Treatment of primary advanced and recurrent endometrial carcinoma with a combination of carboplatin and paclitaxel-long-term follow-up.

There is no generally accepted standard chemotherapy in treatment of advanced and recurrent endometrial carcinoma. Cisplatin and doxorubicin with or without cyclophosphamide are widely used. Response rates have improved with combination chemotherapy compared with single-agent therapy. A platinum analog seems to be an important part of the chemotherapy regimen. Since few patients are cured from their disease and since the duration of response is short, further improvement of this therapy is warranted. During the past years, the taxanes (paclitaxel) are being added to prior evaluated regimens and not only improved response rates are reported but also increased toxicity is observed. In a prospective, phase II, multicenter study, carboplatin (area under the curve = 5) and paclitaxel (175 mg/m(2)) were evaluated in treatment of primary advanced and recurrent endometrial carcinoma. In total, 66 patients were recruited during the years 2000-2004. Eighteen primary advanced tumors and 48 recurrences were treated. All histologic types and tumor grades were allowed. The median follow-up was 57 months (range 37-69 months). The overall response rate was 67% (95% CI 55-78). The complete response rate was 29% and the partial response rate 38%. Primary advanced and recurrent tumors as well as endometrioid and nonendometrioid tumors showed similar response rates. The median response duration was 14 months. The 1- and 3-year survival rates were 82% and 33%, respectively. The main toxicities were hematologic and neurologic (sensory neuropathy). The response rates were encouraging, superior to prior platinum-containing regimens, but response duration and the long-term survival rate were still short. The neurologic toxicity was frequent and was a substantial problem in this series of patients. Further research is highly needed to improve the treatment of advanced and recurrent endometrial cancer.

Prognostic impact of body mass index and effect of overweight and obesity on surgical and adjuvant treatment in early-stage epithelial ovarian cancer.

The present study was performed to find out if the body mass index (BMI) was associated with clinical and pathologic features (age, histology, tumor grade, and substages) and prognosis in early stages (FIGO I-II) of epithelial ovarian cancer. Further aims of the study were to evaluate if overweight or obesity affected the feasibility of optimal surgery and postoperative adjuvant therapy. A total of 635 patients were included in this study. Four percent of the patients were underweight (BMI <18.5), 53% were of ideal body weight (BMI 18.5-25), 31% were overweight (BMI 25-30), and 12% were obese (BMI >30). Overweight and obese patients were significantly (P = 0.006) older than underweight and ideal body weight patients. Tumor grade and histologic type distributions were not different across the BMI strata. FIGO stage (P = 0.011) and presence of ascites (P = 0.007) at primary surgery were associated with the BMI status. A history of cardiovascular disease was significantly (P = 0.006) more common in overweight and obese patients. Survival analyses in the four BMI subgroups did not show any significant differences with regard to recurrence-free survival. The 5-year recurrence-free survival of the complete series was 72%. Overweight and obese patients did not have worse survival than normal weight and underweight patients. Perioperative or postoperative morbidity and adjuvant oncologic treatment were not affected by the BMI. In a multivariate Cox analysis, FIGO substage and tumor grade, but not BMI, were independent and significant prognostic factors with regard to all types of survival rates.

Survival and prognostic factors in early-stage epithelial ovarian carcinoma treated with taxane-based adjuvant chemotherapy.

The present study was undertaken with the question about the outcome (recurrence-free survival, [RFS]) after adjuvant chemotherapy with taxane and carboplatin in the early stages of epithelial ovarian cancer after primary surgery. Treatment-related toxicity was also evaluated. A total of 113 patients were included in this study. The 5-year RFS rate for all 113 patients treated with adjuvant chemotherapy including taxane and carboplatin after primary surgery was 79%. The 5-year RFS rate for 85 patients in FIGO stage I was 85% and for 18 patients in FIGO stage II, it was 44%. For clear-cell carcinomas, the RFS was 87%. In univariate analysis, recurrent disease was associated with both FIGO stage and tumor grade, but in multivariate logistic regression analysis of prognostic factors for tumor recurrences, only FIGO stage (stage I versus stage II) was a significant and independent prognostic factor. However, an odds ratio (OR) of 1.9 for tumor grade (grade 3 versus grades 1-2) demonstrated two times increased risk for recurrence in a patient with a grade 3 tumor compared with grade 1-2 tumors. Furthermore, an OR of 0.39 for lymph node sampling versus no sampling meant 61% reduced risk for recurrence for a patient who had undergone lymph node sampling at surgical staging laparotomy. The major toxicities in the present study were myelosuppression (46%) and neurotoxicity (34%). Despite the use of prophylaxis, severe paclitaxel-related hypersensitivity occurred in three patients (3%).

