Two independent and consecutive randomized clinical trials, conducted by the American Gynecological Oncology Group and by an European–Canadian Intergroup, have shown superiority, in clinical response rate, progression-free survival, and overall survival, of a cisplatin–paclitaxel regimen over cisplatin–cyclophosphamide given as first-line chemotherapy for women with advanced epithelial ovarian cancer. The results of these studies, published with a median follow-up of about 3 years, have been updated with a 6.5-year follow-up: In each case, an 11% absolute gain in survival favoring the paclitaxel arm is shown; this advantage remains both statistically and clinically significant and supports a role for paclitaxel in frontline chemotherapy for advanced ovarian cancer.

Background: Owing to the wide spread perception of a possible benefit from paclitaxel in the second-line situation the Nordic Gynecologic Oncology Group (NGOG) conducted two prospective phase II studies of paclitaxel single agent treatment (175 mg/m(2), three-hour i.v. infusion with standard pre-medication every third week) in patients with relapsing or progressing epithelial ovarian cancer following platinum.Patients and methods: Between 1992-1994 138 patients in total were enrolled of whom 136 received paclitaxel and were included in the toxicity and survival analysis, while 112 were evaluable for response.Results: The overall response rate (CR + PR) was 28% with 16 patients achieving a CR (14%). The estimated median (range) time to progression was 4.1 (0.7-60.7) months. The projected four-year overall survival was 7%, with a median (range) of 9.6 (0.3-60.7) months. A multivariate logistic regression analysis showed that platinum resistance, and WHO performance status at baseline, independently correlated with survival at all three time points (median survival time 9.6, 18, and 24 months). Patients with platinum sensitive tumors and WHO performance status 0 had a median survival of 25.6 months compared to 7.0 months for the rest of the patients (P less than or equal to 0.0001). No serious toxicity was registered.Conclusion: Paclitaxel could safely be administered in an outpatient setting using this schedule. Patients with platinum sensitive tumors and a good performance status were most likely to survive. However, these patients are also most likely to respond to re-treatment with a platinum compound. With reference to the reasonably good tumor control and limited toxicity observed in this study, we conclude that paclitaxel single agent therapy is a viable option in the salvage situation, which in some patients can give long-lasting responses. However, although responses call be induced in a significant number of patients, the survival figures remain poor.

AIM The authors retrospectively analyzed the prognostic significance of p53, mdm-2, DNA ploidy, S-phase fraction (SPF), and traditional clinical and pathologic factors in patients with malignant mixed Müllerian tumors (MMMT) of the uterus. METHODS Between 1970 and 1995, 44 uterine tumors were diagnosed as MMMT (21 stage I, 2 stage II, 10 stage III, and 11 stage IV). Thirty-two were homologous type and 12 were heterologous type. DNA flow cytometry and immunohistochemical analysis for p53 and mdm-2 overexpression were performed on paraffin-embedded archival tissue. RESULTS 68% of the tumors were nondiploid and 61% had an SPF greater than 10%. Sixty-one percent overexpressed p53 and 25% were mdm-2-positive. Furthermore, 91% of the tumors had a mitotic count greater than 10/10 hpf and 95% had high-grade cytologic atypia. Twenty-seven (61%) patients died of tumor and 6 (14%) died of intercurrent disease. Eleven (25%) patients are alive with no evidence of disease. The median follow-up for patients still alive was 59 months (range, 28-178 months). The overall 5-year survival rate was 38%. In a univariate analysis that included stage, histologic type, DNA ploidy, SPF, p53, mdm-2, mitotic index, and age, and with survival as the end point, only stage reached statistically prognostic significance. CONCLUSION The majority of the tumors had obvious signs of aggressiveness such as high grade, high mitotic count, nondiploid pattern, high SPF, and overexpression of p53. This study found that stage is the most important prognostic factor for survival in MMMTs of the uterus.

