Sheldon Weiner

Second-look laparotomy in epithelial ovarian carcinoma. Prognostic factors associated with survival duration

This article that reports on 70 consecutive patients is one of only a few studies of advanced ovarian cancer that have attempted to define predictive factors associated with survival duration after second‐look laparotomy. As in many other investigations, several factors have been analyzed for predicting second‐look outcome. The prognostic variables analyzed in this study included age, stage, histologic grade, residual disease status after initial surgery, and type (cisplatin versus no cisplatin) and number of cycles of chemotherapy. Only stage (P = 0.002) and optimal disease (less than 2 cm residual tumor size) after initial surgery (P < 0.001) were significantly associated with the absence of disease at second‐look laparotomy, and both were significant predictors of second‐look outcome in a multivariate logistic regression model. Their impact on actuarial survival after second‐look laparotomy diminished, however. Actuarial survival after second‐look laparotomy was associated with residual tumor size at second‐look surgery (P = 0.02). According to second‐look findings, the 3‐year actuarial survival rates and standard errors were as follows: no pathologic evidence of disease, 80.7% ± 13.4% 3‐year survival; microscopic disease plus less than or equal to 2 cm residual disease, 49.1% ± 13.1% survival; and gross residual disease (i.e., greater than 2 cm maximum tumor diameter), 29.5% ± 11.4% survival. We also examined the effect of extensive tumor resection at second‐look laparotomy on survival for patients with greater than 2 cm gross residual disease. Optimum resection (less than 2 cm residual tumor mass) resulted in significantly greater survival than suboptimum resection (P < 0.001). This strongly suggests that there is a survival advantage associated with optimum resection at second‐look laparotomy.

Tamoxifen therapy in recurrent epithelial ovarian carcinoma

Thirty-seven patients with recurrent epithelial ovarian carcinoma were entered into a trial of tamoxifen therapy (10 mg BID) to determine the effect on long-term survival. Thirty-one patients were evaluable with follow-up ranging from 6 to 42 months since initiation of hormonal therapy. All patients were heavily pretreated with multiple chemotherapeutic regimens (median 3). There was 1 complete responder (3.2%), 2/31 (6.4%) had a partial response, 6/31 (19.3%) had stable disease, and 22/31 (71%) had progressive disease. Twenty-four patients are dead (23 from advanced carcinoma, 1 from cardiac causes); 5 patients are alive with disease; 2 patients are lost to follow-up. Median survival of nonresponders was 7 months versus 16 months for responders (CR + PR + stable disease) (P = 0.001 life table analysis). Of the 9 responders, 7 had poorly differentiated tumors (grades 3 or 4), and 2 had moderately differentiated tumors (grade 2). Eleven patients had estrogen and progesterone receptor studies (ER, PR). No correlation between response rate and receptor status was evident. We conclude that although significant disease regression is unlikely to result from tamoxifen therapy, there may be a subset of patients who can benefit from the cytostatic properties of hormonal manipulation.

A phase I trial of topically applied trans-retinoic acid in cervical dysplasia-clinical efficacy

Forty-two patients were entered into a phase I trial to evaluate the vitamin A derivative, trans-retinoic acid, in cervical intraepithelial neoplasia. Treatment consisted of four consecutive 24-h applications of retinoids via an inert collagen sponge in a cervical cap. Patients were followed for response at 3-month intervals using cytology, colposcopy, and selected biopsies. Thirty-six patients were evaluable (mild dysplasia, 13; moderate dysplasia, 17; severe dysplasia, 6) with follow-up from 5 to 18 months. Complete regression was seen in 2/14 (14%) patients treated with concentrations of 0.05% → 0.1167% and in 10/22 (45%) patients treated with concentrations of 0.1583% → 0.484% (p < 0.05). One patient with negative biopsies at 12 months has subsequently recurred at 18 months.