SCOTROC 2B: feasibility of carboplatin followed by docetaxel or docetaxel-irinotecan as first-line therapy for ovarian cancer.

The feasibility of combination irinotecan, carboplatin and docetaxel chemotherapy as first-line treatment for advanced epithelial ovarian carcinoma was assessed. One hundred patients were randomised to receive four 3-weekly cycles of carboplatin (area under the curve (AUC) 7) followed by four 3-weekly cycles of docetaxel 100 mg m(-2) (arm A, n=51) or docetaxel 60 mg m(-2) with irinotecan 200 mg m(-2) (arm B, n=49). Neither arm met the formal feasibility criterion of an eight-cycle treatment completion rate that was statistically greater than 60% (arm A 71% (90% confidence interval (CI) 58-81%; P=0.079; arm B 67% (90% CI 55-78%; P=0.184)). Median-dose intensities were >85% of planned dose for all agents. In arms A and B, 15.6 and 12.2% of patients, respectively, withdrew owing to treatment-related toxicity. Grade 3-4 sensory neurotoxicity was more common in arm A (1.9 vs 0%) and grade 3-4 diarrhoea was more common in arm B (0.6 vs 3.5%). Of patients with radiologically evaluable disease at baseline, 50 and 48% responded to therapy in arms A and B, respectively; at median 17.1 months' follow-up, median progression-free survival was 17.1 and 15.9 months, respectively. Although both arms just failed to meet the formal statistical feasibility criteria, the observed completion rates of around 70% were reasonable. The addition of irinotecan to first-line carboplatin and docetaxel chemotherapy was generally well tolerated although associated with increased gastrointestinal toxicity. Further exploratory studies of topoisomerase-I inhibitors in this setting may be warranted.

Lymph node sampling is of prognostic value in early stage epithelial ovarian carcinoma.

PURPOSE: The importance of lymph node involvement as a prognostic factor is still under debate. In the present study, the impact of surgical staging for prognosis in early stages of epithelial ovarian cancer was evaluated in a series of 113 patients. MATERIAL AND METHODS: A retrospective study was carried out at the Department of Gynecological Oncology, Orebro University Hospital, during the period 1994-1998. In a subgroup of 20 out of 113 patients, pelvic lymph node sampling or pelvic lymphadenectomy was included in the standard surgical procedure. In cases of positive lymph nodes, the tumors were upstaged to FIGO Stage III. Pearson's chi-square, the t-test, the log-rank test and Cox multivariate analysis were used in the statistical analyses. RESULTS: The 20 patients with lymph node sampling or lymphadenectomy were compared with the remaining 93 patients without a comprehensive surgical staging procedure. A survival analysis demonstrated a significant (p = 0.005) difference in disease-free survival rates between the two subgroups, where there was a survival benefit in the subgroup of patients who had undergone comprehensive surgical staging. In a Cox proportional hazard regression analysis with disease-free survival as the endpoint, high tumor grade (HR = 3.14) and comprehensive surgical staging with at least a node sampling (HR = 0.09) were significant and independent prognostic factors. CONCLUSION: The benefit in survival after the procedure of lymph node sampling in early stages of epithelial ovarian carcinoma could probably be explained by the fact that the surgical procedure detects otherwise unrecognized Stage III disease.

Prognostic importance of the time interval from surgery to chemotherapy in treatment of ovarian carcinoma.