AIM:The authors analyzed in a retrospective manner the prognostic significance of p53 and mdm-2 expression, DNA ploidy, S-phase fraction (SPF), and traditional clinical and pathological prognostic factors in patients with uterine leiomyosarcomas.MATERIAL:Forty-nine patients were diagnosed with uterine leiomyosarcoma (25 stage I, 4 stage II, 8 stage III, and 12 stage IV). DNA flow cytometric analysis and immunohistochemical staining for p53 and mdm-2 were performed on paraffin-embedded archival tissue from the uterine tumors.RESULTS:Of the 49 patients, 35 (71%) died of disease and 2 died of intercurrent disease. The 5-year survival rate was 33%. FIGO surgical stage, DNA ploidy, SPF, mitotic index, cellular atypia, and tumor grade obtained significance (P < 0.05) in a univariate survival analysis of the leiomyosarcomas. In a multivariate analysis with survival as the end point, stage was found to be the most important factor (P = 0.007); DNA ploidy (P = 0. 045) and SPF (P = 0.041) also had independent prognostic significance. For FIGO stage I tumors, DNA ploidy (P = 0.04) and tumor grade (P = 0.01) were statistically significant in a univariate analysis, while only grade had independent prognostic significance (P = 0.01) in a multivariate analysis. In a univariate analysis including only FIGO stage I and II tumors with disease-free survival as the end point, p53 overexpression (P = 0.0016), DNA ploidy (P = 0.042), and tumor grade (P = 0.008) obtained significance. In a multivariate analysis, only p53 had independent statistical significance (P = 0.01). All p53 immunopositive stage I-II tumors recurred within 28 months from diagnosis.CONCLUSION:This study found that stage represents the most important prognostic factor for uterine leiomyosarcomas. DNA ploidy and SPF had independent prognostic value. DNA flow cytometry is useful in gaining additional prognostic information. In stage I patients, tumor grade gives significant information regarding clinical outcome. In addition, p53 overexpression may predict a higher risk of recurrence in early stage leiomyosarcomas.

This retrospective study evaluates paclitaxel (Taxol) monotherapy in the treatment of advanced ovarian cancer, previously treated with cisplatin. Forty-six patients with FIGO stage IC to IV were given Taxol in doses of 175 mg/m2 and 135 mg/m2 as a 3-h continuous infusion. All patients were given premedication (prednisone, clemastin, cimetidine) to prevent hypersensitivity reactions. One allergic reaction was observed. Thirty-nine patients showed progress of their disease during treatment and seven showed a response (overall response rate 15.2%; 95% c.i. 4.8-25.6%). There were five total (10.9%) and two partial responses. Among 20 patients who had progressed during or within 6 months of prior cisplatin-based therapy two were responders and two showed partial response (10%). Among 26 patients who had responded to cisplatin but suffered recurrence more than 6 months after cisplatin treatment, there were five total responders (19.2%). We conclude that Taxol treatment does not alter the fact that advanced ovarian carcinoma still carries a grave prognosis. Taxol monotherapy treatment of patients not responding to first line platinum treatment or having relapse within six months of completed therapy, seems to have a limited effect. For those patients responding to the first line platinum treatment that lasts for at least six months the effect of Taxol treatment is more encouraging.

In a controlled prospective randomized study the regimen doxorubicin (A) 40 mg/m(2) + melphalan (M) 0.4 mg/kg was compared with A+M+cisplatin (C) 50 mg/m(2) given every four weeks in advanced ovarian cancer, FIGO stage III or IV and with serous or anaplastic histology. From 1981 to 1983, 300 patients entered the study and 295 patients were evaluable for response, toxicity and long-term survival. All patients were followed for at least 10 years. The majority of patients had large residual tumours >2 cm. Patients treated with MAC had a higher response rate compared with patients treated with MA (76% vs, 50%, p<0.01) and treatment with MAC resulted in significantly more pathological complete responders than MA. There was a significant difference in median duration of response (19 months vs. 13 months, p<0.006) and in median survival time (26 months vs. 19 months, p=0.05). After 5- and 10 years a significant difference in progression-free and overall survival was found. The independent prognostic factors in this study were residual tumour after primary surgery, treatment with MAC, tumour grade, ascites, and stage, objective and subjective side effects were significantly worse with MAC, although tolerable. In conclusion, this study shows that incorporating C into MA improves the duration of progression-free survival and overall survival in women with incompletely resected Stage III or Stage IV ovarian epithelial cancer. A 5- and 10-year survival of 25% and 18%, respectively, is impressive.

