Phb Willemse

Randomized trial comparing two combination chemotherapy regimens (CHAP-5 v CP) in advanced ovarian carcinoma.

One hundred ninety-one patients with advanced epithelial ovarian carcinoma were treated with either a combination of doxorubicin and a five-day course of cisplatin alternating with cyclophosphamide and hexamethylmelamine orally for 14 days (CHAP-5) or cyclophosphamide and cisplatin both administered intravenously (IV) on a single day at 3-week intervals (CP). At a median follow-up time of 45 months, treatment with each of these combinations resulted in the same remission rates (80% and 74%, respectively) and exactly the same progression-free survival and overall survival (median, 26 months). Despite adequate hydration, more renal toxicity was encountered in the CP-treated patients than in those who received CHAP-5. Disabling neurotoxicity and severe myelosuppression were encountered more frequently in the patients treated with CHAP-5. Because the toxicity was lower and CP treatment required shorter hospitalization, the single-day regimen was considered preferable for future use. The Karnofsky index was the only independent predictor for response, whereas both this index and the size of residual tumor before chemotherapy were predictive of survival. After correcting for other prognostic factors, it was determined that tumor size associated with improved survival was less than 1 cm. The site of metastases in International Federation of Gynecology and Obstetrics (FIGO) stage IV patients did not influence survival within this category. The results of this study confirm our previous findings that patients with microscopic remnants at second-look have a survival similar to that of patients who are histopathologically free of disease. This makes the significance of so-called pathologically confirmed complete remission questionable. The survival benefit of debulking surgery performed during chemotherapy seems only minimal for patients in whom debulking has already been attempted before treatment. Like others, we have found the CP regimen to have a good therapeutic index.

LONG-TERM SURVIVAL IN OVARIAN-CANCER - MATURE DATA FROM THE NETHERLANDS JOINT STUDY-GROUP FOR OVARIAN-CANCER

In two studies initiated in 1979 and 1981, 377 patients were treated for advanced epithelial ovarian cancer. In the first study patients were randomly assigned to receive Hexa-CAF (hexamethylmelamine, cyclophosphamide, methotrexate, 5-fluorouracil) or CHAP-5 (cyclophosphamide, hexamethylmelamine, doxorubicin, cisplatin for 5 days) and in the second study to receive CHAP-5 or CP (cyclophosphamide, cisplatin on 1 day). Patients who did not respond to Hexa-CAF were offered subsequent treatment that included cisplatin. Median follow-up of patients in the first study was 9.5 years and in the second study 7.7 years. At 10 years 9% of the patients initially treated with Hexa-CAF and 21% of patients assigned to CHAP-5 were alive. Among the 10-year survivors treated with Hexa-CAF, 50% had experienced progressive disease but were alive as a result of retreatment with a cisplatin regimen. The survival curves of both studies revealed that approximately 60% of the patients who reached a complete remission were alive at 5 years and 40% at 10 years. Patients with microscopic disease at second-look had a less favourable outlook: 35% survived 5 years. Not recognised at first publication of both studies was the influence of tumour grade on survival. Before 5 years of follow-up, the good prognosis of grade 1 tumours (well differentiated) could not be detected. About 50% of patients with grade 1 tumours were alive at 5 and 30% at 10 years while these survival rates were halved for the other grades. Combination chemotherapy with cisplatin can enhance survival by more than 10% at 5 and 10 years compared with the best treatment of the precisplatin era: Hexa-CAF.

Value of P-glycoprotein, glutathione S-transferase pi, c-erbB-2, and p53 as prognostic factors in ovarian carcinomas.