In a large study on 1,220 patients with ovarian carcinoma in FIGO stages I-IV, the prognostic importance of the time factor for start of postoperative chemotherapy was studied together with other important factors for long-term survival. The patient series was a total geographic material of ovarian carcinoma patients treated during the years 1975-1993. All patients were followed up for 10 years or until death. The 5-year cancer-specific survival rate of the complete series was 50%. Significant and independent prognostic factors with regard to long-term cancer-specific survival were FIGO stage, histology, tumor grade, and completeness of the primary surgery. Special attention was paid to the prognostic importance of the time interval between primary surgery and the first course of chemotherapy. Patient groups with intervals shorter or longer than the median value were compared. In early-stage disease, no significant difference was noted. In advanced and bulky disease, an interval longer than the median value seemed to be beneficial compared with a shorter interval. However, after correction for other prognostic factors, the interval was not a significant factor (P = 0.647) with regard to the cancer-specific survival rate. Therefore, the time factor should not be an important argument for how to best organize the gynecologic oncology service.

HPV-DNA, vascular space invasion, and their impact on the clinical outcome in early-stage cervical carcinomas.

The present study was designed to analyze the relationship of human papillomavirus (HPV)-DNA, microvessel density, and their impact on clinical outcome in early cervical carcinoma. HPV-DNA was evaluated in 171 cases of cervical carcinoma treated from 1965 to 1990. In 110 cases, the analyses could be performed. A polymerase chain reaction technique was used on paraffin-embedded specimens obtained before the start of therapy. HPV-DNA of any type was detected in 78% (86/110) of all evaluable tumors. HPV16 was the predominant type and was detected in 56% (62/110), HPV18 in 8% (9/110), and HPV35 in 21% (23/110). Patients with tumors containing HPV16 or HPV18 were significantly (P = 0.011) younger than patients with tumors not containing either of these two subtypes. Vascular space invasion and lymph node metastases were observed more frequently in tumors expressing HPV16 and HPV18 (P = 0.002, P = 0.047) than in tumors negative for these HPV strains. Tumors containing HPV16 and HPV18 were significantly (P = 0.012) larger and more frequently (P = 0.005) associated with higher FIGO stages. The cancer-specific survival rate was lower for patients with HPV16- and HPV18-positive tumors, but the difference was not statistically significant. The microvessel density was a non-significant prognostic factor. The overall 5-year survival rate of the complete series was 91%. It was concluded that HPV-DNA was a prognostic factor in early-stage cervical cancer and was associated with the age of the patient, vascular space invasion, lymph node metastases, tumor size, and FIGO stage.

Relation between HPV-DNA and expression of p53, bcl-2, p21WAF-1, MIB-1, HER-2/neu and DNA ploidy in early cervical carcinoma: correlation with clinical outcome.

The purpose of the present study was to analyze the relation between the expression of p53, bcl-2, p21WAF1, MIB-1, HER-2/neu, DNA ploidy and HPV16 or 18 infections with clinical parameters. HPV-DNA was evaluated in 171 early cervical carcinomas treated from 1965 to 1990 and detected by PCR (polymerase chain reaction) on paraffin specimens obtained before therapy was started. HPV-DNA of any type was detected in 78% (86/110) of all tumors, HPV16 was the predominant type and was seen in 56% (62/110), HPV18 in 8% (9/110) and HPV35 in 21% (23/110). Patients with HPV16 or 18 were significantly (P=0.011) younger than patients with tumors not containing these two HPV subtypes. Lymph node metastases were seen more frequently (P=0.047) in tumors expressing HPV16 or 18. Tumor size was associated with the HPV-type. The frequency of DNA aneuploidy was lower in high-risk HPV tumors than in tumors with other HPV subtypes (P=0.014). MIB-1 expression was highly significantly (P=0.00007) associated with presence of HPV16 or 18. The cancer-specific survival rate was lower for patients with HPV16 and 18 positive tumors, but the difference was not statistically significant. The overall 5-year survival rate of the complete series was 91%. In conclusion, the HPV DNA subtype was a prognostic factor in early stage cervical cancer and it was associated with age, positive lymph nodes, tumor size, DNA ploidy and the proliferation marker MIB-1.

A new prognostic model comprising p53, EGFR, and tumor grade in early stage epithelial ovarian carcinoma and avoiding the problem of inaccurate surgical staging.

