Apparent improvement in survival for carcinoma of the cervix following the introduction of chemoradiation--a Will Rogers phenomenon.

The improved survival for bulky cervical cancers (> 4cm) reported with combination platinum based chemoradiation (1999) prompted a move away from surgery as these cases frequently received adjuvant radiotherapy and were exposed to the morbidity of multimodality treatment. The period pre-1999 (Group 1) was compared with post-1999 (Group 2) when chemoradiation was the preferred treatment for bulky operable cervical cancer. Significantly more cases were treated surgically among Group 1 compared with Group 2 (79% vs. 62%; P < 0.001). Switching from surgery to radiotherapy improved survival in both treatment categories (73% vs. 78% and 37% vs. 44%, respectively) but with no improvement in overall survival (70%/ov.s 70%). Survival (86%) was similar in both groups among surgically treated women with tumors < 4 cm, but significantly more in Group 2 with negative nodes received postoperative adjuvant chemoradiotherapy (Groups 1 vs. 2; 16% vs.37.5%: P < 0.001) and overall the surgically treated patients received more not less multimodality treatment (46.5% vs. 59%; P = 0.7).

Diagnostic and therapeutic dilemma associated with atypical glandular cells on liquid-based cervical cytology.

BACKGROUND: In 2008, the management of women in Ireland with atypical glandular cells changed to immediate referral to colposcopy. The optimal management of these women is unclear. A balance between the detection of occult disease and overtreatment is required. METHODS: Our study aim was to document the experience of this policy at the National Maternity Hospital, Dublin. Information from the computerized data management system was analysed with the statistical package SPSS. RESULTS: In 2009, 156 women attended colposcopy following a single atypical glandular cell diagnosis on liquid-based cytology. The mean age was 41 years. Thirty (19.2%) women had abnormal vaginal bleeding, 31 (19.9%) were smokers and 34 (21.8%) had received previous treatment. The colposcopy was satisfactory in 125 (80.1%) and unsatisfactory in 31 (19.9%). Cervical histology was available for 146 (93.6%) women: 57 excisional procedures and 89 diagnostic biopsies. Abnormal histology was detected in 46 women (31.5%). Four women (2.7%) had invasive cancer, five (3.4%) had adenocarcinoma in situ, 21 (14.4%) had cervical intraepithelial neoplasia (CIN) grade 2 or 3 and 16 (11.0%) had CIN1. No abnormality was detected in 100 women (68.5%), including 35 (61.4%) of those who had undergone excisional procedures. The colposcopic impression in this group was unsatisfactory in 10 women (28.6%), glandular abnormalities in six (17.1%), high- and low-grade changes in 12 (34.2%) and six (17.1%) women, respectively, and normal in one (2.9%). The findings were essentially negative in the remaining 10 women: overall, 30 (19.2%) of the 156 women referred to colposcopy had at least CIN2. CONCLUSION: This study confirmed significant levels of high-grade disease in women referred to colposcopy with atypical glandular cells on cytology. Concerns about undetected endocervical disease resulted in high levels of negative excisional biopsies. Alternative strategies, including endometrial sampling, human papillomavirus testing and discussion at clinicopathological meeting, should be considered.

Survival in women with ovarian cancer before and after the introduction of adjuvant paclitaxel; a 25-year, single institution review.

Adjuvant chemotherapy regime for ovarian cancer patients remains to be a contentious issue. The aim of this study was to compare the overall and progression-free survival of women with ovarian cancer before and after introduction of paclitaxel in our unit in 1992. A sample of 112 women who received adjuvant therapy following surgery for ovarian cancer was collected, 68 (61%) received platinum+alkylating agent before 1992 and later 44 (39%) received platinum+paclitaxel. Five-year survival was same in both treatment groups when there was no macroscopic disease after surgery (78% versus 70%) and when residual disease was <2 cm (50% versus 40%). Survival was greater in women with residual disease >2 cm in the platinum+paclitaxel group (50% versus 24%), (p = 0.04). However, progression-free survival was similar in both groups irrespective of stage or residual volume of disease. Therefore consideration to selective use of paclitaxel could reduce patient morbidity and costs significantly.

