Earl A. Surwit

Improved therapeutic index of carboplatin plus cyclophosphamide versus cisplatin plus cyclophosphamide: final report by the Southwest Oncology Group of a phase III randomized trial in stages III and IV ovarian cancer.

PURPOSE To compare cisplatin-cyclophosphamide versus carboplatin-cyclophosphamide as primary chemotherapy for stage III (suboptimal) and stage IV ovarian cancer. PATIENTS AND METHODS Three hundred forty-two patients were randomly assigned to treatment with six courses of intravenous (i.v.) cisplatin 100 mg/m2 plus i.v. cyclophosphamide 600 mg/m2, or i.v. carboplatin 300 mg/m2 plus i.v. cyclophosphamide 600 mg/m2. RESULTS The estimated median survivals were 17.4 and 20.0 months for the cisplatin and carboplatin study arms, respectively. The null hypothesis of a 30% survival superiority with the cisplatin arm was rejected at the P = .02 level. Clinical response rates were 52% for the cisplatin arm and 61% for the carboplatin arm. Pathologic complete response rates were similar for both study arms. There was less thrombocytopenia on the cisplatin arm (P less than .001); however, there was less nausea and emesis (P less than or equal to .001 for courses 1 to 5), renal toxicity (P less than .001), anemia (P = .01), hearing loss (P less than .001), tinnitus (P = .01), neuromuscular toxicities (P = .001), and alopecia (P less than .001) on the carboplatin arm. CONCLUSION Carboplatin-cyclophosphamide proved to have a significantly better therapeutic index than cisplatin-cyclophosphamide in patients with stage III (suboptimal) and stage IV ovarian cancer.

Combined laparoscopic and vaginal surgery for the management of two cases of stage I endometrial cancer

Two postmenopausal patients with stage I adenocarcinoma of the endometrium who were managed with a combined laparoscopic and vaginal approach are presented. Surgical-pathologic staging was performed laparoscopically, with exploration of the abdomen and procurement of peritoneal cytology and pelvic and para-aortic lymph nodes. The adnexa were ligated and mobilized laparoscopically and removed with the vaginal hysterectomy. This approach offers decreased morbidity to the patient yet still obtains the same pathologic information and surgical goal as the traditional transabdominal approach.

The role of laparoscopic lymphadenectomy in the management of cervical carcinoma

Laparoscopic lymphadenectomy was performed on 18 patients with invasive carcinoma of the cervix prior to definitive radiation therapy and/or radical hysterectomy. Ten patients underwent pelvic and para-aortic lymphadenectomies prior to planned radiotherapy. Two of these patients had grossly positive pelvic nodes, and one had a microscopically positive para-aortic node. Eight patients with early disease were considered candidates for radical hysterectomy and underwent laparoscopic lymphadenectomy. Three of these patients were found to have positive pelvic lymph nodes and the hysterectomy was abandoned. Five patients underwent radical hysterectomies immediately following their laparoscopic procedures. The average number of lymph nodes removed laparoscopically in these patients was 31.4; the average number of additional lymph nodes resected at laparotomy with the radical hysterectomy was 2.8. A single microscopically positive parametrial lymph node was found on permanent section in 1 patient with radical hysterectomy. No significant complications were associated with the laparoscopic lymphadenectomies. Nine of the 13 patients who underwent laparoscopic procedures only were discharged on Postoperative Day 1. The ability to perform pelvic and para-aortic lymphadenectomy allows for complete surgical staging of carcinoma of the cervix laparoscopically.

CHARACTERIZATION OF A NEW HUMAN ENDOMETRIAL CARCINOMA (RL95-2) ESTABLISHED IN TISSUE CULTURE

SummaryA new human endometrial cell line, RL95-2, derived from a Grade 2 moderately differentiated adenosquamous carcinoma of the endometrium has been passaged successfully in cell culture for more than 2 yr. The cells are characteristically epithelioid with well-defined junctional complexes, tonofilaments, filopodialike extensions, and surface microvilli. Nuclei are large, irregular, and invaginated frequently with multiple, prominent, lamellar nucleoli. The cells have a log phase doubling time of 22 to 34 h followed by continued growth at a reduced rate with no apparent plateau phase. They exhibit a strong tendency for piling up as well as for the formation of glandlike dome structures. Karyotypically the line is trisomic 8 (47,XX,+8) and has an 8% frequency of polyploidization. Both cytoplasmic and nuclear estrogen receptors are present. Antihuman α-keratin characterizes the cell line as epithelial, nonstromal. The RL95-2 cell line may provide a useful in vitro system for the investigation of the endocrine regulation of endometrial neoplasia.

IN-VITRO CLONOGENIC ASSAY FOR PREDICTING RESPONSE OF OVARIAN CANCER TO CHEMOTHERAPY

95 clinical trials of anticancer drugs were done in 40 patients with advanced ovarian cancer who had undergone an in-vitro soft-agar human tumour stem-cell assay for drug sensitivity. In the 95 clinical trials, 13 of 21 patients responded clinically to drugs predicted to be effective in vitro, while in 73 of 74 instances in which drug resistance had been predicted in vitro there was no response to treatment. 2 patients achieved a complete remission of 1 and 12+ months and 11 had partial remissions lasting a median of four months. Prediction of in-vitro resistance was 99% accurate. The 62% complete or partial remission rate to agents with proven in-vitro efficacy was achieved in extensively pretreated ovarian cancer patients who were unlikely to respond to empirically chosen secondary agents. The human tumour stem-cell assay, in which ovarian tumour colony-forming units are grown in a two-layer agar-culture system incorporating tests for drug sensitivity or resistance, can be effectively used to plan a suitable chemotherapy regimen for ovarian cancer patients.

Double-blind crossover study of the antiemetic efficacy of high-dose dexamethasone versus high-dose metoclopramide.