PURPOSE To determine the prognostic value of immunostaining of P-glycoprotein (P-gp), glutathione S-transferase (GST) pi, c-erbB-2, and p53 in patients with advanced-stage ovarian carcinoma. PATIENTS AND METHODS Immunostaining of P-gp, GST pi, c-erbB-2, and p53 was performed on 89 primary tumors and 38 residual tumors after chemotherapy (P-gp and GST pi) in patients with advanced ovarian carcinoma treated with platinum- and doxorubicin-containing chemotherapy. The results of immunostaining were related to clinicopathologic prognostic factors, response to chemotherapy, and progression-free survival (PFS) and overall survival. RESULTS P-gp and GST pi immunoreactivity were present in 13 (15%) and 79 cases (89%), respectively, and were not associated with any other prognostic factor or PFS or overall survival. C-erbB-2 immunoreactivity was present in 18 cases (20%) and was associated with undifferentiated histiotype (P < .05), but not with PFS or overall survival. p53 immunoreactivity was present in the nuclei of 31 cases (35%) and cytoplasm of nine cases (10%). Nuclear p53 staining was associated with grade III tumors, presence of more than 1-L ascites, and residual tumor after first laparotomy more than 2 cm. Nuclear p53 staining was associated with shorter PFS (relative risk [RR], 3.3; 95% confidence interval [CI], 2.0 to 5.6) and overall survival (RR, 2.6; 95% CI, 1.7 to 3.8). After adjustment for presence of more than 1-L ascites or age more than 50 years, nuclear p53 staining did not retain independent prognostic significance in stage III/IV tumors. The frequency of P-gp staining in residual tumors after chemotherapy (18 of 38 cases) was higher in comparison to untreated tumors (13 of 89 cases) (P < .001). No combination of prognostic parameters was able to predict response to chemotherapy adequately. CONCLUSION Nuclear immunoreactivity of p53 in ovarian carcinomas is associated with shorter PFS and overall survival and determinants of more aggressive tumor growth. The higher frequency of P-gp immunoreactivity in residual tumors after chemotherapy points to induction of P-gp in ovarian carcinomas by doxorubicin-containing combination chemotherapy. The determination of P-gp, GST pi, c-erbB-2, and p53 does not permit more adequate prediction of response to chemotherapy.

Phase II study of subcutaneous interleukin-2 in unselected patients with advanced renal cell cancer on an outpatient basis.

PURPOSE A single-institution phase II study was undertaken to evaluate the efficacy and toxicity of interleukin-2 (IL-2) administered by subcutaneous injection. PATIENTS AND METHODS Twenty-seven unselected patients (15 male) with a mean age of 60 years (range, 42 to 76 years) who had advanced renal cell cancer were treated as outpatients. IL-2 was given once a day, 5 days per week for 6 weeks. During the first 5-day cycle, 18 x 10(6) IU was given once daily; in the following cycles, the doses in the first 2 days were reduced to 9 x 10(6) IU. After a 3-week rest period, treatment was repeated in patients who had a response or stable disease (SD). To prevent pyretic reactions, patients also received acetaminophen (250 to 500 mg given orally every 4 to 6 hours). RESULTS After 6 weeks, 26 patients were assessable for response. Two patients (8%) had a complete remission (CR), four (15%) had a partial remission (PR), and 13 (50%) had SD. A second cycle of 6 weeks was given to 19 patients; one patient with a PR and six with SD showed progression. Duration of the CR was 17+ and 19+ months, and length of the PR was 2, 8, 11, and 11+ months. The median survival of the patients who were nonresponders and responders was 10 and 20+ months, respectively, and for all patients was 13 months. One patient died as a result of myocardial infarction and brain stem ischemia. Systemic side effects in the other patients were tolerated and accepted, and included transient inflammation and local induration at the injection sites, fever and chills, and nausea. CONCLUSION Subcutaneous IL-2 is clinically active, has an acceptable toxicity, and can be given to patients with concomitant disease.

Acute and long-term toxicity following radiotherapy alone or in combination with chemotherapy for locally advanced cervical cancer

Randomised studies in locally advanced cervical cancer patients showed that cisplatin should be given concurrently with radiotherapy, because of a better long-term survival compared to radiotherapy alone. This increases the relevance of treatment related toxicity. This review summarises the acute and long-term toxicity of radiotherapy given with or without chemotherapy for cervical cancer. Acute toxicity (all grades) of radiotherapy is reported in 61% of the patients in the rectosigmoid, in 27% as urological, in 27% as skin and in 20% as gynaecological toxicity. Moderate and severe morbidity consists of 5% to 7% gastrointestinal and 1% to 4% genitourinary toxicity. Adding chemotherapy to radiotherapy increases acute haematological toxicity to 5% to 37% of the patients and nausea and vomiting in 12% to 14%. Late effects of radiotherapy include gastrointestinal, urological, female reproductive tract, skeletal and vascular toxicity, secondary malignancies and quality of life issues. For at least 20 years after treatment, new side effects may develop. Gastrointestinal toxicity usually occurs in the first 2 years after treatment in about 10% of the patients. The incidence of moderate and severe urological toxicity can increase up to 10% and rises over time. Gynaecological toxicity usually occurs shortly after treatment while skeletal and vascular toxicity can occur years to decades later. Thus far, no increase in late toxicity has been observed after the addition of cisplatin to radiotherapy. Finally, methods to prevent or decrease late toxicity and therapeutical options are discussed. However, most randomised studies still have a limited follow-up period.

