A randomized phase II study investigating the addition of the specific COX-2 inhibitor celecoxib to docetaxel plus carboplatin as first-line chemotherapy for stage IC to IV epithelial ovarian cancer, Fallopian tube or primary peritoneal carcinomas: the DoCaCel study.

BACKGROUND: In ovarian cancer, cyclooxygenase-2 (COX-2) overexpression is prognostic for poor survival. We investigated the efficacy of celecoxib (C), a selective COX-2 inhibitor, added to docetaxel (Taxotere)/carboplatin (DC) in advanced ovarian cancer. PATIENTS AND METHODS: In a phase II, randomized study, 400 mg celecoxib b.i.d. was added to first-line DC treatment (DCC). Celecoxib was to be continued after DC termination up to 3 years. Study end points were tolerability, progression-free survival (PFS) and overall survival (OS). RESULTS: 151 of 196 eligible patients were diagnosed with stage IIIC/IV disease. Median follow-up for patients alive was 32.3 months. Celecoxib was used during a mean of 8.5 months. Twenty-three of 97 DCC patients stopped celecoxib prematurely, mainly due to skin reactions. Complete biochemical response was achieved in 51/78 DC patients (65%) versus 57/78 DCC patients (75%, not significant). In both study arms, median PFS was 14.3 months and median OS 34 months. COX-2 was expressed in 82% of 120 tumor samples retrospectively recovered. The PFS and OS of patients with intermediate/high COX-2 expression were similar to that in the other patients. CONCLUSION: Celecoxib did not influence PFS and OS, but interpretation of results is hampered by premature celecoxib discontinuation.

Implementation of trastuzumab in conjunction with adjuvant chemotherapy in the treatment of non-metastatic breast cancer in the Netherlands.

Trastuzumab in conjunction with adjuvant chemotherapy markedly improves outcome. In the Netherlands, a national guideline was released in September 2005 stating that trastuzumab should be given in conjunction with adjuvant chemotherapy in women with HER2-positive breast cancer. Aim of this study was to identify the number of women with HER2-positive breast cancer and to evaluate the level of implementation of adjuvant trastuzumab in clinical practice nationwide. Women diagnosed with primary breast cancer between September 2005 and January 2007 were selected from the Netherlands Cancer Registry (NCR). HER2 status, adjuvant treatment and reasons to withhold trastuzumab were registered. 14,934 Breast cancer patients were diagnosed in this period of whom 1,928 (13%) had a HER2-positive tumour. Of all HER2-positive women receiving adjuvant chemotherapy, 66 (6%) did not receive trastuzumab. This percentage decreased from 10% at the time of introduction of the guideline to 4% in the study period September 2005-December 2006. Most common reasons to withhold trastuzumab were cardiovascular disease (29%) and patient refusal (21%). Of all HER2-positive patients who received adjuvant chemotherapy, 94% received trastuzumab. The implementation of trastuzumab in clinical practice was realized within 8 months after introduction of the new guideline.

Long-term morbidity of adjuvant whole abdominal radiotherapy (WART) or chemotherapy for early stage ovarian cancer.

UNLABELLED: The aim of the study was to evaluate long-term toxicity of adjuvant treatment in early stage ovarian cancer survivors. Data from all patients treated in one hospital for early stage ovarian cancer diagnosed between 1980 and 1990 were collected using a structured data form. In 93 FIGO stages I and II patients, cytoreductive and staging surgery was performed; 15 received no adjuvant treatment (controls), 39 whole abdominal radiotherapy (WART) and 39 platin-based chemotherapy. Median age at diagnosis was 54 years (range 21-83 years). During follow-up, 49/93 (53%) patients have died with a median overall survival of 18.4 years (95% CI 12.8-23.9). In both the radiotherapy and the chemotherapy group, 50% of patients reported long-term side-effects (all grades) versus 13% of controls. Two patients in the WART group died from bowel complications. Secondary malignancies were observed in 16 patients. Of all patients alive at the last follow-up, 12/17 (71%) patients treated with radiotherapy and 11/18 (61%) treated with chemotherapy experienced long-term morbidity versus 2/9 (22%) controls (P=0.03). IN CONCLUSION: Long-term follow-up of early stage ovarian cancer patients showed lasting GI morbidity in the survivors treated with adjuvant radiotherapy, which has therefore become obsolete. Cisplatin-based chemotherapy caused peripheral neuropathy versus virtual absence of problems in the survivors of just surgery, emphasising the need for strict criteria before instigating adjuvant treatment.

