine patients delaying planned administration in eight of 35 cycles. Five patients developed anaemia and six thrombocytopenia. Neurotoxicity affected seven patients and varying degrees of tinnitus six patients. Neurotoxicity and myelosuppression were indications for cessation of treatment in 8 patients receiving less than three cycles. Analysis revealed no significant association between toxicity and prior cisplatin exposure, age or the amount of high-dose cisplatin administered. This series reveals that it is possible to achieve good response rates using high-dose cisplatin without encountering debilitating neurotoxicity.
Adult↗
Experience with ifosfamide in the EORTC Soft Tissue and Bone Sarcoma Group.
The Soft Tissue and Bone Sarcoma Group of the European Organization on Research and Treatment of Cancer has conducted a number of studies of chemotherapy in advanced disease over the past 15 years. Following the discovery that the CYVADIC regimen (cyclophosphamide/vincristine/doxorubicin/dimethyl imidazole carboxamide) was less active than had been reported originally, the individual components of CYVADIC were studied. This showed that doxorubicin had considerable activity and that ifosfamide 5 g/m2 given over 24 hours was at least as active as cyclophosphamide. Subsequent studies have therefore centered on a combination of doxorubicin and ifosfamide. A large randomized trial showed no significant benefit of doxorubicin/ifosfamide over single-agent doxorubicin, but the doses of doxorubicin were different. More recently, using bone marrow growth factors, it has been possible to increase the doxorubicin dose to that given as a single agent and also maintain the ifosfamide dose. This is now being tested in a randomized trial to determine whether improved response rates and other indicators of outcome will be seen.
Antineoplastic Combined Chemotherapy Protocols↗
Interferon-alpha 2b in the treatment of follicular lymphoma: preliminary results of a trial in progress.
Since 1985 the combination of chlorambucil (10 mg daily, initially for six weeks, then alternating fortnights for 12 weeks) and interferon-alpha 2b (Schering-Plough; 2 x 10(6) U/m2 three times weekly by subcutaneous injection for 18 weeks) has been compared in a randomised trial with chlorambucil alone in previously untreated patients with stage III or IV follicular lymphoma. Responding patients have subsequently been randomised to receive maintenance interferon-alpha 2b or no further treatment. Of the 124 treated patients, 108 are evaluable for response with a median follow-up of 30 months. The major toxicity was myelosuppression which was more frequent with chlorambucil and IFN alpha 2b in combination than with chlorambucil alone (P less than 0.01). There was no treatment-related mortality. Actuarial survival at three years is 75% for all patients, regardless of therapy. There was no significant difference in response rate according to initial therapy. For the 60 patients achieving a good response to initial therapy who have entered the second part of the trial, there has been a significant prolongation of remission duration in favour of maintenance IFN-alpha 2b (median not yet reached versus two years for the 'no treatment' arm, P less than 0.015). Fewest relapses have been seen in patients who received IFN-alpha 2b throughout. Accrual to this trial continues; this preliminary analysis indicates that maintenance IFN-alpha 2b may extend remission duration in follicular lymphoma.
Adult↗
Doxorubicin plus ifosfamide with rhGM-CSF in the treatment of advanced adult soft-tissue sarcomas: preliminary results of a phase II study from the EORTC Soft-Tissue and Bone Sarcoma Group.
Doxorubicin and ifosfamide are the two most active agents used in the treatment of advanced inoperable soft-tissue sarcoma, but their use in combination produces dose-limiting myelosuppression. To explore the feasibility of combining optimal doses of both drugs, doxorubicin (75 mg/m2) and ifosfamide (5 g/m2) were given every 3 weeks with recombinant human granulocyte/macrophage-colony-stimulating factor (rhGM-CSF; 250 micrograms m-2 day-1) by subcutaneous injection for up to 14 days after each course. A total of 52 patients with progressive metastatic soft-tissue sarcoma were entered, none having received prior chemotherapy. One patient was ineligible and received no treatment after registration. Preliminary analysis of six cycles of chemotherapy revealed that the full protocol dose intensity had been administered to the majority of patients. Although the median leucocyte and neutrophil counts did not fall with subsequent courses of chemotherapy, the duration of neutropenia increased with each course delivered. Cumulative thrombocytopenia was a major dose-limiting toxicity and was the main reason for any dose modifications that occurred. Although 26 patients experienced infections after one or more courses of treatment, in only 7 was admission required for parenteral antibiotics. One patient died as a result of septicaemia after the first cycle of treatment. To date, there have been 22 responses (43%) with 8% complete remissions. It appears that the administration of rhGM-CSF allows this high-dose regime of chemotherapy to be given safely and the early encouraging response rate adds support to the concept that increasing the dose of doxorubicin improves the outlook for patients with advanced soft-tissue sarcomas.