Long-term Follow-up of Cardiovascular Risk Factors in Patients Given Chemotherapy for Disseminated Nonseminomatous Testicular Cancer

OBJECTIVE To assess cardiovascular risk factors over time in patients who received chemotherapy for disseminated testicular cancer and were apparently cured. DESIGN Cohort study. SETTING Referral center. PATIENTS Fifty-seven consecutive patients (median age, 28 years; range, 16 to 43 years) who received cisplatin-containing chemotherapy between 1978 and 1985. MEASUREMENTS Serum cholesterol and high-density lipoprotein (HDL) levels, body mass index (BMI), blood pressure, kidney function, and hormonal status were monitored during follow-up after chemotherapy (median follow-up, 88 months; range, 56 to 143 months). The BMI and cholesterol values obtained 4 to 6 years after chemotherapy were compared with values from a sample of healthy, age-matched Dutch men; the cholesterol level was also compared with that of 31 patients treated with orchidectomy for stage I disease. RESULTS The mean cholesterol level in patients at the start of chemotherapy was 3.96 +/- 0.98 mmol/L [153 +/- 38 mg/dL], increasing 4 to 6 years later to 6.12 +/- 1.20 mmol/L [237 +/- 46 mg/dL] (P less than 0.001); 49 of 57 patients had an elevated low-density lipoprotein (LDL) cholesterol level (greater than 3.4 mmol/L [130 mg/dL]), with a mean level of 4.47 +/- 1.05 mmol/L [173 +/- 41 mg/dL]. Compared with a sample of healthy Dutch men, the chemotherapy group had an elevated cholesterol level (P less than 0.05). At 4 to 6 years, the mean HDL cholesterol level was 0.76 +/- 0.18 mmol/L [29 +/- 7 mg/dL], which was low compared with that of the healthy Dutch men (P less than 0.05). The mean BMI for all patients was 2.8% higher than expected 4 to 6 years after chemotherapy (P less than 0.01) but was not higher than expected 7 to 10 years after chemotherapy. CONCLUSIONS In addition to other known late side effects of chemotherapy in patients with testicular cancer, hypercholesterolemia and overweight might represent risk factors for cardiovascular disease in such patients, especially in those who are younger.

Malignant struma ovarii treated by ovariectomy, thyroidectomy, and 131I administration

A 36‐year‐old woman presented with an intraperitoneally disseminated malignant struma ovarii, diagnosed by histopathology and 131I scintigraphy. The serum thyroglobulin level was elevated, and immunoperoxidase staining for thyroglobulin was positive for disease both in the tumor cells lining the follicles and in the colloid. The patient was treated successfully by a bilateral ovariectomy followed by a total thyroidectomy and administration of radioactive iodine. The clinical behavior and the presence of thyroglobulin in both serum and tumor tissue demonstrate the similarity between neoplastic thyroid tissue in the ovary and in the thyroid gland.

Local antitumour treatment in carcinoma patients with bispecific-monoclonal-antibody-redirected T cells