A phase II trial of mitomycin, vincristine, bleomycin, and cisplatin (MOBP) as neoadjuvant therapy in high-risk cervical carcinoma

Twenty patients with locally advanced or metastatic cervical carcinoma were treated with mitomycin, vincristine, bleomycin, and cisplatin (MOBP), prior to radiotherapy (RT) of curative intent. Five patients had stage I disease, 2 stage II, 10 stage III, and 3 stage IV. All but one patient with stage I and II disease had nodal metastases. Patients received two courses of MOBP prior to and cisplatin q 3 weeks during RT. Response rates after completion of MOBP and prior to RT were as follows: 3/18 (16.6%) patients had a complete response (CR), 10/18 (55.5%) had a partial response (PR), 3/18 (16.6%) had improvement, and 2/18 (11.1%) had no response (NR). Five patients developed radiation complications. Of 7 patients with stage I and II disease, 6 (86%) currently have no evidence of disease (NED) (median 27 months). Of 13 patients with advanced disease, 3 (23%) are NED (median 17 months), 8 (61.5%) have expired, and 2 (15.4%) are alive with disease. MOBP is associated with significant response rates in the untreated patient but has not improved survival in patients with advanced disease. Patients with early disease and positive nodes may benefit from this regimen.

DNA ploidy, grade, and stage in prognosis of uterine cervical cancer

A retrospective study of 56 cases of uterine cervical squamous carcinoma evaluated DNA content, histological grade, and clinical stage as indicators of prognosis. Minimum survivor follow-up was 24 months. Following standard radiation therapy, there were 40 cures and 16 treatment failures. DNA content was measured by flow cytometry of pretreatment biopsies removed from paraffin. There were 18 diploid cases and 38 aneuploid (67.9%). Aneuploid cases included 6 with very high G2-M peaks (greater than or equal to 15% of the cell sample). DNA ploidy correlation with prognosis was not statistically significant. However, both grading by a multiple parameter method (P less than 0.0133) and staging (P less than 0.0064) were significant prognostic factors. Higher grade and stage correlated with treatment failure.

A phase II study of two topotecan regimens evaluated in recurrent platinum-sensitive ovarian, fallopian tube or primary peritoneal cancer: A Gynecologic Oncology Group Study (GOG 146Q)

OBJECTIVE To evaluate the efficacy and safety of topotecan in patients with recurrent ovarian, primary peritoneal, and fallopian tube carcinomas. METHODS A randomized phase II analysis of platinum-sensitive patients with measurable disease was performed independently assessing intravenous topotecan 1.25 mg/m2 daily×5 every 21 days (regimen I) and topotecan 4.0 mg/m2/day on days 1, 8, and 15 of a 28-day cycle (regimen II). All patients were treated until disease progression, unmanageable toxicity, or patient refusal. Insufficient accrual related to regimen I resulted in a redesign of the study as a single arm phase II trial assessing only regimen II. More complete efficacy data is presented for regimen II as enrollment on regimen I was insufficient for some analyses. RESULTS A total of 81 patients were enrolled. One patient was ineligible. Fifteen patients received regimen I, while 65 patients were treated with regimen II. The response rate on regimen I (daily×5) was 27% (90% CI: 10-51%) and 12% (90% CI: 6-21%) on regimen II (weekly). The median PFS and OS were 4.8 and 27.8 months, respectively, for regimen II. Grade 3/4 neutropenia rate was 93% with daily×5 dosing and 28% for weekly treatment. Febrile neutropenia was very low in both groups. CONCLUSION The weekly regimen of topotecan appeared less active but resulted in less toxicity than the daily regimen in platinum-sensitive recurrent ovarian cancer patients.

Cervical tissue uptake of all-trans-retinoic acid delivered via a collagen sponge-cervical cap delivery device in patients with cervical dysplasia.

The present study was undertaken to evaluate the systemic absorption and cervical tissue uptake of all-transretinoic acid (TRA), delivered via a collagen spongecervical cap delivery device in patients with intraepithelial cervical dysplasia. Ten patients with histologically proven mild or moderate cervical dysplasia were included in this pharmacologic study. The two TRA concentrations (0.05% and 0.372%) selected for study represent the starting and maximally tolerated doses used in phase I clinical trial. All-trans-retinoic-11-3H acid (3H-TRA, 500 μCi) was used to facilitate cervical tissue uptake studies. Cervical biopsies and post-treatment blood samples were obtained from each patient after TRA exposure. The uptake of TRA into cervical tissues four hours after drug administration was significantly increased at the maximally tolerated TRA dose. There was a rapid decrease in cervical tissue concentration of TRA at the 0.372% dose between 4 and 24 h after drug exposure, suggesting a relatively short elimination half-life of TRA in cervical tissues. HPLC analysis of post-treatment blood samples indicate that there was no systemic absorption of TRA after local cervical administration.