Early stage endometrial carcinoma--a study of management and outcome.

The surgical management of early stage endometrial carcinoma is controversial. The benefits of pelvic lymphadenectomy and administration of radiotherapy in this group have been disputed. We aimed to document the experience of stage 1 endometrial carcinoma at the National Maternity Hospital during the 10 year period 1989-1998 and to evaluate and compare clinical outcomes between retrospectively-assigned low and high-risk tumour groups. Seventy seven women were diagnosed with Stage 1 endometrial carcinoma in this period. Thirty-nine women had low-risk and 38 had high-risk tumours. Women with high-risk tumours were older and had a higher rate of lymph-vascular space invasion by tumour on histological examination. Three women (3.9%) developed disease recurrence and died of their disease; one low-risk and two high-risk tumour patients. Survival without recurrence did not differ between the two risk groups. No consistent pattern existed in surgical staging between the two risk groups. A prospectively-assigned definition of risk would minimise variations in clinical practice by providing a basis for a more tailored approach to adjuvant treatments.

Cervical screening history in patients with early stage carcinoma of the cervix.

This study aimed to examine whether a decade of heightened publicity on issues relating to cervical screening has changed the screening profile of women presenting with cervical cancer at the National Maternity Hospital. The screening history of 100 women diagnosed with early/surgically treated cervical cancer between 1998 and 2002 was compared with a similar study conducted in 1982 /1990. The percentage of women never screened was similar - 24 %( 2002) and 23% (1990). The interval between last recorded smear and diagnosis of disease was greater than 5 years in 45.6% and 41.7% respectively. Overall 60% of women in the recent period had either failed to avail of screening or were not screened within 5 years of diagnosis compared with 64% in 1990. Multiparous women comprised 90% of the study group and 50% of those inadequately screened were attending their general practitioner on a regular basis - therefore affording a potential for opportunistic screening The current method of screening has failed in this group and has not improved in 10 years despite of increased population awareness and greater opportunities for screening than ever before and would support an argument for a National Screening Program.

Phase 1 drug interaction study of suramin and warfarin in patients with prostate cancer.

Potential interaction between suramin and warfarin was evaluated when coadministered to patients with cancer. Thirteen men with advanced hormone-refractory prostate cancer were initially stabilized with warfarin to a prothrombin time (PT) of 2 +/- 0.2 International Normalized Ratio (INR) during a lead-in period of 4 weeks. A baseline daily warfarin dose was established, and treatment with suramin plus hydrocortisone was then started. The effect of suramin on the anticoagulant activity of warfarin was assessed in each patient by comparing his baseline warfarin dose with average daily doses required to maintain the same INR level over each of the initial 6 weeks of a 12-week course of suramin treatment. The average daily dose of warfarin required to maintain PT at 2 +/- 0.2 INR decreased from a baseline value of 4.2 to between 3.4 and 4.0 during the 6 weeks of suramin plus warfarin treatment. Despite failing to demonstrate equivalence applying a 90% confidence interval approach, required reductions in warfarin dose were clinically minor and the combination was well tolerated. Based on these results, the eligibility criteria for a large ongoing randomized study were amended to allow entry of men receiving warfarin therapy. This interaction study, together with experience gained in a larger trial setting, has confirmed that warfarin and suramin can be safely coadministered, provided that coagulation status is appropriately monitored.

Serum prostate-specific antigen decline as a marker of clinical outcome in hormone-refractory prostate cancer patients: association with progression-free survival, pain end points, and survival.