In a pilot clinical study carcinoma patients with malignant ascites or pleural exudates have been treated locally with autologous lymphocytes activated ex vivo and redirected towards tumour cells with bispecific monoclonal antibodies. BIS-1, the bispecific monoclonal antibody used in this study, combines specificity against a tumour-associated antigen, AMOC-31, present on carcinomas, with a specificity against the CD3 complex on T lymphocytes. Patients selected for treatment had malignant pleural or peritoneal effusions. Treatment consisted of isolating autologous peripheral blood lymphocytes, ex vivo activation, incubation with bispecific monoclonal antibodies and injection at the effusion site of these BIS-1-redirected lymphocytes. To evaluate the effects of the bispecific monoclonal antibody, five patients received treatments with activated lymphocytes without bispecific antibodies. Effusion samples taken before and at various times after treatment were analysed by immunocytology and for the presence of the soluble factors carcinoembryonic antigen (CEA), interleukin-6 (IL-6), tumour necrosis factor (TNF), C-reactive protein and soluble CD8. In this way both immune activation and anti-tumour activity could be monitored. Conjugate formation between tumour cells and activated lymphocytes was seen as soon as 4 h after injection of BIS-1-redirected activated lymphocytes, followed by a disappearance or reduction of tumour cells after 24–48 h. In parallel with this, the soluble tumour marker CEA decreased in the effusion fluid following injection with the BIS-1-redirected lymphocytes. Furthermore, a steep increase in local granulocyte numbers was observed in the effusion fluid, which reached a maximum 24–48 h after the start of the treatment. Also levels of IL-6 and TNF were greatly elevated. The data suggest tha the treatment induces both antitumour activity and a strong local inflammatory reaction. This is accompanied by no or only minor local and systemic toxicity, i.e. mild fever, which disappeared as the local inflammatory reaction diminished 48–72 h after treatment.

Tamoxifen effects on subjective and psychosexual well-being, in a randomised breast cancer study comparing high-dose and standard-dose chemotherapy

To evaluate the impact of tamoxifen on subjective and psychosexual well-being in breast cancer patients in relation to type of prior chemotherapy and menopausal status. Longitudinal interview study in breast cancer patients during and after adjuvant tamoxifen use. Menopausal status was defined by last menstrual period and serum oestradiol and FSH levels. Gynaecology outpatient clinic, Tertiary Referral Hospital, January 1995 to September 1999. Breast cancer patients <56 years of age, participating in a randomised trial comparing adjuvant high-dose (n=45) and standard-dose (n=53) chemotherapy, followed by radiotherapy and tamoxifen. Relative incidence and correlation of subjective and psychosexual symptoms during and after tamoxifen. During tamoxifen the most frequent complaints were hot flushes (85%), disturbed sleep (55%), vaginal dryness and/or dyspareunia (47%), decreased sexual desire (44%) and musculo-skeletal symptoms (43%). Disturbed sleep correlated with hot flushes (P<0.0005) and concentration problems (P<0.05). Decreased sexual interest correlated with vaginal dryness (P<0.0005) and/or dyspareunia (P<0.0005). In the high-dose group more patients became postmenopausal (95% vs 33%) and more patients reported symptoms than in the standard-dose group (P<0.05). After discontinuation of tamoxifen, symptoms decreased significantly. However, hot flushes, disturbed sleep and vaginal dryness persisted more often in patients who remained postmenopausal after high-dose chemotherapy (P<0.05). Overall, during tamoxifen patients reported many symptoms. More patients become postmenopausal after high-dose chemotherapy, and they remain often symptomatic after tamoxifen.

Ovarian cysts in women receiving tamoxifen for breast cancer

SummaryTamoxifen is a nonsteroidal anti-oestrogen with gynaecological side-effects. Only recently, ovarian cyst formation during tamoxifen treatment has been reported. The present study aimed to evaluate patient-related parameters that determine ovarian cyst formation in women using tamoxifen for breast cancer. A cross-sectional study was performed in 142 breast cancer patients using tamoxifen. Forty-five patients were also examined prior to tamoxifen treatment. Gynaecological assessment, transvaginal ultrasonography (TVU) and serum oestradiol (E2) and follicle stimulating hormone (FSH) analysis were performed. Follow-up assessments were performed twice a year. Uni- or bilateral ovarian cysts were detected by TVU in 24 tamoxifen-using patients and in one patient before tamoxifen treatment. Multiple regression analysis showed that cyst development is related (multiple R = 0.73) to high E2 (P < 0.001), younger age (P < 0.001) and absence of high-dose chemotherapy (P = 0.007). Patients with ovarian cysts had higher serum E2 levels compared to patients without cysts (1.95 vs 0.05 nmol l–1; P < 0.001). All patients after high-dose chemotherapy or older than 50 years had E2 < 0.10 nmol l–1 and/or amenorrhoea > 1 year and did not develop ovarian cysts. Patients still having a menstrual cycle during tamoxifen had a high chance (81%) of developing ovarian cysts. Breast cancer patients receiving tamoxifen only develop ovarian cysts if their ovaries are able to respond to FSH stimulation as shown by E2 production.