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.

Early serum CA125 response and outcome in epithelial ovarian cancer.

The prognostic value of serum CA125 levels before and after two courses of chemotherapy was assessed in 50 patients with advanced epithelial ovarian cancer. Patients with serum CA125 values below 35 U/ml after two courses were significantly more likely to achieve complete remission and had a significantly longer median survival. In multivariate analysis, serum CA125 levels after two courses were the most important independent prognostic factor: it was possible to predict survival status at 12 months with an overall accuracy of 93%. Serum CA125 can be used to evaluate quantitatively chemotherapeutic response and at an early stage classify patients into good and poor risk groups. Such an approach would facilitate the selection of appropriate therapy and could reduce toxicity.

Experience with bleomycin, ifosfamide, and cisplatin in primary and recurrent cervical cancer.

The unfavorable prognosis for patients with advanced and bulky early stage cancer of the cervix may be improved by initial neoadjuvant cytoreductive chemotherapy. In a phase II study using ifosfamide in combination with cisplatin/bleomycin (BIP) in advanced and recurrent cervical cancer, we demonstrated a response rate of 69%. To determine whether this high response rate was a result of patient selection, and to assess the influence of combination chemotherapy on survival in patients with recurrent disease, a retrospective analysis of five phase II studies of bleomycin, ifosfamide, and cisplatin combinations was performed. The type of chemotherapy regimen (BIP v others) was the most significant factor in determining the likelihood of response. Combination chemotherapy did not appear to confer a survival advantage in patients with recurrent disease. The BIP regimen produced rapid responses with acceptable toxicity, and had potential for use as neoadjuvant therapy prior to radical radiotherapy in patients with advanced and bulky early stage disease. In an initial pilot study of this approach, 13 of 19 patients (68%) with primary inoperable disease had significant tumor regression prior to radical local radiotherapy. Interim analysis of the first 66 patients entered into a randomized study evaluating this approach has shown complete clinical tumor resolution after radical radiotherapy in 24 of 32 patients (75%) treated with up to three cycles of BIP prior to radiotherapy compared with 19 of 34 patients (56%) treated with radiotherapy alone. There has been no evidence that neoadjuvant chemotherapy enhances the acute toxic effects of pelvic radiotherapy. Therefore, this approach has potential to improve therapeutic outcome in patients with poor-prognosis primary disease.

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.

Residual disease after cone biopsy: completeness of excision and follow-up cytology as predictive factors.

Residual disease was identified in the hysterectomy specimen in 19 of 65 patients (29%) previously found to have cervical intraepithelial neoplasia and in four of 19 (21%) found to have early stromal invasion on histologic examination of a cone biopsy. Residual disease was found in six of 34 cases (18%) of cervical intraepithelial neoplasia and zero of 12 cases of early stromal invasion after complete excision, and in 13 of 31 cases (42%) of cervical intraepithelial neoplasia and four of seven cases (57%) of early stromal invasion after incomplete excision by cone biopsy. Sixteen of 28 women (57%) with abnormal cytology after cone biopsy were found to have residual disease at the time of hysterectomy. In contrast, no residual disease was found in 35 patients who had no evidence of cytologic abnormality after the initial treatment. The finding of abnormal cytology after cone biopsy is shown to be a more useful prognostic indicator than histologic examination of excision margins. Therefore, we believe that a policy of expectant management, based on regular cytologic examination, is justified when histologic assessment has shown the lesion to extend to the line of excision.

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.

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.

The potential for adjuvant therapy in early-stage cervical cancer.

Adjuvant therapy may potentially improve prognosis in women with early-stage cervical cancer who are at high risk of relapse after primary therapy. Patients with lymph node involvement at surgery are at high risk of recurrence and may benefit from adjuvant therapy, but many patients are treated with radical radiotherapy. At present there is no method of accurately identifying patients at high risk of recurrence in the latter group. A retrospective analysis of 141 surgically managed cases with stage I/II a cervical cancer is presented. The study aims were to characterize patients at high risk of relapse, identify independent prognostic variables predicting for relapse and, using these variables, develop a model, that would accurately predict high-risk patients. Univariate analysis identified depth of invasion, substage, lymph node involvement, lymphatic and blood vessel invasion and tumour differentiation as significant prognostic variables. After stratification for depth of invasion, which did not conform to the proportional hazards assumption implicit in the Cox model, Cox regression analysis showed substage, lymphatic and vascular invasion and histological tumour type to be independent prognostic variables. Using these variables, classification models were constructed that would be applicable to patients treated with either surgery or radiotherapy. Applying the models to 110 cases with greater than 18 months follow-up, 11/18 (61%) and 11/19 cases (58%) predicted as being at high risk of relapse have developed recurrence. Highly active chemotherapy is now available for this disease. We have demonstrated that combined bleomycin, ifosfamide and cisplatin (BIP) is one of the most active regimens in this disease. BIP produces cytoreduction in around 70% of patients with recurrent and primary advanced disease. Responses are achieved rapidly and acute radiotherapy toxicity is not enhanced by giving chemotherapy prior to radical local radiotherapy. A multicentre, prospective randomized trial testing the role of BIP as adjuvant therapy in patients with positive nodes at radical hysterectomy is now in progress. A complementary study testing the role of adjuvant chemotherapy in high-risk patients treated with radical radiotherapy is in preparation.