Safety and pharmacology of paclitaxel in patients with impaired liver function: a population pharmacokinetic-pharmacodynamic study.

AIMS: To assess quantitatively the safety and pharmacology of paclitaxel in patients with moderate to severe hepatic impairment. METHODS: Solid tumour patients were enrolled into five liver function cohorts as defined by liver transaminase and total bilirubin concentrations. Paclitaxel was administered as a 3-h intravenous infusion at doses ranging from 110 to 175 mg m(-2), depending on liver impairment. Covariate and semimechanistic pharmacokinetic-pharmacodynamic (PK-PD) population modelling was used to describe the impact of liver impairment on the pharmacology and safety of paclitaxel. RESULTS: Thirty-five patients were included in the study, and PK data were assessed for 59 treatment courses. Most patients had advanced breast cancer (n = 22). Objective responses to paclitaxel were seen in four patients (11%). Patients in higher categories of liver impairment had a significantly lower paclitaxel elimination capacity (R2 = -0.38, P = 0.05), and total bilirubin was a significant covariate to predict decreased elimination capacity with population modelling (P = 0.002). Total bilirubin was also a significant predictor of increased haematological toxicity within the integrated population PK-PD model (P < 10(-4)). Data simulations were used to calculate safe initial paclitaxel doses, which were lower than the administered doses for liver impairment cohorts III-V. CONCLUSIONS: Total bilirubin is a good predictor of paclitaxel elimination capacity and of individual susceptibility to paclitaxel-related myelosuppression in cancer patients with moderate to severe liver impairment. The proposed, adapted paclitaxel doses need validation in prospective trials.

Granulosa cell tumors of the ovary: the clinical value of serum inhibin A and B levels in a large single center cohort.

OBJECTIVES: In patients with a granulosa cell tumor of the ovary, the value of serum inhibin A and B concentrations for the assessment of disease status was investigated. METHODS: In 30 consecutive patients with a stage I-III granulosa cell tumor, inhibin A and B concentrations were measured in pre- and post-treatment serum samples. Clinical data concerning diagnosis, treatment and follow-up of these patients were related to serum inhibin A and B concentrations. Serum samples from 41 premenopausal females with cervical dysplasia served as controls. RESULTS: In 30 patients, 13 (43%) recurrences were observed during a median follow-up of 10 years (range 1-31 years). Serum inhibin A and B concentrations were elevated in respectively 67% and 89% of the patients at diagnosis, and in 58% and 85% at recurrence. Inhibin A and B concentrations were normal in all controls. Sensitivity of inhibin A testing for the diagnosis of granulosa cell tumor was 67% with a specificity of 100%, compared to 89% and 100% respectively for inhibin B (ns). Elevations in serum inhibin B concentrations predated recurrences by a median of 11 months. None of the patients in remission showed increased concentrations of inhibin A and B. CONCLUSION: Inhibin B seems to be the predominant form of inhibin secreted by granulosa cell tumors and appears to reflect disease status more accurately than inhibin A. Measurement of serum inhibin B concentrations may be preferred for the follow-up of granulosa cell tumors.

The clinical trail of TRAIL.

The naturally occurring tumour necrosis factor related apoptosis-inducing ligand (TRAIL) induces apoptosis through two death receptors, death receptor 4 (DR4) and death receptor 5 (DR5), that are expressed on the cell membrane. Binding of the ligand to the death receptors leads to activation of the extrinsic apoptosis pathway. Chemotherapy on the other hand stimulates the intrinsic apoptosis pathway via activation of p53 in response to cellular damage. Many cancer cells have mutations in p53 causing resistance to chemotherapy-induced apoptosis. Concomitant signalling through the extrinsic pathway may overcome this resistance. Moreover, enthusiasm for TRAIL as an anticancer agent is based on the demonstration of rhTRAIL-induced selective cell death in tumour cells and not in normal cells. In this review, we provide an overview of the TRAIL pathway, the physiological role of TRAIL and the factors regulating TRAIL sensitivity. We also discuss the clinical development of novel agents, i.e. rhTRAIL and agonistic antibodies, that activate the death receptors.