Epithelial ovarian carcinoma rarely occurs because of a single event. Therefore, no single biological tumor factor will give accurate prognostic information for all ovarian cancer patients. On the other hand, a combination of two or more independent factors may yield an improved overall prognostic index. Because FIGO stage is included in most of the previously presented models, inaccurate surgical staging in patients with apparently early disease has been a problem. In a series of 226 patients with epithelial ovarian carcinomas in FIGO stages IA-IIC, a number of clinicopathological factors (age, FIGO stage, histopathologic type, and tumor grade) were studied in relation to the biological factors p53 and epidermal growth factor receptor (EGFR), important regulators of the apoptosis and mitosis. Immunohistochemical techniques were used. All patients received adjuvant radiotherapy or chemotherapy after the primary surgery. Expression of p53 was significantly associated with the tumor grade and disease-free survival (DFS). EGFR expression was also associated with DFS. In a Cox multivariate analysis, tumor grade, p53 status, and EGFR status were all independent and significant prognostic factors with regard to DFS. A prognostic model was proposed using these factors. A low-risk group, an intermediate-risk group, and a high-risk group were defined. DFS amounted to 89% in the low-risk group (grades 1-2, p53-negative, and EGFR-negative), 66% in the intermediate-risk group (grade 3, p53-negative, and EGFR-negative or grades 1-2, p53-positive or EGFR-positive) and 39% in the high-risk group (grade 3, p53-positive, and EGFR-positive).

Consolidation treatment of advanced ovarian carcinoma with radiotherapy after induction chemotherapy.

In a prospective randomized trial, consolidation treatment with radiotherapy or chemotherapy was compared with no treatment in a series of 172 patients with epithelial ovarian carcinoma, FIGO stage III, with complete surgical remission after primary cytoreductive surgery and induction chemotherapy. In the subgroup with complete pathological remission, progression-free survival (PFS) was significantly (P = 0.032) better in the radiotherapy group (56%) than in the chemotherapy group (36%) and the untreated control group (35%). The number of recurrences was lowest in the radiotherapy group. The overall relapse rate was reduced by 33% and the pelvic recurrences by 43% by consolidation radiotherapy. On the other hand, treatment-related side effects were more frequent in the radiotherapy group.

Consolidation treatment of advanced (FIGO stage III) ovarian carcinoma in complete surgical remission after induction chemotherapy: a randomized, controlled, clinical trial comparing whole abdominal radiotherapy, chemotherapy, and no further treatment.

In a prospective randomized trial, consolidation treatment with radiotherapy or chemotherapy was compared with no treatment in a series of 172 patients with epithelial ovarian carcinoma, FIGO stage III, with complete surgical remission after primary cytoreductive surgery and induction chemotherapy. In the subgroup with complete surgical and pathologic remission, progression-free survival was significantly (P = 0.032) better in the radiotherapy group (56% at 5 years) than in the chemotherapy group (36% at 5 years) and the untreated control group (35% at 5 years). Overall survival was also most favorable in the radiotherapy group (69% at 5 years). The number of recurrences was lowest in the radiotherapy group. In the subgroup with microscopic residual carcinoma there were no significant differences in survival between the radiotherapy and the chemotherapy-treated patients. Early and late radiation reactions were recorded. Treatment-related side effects were seen most frequently in the radiotherapy group. Late intestinal radiation reactions of a severe type were recorded in 10%.

The prognostic importance of p53, bcl-2, and bax in early stage epithelial ovarian carcinoma treated with adjuvant chemotherapy.

Epithelial ovarian cancer is one of the major causes of death among women. The increasing knowledge about molecular events involved in the early stages of ovarian tumorigenesis may provide the basis for management in the future. In a series of 109 patients with epithelial carcinomas in FIGO stages IA-IIC, a number of clinicopathologic prognostic factors (age, FIGO stage, histopathologic type, and tumor grade) were studied in relation to the biologic factors p53, bcl-2, and bax, which are important regulators of apoptosis. Immunohistochemical techniques were used. All the patients received adjuvant chemotherapy after the primary surgery. Univariate analysis showed that expression of p53 was significantly associated with tumor grade (P = 0.014), probability of persistent disease (P = 0.016), and cancer-specific survival rate (P = 0.007). Positive bcl-2 staining was associated with endometrioid tumor subtype (P = 0.029) and a favorable tumor grade distribution (P = 0.034), but not with the survival status. The combined p53-bcl-2 expression was related to histopathologic subtype (P = 0.032), tumor grade (P = 0.011), persistent disease (P = 0.014), and risk of dying due to the disease (P = 0.039). The bax status was not a prognostic factor, but the combined p53-bax expression showed an association with FIGO stage (P = 0.014), tumor grade (P = 0.034), persistent disease (P = 0.006), and risk of dying due to the disease (P = 0.039). The combined bcl-2-bax expression was related to histopathologic subtype (P = 0.045) and tumor grade (P = 0.022). In a multivariate Cox analysis, tumor grade (P = 0.014), and p53 status (P = 0.020) were independent and significant prognostic factors with regard to the cancer-specific survival rate.