All 426 patients with ovarian malignancies registered in the population-based Tumor Registry of the Southeast region of Sweden during 1984 to 1987 were analyzed by survey of the hospital records and population registry data. After comparison with other population-based materials, it seems that the overall survival figures have improved in ovarian cancer. Excluding patients diagnosed at autopsy a 5-year corrected survival of 43% was recorded. Among patients aged under 45 years the corrected 5-year survival was 72%. In a Cox's regression analysis age and stage were significant predictors of cancer death while histology (epithelial vs. non-epithelial), although significant in the univariate analysis, did not add prognostic information in the multivariate model. The relative cancer death rate was 6.4 for patients aged over 74 years compared with those aged under 45 (p < 0.0001), and 13.8 for FIGO stage IV compared to stage I (p < 0.0001). For patients with advanced stage tumors (FIGO stage III or IV) postoperative residual tumor, stage, and age were independent prognostic factors in a multivariate analysis. The corrected cancer death rate was 2.0 for patients with > 1 cm relative to < or = 1 cm postoperative residual tumor nodule(s) (p < 0.0001).

Background. The morphologic spectrum of ovarian mucinous tumors is well known, but the features that predict aggressive behavior are still controversial.Methods. Ninety-two cases of primary ovarian mucinous tumors with atypical epithelial proliferation and/or stromal invasion were analyzed histologically and by DNA flow cytometry, and the results were correlated with clinical findings.Results. The authors reviewed 57 intestinal mucinous borderline tumors (IMBT), 3 endocervicallike mucinous borderline tumors (EMBT), 21 noninvasive mucinous carcinomas (NIMC), and 11 invasive mucinous carcinomas (IMC). The 5-year survival rate for Stage I tumors was: IMBT 100%, EMBT 100%, NIMC 94% and IMC 60%. The 5-year survival of Stage II-IV tumors was: IMBT 50%, NIMC 33% and IMC 0%. Forty-four IMBTs were diploid, and 4 were aneuploid. All six high stage IMBTs were diploid. Two EMBTs were diploid, and one was aneuploid. There were seven diploid, four polyploid, and six aneuploid NIMCs. Two of the three lethal NIMCs were aneuploid. Four IMCs were diploid, and four were aneuploid. Of these, only the diploid Stage I IMCs were nonlethal. All NIMCs that recurred or presented with metastases had been sampled inadequately. High stage tumors with pseudomyxoma peritonei (PP)-type lesions often were associated with pseudomyxoma ovarii of the cellular type.Conclusions. Mucinous tumors with stromal invasion or presenting with PP had a definite malignant behavior. All other atypical mucinous tumors, when confined to the ovary and optimally sampled, had an excellent prognosis. DNA ploidy analysis may prove useful in determining the risk of progression, especially in Stage I IMCs.

In a previously reported phase I study of carboplatin administered ip to patients with ovarian cancer at our clinic, it was determined that the recommended dose for phase II was 500 mg/m2. In this study, this dose was given to 47 patients with the purpose of determining the relapse-free interval and toxicity. Four courses were given with a 28-day interval in an escalated fashion. Median age of patients was 55 years. Karnofsky index was 100 in 98% of the patients. Thirty-one patients had FIGO stage I and 16 patients had FIGO stage II ovarian cancer. Median time to recurrence has not yet been reached among 43 evaluable patients after a median (range) follow-up time of 26.2 (5.5-45.9) months. Recurrent disease was documented in 10 patients (23%). The relapse site was intraabdominal in 7 and extraabdominal in 1 patient. Two patients had combined intra- and extraabdominal relapse sites. Thirty-six of 43 patients went through second-look surgery. The total number of treatment cycles given to evaluable patients was 154. In the patient group with relapsed tumor, ⩾3 courses were administered to 60%, whereas nonrelapsed patients had ⩾3 courses in 94% (P = 0.019). The reason for this distribution was higher toxicity and more frequent catheter-related problems in patients with relapsed tumor. Median (range) disease-free interval for relapsed patients was 11.5 (5.5-26.6) months. Myelosuppression, especially thrombocytopenia, was the dose-limiting systemic toxicity. The overall hematologic toxicity (all courses) was median(range) WBC 3.9(0.3-25.0) × 109/liter, PLTC 212(7-961) × 109/liter, and Hb 109(75-153) g/liter. WHO grade 4 toxicity for WBC was observed in 6.7%, for PLTC in 17.8%, and for Hb in 0% of the patients. Day to nadir values for WBC, PLTC, and HB were in median (cycle 1-4) 18, 16, and 18 days, respectively. Subjective toxicity was mild. In conclusion, ip carboplatin as a single-agent drug in first-line adjuvant chemotherapy of early-stage ovarian cancer has shown moderate activity. The administered dose in this study was safe, with acceptable toxicity.

