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

PURPOSE: To 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. PATIENTS AND METHODS: Between 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. RESULTS: Both 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). CONCLUSION: The 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.

Carboplatin and retroperitoneal fibrosis.

A patient treated for ovarian epithelial cancer by total abdominal hysterectomy (TAH), bilateral salpingo-oophorectomy (BSO), total omentectomy and five courses of single agent carboplatin chemotherapy, developed retroperitoneal fibrosis. This was diagnosed at exploratory laparotomy 6 months after completing treatment. No predisposing drug history existed in this patient. We believe that there have been no previous reports of an association between retro peritoneal fibrosis and carboplatin treatment.

Glycoprotein patterns in normal and malignant cervical tissue.

Glycoproteins from normal and malignant human cervix were studied using an organ culture system and compared by gel electrophoresis and autoradiography. Five glycoproteins of 178 kDa, 95 kDa, 93 kDa, 82 kDa and 38 kDa and 1 glycolipid (46 kDa) were detected more frequently in squamous carcinomas. Certain glycoproteins were shown to be oncofoetal and some had affinity for Concanavalin A (Con A). The 82 kDa glycoprotein was present in 16/17 squamous carcinomas but in only 1/13 normal cervices. This band represented a glycoprotein containing glucosamine, mannose, small quantities of methionine and no fucose. These preliminary results suggest that these glycoproteins and in particular the 82-kDa glycoprotein are worthy of further investigation and characterisation.

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.

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.

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.

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.

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.

The role of ifosfamide in cervical cancer.

A series of phase II studies using ifosfamide as a single agent and in combination with cisplatin and bleomycin (BIP) in advanced and recurrent cervical cancer were coordinated at the West Midlands Cancer Research Campaign Clinical Trials Unit, Birmingham, UK. The aim of these studies was to identify single agents and combination regimens that might be of value for palliation and have potential for neoadjuvant and adjuvant therapy in primary treatment. Ninety-eight patients were studied. Seventy-nine patients with disease not amenable to radical local therapy were treated with single-agent ifosfamide or the BIP combination. In 30 patients treated with single-agent ifosfamide, ten objective responses (33%) were seen, with one complete response. In 49 patients treated with BIP, 34 objective responses (69%) were seen, with ten complete responses (20%). Eleven (79%) of 14 patients with primary inoperable disease had at least a 50% reduction in tumor bulk before radical local radiotherapy. Toxicity resulted in alopecia, nausea and vomiting, myelosuppression, infection, reduction in renal function, and disturbance of consciousness. There was no evidence that neoadjuvant chemotherapy enhanced the acute toxic effects of pelvic radiotherapy. These data indicate that ifosfamide is highly active in cervical cancer and that in combination with bleomycin and cisplatin, it can be used for effective palliation and cytoreduction in around 70% of patients. Ifosfamide-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 randomized trials.

Radiotherapy in the management of vaginal intraepithelial neoplasia after hysterectomy.

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.

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.

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.

Recurrent female pelvic cancer: assessment with transrectal ultrasonography.

Fifty-two women with symptoms or signs suggesting pelvic recurrence of biopsy-proved pelvic cancer were assessed in a prospective trial by clinical examination, transabdominal pelvic ultrasonography (TAU), computed tomography (CT), and transrectal pelvic ultrasonography (TRU). TRU significantly added to the information from TAU in the measurement of abnormalities on the pelvic sidewalls, and to TAU and CT in the measurement of abnormalities in the central and presacral regions of the pelvis. Results of this preliminary study suggest that TRU may provide information complementary to that from CT in women with suspected recurrence of gynecologic cancer.

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 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.

Assessment of bleomycin, adriamycin and mitomycin-C in the treatment of recurrent cervical cancer.

Twenty women with recurrent squamous cell carcinoma of the cervix were treated with bleomycin followed by adriamycin and mitomycin-C. Treatment was repeated every 28 days. In 18 patients who could be assessed there was one complete response and five partial responses (response rate 33%). Two partial responses were seen in 13 lesions arising from previously irradiated sites of disease (response rate 23%). Three complete responses and three partial responses were observed in 10 lesions arising from non-previously irradiated sites of disease (response rate 60%). In all responding cases tumour regression was noted before the end of the third cycle of treatment. Toxicity was predictable and manageable. These results suggest that chemotherapy may be used as a cytoreductive procedure before radical local treatment.

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.