PURPOSE: Validated end points are lacking for clinical trials in hormone-refractory prostate cancer (HRPC). Controversy remains regarding the utility of a posttreatment decline of prostate-specific antigen (PSA). The purpose of this study was to determine whether posttreatment declines in PSA were associated with clinical measures of improvement in a randomized phase III trial of suramin plus hydrocortisone versus placebo plus hydrocortisone. PATIENTS AND METHODS: A total of 460 HRPC patients were randomized to receive suramin plus hydrocortisone (n = 229) or placebo plus hydrocortisone (n = 231). All patients had symptomatic, metastatic HRPC requiring opioid analgesics. Clinical end points evaluated included overall survival, objective progression-free survival (OPFS), and time to pain progression (TTPP). An evaluation of overall survival, OPFS, and TTPP as a function of a PSA decline of > or = 50%, lasting at least 28 days, was undertaken by using a landmark analysis at 6, 9, and 12 weeks. A multivariate analysis of the impact of PSA decline was performed on these clinical end points. RESULTS: A decline in PSA of > or = 50% lasting > or = 28 days was significantly associated with a prolonged median overall survival, OPFS, and TTPP, both in the entire group and the suramin plus hydrocortisone group at all three landmarks in both univariate and multivariate analysis. CONCLUSION: In this prospective, randomized trial of suramin plus hydrocortisone versus placebo plus hydrocortisone, a posttherapy decline in PSA of > or = 50%, lasting 28 days, was associated with prolonged median overall survival, improved median progression-free survival, and median TTPP. This analysis suggests that a posttreatment decline in PSA may be a reasonable intermediate end point in HRPC trials and calls into question the clinical utility of preclinical assays evaluating the in vitro effect of given agents on PSA secretion.

Suramin therapy for patients with symptomatic hormone-refractory prostate cancer: results of a randomized phase III trial comparing suramin plus hydrocortisone to placebo plus hydrocortisone.

PURPOSE: Suramin is a novel agent that has demonstrated preliminary evidence of antitumor activity in hormone-refractory prostate cancer (HRPC). A prospective randomized clinical trial was designed to evaluate pain and opioid analgesic intake as surrogates for antitumor response in HRPC patients with significant, opioid analgesic-dependent pain. PATIENTS AND METHODS: A double-blind, placebo-controlled trial randomized patients to receive a 78-day, outpatient regimen of either suramin plus hydrocortisone (HC, 40 mg/d) or placebo plus HC. Treatment assignment was unblinded when either disease progression or dose-limiting toxicity occurred; placebo patients were allowed to cross-over to open-label suramin plus HC. In addition to pain and opioid analgesic intake, prostate-specific antigen (PSA) response, time to disease progression, quality of life, performance status, and survival were compared. RESULTS: Overall mean reductions in combined pain and opioid analgesic intake were greater for suramin plus HC (rank sum P =.0001). Pain response was achieved in a higher proportion of patients receiving suramin than placebo (43% v 28%; P =.001), and duration of response was longer for suramin responders (median, 240 v 69 days; P =.0027). Time to disease progression was longer (relative risk = 1.5; 95% confidence interval, 1.2 to 1.9) and the proportion of patients with a greater than 50% decline in PSA was higher (33% v 16%; P =.01) in patients who received suramin. Neither quality of life nor performance status was decreased by suramin treatment, and overall survival was similar. Most adverse events were of mild or moderate intensity and were easily managed medically. CONCLUSION: Outpatient treatment with suramin plus HC is well tolerated and provides moderate palliative benefit and delay in disease progression for patients with symptomatic HRPC.

Endometrial pipelle biopsy compared to conventional dilatation and curettage.

Dilatation and curettage (D + C) is the most common operation performed in Britain. The liberal use of D + C has been criticised. The objective of this study was to evaluate the use of outpatient endometrial pipelle biopsy and determine its safety in terms of detecting abnormalities. Complications and financial costs were also evaluated. Data were reviewed from an active gynaecological unit from February 1993 to January 1995. A total of 303 D + Cs and 104 endometrial pipelle biopsies were performed in this period. Nine malignancies were detected by D + C and 1 by pipelle biopsy. A total of 24 and 3 benign abnormalities were detected by each method respectively. There was a higher complication rate in the D + C group but the failure rate was higher in the endometrial pipelle biopsy group. The monetary savings over this period is estimated at 20,307 pounds. There were no missed malignancies to our knowledge over the 8 yr period since endometrial pipelle biopsy was introduced to the hospital.

