Improved survival after concurrent weekly cisplatin and radiotherapy for cervical carcinoma with assessment of acute and late side-effects.

AIMS: A recent meta-analysis has shown a survival advantage for the addition of concurrent chemotherapy to radiotherapy in the treatment of cervical carcinoma. Controversy persists about the most appropriate chemotherapy schedule and whether similar results for tumour control and toxicity may be achieved with optimally delivered radiotherapy. A single-centre experience of a concurrent chemotherapy regimen is presented. MATERIALS AND METHODS: All women treated with concurrent chemoradiotherapy at a university hospital from 1 January 1999 to 1 May 2002 were identified. Acute and late complications were scored using the National Cancer Institute Common Toxicity Criteria and RTOG/ EORTC system, respectively. Univariate and multivariate analyses were carried out to examine the relationship between demographics, stage, overall treatment time, radiotherapy dose, selectron insertion, number of chemotherapy cycles and occurrence of acute and late toxicity. RESULTS: Seventy-nine women received concurrent weekly cisplatin (40 mg/m2) with radiotherapy. Thirty-eight per cent had early tumours (FIGO IIA or less) and 62% had locally advanced tumours. Twenty-eight per cent of women had surgery as part of primary treatment. Radiation technique included external-beam pelvic radiotherapy (EBRT) (45-50.4 Gy in 25-28 fractions) and medium-dose rate brachytherapy single insertion (25-27 Gy to point A) or EBRT alone. Median overall treatment time was 49 days (range 23-91 days). Three-year survival rate was 87% (95% confidence interval [CI] 79-95%). Three-year, progression-free survival rate was 75% (95% CI 65-85%). At a median follow-up of 35 months: 27 (34%) women experienced 45 episodes of acute grade 3 or 4, and eight women (10%) experienced 12 late grade 3 or 4 complications. CONCLUSIONS: Weekly cisplatin 40 mg/m2 concurrent with radiotherapy is well tolerated when given to an unselected population of patients. Survival rates seem to be excellent, with both local control and overall survival being at least as good as those in published randomised trials.

Randomized trial comparing aminoglutethimide with high-dose medroxyprogesterone acetate in therapy for advanced breast carcinoma.

A total of 218 postmenopausal patients were entered in a prospective randomized trial comparing aminoglutethimide (AG) and high-dose medroxyprogesterone acetate (MPA) as second-line hormonal therapy for advanced breast carcinoma. All responses were assessed by the criteria of the International Union Against Cancer. The response rates were 27% (29 of 106 patients) for AG and 31% (35 of 112) for MPA, but if stabilization of previously progressive disease is included, then the overall response rates were 51% (54 of 106) and 54% (61 of 112) for patients receiving AG or MPA, respectively. There was no difference in response to the two drugs at any site of disease, and the durations of response and survival were identical for the two drugs. The time to response was significantly shorter for patients treated with MPA (median, 8.7 wk) than for those treated with AG (median, 15.3 wk) (chi 2 = 9.96, 1 df, P = .0016). The percentage of patients experiencing toxic effects was equivalent in both arms, although the patterns and time courses of these effects were different.

Combination bleomycin, ifosfamide, and cisplatin chemotherapy in cervical cancer.

We report a phase II study of bleomycin, ifosfamide, and cisplatin (BIP) in cervical cancer. Our aims were to assess response rate, toxicity, and survival in women treated with this combination. Among 49 patients, 34 objective responses (69%) were seen, with 10 complete responses (20%). Toxic effects were assessed in 186 treatment cycles. All patients had alopecia and nausea and vomiting. Other effects included myelosuppression, infection, reduction in renal function, and disturbance of consciousness. These data indicate that BIP is highly active against advanced and recurrent cervical cancer.

Cisplatin, etoposide, and radiotherapy in regional inoperable squamous cell carcinoma of the bronchus.