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.

A pilot study using 99mTc to measure lead and platinum in the human kidney.

A pilot study has been conducted to investigate the hypothesis that the chemotherapeutic drug, cisplatinum, can mobilize skeletal lead. In vivo measurements of lead and platinum in the kidney of chemotherapy patients were performed with the technique of x-ray fluorescence, using 99mTc in a backscatter geometry. The results of the pilot study were inconclusive; the majority of patients exhibited no evidence of kidney lead at the level of system sensitivity, and negligible blood and urine lead levels.

Can we predict a high risk group in stage I epithelial ovarian cancer?

A retrospective review of 373 patients with stage I invasive epithelial ovarian cancer was undertaken over a 5 year period to develop a model to characterize the patient at high risk. Actuarial 5-year survival was 70%. To identify factors with an independent effect on 5-year survival, a logistic regression analysis was performed. Adjuvant chemotherapy, histologic grade and peritoneal washings, were identified as independent variables. A model to determine the predictivity of survival was created using a learning sample (2/3 of the cases) and the model was then used to reclassify a validation sample (1/3 of the cases). Using all the independent variables, outcome was predicted correctly in 78% of cases. However the model failed to improve identification of those at risk of recurrence (specificity of 53%).

Characterization of high- and low-grade cervical intraepithelial neoplasia.

A need exists to characterize the various grades of cervical intrapithelial neoplasia (CIN), and attempt to differentiate between high- and low-grade lesions, that may have different behavioral and progressive potentials. The identification of patients with high- or low-grade CIN is useful, as it may allow identification of those patients that have true cancer precursors. Fifty patients referred for colposcopy with abnormal cytology were studied. Univariate analysis identified three factors as important predictors of histologic grade; the colposcopic opinion, lesion surface area and the index cytology (P < 0.005). Colposcopic opinion was associated with the index cytology (P < 0.01) and the lesion surface area (P < 0.005). Only the colposcopic opinion and the index cytologic smear appeared in the final model using a stepwise logistic regression analysis, indicating their independent prognostic importance in prediction of grade of abnormality in cervical intraepithelial neoplasia. The study demonstrates the value of colposcopic training and experience being necessary prior to utilizing excisional treatment methods if overtreatment is to be avoided.

The effect of ethnic origin on the rate of spontaneous late mid-trimester abortion.

The effect of ethnic origin on perinatal outcome is well recognized. An effect on the rate of spontaneous abortion has not been previously documented, to our knowledge. We report the results of a retrospective survey of late mid-trimester abortions (20 to 26 weeks gestation) at Dudley Road Hospital, Birmingham, England. The aims of the study were to document the rate of spontaneous late mid-trimester abortion by ethnic origin and to define any differences in these groups, both medically and as a result of histological examination of the abortus, that might account for observed differences. Over an 18-month period, during which 6508 infants beyond 26 weeks gestation were delivered, 30 late mid-trimester spontaneous abortions occurred (13 black, 10 white, 7 Asian). Abortion rates per 1000 deliveries were 12.9 for blacks, 3.6 for whites, and 2.7 for Asians. The differences between ethnic groups were statistically significant (chi 2 = 17.4; P = .0002). The black women experiencing spontaneous mid-trimester abortion were of higher mean parity and were more likely to have undergone a previous therapeutic termination. Review of pathology reports revealed more cases of chorioamnionitis and fetal pneumonia in this group. Although these results should be interpreted with caution, a relationship clearly exists between ethnic origin and late mid-trimester loss. Further study is warranted to establish the cause.

Loop diathermy excision of the cervical transformation zone in patients with abnormal cervical smears.