Immunohistochemical expression of p53, bcl-2, and p21(WAF1/CIP1) in early cervical carcinoma: correlation with clinical outcome.

The objective of this study was to assess the value of p53, bcl-2, and p21(WAF1/CIP1) immunoreactivity as predictors of pelvic lymph node metastases (LNM), recurrences, and death due to the disease in early stage (FIGO I-II) cervical carcinomas. FIGO stage, type of histopathology, and tumor grade were also evaluated in this series of patients treated by radical hysterectomy (Wertheim-Meigs) between 1965 and 1990. A total of 172 patients were included. A tumor was regarded as positive when more than 30% of the neoplastic cells exhibited immunoreactivity. Positive immunostaining was found in 8.9% for p53, in 43.5% for bcl-2, and in 25.0% for p21(WAF1/CIP1). None of them was able to predict LNM or clinical outcome. Presence of LNM, tumor recurrence, and death from disease were significantly associated with the FIGO stage (P = 0.014, P = 0.009, and P = 0.001, respectively). The 5-year cancer-specific survival rate was 91.6% and the overall survival rate was 90.5%. It was concluded that immunohistochemically detected p53, bcl-2, and p21(WAF1/CIP1) appeared to be of no predictive value with regard to LNM, tumor recurrences, or long-term survival in early cervical carcinomas.

The prognostic value of a histologic grading system, DNA profile, and MIB-1 expression in early stages of cervical squamous cell carcinomas.

This study evaluated the prognostic importance of a new grading system focusing on the invasive tumor front, DNA profile, and the proliferation marker MIB-1. A complete geographic series of 172 women treated with radical hysterectomy (Wertheim-Meigs) for FIGO stage I-II cervical carcinomas was the target population. The analyses were performed on 141 (82%) squamous cell carcinomas of the complete series. During the period of observation (mean 222 months), 17 recurrences (12.1%) were encountered. Prognostic factors for disease-free survival were lymph node status (P < 0.000001), radical surgical margins (P = 0.00004), and tumor size (P = 0.002). The complete score of the invasive front grading system (IFG), and the individual scores of two variables-pattern of invasion and host response-were all significantly (P = 0.002, P = 0.007, P = 0.0001) associated with pelvic lymph node metastases. Host response was the single most important factor in the IFG system, and it was superior to the complete score in predicting lymph node metastases. The total IFG score was also a significant (P = 0.003) prognostic factor for disease-free survival. DNA ploidy, S-phase fraction, and MIB-1 expression were nonsignificant factors in predicting pelvic lymph node metastases and disease-free survival of the patient. The IFG in the original or modified versions could predict low- and high-risk groups of tumors and therefore be of value in treatment planning for these patients.

The prognostic value of histopathologic grading parameters and microvessel density in patients with early squamous cell carcinoma of the uterine cervix.

The purpose of this study was to investigate the prognostic importance of clinical and histopathologic factors, including malignancy grading systems (MGS), partial index (PI), invasive front grading (IFG), and microvessel density. A complete geographic series of 172 early stage (FIGO I-II) cervical carcinomas treated by Wertheim-Meigs surgery during the period 1965-1990 was studied. The patients were followed up for at least 10 years. Significant prognostic factors for disease-free survival were lymph node status (P < 0.0000001), radical surgical margins (P = 0.00003), and tumor size (P = 0.008). In a multivariate Cox analysis it was shown that lymph node status was the single most important prognostic factor with regard to disease-free survival. The total MGS and the PI scores were highly significantly (P = 0.0001) associated with pelvic lymph node metastases and disease-free survival rate in squamous cell carcinomas. The MGS and the PI systems were superior to the IFG system in predicting lymph node metastases. The total IFG score was also a statistically highly significant (P = 0.003) prognostic factor with regard to disease-free survival in both univariate and multivariate analyses. Microvessel density was a nonsignificant prognostic factor. There was a highly significant (P = 0.002) association between vascular space invasion of tumor cells and the presence of lymph node metastases. In conclusion, histopathologic malignancy grading systems provide valuable prognostic information in patients with early stage squamous cell carcinomas of the uterine cervix.