Granulosa and theca cell tumors of the ovary account for 2-3% of ovarian malignancies. This study includes 54 patients with the diagnosis of granulosa cell tumors of the ovary treated between 1953 and 1987. Median age at diagnosis was 57 (27-83) years. The lesions were staged according to FIGO. The number of patients in various stages was IA, 41; IB, 3; IC, 3; IIB, 6; and III, 1. Median tumor size, 11 cm; range, 0.5-30 cm. Post-menopausal bleeding was diagnosed in 48%, MHC in 37%, proliferative endometrium in 32%, and atypia of endometrial cells in 13% of the cases. Fifty patients were treated with primary surgery, 48 patients were treated with adjuvant external radiotherapy, and 3 patients received complementary chemotherapy. The survival rates in stage I were 94 and 88% after 5 and 10 years, respectively, and in stages II-III were 44% after 5 and 10 years. Overall survival was 90% at 5 years. The frequency of observed mitosis influenced the survival rate: with less or equal 4/10 HPF the survival was 100% in 5 years, with 5-9/10 HPF the survival was 80% in 5 years with a median survival time of 9 years, and with more or equal 10/10 HPF the longest survival was 4 years. At the end of the study, 45 patients (83%) are alive with no evidence of disease, 1 patient is alive with disease, 4 patients are dead of recurrent disease, and 4 patients are dead from intercurrent disease. Endometrial carcinoma was detected in 5 patients. The total survival is better than that with epithelial ovarian cancer as the hormonal symptoms make an early diagnosis possible. Stage for stage the survival is equal. There is an increased incidence of endometrial carcinoma and concomitant other malignancies. The mitotic rate is a well-defined parameter and influences the survival significantly and should be considered the most important prognostic factor at treatment planning.

International Journal of Gynecology & ObstetricsVolume 44, Issue 3 p. 308-309 Citations from the literature oncology Intraperitoneal high-dose cisplatin and etoposide with systemic thiosulfate protection in second-line treatment of advanced ovarian cancer H. Malmstrom, H. MalmstromSearch for more papers by this authorS. Rasmussen, S. RasmussenSearch for more papers by this authorE. Simonsen, E. SimonsenSearch for more papers by this author H. Malmstrom, H. MalmstromSearch for more papers by this authorS. Rasmussen, S. RasmussenSearch for more papers by this authorE. Simonsen, E. SimonsenSearch for more papers by this author First published: March 1994 https://doi.org/10.1016/0020-7292(94)90217-8AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume44, Issue3March 1994Pages 308-309 RelatedInformation

This is a preliminary report from an ongoing phase II study, in which clinical and pathologic tumor response rates after single-agent paclitaxel (Taxol(R)) treatment are being investigated. The study population in this analysis consisted of 27 previously untreated International Federation of Gynecology and Obstetrics stage III ovarian cancer patients, suboptimally resected at primary surgery. The initial paclitaxel dose was 175 mg/m(2) (3-h intravenous infusion) with planned dose modifications in subsequent cycles. The treatment-free interval was 3 weeks. A total of 174 paclitaxel courses have been administered. It has been possible to increase the initial dose to greater than or equal to 200 mg/m(2) in 20 patients. Clinical response after six cycles can be evaluated in 23 patients, with complete responses in 6 patients and partial responses in 8 patients, giving an objective clinical response rate of 61%. In 17 patients with a residual tumor size of 2-5 cm after primary surgery, a pathologic response rate (macro and microscopic tumor-free) of 29% has been noted. Toxicity has mainly consisted of leukopenia and neutropenia, both easily controlled. Other toxic events have been myalgia/arthralgia and peripheral neuropathy.