[The role of trastuzumab in mammary carcinoma in The Netherlands]. / De plaats van trastuzumab bij het mammacarcinoom in Nederland.

Trastuzumab is the first humanised monoclonal antibody to demonstrate activity in patients with HER2/neu-positive breast cancer. It has taken almost 20 years of research from the first description of HER2/neu as an unfavourable prognostic factor until the development of a clinically applicable antibody that has now shown convincing activity in the adjuvant setting: not only progression-free survival (HR: 0.48-0.54) but also distant disease-free survival (HR: 0.47-0.49) and overall survival (HR: 0.41-0.67) were improved after four years. It is a good thing, therefore, that shortly after the publication of these striking results, the specialists concerned have designated trastuzumab in combination with chemotherapy as the standard adjuvant treatment for patients with HER2/neu-positive rumours. This decision anticipates the formal registration for this indication and the rules for reimbursement. Nevertheless, this effective form of treatment may not be withheld from the patients concerned in the Netherlands merely on formal grounds, since there can be no doubt as to the indication.

Molecular prognostic markers in ovarian cancer: toward patient-tailored therapy.

In ovarian cancer the ceiling seems to be reached with chemotherapeutic drugs. Therefore a paradigm shift is needed. Instead of treating all patients according to standard guidelines, individualized molecular targeted treatment should be aimed for. This means that molecular profiles of the distinct ovarian cancer subtypes should be established. Until recently, most studies trying to identify molecular targets were single-marker studies. The prognostic role of key components of apoptotic and prosurvival pathways such as p53, EGFR, and HER2 has been extensively studied because resistance to chemotherapy is often caused by failure of tumor cells to go into apoptosis. However, it is more than likely that different ovarian cancer subtypes with extensive molecular heterogeneity exist. Therefore, exploration of the potential of specific tumor-targeted therapy, based on expression of a prognostic tumor profile, may be of interest. Recently, new profiling techniques, such as DNA and protein microarrays, have enabled high-throughput screening of tumors. In this review an overview of the current status of prognostic marker and molecular targeting research in ovarian cancer, including microarray studies, is presented.

Guideline adherence for early breast cancer before and after introduction of the sentinel node biopsy.

This population-based study aimed to analyse variations in surgical treatment and guideline compliance with respect to the application of radiotherapy and axillary lymph node dissection (ALND), for early breast cancer, before and after the sentinel node biopsy (SNB) introduction. The study included 13 532 consecutive surgically treated stage I-IIIA breast cancer patients diagnosed in 1989-2002. Hospitals showed large variation in breast-conserving surgery (BCS) rates, ranging between 27 and 72% for T1 and 14 and 42% for T2 tumours. In multivariate analysis marked inter-hospital and time-dependent variation in the BCS rate remained after correction for case-mix. The guideline adherence was markedly lower for elderly patients. In 25.2% of the patients aged > or = 75 years either ALND or radiotherapy were omitted. The proportion of patients with no ALND after an SNB increased from 1.8% in 1999 to 37.8% in 2002. However, in 2002 also 12.2% of the patients with a positive SNB did not have an ALND. Guideline compliance for BCS, with respect to radiotherapy and ALND, fell since the SNB introduction, from 96.1% before 2000 to 91.4% in 2002 (P < 0.001). Noncompliance may however reflect patient-tailored medicine, as for elderly patients with small, radically resected primary tumours. The considerable variation in BCS-rates is more consistent with variations in surgeon preferences than patient's choice.

A randomized phase II study of paclitaxel with carboplatin +/- amifostine as first line treatment in advanced ovarian carcinoma.