Recurrent ovarian carcinoma: diagnosis and second-line therapy.

Approximately 10% of patients with ovarian cancer will develop a recurrence. Successful treatment of recurring disease has been documented, and recent developments in chemotherapy are encouraging. In our study, CA125 Tumour Marker was a useful marker to monitor the course of such disease, and detected recurring ovarian cancer at a sub-clinical level, leading to earlier diagnosis. This may have implications for outcome.

Resistance to oxidants associated with elevated catalase activity in HL-60 leukemia cells that overexpress multidrug-resistance protein does not contribute to the resistance to daunorubicin manifested by these cells.

PURPOSE: It has been recognized that enhanced antioxidant defenses can contribute to the resistance of cancer cells displaying multidrug resistance (MDR) that arises in conjunction with the overexpression of P-glycoprotein (Pgp). The purpose of this study was to determine if the defenses against oxidant stress in MDR human leukemia cells (HL-60/AR) that overexpress multidrug-resistance-associated protein (MRP), but not Pgp, contribute to the mechanism of drug resistance in this cell line. METHODS: HL-60/AR cells were evaluated in comparison with wild-type cells with respect to sensitivity to the oxidants hydrogen peroxide (H2O2) and tert-butyl hydroperoxide (t-BuOOH), the activities and amounts of the antioxidant enzymes catalase and glutathione peroxidase (GSH-Px), and the effects that manipulation of the activities of these enzymes may have on cellular sensitivity to the oxidants and to daunorubicin. We also evaluated the ability of the cells to generate daunorubicin semiquinone free radical as measured by electron spin resonance (ESR) spectroscopy. RESULTS: HL-60/AR cells were > 10-fold resistant to the cytotoxic effects of the H2O2 or t-BuOOH as compared with parental, drug-sensitive HL-60 cells. This phenomenon could be attributed largely to elevated activity and protein levels of catalase in HL-60/AR cells. Furthermore, inhibition of catalase by 3-amino-1,2,4-triazole (AT) diminished the resistance of HL-60/AR to these oxidants by > 80% or > 50%, respectively. Despite these findings, AT was incapable of causing sensitization of HL-60/AR cells to the cytotoxic effects of daunorubicin. We found that the activity and amount of selenium-dependent glutathione peroxidase (GSH-Px) was no greater in HL-60/AR cells than in HL-60 cells. Cultivation of cells in selenium-deficient medium caused a marked reduction in GSH-Px activity in HL-60/AR cells and a profound inhibition of GSH-redox cycling manifested by a decrease in baseline hexose monophosphate shunt activity (HMPS) and markedly blunted stimulation of the HMPS by the oxidant t-BuOOH in both wild-type and resistant cells. These variations in GSH-Px activity and GSH-redox cycling, however, were not associated with an alteration in cellular sensitivity to daunorubicin. The failure of catalase inhibition or selenium manipulation of GSH-Px activity to affect daunorubicin cytotoxicity was not due to the inability of these cells to produce free-radical species of daunorubicin, since ESR studies revealed that the generation of daunorubicin semiquinone free radical by HL-60/AR cells was equal to and, in fact, 3-fold that obtained with HL-60 cells. CONCLUSIONS: In comparison with parental HL-60 cells, MRP-overexpressing HL-60/AR cells have demonstrable alterations in antioxidant defenses that are manifested by cellular resistance to the cytotoxic effects of H2O2 and t-BuOOH and by elevated protein levels and activity of catalase. Whether these alterations are epiphenomena or are related to overexpression of MRP remains to be determined. However, it does appear that the enhanced antioxidant defenses observed in HL-60/AR cells do not contribute to the resistance to daunorubicin manifested by this cell line. Although HL-60/AR cells generate daunorubicin semiquinone free radical to an extent equal to or greater than that observed in HL-60 cells, the failure of alterations in GSH-Px activity or inhibition of catalase to change the sensitivity of HL-60/AR cells to daunorubicin suggests that the cytotoxicity of daunorubicin in these cells in not mediated through H2O2 or other peroxide species detoxified by these enzymes.