Adult↗
Short-duration (three cycles) cisplatin combination chemotherapy with alkylating agent consolidation in advanced epithelial ovarian cancer.
Forty-eight patients with advanced epithelial ovarian cancer were treated with a two-part cytotoxic regimen consisting of three cycles of cisplatin-based induction therapy followed by five cycles of escalating doses of cyclophosphamide, all given at 3-weekly intervals. The total cisplatin dose was 225 mg/m2. Seventeen patients with optimal primary surgery received chemotherapy only, while 17 of the 31 patients with suboptimal primary surgery underwent optimal interval cytoreductive surgery at the end of induction (cisplatin) therapy. Median survival for all patients was 15.4 months. Median survival was 15 months for patients with optimal primary surgery and 22 months for patients who had optimal secondary cytoreduction. Only 10 patients suffered WHO grade 3 or greater toxicity during therapy. This study suggests that the total dose of cisplatin can be reduced for patients with advanced ovarian carcinoma, resulting in reduced overall toxicity, without compromising response or response duration. A randomized trial to test this concept is now underway.
Antineoplastic Combined Chemotherapy Protocols↗
Phase II study of nimustine in metastatic soft tissue sarcoma. European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group.
The EORTC Soft Tissue and Bone Sarcoma Group has conducted a phase II trial in 33 eligible patients with metastatic soft tissue sarcoma with nimustine 100 mg/m2 every 6 weeks. In 31 evaluable patients there were 3 (10%) partial responses lasting 4.5, 6 and 7.5 months, and 5 cases of stable disease. 12 patients had progressive disease and 11 patients early progressive disease. Toxicity consisted mainly of leukopenia and thrombocytopenia and nausea and vomiting. It is concluded that nimustine has only minor activity in soft tissue sarcoma.
Adult↗
EORTC joint ventures in quality control: treatment-related variables and data acquisition in chemotherapy trials.
In multicentre studies, non-compliance with the protocol may limit the chances of reaching a correct conclusion. A procedure to examine the administration of chemotherapy in multicentre EORTC protocols has been developed. General aspects are covered in a mailed questionnaire on the prescription of drugs with rounding up or down of dosages, local facilities for preparation and the procedure for preparation and administration. More detail is collected during a quality control site visit. Ten centres have been visited and there was significant variation between centres in the organisation of chemotherapy administration. However, more striking differences were noted between the type and quality of hospital files. The lack of systematic recording of sequence, timing and doses of chemotherapy and, in particular, treatment related toxicity, is a major difficulty limiting the effectiveness of quality control. These shortcomings emphasise the need for standardisation of some aspects of case records and a suggested check-list has been drafted.
Antineoplastic Agents↗
Interferon alfa-2b in addition to chlorambucil in the treatment of follicular lymphoma: preliminary results of a randomized trial in progress.
One hundred and twenty four patients with follicular lymphoma (32 with Stage III and 92 with Stage IV disease) have been randomized to receive chlorambucil alone or chlorambucil plus interferon alfa-2b. Responding patients are then randomized to receive either interferon alfa-2b maintenance therapy for up to 12 months or no further treatment. One hundred and eight patients are evaluable for response, the remainder are still receiving initial therapy. Clinical remission (complete or good partial remission) was achieved in 42/59 (71%) patients receiving chlorambucil alone and in 27/49 (55%) patients receiving the combination (P = NS). Preliminary analysis of remission duration shows a trend in favour of those patients receiving interferon throughout (P = 0.02). There is no significant difference between the groups in terms of survival, at a median follow up of 2.5 years. Interferon-associated toxicity was minor in most patients but led to discontinuation of therapy in six cases. Larger trials with longer follow-up periods are needed to confirm the beneficial role of interferon in the treatment of follicular lymphoma.