Prognostic importance of DNA ploidy and p53 in early stages of epithelial ovarian carcinoma.

Patients with early stages (FIGO stages IA-IIC) of ovarian cancer continue to experience tumor relapses and they succumb due to their disease after seemingly adequate adjuvant therapy. In a series of 113 patients treated with adjuvant radiotherapy 4-6 weeks after primary surgery, the DNA content and p53 status of the tumors were studied and related to other known prognostic factors (age, FIGO stage, histopathologic type, and tumor grade). The DNA analyses were done by flow cytometry and p53 expression was studied by immunohistochemistry on formalin-fixed and paraffin-embedded tissue. DNA analyses of 103 tumors could be made and the p53 status was determined in 106 cases. Univariate analyses showed that both p53-positivity and aneuploidy of the ovarian tumors were strongly associated with tumor grade. There was also a strong association between p53 expression of the tumors and DNA aneuploidy (DNA index >1.10 and S-phase fraction >11.5%). P53-positivity and tumor grade were the only significant factors for the risk of tumor recurrence. DNA and p53 status alone were not adequate predictive factors to identify clinically relevant subgroups of patients who would benefit from adjuvant postoperative therapy. Tumor grade remains the most important prognostic factor with regard to the risk of tumor recurrence and the cancer-specific survival rate in early stage ovarian carcinoma. Overexpression of p53 also increases the risk of tumor recurrence.

The growth factor receptors HER-2/neu and EGFR, their relationship, and their effects on the prognosis in early stage (FIGO I-II) epithelial ovarian carcinoma.

Epithelial ovarian cancer is a heterogeneous disease and many biologic and molecular factors are important for its development and progression, including growth rate, metastatic potential, chemo- and radiosensitivity, and prognosis. Even in the early stages (FIGO I-II), many questions persist about the biologic behavior, optimal treatment, and prognosis. In a series of 106 patients with epithelial ovarian cancers in FIGO stages IA-IIC, a number of known prognostic factors (age, FIGO stage, histopathologic type, and tumor grade) were studied in relation to two important growth factor receptors for oncogenesis (HER-2/neu and EGFR). Immunohistochemical techniques were used. All patients received adjuvant radiotherapy 4-6 weeks after the primary surgery. In a univariate analysis, the expression of the HER-2/neu receptor was not associated with any of the clinicopathologic factors studied or survival status. Positive EGFR staining was associated with poor survival in a univariate analysis. Co-expression of HER-2/neu and EGFR was most frequently seen in serous tumors and positive staining for HER-2/neu alone was associated with mucinous tumors. Both endometrioid and clear cell tumors belonged to the largest subgroup with concomitant negativity for both HER-2/neu and EGFR. In a multivariate Cox analysis, the tumor grade and EGFR status of the tumors were independent and significant prognostic factors. A therapeutic strategy for epithelial ovarian cancer might be to decrease EGFR expression by gene therapy in combination with adjuvant radiotherapy or chemotherapy.

P53, bcl-2, and bax: their relationship and effect on prognosis in early stage epithelial ovarian carcinoma.

The prognosis of ovarian carcinoma, even in the early stages (FIGO I-II), continues to present a challenge despite advances in the understanding of pathophysiology and treatment. In a series of 106 patients with epithelial carcinomas in FIGO stages IA-IIC, a number of prognostic factors (age, FIGO stage, histopathologic type, and tumor grade) were studied in relation to important regulators of apoptosis (p53, bcl-2, and bax). Immunohistochemical techniques were used. All the patients received adjuvant radiotherapy after the primary surgery. Univariate analysis showed that expression of p53 was highly significantly associated with tumor grade (P = 0.007) and survival status (P = 0.046). Positive bcl-2 staining was associated with serous (P = 0.0002) and endometrioid tumor subtypes, but not with the survival rate. A positive bax status was associated with younger age (P = 0.012) and a more favorable probability of survival. A significant association between the bcl-2 and bax status of the tumors and histopathologic subtypes and grades was noted. The most favorable subgroup of tumors was that with a combination of positive bax staining and negative p53 staining. In a multivariate Cox analysis, tumor grade (P = 0.0006) and bax status (P = 0.020) were independent and significant prognostic factors.