Thirty-three ambulatory patients with limited stage, inoperable, squamous cell carcinoma of the bronchus were administered cisplatin (60 mg/m2 IV on day 1) and etoposide (VP-16) (400 mg/m2 orally in divided doses over days 3, 4, and 5). This regimen was repeated every 28 days for a maximum of six courses. Radiotherapy was given to patients who did not respond to chemotherapy for urgent relief of local symptoms, or as adjuvant to chemotherapy in responding patients. Response to chemotherapy was assessable in 28 patients. Patients experiencing early death were included in the evaluation. Ten patients (36%) had progressive disease and nine (32%) had stable disease during chemotherapy. Eight patients achieved radiologically verified partial response (PR) and one, a complete response (CR) verified bronchoscopically, yielding an overall response rate of 32%. Of responding patients who proceeded to radiotherapy, one patient showing PR was converted to a CR; another patient with PR improved, although not to CR. The median survival of 33 patients was 49 weeks. There were two deaths among nine responding patients (at 38 and 48 weeks), and nine deaths among 19 nonresponders (six before the 27th week). The principle toxic reactions were nausea and vomiting, which were serious (greater than grade 2) in 29 of 33 patients. All patients receiving more than one course of chemotherapy suffered total alopecia. Cisplatin/etoposide is an effective combination in some patients with regional, squamous cell lung cancer, but randomized trials comparing it to radiotherapy alone are required to establish real survival benefit.

A prospective randomized trial to evaluate different oral dose regimens of medroxyprogesterone acetate in women with advanced breast cancer.

A prospective randomized study was conducted to try to answer two questions: is a loading dose of medroxyprogesterone acetate (1000 mg p.o. q.d.s. for 48 h) superior to conventional dosing; and does an oral maintenance dose of 1000 mg daily offer any advantage over 500 mg daily in women with advanced breast cancer who have failed to respond to, or have relapsed after, tamoxifen? Of 211 patients randomized, 207 were evaluable. There was no improvement in response rates, time to response, response duration or overall survival as a result of the loading dose. When comparing high and low maintenance doses, there was a significant difference in response rates (48% versus 32%; chi 2 = 10.09, df = 2, P = 0.006) and survival (66% versus 41% alive at 12 months; chi 2 = 9.06, df = 1, P = 0.003) in favour of the higher dose regimen, although there was no significant difference in the duration of response. There was no additional toxicity attributable to the loading dose regimen, but side effects were more frequent with the high dose maintenance schedule (141 of 201 adverse effects occurring in these two groups) although the incidence of severe toxicity was similar with both high dose and low dose treatments.

A randomized trial comparing whole abdominal radiotherapy with chemotherapy following cisplatinum cytoreduction in epithelial ovarian cancer. West Midlands Ovarian Cancer Group Trial II.

The potential role of consolidation therapy has been tested in a randomized trial in ovarian cancer. Patients were randomized to receive either whole abdominal radiotherapy using the moving strip technique (n = 56) or one year of chlorambucil (n = 53) following primary surgery, five courses of cisplatinum 100 mg/m2, and second look laparotomy. Overall survival at two years was 35%. There was no significant difference in survival between the two groups, and in spite of the observation that approximately 50% of the patients were optimally debulked prior to consolidation, no subgroups in either arm could be identified who might benefit from consolidation therapy. Toxicity was considerable in both arms, and almost 50% of patients were unable to complete the planned treatment in both arms. These results suggest that after primary surgery and cisplatinum chemotherapy, there is no indication for consolidation therapy with either radiotherapy or alkylating agents.

Alterations in follicular dynamics and steroidogenic abilities induced by heat stress during follicular recruitment in goats.

We investigated the changes in follicular dynamics and steroidogenic activity during heat stress in goats. Adult female goats were exposed to heat stress at 36 degrees C and 70% relative humidity for 48 h and then injected with prostaglandin (PG) F2alpha (the time of PGF2alpha injection was designated as 0 h). In experiment 1, every follicle greater than 2 mm in diameter was monitored by ultrasonography to investigate the follicular dynamics, and plasma concentrations of FSH, LH, progesterone, and oestradiol were measured from -48 h to 120 h. In experiment 2, the follicles were recovered from the goats at 48 h, and the concentration of oestradiol, the aromatase activity, and the LH receptor level in the follicles were determined. In control (non-heat-stressed) goats, ovulatory follicles were mainly recruited from -24 h to 0 h, whereas no follicles recruited during that period were ovulated in the heat-stressed goats. The timing of the recruitment of ovulatory follicles was delayed by heat stress by approximately 24 h. The plasma concentration of oestradiol in the heat-stressed goats was significantly lower from 36 to 54 h compared with the controls, although the concentrations of FSH and progesterone did not differ between the treatments. In addition, the concentration of oestradiol, the aromatase activity, and the LH receptor level in the follicles from heat-stressed goats were significantly lower compared with the controls. These results indicate that heat stress during follicular recruitment suppresses subsequent growth to ovulation, accompanied by decreased LH receptor level and oestradiol synthesis activity in the follicles.