Adult↗
Out-patient peritoneal lavage cytology in the detection of residual epithelial ovarian cancer.
Peritoneal lavage fluid cytology was performed in 87 out-patients with histologically proven epithelial ovarian cancer undergoing primary management. A total of 246 peritoneal lavages were attempted, usually with temporary cannulae (n = 229). From these, 184 samples were obtained, of which 156 (85%) were suitable for cytological analysis. The sensitivity of peritoneal lavage fluid cytology in 67 patients with known residual disease was 57% whereas serum CA 125 levels were elevated in 58 (87%). Pre- and post-treatment peritoneal lavage fluid cytology had prognostic value, but this was less than that of serum CA 125 measurements.
Adult↗
Association between serum albumin and mortality from prostatic cancer.
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Humans↗
Feasibility and outcome of complete secondary tumor resection for patients with advanced ovarian cancer.
From November 1981 to July 1985, 124 women with International Federation of Gynecology and Obstetrics (FIGO) stage III ovarian cancer were treated in prospective studies of surgery and chemotherapy in our institution. Patients with no macroscopic cancer after primary surgery (n = 16) received five cycles of adjuvant cis-platinum; those with residual cancer after primary laparotomy (n = 108) underwent a second surgical debulking after three or five cycles of cis-platinum-based cytoreductive chemotherapy. Total macroscopic tumor clearance was achieved in 26 of these 108 patients. Fourteen patients with total tumor excision at primary laparotomy remain in complete clinical remission a minimum of 36 months after diagnosis, but the median progression-free interval for the other two groups was 9 and 17 months, respectively. The survival for women who have total tumor clearance only at secondary surgery after chemotherapy is inferior to that for women with primary macroscopic tumor excision followed by chemotherapy.
Adult↗
A phase II study of ifosfamide in endometrial cancer.
Around 32% of all patients with endometrial carcinoma relapse after primary therapy. The outlook for these patients is poor. Ifosfamide (IFX) has activity in a number of gynaecological malignancies and was selected for evaluation in this disease. The aims of this study were to assess the activity and toxicity of IFX in recurrent endometrial carcinoma no longer amenable to radical local treatment. In all, 16 evaluable patients with symptomatic advanced metastatic or recurrent disease entered a phase II study of this drug. Patients received IFX (5 g/m2) as a 24-h infusion, with mesna (8 g/m2) given during and for 12 h following IFX to prevent urothelial toxicity. Treatment was repeated every 21 days. Two patients showed evidence of response [one complete response (CR) of 3 months and one partial response (PR) lasting 5 months]. Most patients experienced nausea and vomiting, and WHO grade 3/4 alopecia invariably occurred after two or more cycles. Four patients developed severe (grade 3/4) IFX/mesna CNS toxicity, and four other patients had mild (grade 1/2) CNS toxicity. Significant myelosuppression was seen in 3/41 cycles. Haematuria was uncommon and invariably mild. There were two toxic deaths (one due to grade 4 CNS toxicity and one due to septicaemia). IFX has activity in endometrial carcinoma, but responses are of limited duration and toxicity is considerable.
Adenocarcinoma↗
Phase II studies of ifosfamide alone and in combination in cancer of the cervix.
A series of phase II studies using ifosfamide (IFX) as a single agent and in combination with cisplatin and bleomycin (BIP) in advanced and recurrent cervical cancer have been coordinated at the West Midlands CRC Clinical Trials Unit (Birmingham, UK). The aims of these studies were to identify single agents and combination regimens that may be of value for palliation and have potential for use as neoadjuvant and adjuvant therapy at the time of primary treatment. A total of 79 patients with disease non-amenable to radical local therapy were treated with single-agent IFX or the BIP combination. In 30 patients treated with single-agent IFX, 10 objective responses (30%) were seen, with 1 complete response. In 49 patients treated with BIP, 34 objective responses (69%) were seen, with 10 complete responses (20%). Toxicity included alopecia, nausea and vomiting, myelosuppression, infection, reduction in renal function and disturbance of consciousness. These data indicate that IFX is highly active in cervix cancer and, in combination with bleomycin and cisplatin, can be used for effective palliation and cytoreduction in greater than 70% of patients. IFX-containing regimens have potential for use as neoadjuvant and adjuvant therapy in patients at high risk of recurrence with conventional treatment. These hypotheses are currently being tested in prospective randomised trials.