Adjuvant radiotherapy in stage I-II epithelial ovarian cancer.

OBJECTIVE: The purpose of this study was to assess the efficacy and side-effects of abdominopelvic irradiation applied as adjuvant postoperative therapy in early stage ovarian carcinomas. METHODS: From 1 January 1988 to 31 December 1993, 113 patients with FIGO stage IA-IIC epithelial ovarian carcinoma were treated with postoperative radiotherapy. Whole abdominal irradiation or lower abdominopelvic irradiation was used. The dose of specification was 20 Gy to the upper part of the abdominal cavity and 40 Gy to the lower part of the abdomen and the pelvic region. RESULTS: Primary cure was achieved in 110 patients (97%). During the period of follow-up, 33 cases of tumor recurrences (30%) were recorded. Abdominopelvic metastases were most frequent (18%). The overall 5-year survival rate for the complete series was 69% and the cancer-specific survival rate was 72%. Tumor grade was an independent and significant prognostic factor (Cox multivariate analysis; p = 0.007). Early radiation reactions of any type were noted in 93% of the cases and, in 11%, discontinuation of radiotherapy was necessary. Late radiation reactions were noted in 58% of the cases and the most common side-effect was diarrhea, but in most cases these reactions were of limited clinical significance. The incidence of severe bowel toxicity was 10% and, in two patients ( 1.8%), surgery was necessary due to late radiation reactions. CONCLUSIONS: Adjuvant abdominopelvic radiotherapy is one option among others (e.g. various types of chemotherapy or no further treatment) in primary treatment of early stage ovarian carcinoma. The optimal adjuvant therapy for this group of patients is not known today and further prospective and randomized studies are needed.

Randomized trial of recombinant human interleukin-3 versus placebo in prevention of bone marrow depression during first-line chemotherapy for ovarian carcinoma.

PURPOSE: To determine whether recombinant human interleukin-3 (rhIL-3) reduces bone marrow depression and improves chemotherapeutic schedule adherence in ovarian cancer patients receiving first-line combination chemotherapy. PATIENTS AND METHODS: In a randomized multicenter study, 185 patients received carboplatin (dose based on projected area under the concentration-time curve [AUC]=4) and cyclophosphamide (750 mg/m2) day 1, every 3 weeks for six cycles. Patients were randomized to receive rhIL-3 (5 microg/kg) or placebo once daily subcutaneously on days 3 to 12. RESULTS: Adherence to chemotherapeutic regimen, mean chemotherapy cycle length, tumor response rate, and median survival at 24 months did not differ between groups. The number of side effects-primarily allergic reactions, flu-like symptoms and fever-were higher in the rhIL-3 group, which resulted in 21 discontinuations compared with one in the placebo group. Compared with placebo, the rhIL-3 group had higher platelet counts day 1 of cycles 2 to 6. The number of patients with World Health Organization (WHO) grade IV thrombocytopenia or number of platelet transfusions did not differ. Leukocyte counts differed only in cycles 1 and 2 between groups. The leukocyte nadir occurred earlier in the rhIL-3 (day 12) than in the placebo group (day 15, P=.006). Leukocytes and neutrophils were only higher in the rhIL-3 group day 1 of cycle 2. In cycles 4 and 5, more patients with WHO grade IV neutropenia received rhIL-3 (P < .005). Eosinophil counts were higher day 1 of cycles 2 to 6 in the rhIL-3 group (P < .0001). CONCLUSION: rhIL-3 had stimulatory hematopoietic effects. This did not result either in reduction of platelet transfusions or in improvement of chemotherapeutic schedule adherence. There were more side effects in the rhIL-3 group than in the placebo group. rhIL-3 at 5 microg/kg/d is, therefore, not of clinical benefit in this chemotherapeutic regimen.