Phase I trial of carboplatin-cyclophosphamide and iproplatin-cyclophosphamide in advanced ovarian cancer: a Southwest Oncology Group study☆

The Southwest Oncology Group has carried out a phase I clinical trial of carboplatin plus cyclophosphamide and iproplatin plus cyclophosphamide in 20 patients with stages III and IV ovarian cancer prior to initiating a phase III trial to compare these platinum analog-cyclophosphamide combinations with standard cisplatin-cyclophosphamide therapy. Myelosuppression proved the dose-limiting toxicity of both the carboplatin (300 mg/m2) plus cyclophosphamide (600 mg/m2) and iproplatin (180 mg/m2) plus cyclophosphamide (600 mg/m2) regimens. Evaluating up to six courses of therapy (repeated at 4-week intervals), the median nadir WBC and platelet counts associated with carboplatin-cyclophosphamide therapy were 1800 (range, 900-4000) and 69 000 per microliter, respectively, and those associated with iproplatin-cyclophosphamide therapy were 1400 (1100-1600) and 140 000 per microliter, respectively. Although the starting doses of carboplatin and iproplatin required a median decrease of 25%, the median doses of each administered through six courses of therapy were 300 and 180 mg/m2, respectively. Neither nephrotoxicity nor neuropathy were experienced by the patients, but mild to moderate nausea and vomiting occurred in more than 75% of those treated with either drug combination. Alopecia of mild to severe degree was observed in 40% of patients. Although the results of this phase I trial are still preliminary, we can recommend for future phase III trials 300 mg/m2 carboplatin and 180 mg/m2 iproplatin when combined with 600 mg/m2 cyclophosphamide repeated a 4-week intervals for six treatment courses.

Primary chemotherapy for high-risk recurrence cervix cancer

As has been discussed in previous chapters patients with lymph node positive, stages I and II and advanced stages III and IV cervix cancer have poor prognoses, regardless of local treatment type (Tables 1 and 2, respectively). For example, the 5-year survival rate has been reported to be as low as 54% in patients with lymph node positive, stage IB disease [1] and 30–40% in patients with bulky, stage III disease [2]. Recurrences in these high-risk groups occur both locally and distally in similar frequencies. The utilization of more aggressive regional therapy techniques in advanced disease as described by Aristizabal et al. in an earlier chapter has been associated with significantly higher control rates of local disease, but patients continue to die from systemic metastases. Clearly, new multimodality treatment programs must be directed toward the sterilization of both bulky, localized disease and distant, microscopic metastases.

The role of lymphangiography in vulvar carcinoma

The records of all patients with vulvar carcinoma seen at Washington University School of Medicine between 1970 and 1983 were reviewed to determine the role of lymphangiography in the management of patients with vulvar malignancy. Forty-three patients were identified who had a preoperative lymphangiogram followed by radical vulvectomy and lymph node dissection. Thirty-two films were available for review. Seventy-seven sets of lymph nodes were obtained from the 32 patients. Overall diagnostic accuracy was 42 of 77 (54.5%), with a sensitivity of three of 19 (15.7%) and a specificity of 39 of 59 (66.1%). Corresponding values for inguinal nodes were 26 of 57 (45.6%), two of 16 (12.5%), and 24 of 41 (58.5%), respectively. Accuracy rates for pelvic nodes were 16 of 21 (76.2%) with a sensitivity rate of one of three (33%) and a specificity of 15 of 18 (83%). Negative scans were more likely to be accurate than positive scans, 88.6% versus 30%. While a negative lymphangiogram may be helpful in predicting the absence of metastases, its poor specificity limits its widespread usefulness.