Adult↗
Neoadjuvant bleomycin, ifosfamide and cisplatin in cervical cancer.
Patients with advanced and bulky early-stage cancer of the cervix have an unfavourable prognosis, which may be improved by initial neoadjuvant, cytoreductive chemotherapy. In a phase II study, coordinated at the West Midlands CRC Clinical Trials Unit, Birmingham, using ifosfamide (IFX) in combination with cisplatin and bleomycin (BIP) in advanced and recurrent cervical cancer, we demonstrated a response rate of 69%. This regimen produces rapid responses with acceptable toxicity and has potential for use as neoadjuvant therapy prior to radical radiotherapy in patients presenting with advanced and bulky early-stage disease. In an initial pilot study of this approach, 13 of 19 patients (68%) with primary inoperable disease showed significant tumour regression prior to radical local radiotherapy. Interim analysis of the first 66 patients entered into a randomized study evaluating the value of this approach has shown complete clinical tumour resolution after radical radiotherapy in 24/32 patients (75%) treated with up to three cycles of BIP prior to radiotherapy vs 19/34 patients (56%) treated with radiotherapy alone. There was no evidence that neoadjuvant chemotherapy enhances the acute toxic effects of pelvic radiotherapy. This approach has the potential for improving the outlook in patients with poor-prognosis primary disease.
Adult↗
A five-drug alternating chemotherapy regimen for patients with advanced epithelial ovarian cancer.
Twenty-six patients, 22 previously untreated, with FIGO stage III/IV epithelial ovarian cancer were treated with a five-drug combination regimen consisting of cycles of cisplatinum (60 or 75 mg/m2 IV) and cyclophosphamide (600 or 750 mg/m2 IV) [CP], alternating every 3 weeks with cycles of adriamycin [50 mg/m2 IV], bleomycin [15 mg IV], and chlorambucil [6 mg/m2 orally for 7 days] [ABC]. A total of six cycles, CP x 3 and ABC x 3, were planned. There was a 67% response rate with 7 complete and 5 partial remissions in 18 patients with evaluable disease. Median progression-free interval was 13 months and median survival 24 months for the whole group. The regimen was well tolerated with WHO toxicity greater than 2 in only 5 patients and treatment delay occurring in only 18 of 128 cycles [14%] in 11 patients. The toxicity of combination cytotoxic regimens can be reduced by alternating cycles of therapy. A randomized trial comparing such a regimen with nonalternating therapy would be necessary to determine whether the response rate and duration of response are compromised when the cumulative dose of cisplatinum is reduced.
Aged↗
Ifosfamide plus doxorubicin in previously untreated patients with advanced soft tissue sarcoma. The EORTC Soft Tissue and Bone Sarcoma Group.
The objective of this phase II trial was to assess the therapeutic activity and toxicity of doxorubicin plus ifosfamide in previously untreated patients with advanced soft tissue sarcoma. Treatment was doxorubicin 50 mg/m2 followed by a 24 h infusion of ifosfamide 5 g/m2 plus mesna 2.5 g/m2 repeated every 3 weeks until disease progression or unacceptable toxicity occurred. Of 203 patients entered, 175 were evaluable for response. The response rate was 35% (95% CI 28-42%), with 9% of the patients achieving a complete remission and 26% a partial remission. The median time to progression was 29 weeks for all evaluable patients, and 67, 40 and 28 weeks for complete and partial responders and patients with stable disease, respectively. The median duration of survival was 58 weeks. Myelosuppression was the dose-limiting toxicity, resulting in leukopenia (WHO grade 3 and 4) in 73% of evaluable treatment courses. Other side-effects were rare and usually well manageable.
Adolescent↗
Doxorubicin in relapsed soft tissue sarcoma: justification of phase II evaluation of new drugs in this disease. An EORTC Soft Tissue and Bone Sarcoma Group Study.
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Adult↗