Outpatient loop diathermy conization as an alternative to inpatient knife conization of the cervix.

A knife cone biopsy of the cervix is usually performed as an inpatient procedure under general anesthesia and is associated with significant morbidity. Loop diathermy conization was performed under local anesthesia on colposcopy outpatients as an alternative to knife conization. In 33 consecutive patients studied the procedure was well tolerated, there were no operative complications, and a satisfactory specimen for histologic examination was obtained in every case. One case of unsuspected invasive cancer and two of suspected microinvasive cancer were diagnosed. The diagnosis of cervical precancer was made in 24 (73%) of the cases. The introduction of outpatient loop diathermy conization of the cervix instead of knife conization would decrease hospitalization costs, avoid the need for general anesthesia and potentially reduce short-term patient morbidity.

En bloc radical vulvectomy and lymphadenectomy with modifications of separate groin incisions.

A new modification of radical vulvectomy and lymphadenectomy through separate groin incisions involves dissection of the intervening skin bridge and allows an en bloc dissection. The results in 26 women treated with this technique are compared with those of seven treated with separate incisions without an en bloc dissection. All 33 women had squamous carcinoma of the vulva and were treated between 1985-1989. The incidence of advanced disease was high, with nodal metastases present in 52% of cases. Dissection of the tissue beneath the skin bridge did not alter the morbidity of the procedure in terms of the incidence of wound infection, number of units of blood transfused, or duration of hospitalization. The only case of an isolated recurrence in the skin bridge occurred in a woman who did not have an en bloc dissection, although there was no significant difference in the overall local recurrence rate between the groups. Further evaluation with larger numbers is required, but we suggest that an en bloc dissection using separate incisions may reduce the risk of isolated recurrence in the skin bridge, particularly in patients with advanced disease.

Distant metastases following surgical treatment of cervical carcinoma.

Fifty patients with early carcinoma of the cervix were treated by radical hysterectomy and pelvic lymphadenectomy. Twelve patients (24%) had positive nodes and received adjuvant pelvic radiotherapy. The mean duration of follow-up was seven years and all patients had at least four years follow-up. Five patients died from recurrence; four from isolated distant metastases and one from a pelvic side wall recurrence. The disease-free interval for patients with distant metastases was six months to two years and the metastases were to lung and bone.

Cytological screening history of patients with early invasive cervical cancer.

The value of population screening for cervical cancer has recently been questioned. The purpose of this study was to examine the cytological screening history in 100 consecutive patients undergoing Wertheim's hysterectomy for early invasive cervical cancer. Twenty three per cent of the patients were never screened; the screening history was unavailable in 11%; the patient was referred appropriately in 21%; there was a delay in referral for gynaecological assessment in 21%; the patient's previous cervical smear before referral was normal in 24%. If population screening in Ireland is to have an impact on mortality from cervical cancer, the results of this study indicate that greater attention needs to be given not only to extending the number of women screened, but also to increasing the frequency of screening and to improving the clinical response to an abnormal smear.

A clinical review of cervicography.

A new investigative modality, cervicography, has been advocated for cervical screening. In the first 51 patients referred for colposcopy because of an abnormal cervicogram, none had invasive cancer and 75% had preinvasive cancer. The cervicogram appears superior to cytology but inferior to colposcopy in the detection of cervical pathology. Based on the available evidence, however, cervicography cannot be recommended for universal screening. It may have a role in the follow-up of patients with a mildly abnormal cervical smear, but the optimum management remains early referral for colposcopy.