Nausea and vomiting remain common and debilitating side effects of therapy with many anticancer drugs. Recent reports have shown that both metoclopramide and dexamethasone are effective drugs for the treatment of severe nausea and vomiting caused by cis-platinum. A double-blind crossover study comparing the antiemetic properties of high-dose oral and intravenous regimens of metoclopramide and dexamethasone in outpatients was carried out. Standardized patient questionnaires and interviews were used to evaluate response. Dexamethasone and metoclopramide protected against more than five episodes of emesis in 48% and 40% of patients, respectively. Nausea persisted for less than six hours in 45% of patients on dexamethasone and in 37% on metoclopramide. The antiemetic efficacy of both regimens was retained through repeated courses of chemotherapy. Side effects were minimal with dexamethasone; however, 33% of patients experienced unacceptable extrapyramidal side effects to metoclopramide. Patient preference was significantly in favor of dexamethasone: 70% of patients chose to continue dexamethasone compared to 22% who preferred metoclopramide and 8% who chose other antiemetics. Dexamethasone was the preferred antiemetic in this patient population due to minimal side effects.

Laparoscopic staging of the patient with incompletely staged early adenocarcinoma of the endometrium.

Objective: To determine the feasibility of laparoscopic staging in patients with presumed early stage but incompletely surgically staged adenocarcinoma of the endometrium. Methods: Thirteen patients with incompletely staged adenocarcinoma of the endometrium underwent laparoscopic staging. The women ranged in age from 36‐74 years (mean age 64) and weighed 132‐201 1b (mean 147.5). The interval between hysterectomy and laparoscopic staging ranged from 14‐63 days, for an average of 47. All patients underwent inspection of the entire intraperitoneal cavity, procurement of pelvic washings, and/or pelvic or para‐aortic lymphadenectomy, and two patients had remaining ovaries removed. Results: Extrauterine disease was found in three patients: One had intraperitoneal washings positive for adenocarcinoma, and two had pelvic lymph nodes positive for microscopic carcinoma. The average number of lymph nodes removed was 17.5. There were no intraoperative complications. Estimated blood loss averaged less than 50 mL, and the mean hospital stay was 1.5 days. Conclusion: Our initial experience indicates that this is a safe, effective procedure that offers a short hospital stay. We consider laparoscopic staging an attractive option for some patients with incompletely staged early adenocarcinoma of the endometrium. (Obstet Gynecol 1994;83:597‐600)

Pharmacologic studies of anticancer drugs with the human tumor stem cell assay

SummaryTo optimize the human tumor stem cell assay (HTSCA) for clinical and research purposes we have carried out in vitro pharmacology studies. Useful observations were made in four areas. (1) Drug assay design: The predictive accuracy of the HTSCA depends on the in vitro testing of drug concentrations of less than 10% of those which are pharmacologically achievable with standard in vivo drug doses. The use of unrealistically high in vitro concentrations can accurately predict clinical drug resistance, but is likely to yield high false-positive rates of clinical response prediction. (2) Drug scheduling: For certain schedule-dependent drugs, as well as those with a prolonged plasma half-life and those used according to a repeated daily schedule, prolonged in vitro exposure (rather than 1 h) may be needed to provide an adequate in vitro design. For an accurate prediction of sensitivity of tumor colony-forming units (TCFUs) to continuous drug contact in the agar, concentrations should be in the range of 1/300 that used for the standard 1-h exposure prior to plating. (3) Drug combinations: In preliminary studies of combination chemotherapy in vitro we commonly observed at least additive effects with low doses of cis-platinum plus either vinblastine or adriamycin. (4) Drug bioactivation: Rat liver microsomes or S-9 fraction were used to activate cyclophosphamide for in vitro effect, and satisfactory dose-response curves were observed for the inhibition of TCFUs. Such pharmacologic studies will be required for a wide variety of standard and new agents and will probably become a regular aspect of investigation of new anticancer drugs.

PHASE II RANDOMIZED TRIAL OF CISPLATIN CHEMOTHERAPY REGIMENS IN THE TREATMENT OF RECURRENT OR METASTATIC SQUAMOUS CELL CANCER OF THE CERVIX: A SOUTHWEST ONCOLOGY GROUP STUDY

Cisplatin has proven to be the most active single agent in the treatment of metastatic and recurrent squamous cell cancer of the cervix. In a previous southwest Oncology Group (SWOG) pilot study, the addition of cisplatin to a mitomycin-C, vincristine, and bleomycin (MVB) regimen resulted in a relatively high percentage of durable complete responses. To gain more experience with cisplatin-based chemotherapy regimens, the SWOG initiated a phase II randomized trial of cisplatin, mitomycin-C plus cisplatin (MC), and MVB plus cisplatin (MVBC) in 119 patients with advanced squamous cell cancer of the cervix and no prior chemotherapy exposure. Because of slow patient accrual early in the trial, the cisplatin arm was discontinued. Five patients were declared ineligible according to protocol criteria. The three treatment groups were relatively well matched for age, prior radiation exposure, and sites of measurable disease. The overall objective response rates for cisplatin, MC, and MVBC treated patients were 33%, 25%, and 22%, respectively. Median response durations were greater than 6 months. Median survival durations associated with cisplatin, MC, and MVBC treatment were 17.0, 7.0, and 6.9 months, respectively. There were no drug-related deaths. Severe or life-threatening leukopenia and thrombocytopenia were observed in 18% to 24% of patients treated with MVBC and MC, but in none of those receiving cisplatin alone. We conclude that the low response rates and short durations of both response and survival observed in patients randomized to the two chemotherapy combinations suggest that only enhanced toxicity was gained through the addition of mitomycin-C or MVB to cisplatin in patients with advanced cervix cancer.

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.