OBJECTIVE: To determine the efficacy and morbidity of fine loop diathermy excision of the cervical transformation zone as applied to the management of outpatients with abnormal cervical smears. DESIGN: Prospective programme trial with six month follow up. SETTING: Two hospital based colposcopy clinics. PATIENTS: 616 Patients aged 16-60 with abnormal cervical smears. INTERVENTIONS: After colposcopic and cytological assessment excision of the cervical transformation zone by fine loop diathermy under local anaesthesia in the outpatient department. MAIN OUTCOME MEASURES: Time to complete the treatment, immediate morbidity in terms of discomfort and bleeding, and cytological and colposcopic findings at six months. RESULTS: Treatment was completed in a mean of 3.47 minutes (SD 1.99). Immediate morbidity was minimal, and histological specimens were adequate in over 90% of cases. Almost two thirds of patients were treated at their first visit to the clinic. 58 Patients (9.4%) failed to attend for follow up at six months and one had had a hysterectomy. Of the 557 patients who attended for colposcopic and cytological follow up at six months, 506 (91%) were normal cytologically and 19 (3.4%) had histologically confirmed persistence of cervical intraepithelial neoplasia. The overall confirmed failure rate of the technique was 4.4%. CONCLUSION: Loop diathermy excision is an effective treatment with low morbidity and is an appropriate modality for patients with abnormal cervical smears.

Groin recurrence following Stage 1A squamous cell carcinoma of the vulva.

BACKGROUND: It has been well established that stage 1 squamous cell carcinomas of the vulva with a depth of stromal invasion less than 1 mm have a <1% risk of lymph node involvement. The treatment for these stage 1A tumours has therefore been to perform radical wide local excision without removal of groin nodes. CASE: We present two cases of stage 1A microinvasive cancer of the vulva that presented with groin recurrence 3 months and 3 years following their primary surgery respectively. CONCLUSION: The current management of stage 1A tumours may need to be re-evaluated to include some form of lymph node assessment in view of these rare but nonetheless aggressive tumours.

Colposcopically directed punch biopsy: a potentially misleading investigation.

OBJECTIVE: To determine the relation between the histology of an initial colposcopically directed punch biopsy and a subsequent diathermy loop excision biopsy of the transformation zone, and the effect of lesion size on this relation. DESIGN: Prospective observational study of loop diathermy excision biopsies of the cervical transformation zone. SETTING: Academic unit colposcopy clinics at The Birmingham and Midland Hospital for Women and Dudley Road Hospital, Birmingham. SUBJECTS: 243 women managed by colposcopy and directed punch biopsy followed by loop diathermy excision. OUTCOME MEASURES: The histology of the punch biopsy and the excised transformation zone and the size of the abnormal lesion. RESULTS: In 132 (54%) of the 243 women the histology of the punch biopsy and loop excision specimen did not agree. In 62 (47%) of these 132 women a more severe lesion was found in the excised transformation zone, including three unsuspected adenocarcinoma in situ and one stage Ia1 cancer. In 39 (41%) of the 96 women in whom a lesion of CIN 3, or greater severity, was found in the loop excision specimen, the paired punch biopsy had suggested a lesion of lesser severity. In small area lesions, the punch biopsy was more likely to show more severe disease than the loop excision specimen (P = 0.0014). CONCLUSIONS: The results suggest that directed punch biopsy is an inadequate endpoint by which to judge the severity of an epithelial lesion. The findings have important implications for patient management and the design of trials and cast doubt on the results of studies using punch biopsy as an endpoint.

Problems of peritoneal access in intraperitoneal treatment and monitoring of ovarian cancer.

A total of 154 peritoneal lavages was attempted through either a permanent (17) or a temporary percutaneous cannula (137) in 59 ovarian cancer patients undergoing intraperitoneal treatment or monitoring. Seven of the eight permanent catheters were removed because of complications; intraperitoneal adhesions were a major problem in this group. Overall, 137 temporary catheters were inserted (14G Venflon i.v. cannula in 119, Verres needle in 15, and a Trocath peritoneal dialysis catheter in 3 instances) but it was not possible to perform a peritoneal lavage in 42 (30%). Access to the peritoneal cavity was unsatisfactory on 29 (34%) occasions when a Venflon cannula was used, either because there was inadequate flow of lavage fluid into the peritoneal cavity or this was limited by pain. Perforation of the bowel occurred in 12 (9%) cases but there was no significant morbidity. Problems with achieving reliable peritoneal access using either permanent or temporary catheters may limit the potential advantages of the intraperitoneal route for treatment and monitoring.