OBJECTIVE: Will amifostine (A) protect against chemotherapy-induced neuro- and myelotoxicity. PATIENTS AND METHODS: Ninety ovarian cancer patients were randomized to receive standard paclitaxel + carboplatin without (PC) or preceded by amifostine 740 mg/m(2) (PC + A). RESULTS: The mean baseline values of hemoglobin, leukocyte, and platelets were slightly lower in the amifostine group, but the mean percentual decrease of these parameters after each treatment cycle showed no difference between both arms. Symptoms of neurotoxicity remained absent in 40% PC vs. 49% PC + A cycles; sensory neurotoxicity grade I occurred in 45% vs. 48% and grade II in 12% PC vs. 2% of PC + A cycles (overall P < 0.001). Nausea grade II was reported in 2% vs. 6% (P = 0.007) and vomiting grade II in 1% of PC vs. 8% PC + A cycles (P < 0.001). Amifostine was temporarily interrupted in five patients due to hypotension, but no dose reductions were indicated. Quality of life questionnaires showed no difference in neurotoxicity scores between both study arms at treatment completion. The median progression-free survival was 16 vs. 22 months (n.s.) for PC and PC + A patients. In a pooled analysis of four randomized studies, amifostine diminished the risk of developing neurotoxicity grade II-III (Odds Ratio 0.3, 95% confidence interval 0.15-0.63, P < 0.05), but had no effect on the risk for bone marrow toxicity. CONCLUSION: Amifostine shows only minor but significant activity in diminishing neurotoxicity without preventing paclitaxel + carboplatin-induced bone marrow toxicity.

A phase I study of intraperitoneal topotecan in combination with intravenous carboplatin and paclitaxel in advanced ovarian cancer.

The aim of this study was to determine the maximum tolerated dose (MTD) of intraperitoneal (i.p.) topotecan combined with standard doses of intravenous (i.v.) carboplatin and paclitaxel and to investigate its pharmacokinetics. Women with primary ovarian cancer stage IIb - IV received six cycles of i.v. carboplatin and paclitaxel with escalating topotecan doses i.p. of 10, 15, 20 and 25 mg/m(2). Twenty-one patients entered this trial. Febrile neutropenia, thrombocytopenia requiring platelet transfusion and fatigue grade 3 were dose-limiting toxicities (DLT) at 25 mg/m(2) i.p. and 20 mg/m(2) i.p. of topotecan was considered to be the MTD. The mean plasma t(1/2) was 3.8 +/- 2.3 h for total topotecan and 4.4 +/- 3.9 h for active lactone. The area under the curve (AUC) was proportional with dose, R = 0.54, p < 0.05 for total topotecan and the peritoneal / plasma AUC ratio was 46 +/- 30. Fifteen patients who completed treatment had a median progression-free survival (PFS) of 27 months. In this setting the MTD of topotecan is 20 mg/m(2) i.p. The efficacy of this regimen should be explored further in a formal phase III study.

Endothelial cell effects of cytotoxics: balance between desired and unwanted effects.

Since Folkman defined angiogenesis more than 25 years ago as the most important process in tumour growth and metastasis, specific anti-angiogenic agents have been developed. One obvious route to block this process was until recently overlooked, however. Tumour endothelial cells are different from normal endothelial cells and may respond differently to conventional cytotoxics. Chemotherapeutic-induced vascular toxicity has been observed in various clinical studies and seems to be based on endothelial cell damage as seen in vitro in human umbilical vein endothelial cells (HUVEC) models with protracted low-dose cytostatic exposure. Translated into the clinical setting, such "metronomically" administered chemotherapy could lead to anti-angiogenesis enhancing anti-tumour efficacy of cytostatic drugs. This paper reviews the desired anti-tumour endothelial activity versus the unwanted general vascular toxicity of cytostatic drugs. Several ways to enhance the anti-tumour activity and to circumvent the unwanted vascular toxicity of these "accidental" anti-angiogenic drugs will be discussed.

Paclitaxel and carboplatin concurrent with radiotherapy for primary cervical cancer.

BACKGROUND: Concurrent radiochemotherapy is currently considered the new standard treatment in locally advanced cervical cancer. PATIENTS AND METHODS: Eight women with cervical cancer stage IB2-IVA were treated with standard radiation therapy in combination with standard carboplatin (AUC=2, once weekly, x 6) and escalating doses of paclitaxel (60 mg/m2, once weekly, x 4, then x 5 and x 6). RESULTS: At the lowest dose level, four weekly paclitaxel cycles in six patients, three developed grade III diarrhoea and one severe radiation enteritis several weeks after radiotherapy. Two patients did not achieve complete remission and underwent additive salvage hysterectomy. All patients remained free of local recurrence, but one patient had distant metastases after 13 months. The median disease-free survival was 25 months with a median follow-up of 26 months. CONCLUSION: Standard pelvic radiotherapy in combination with weekly carboplatin and paclitaxel is poorly tolerated due to dose-limiting diarrhoea.

