J. J. Mould

Neoadjuvant bleomycin, ifosfamide and cisplatin in cervical cancer.

SummaryPatients 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.

Radiotherapy in the management of vaginal intraepithelial neoplasia after hysterectomy

Summary. Intravaginal radium was used to treat 11 patients who were found to have vaginal intraepithelial neoplasia (VAIN) following hysterectomy for cervical intraepithelial neoplasia. All were discovered by cytological follow‐up, were colposcopically assessed and diagnosis was confirmed by histological examination before treatment. Nine of 10 patients questioned continue to enjoy satisfactory sexual intercourse after treatment but 6 of 8 premenopausal patients subsequently became oestrogen deficient and required hormone replacement therapy. No other significant morbidity has been observed. All remain cytologically and colposcopically free of disease after a median follow‐up of 26 months. We conclude that radiotherapy is an effective treatment of VAIN following hysterectomy.

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.

A phase II study of ifosfamide in endometrial cancer

SummaryAround 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.

Phase II studies of ifosfamide alone and in combination in cancer of the cervix.

SummaryA 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 >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.

Phase II study of combination 4′-epidoxorubicin and mitomycin C in recurrent epithelial ovarian cancer

SummaryThirty-three evaluable patients who had epithelial ovarian cancer that had not responded to treatment were entered into a phase II study of combination epirubicin and mitomycin C. Epirubicin (65 mg/m2) and mitomycin C (4 mg/m2) were administered separately, each as an i.v. bolus every 4 weeks. Ten patients (30%) had a complete or partial responses. The median duration of response was 20 weeks (range, 9–53). The regimen was well tolerated. Myelotoxicity occurred in four patients requiring hospitalization for septicaemia. Eleven patients had a blood transfusion. Alopecia was common, and nausea and vomiting, though frequent, usually mild. Cardiological toxicity was observed in one patient only. She developed congestive cardiac failure after an acute myocardial infarction. This regimen is active in advanced ovarian cancer that has not responded to prior treatment and warrants further study combination with other active drugs as a first-line regimen for ovarian cancer.

Phase II clinical trials of cisplatin-then-paclitaxel and paclitaxel-then-cisplatin in patients with previously untreated advanced epithelial ovarian cancer

PURPOSEnTo examine the activity and safety of two sequentially scheduled chemotherapy regimens comprising four cycles of paclitaxel (pctx) 200 mg/m2/3 hours then four cycles ofcisplatin (cisDDP) 100 mg/m2, and vice versa, in patients with previously untreated advanced ovarian cancer.nnnPATIENTS AND METHODSnBetween January 1994 and February 1996, we recruited 30 patients to the pctx-then-cisDDP regimen and 29 to cisDDP-then-pctx, in parallel phase II trials.nnnRESULTSnBoth regimens were predictably active with responses seen in 22 of 30 patients (OR 74%; CR 27%, PR 47%) treated with pctx-then-cisDDP, as against 13 of 21 patients (OR 62%; CR 38%, PR 24%) treated with cisDDP-then-pctx. The OR rate to four cycles of pctx (induction) was 43%, with 27% disease progression; the OR to four cycles of cisDDP (induction) was 57%, with 5% progression. However, progression rates across both induction and consolidation phases were 16% (pctx-then-cisDDP) and 29% (cisDDP-then-pctx). Both regimens were unacceptably neurotoxic. II patients suffering grade 3 sensory neurotoxicity (5 on pctx-then-cisDDP, 6 on cisDDP-then-pctx) and 20 having grade 3 deafness (9 on pctx- then-cisDDP, 11 on cisDDP-then-pctx).nnnCONCLUSIONnThe activity of these sequential regimens justifies their further development using the less neurotoxic platinum analogue carboplatin, perhaps combining paclitaxel with other platinum non-cross resistant drugs.

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.

Short-Duration (Three Cycles) Cisplatin Combination Chemotherapy with Alkylating Agent Consolidation in Advanced Epithelial Ovarian Cancer

Abstract Forty-eight patients with advanced epithelial ovarian cancer were treated with a twopart 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/m 2 . 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.

Studies of ifosfamide in cervical cancer

PHASE II-STUDY OF IFOSFAMIDE(IFS) + ADRIAMYCIN(ADM) IN ADVANCED SOFT TISSUE SARCOMA IN ADULTS A PRELIMINARY ANALYSIS. d. SchUtte*, P.Dombernowsky, H.Mouridsen, A. Santorc, W.Stewart, R.Somers, d.Rou~ss@, A.v.Oosterom, G. Blackledge, H.M.Pinedo, D.Green and D.Thomas f o r the EORTC Soft Tissue and Bone Sarcoma Group. *Innere Un ivers i t~ ts k l i n i k und P o l i k l i n i k (Tumor fo rschung) , Essen.