Phase II evaluation of megestrol acetate in previously treated patients with advanced breast cancer: relationship of response to previous treatment.

Thirty-seven patients with advanced breast cancer were treated with megestrol acetate 160 mg daily. All patients except two had been heavily pre-treated with hormonal therapy; eight patients also received chemotherapy. Complete and partial responses occurred in 25% with a mean duration of 5 months (range 2-24 months). A further 38% of patients had static disease for 2 months or greater. Seven patients had previously received medroxyprogesterone acetate, and responses were seen even in patients who had failed to respond to this therapy. This was thought to be due to the higher levels of progestogenic activity which can be routinely achieved with megestrol acetate. Toxicity was minimal, and we would therefore consider that megestrol acetate should be the progestogen of choice in advanced breast cancer.

Phase II study of mitoxantrone in epithelial ovarian cancer.

Forty-six patients with advanced epithelial ovarian cancer were treated with mitoxantrone (14 mg/m2) given iv every 3 weeks. All patients had evaluable disease. Forty-one patients had had previous treatment, 38 with cisplatin. Twelve patients achieved partial response (two had had no previous treatment; ten had received previous treatment with cisplatin with or without other agents); two of the responders, both previously treated with cisplatin, achieved complete clinical remissions. Median duration of response was 24 weeks (range, 10-30). Toxicity was acceptable, with minimal subjective toxicity. Hematological toxicity was dose-limiting, but it was possible to increase the dose on one or more courses by 2 mg/m2 in 16 patients. The drug was given as a bolus, and there was no evidence of acute cardiac side effects. These data suggest that mitoxantrone has significant activity in epithelial ovarian cancer and deserves further study.

Long-term risk of salvage cystectomy after radiotherapy for muscle-invasive bladder cancer.

OBJECTIVES: To establish the long-term outcome for muscle-invasive transitional cell carcinoma of the bladder treated by radiotherapy with or without neoadjuvant cisplatin. METHODS: 159 patients with T2-T4a NX M0 bladder cancer were entered into a prospective randomized trial between June 1984 and June 1988. Follow-up was by 3-monthly cystoscopy in the first year, 6-monthly the next 2 years and yearly thereafter. Salvage surgery was performed at the discretion of the participating clinician. RESULTS: Minimum follow-up was 9 (median 11) years, at which time 29 patients (18%) remain alive. Median survival was 24 months with no difference between the treatment groups (chi(2) = 0.08, p = 0.77). Overall cystectomy rate was 24% (radiotherapy alone 20%, combined therapy 28%; p = 0.24). Median time to cystectomy from primary treatment was 12 months; range 56 days to 10 years. The risk of cystectomy was 11, 10 and 7% for the first, second and third years after radiotherapy respectively, and 8% in total after the third year. The proportion of patients alive in each successive year who had required a cystectomy was between 20 and 30% for 5 of the first 8 years after treatment. CONCLUSIONS: Salvage cystectomy is necessary in a quarter of patients after radiotherapy and this can be needed up to 10 years after treatment. During this time, multiple invasive procedures are likely to be performed, resulting in significant patient morbidity and cost. Patients should be fully counselled about the need for prolonged surveillance and the persisting risk of salvage surgery when deciding between primary cystectomy and radiotherapy.

Cis-diamminedichloroplatinum (DDP) as initial treatment of invasive bladder cancer.

Cis-diamminedichloroplatinum (DDP) was used as the initial treatment in a pilot study of 17 patients with biopsy-proven transitional cell carcinoma of the bladder. No patient had received any previous radiotherapy or chemotherapy. The clinical stages of the tumours were T2 (2 patients), T3 (13) and T4 (2). Before treatment the tumours were assessed by cystoscopy, biopsy, examination under anaesthesia (EUA), computed axial tomography (CT scan) and ultrasound. DDP was given at a dose of 100 mg/m2 intravenously with hydration using mannitol and saline. Each patient received three treatments at 3-weekly intervals. Twelve days after the third treatment, response was assessed by cystoscopy, biopsy, EUA, CT scan and ultrasound. Eleven of the 17 patients had a partial response. Survival was significantly increased in responders compared with non-responders. Seven patients had a low creatine clearance following treatment, 5 had audiograms showing evidence of ototoxicity and 2 developed leucopenia during treatment. This study confirmed the activity of DDP in bladder cancer and showed that it was active in producing a response in the primary tumour in 11 of 17 patients.