Long-term survivors of ovarian malignancies after cisplatin-based chemotherapy; cardiovascular risk factors and signs of vascular damage.

Male germ cell tumour patients treated with cisplatin-based chemotherapy frequently develop cardiovascular risk factors and disease, but sparse information is available about long-term complications of this type of chemotherapy in women. We investigated the prevalence of cardiovascular risk factors and vascular damage in 21 women (median age 39 years; range 26-57 years) with an epithelial or germ cell tumour of the ovary cured by cisplatin-based chemotherapy after a median follow-up of 14 years (range 3-21 years). Hypercholesterolaemia was present in 62%, obesity in 24%, hypertension in 14%, insulin resistance in 14%, and microalbuminuria in 24% of patients. Microalbuminuria was more frequent in long-term cancer survivors than in a female background population with a similar age (23.8 versus 3.2%; P<0.05). A substantial portion of young female patients cured by cisplatin-based chemotherapy are likely to develop cardiovascular risk factors and signs of endothelial damage at an early stage.

[The effects of tamoxifen on the female genital tract]. / Tamoxifen en gynaecologische bijwerkingen.

Tamoxifen has both agonistic and antagonistic effects on the female genital tract, depending on the ambient oestradiol concentration and the menopausal status of the patient. In postmenopausal women tamoxifen has an oestrogen agonistic effect on the vaginal epithelium, the uterine myometrium and the endometrium. It may induce benign cystic hyperplasia of the endometrial stroma and cause an increase in poly formation. The risk of endometrial cancer increases 2-3-fold after an exposure of up to 5 years. In asymptomatic tamoxifen users, gynaecological surveillance is not recommended. However, if there is postmenopausal bleeding, then transvaginal ultrasonography and histology of the endometrium are indicated. Tamoxifen can aggravate hot flushes and have a negative effect on sexual function. In premenopausal women, tamoxifen may induce ovarian cysts resulting in high serum-oestradiol levels. Oligomenorrhoea and amenorrhoea will occur in half of the patients. Tamoxifen has an antagonistic effect on the endometrium in premenopausal women and is associated with hot flushes and impaired sexual functioning. Teratogenic effects on the foetus have been described. Despite its gynaecological side effects, the benefits of tamoxifen in breast-cancer treatment outweigh the risks. Patients need to be informed about these side effects. Irregular or postmenopausal blood loss must always be reported to the treating physician.

Intraperitoneal cisplatin versus no further treatment: 8-year results of EORTC 55875, a randomized phase III study in ovarian cancer patients with a pathologically complete remission after platinum-based intravenous chemotherapy.

First-line intravenous chemotherapy (CT) following debulking surgery is associated with prolonged survival, in particular in patients who achieve a pathological complete remission (pCR) at second-look surgery but in whom a high rate of relapses still occurs. Between 1988 and 1997, 153 patients in pCR following platinum-based intravenous CT were randomized between four courses of intraperitoneal cisplatin (P) (90 mg/m2 every 3 weeks) or observation. Overall survival (OS) was the primary endpoint, while progression-free survival (PFS) was a secondary endpoint. This intent-to-treat analysis includes 16 patients who were not eligible and 17 patients who had protocol violations. The two groups were well balanced in terms of age (median = 55 years), performance status (78% P.S. O), FIGO stage (96% stage III), histology (serous in 66%), grade (2 or 3 in 80%), and residuum before intravenous CT (>1 cm in 40%). Intraperitoneal CT was delivered mainly through intraperitoneal catheters (Port-a-Cath 61% and Tenckhoff 25%). Side effects of intraperitoneal cisplatin included vomiting [> or =grade 2 (82%)], rise in serum creatinine [> or =grade 2 (14%)], abdominal pain [grade 1-2 (38%)], and neurotoxicity [grade 2-3 (15%)]. After a median follow-up of 8 years, 80 patients (52%) have progressed with no difference in the pattern of relapse between the two groups and 75 patients (49%) have died; the respective hazard ratios for PFS and OS with 95% CI are 0.89 (0.59-1.33) and 0.82 (0.52-1.29). These results are suggestive of a treatment benefit but do not support a change in clinical practice. Other randomized clinical trials of intraperitoneal CT are reviewed and briefly discussed.

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.