Peritoneal access devices (port-catheters) were subcutaneously implanted in 125 patients for intraperitoneal chemotherapy of ovarian cancer. In 98% of patients Pharmacia's Port-A-Cath was used. Four hundred sixty-five intraperitoneal courses were given to these patients, with a median of 4 courses per patient (range 0-8). The first course was given 0-60 days (median 11 days) after Port-A-Cath implantation. In 125 patients, 27 (21.6%) complications of severe or moderate degree during the treatment were registered. In 81% of the patients, the treatment was given according to chemotherapy protocol as outlined. In 7% of the patients, early termination was related to the use of Port-A-Cath and in 12% related to chemotherapy. The probability for proper functioning of Port-A-Cath was 0.74 at 6 months and 0.69 at 1 year after implantation. The mean observation time was 13.6 months, median 10.5 (range 0.3-59.6 months). Total patient access time was 141.9 years. In conclusion, the complication rate after implantation of intraperitoneal access devices is acceptable. The rate of infections associated with the system is lower than that associated with open catheter systems.

Eight hundred thirty-nine clinical stage I endometrial carcinoma patients diagnosed between 1979 and 1988 were treated at the University Hospital in Linköping. Forty-two (5%) had uterine papillary serous carcinoma of which 52% died of their disease. The recurrence rate, defined as new evidence of disease 6 months or more after termination of the initial treatment, was 31% among the UPSC patients compared to 6% in the non-UPSC group. The site of recurrence also differed significantly between the two groups, with the abdomen as the most common site among UPSC patients (46%) and the vagina (34%) among the ordinary adenocarcinoma patients. All UPSC patients with recurrence died of their malignancy compared to 61% of the ordinary adenocarcinoma patients. Ninety percent of isolated vaginal recurrences in ordinary adenocarcinoma patients (17) were diagnosed at a scheduled outpatient checkup. Of these, 13 are alive with no known disease after treatment.

Several randomized trials of various malignancies treated with cisplatin indicate a dose-response relationship with higher MST and longer survival achieved with high-dose compared to standard dose cisplatin regimens. Thirty-five patients with stages II-IV ovarian cancer with refractory cancer at second look or recurrent disease were treated second line with intraperitoneal (ip) combination chemotherapy of high-dose cisplatin (100-200 mg/m2) plus etoposide (350 mg/m2) in 1-6 cycles. Sodium thiosulfate was given as an intravenous antidote to cisplatin. A WBC nadir <2.0 × 109/liter was registered in 39 courses and a platelet nadir <50 × 109/liter in 3 courses. Severe nephrotoxicity was observed in 2 patients. Nonhematologic and nonrenal toxicity was mild except for vomiting and nausea and alopecia. No severe neurotoxicity was observed. A total of 127 courses were administered. Total median administered dose was 960 mg and 49 mg/m2/week. Treatment was changed in 5 (14%) patients due to severe nausea and vomiting, in 4 (11%) patients due to PAC problems, and in 2 (6%) patients due to nephrotoxicity. In 4 (11%) patients the dose was reduced due to hematologic toxicity. No toxic death was recorded. Median survival time from date of diagnosis was 21.8 (mean 37.9) months and the median progression-free survival from start of ip chemotherapy was 13.7 months. For patients with MRD ⩽2 cm the MST was 18.1 months. At the closing point of this study after a median follow-up time of 16.1 (range, 4.6-55.6) months, 7 (20%) patients were alive without evidence of progression, 4 (11%) were alive with cancer, and 23 (66%) were dead of cancer and 1 (3%) was dead of intercurrent disease.

Between January 1, 1988 and December 31, 1990, a new high-intensity treatment was delivered to 10 patients with clinical stage I uterine papillary serous carcinoma (UPSC) and 21 patients with clinical stage I, FIGO grade 3 endometrial adenocarcinoma. The treatment consisted of a radical hysterectomy and bilateral salpingo-oophorectomy with pelvic lymph node sampling, adjuvant external pelvic radiation, and four courses of cis-platinum/epirubicin. The clinical outcome was compared to that of a historical control group treated before 1988 with surgery and radiation. None of the high-intensity treated UPSC patients died or relapsed during a median observation time of 32 months. There was a significantly better survival in the high-intensity treated UPSC group compared to the controls. The UPSC patients diagnosed after January 1, 1988 showed a trend toward better survival compared to those diagnosed before this date, whether they had received high-intensity treatment or not. No significant difference in survival was observed in the non-UPSC group subjected or not to the high-intensity treatment.