Neo-adjuvant (pre-emptive) cisplatin therapy in invasive transitional cell carcinoma of the bladder.

Following 2 pilot studies which showed 57 and 61% response rates to intravenous cisplatin for transitional cell carcinoma of the bladder prior to definitive treatment, the West Midlands Urological Research Group (WMURG) and the Australian Bladder Cancer Study Group (ABCSG) independently began randomised trials to test the survival benefit of neo-adjuvant intravenous cisplatin prior to radiotherapy in T2-T4 M0 transitional cell carcinoma of the bladder. Both trials failed to recruit their target numbers of 250 patients in the West Midlands and 320 in Australia. Since they had similar treatment protocols and eligibility criteria, they were combined in an overview analysis, achieving a total number of 255 patients. Each treatment group was compared with its own control group and the differences were pooled to give an overall result. There was no difference in survival between treated and control patients. The odds ratio was 1.13 with the control groups faring marginally better than the chemotherapy groups. Even with 255 patients the 95% confidence interval of the odds ratio was wide (0.80-1.57). Although there is no clear evidence of a clinically worthwhile benefit from neo-adjuvant cisplatin, this approach must be tested in a larger study using combination treatments with greater activity in metastatic disease.

Phase II study of ifosfamide in cervical cancer.

Thirty patients with symptomatic, progressive squamous cell carcinoma of the uterine cervix no longer amenable to surgery or radiotherapy were entered in a phase II study of ifosfamide (IFX). Patients were treated with IFX (5 g/m2 iv given over 24 hours) and concomitant mesna (total dose, 9.2 g/m2 iv given over 36 hours) every 21 days. One complete response (duration, 10+ months) and nine partial responses were observed, with an overall median response duration of 6.5 months. The median survival of responding patients was 11 months. Objective response rates for lesions arising in previously irradiated sites (four of 22) were significantly lower than for lesions arising in nonirradiated sites (15 of 28) (P = 0.018). There were two treatment-related deaths: one due to leukopenia-associated infection in a patient with peritonitis and severe central nervous system toxicity and one due to central nervous system toxicity without complicating factors. One other patient developed severe but reversible encephalopathy. In all remaining patients hemorrhagic cystitis and hematological and gastrointestinal toxic effects were predictable and manageable. Treatment was delayed for 1 week due to toxicity on seven of 101 occasions: four of these delays were due to mild, reversible impairment of renal function and three were due to leukopenia. Complete though reversible alopecia occurred in 22 of 30 patients. The results indicate that IFX is active in cervical cancer and deserves further study in this setting.

Phase II studies of bleomycin, ifosfamide and cis-platinum in advanced and recurrent cervical carcinoma.

We report the results of phase II studies using a combination of ifosfamide, cis-platinum and bleomycin (BIP) in advanced and recurrent cervical cancer. Fifty-one patients have been studied. In 37 patients with disease not amenable to radical local therapy 27 objective responses (73%) were seen with 7 complete responses. Eleven of 14 patients (79%) with primary inoperable disease had at least a 50% reduction in tumour bulk prior to radical local radiotherapy. All patients experienced alopecia, nausea and vomiting. Other toxicity included myelosuppression, infection, reduction in renal function and disturbance of consciousness. There was no evidence that primary chemotherapy enhanced the acute toxic effects of pelvic radiotherapy. These data indicate that BIP is highly active in cervical cancer and can be used for effective palliation and cytoreduction in more than 70% of patients.

Failure of second-look laparotomy to influence survival in epithelial ovarian cancer.

The survival benefit of second-look laparotomy after completion of primary chemotherapy in patients with epithelial ovarian cancer has been assessed in a prospective randomised trial of 166 patients. Patients were randomised into three groups. All were initially treated with cisplatin (100 mg/m2 x 5) after primary laparotomy. Group A (n = 53) was scheduled to have a second-look laparotomy, followed by cyclical oral chlorambucil. Group B (n = 56) was scheduled to have a second-look laparotomy, followed by total abdominal and pelvic irradiation, and group C (n = 57) received oral chlorambucil as for group A but had no second-look operation. With a median follow up of 46 months (range 21-64), no differences in survival were noted between the three groups. The median survival for group A was 21 months (95% CI 11-31 months), for group B 15 months (11-19), and for group C 17 months (8-26). Thus second-look laparotomy after completion of first-line single-agent cisplatin chemotherapy did not confer any survival benefit on patients with epithelial ovarian cancer.