R. de Wit

Weekly high-dose cisplatin is a feasible treatment option: analysis on prognostic factors for toxicity in 400 patients

In the present study we describe the toxicity of weekly high-dose (70–85u2009mgu2009m−2) cisplatin in 400 patients (203 men, 197 women; median age 54 years) with advanced solid tumours treated in the period 1990–2001 who took part in phase I/II trials, investigating the feasibility and efficacy of weekly cisplatin alone, or in combination with paclitaxel or etoposide. Cisplatin was administered in 250u2009ml NaCl 3% over 3u2009h, for six intended administrations. The mean number of administrations was 5.3 (range, 1–6 administrations). Reasons not to complete six cycles were disease progression (7.5%), haematological toxicity (9%), nephrotoxicity (7%), ototoxicity (2.5%), neurotoxicity (1%), gastrointestinal toxicity (1%), cardiovascular complications (0.5%) or a combination of reasons including noncompliance and patients request (5.5%). Logistic regression analysis was used to evaluate baseline parameters for prognostic value regarding toxicity. Leukopenia correlated with etoposide cotreatment, and thrombocytopenia with cisplatin dose and prior (platinum-based) chemotherapy. Risk factors for nephrotoxicity were older age, female gender, smoking, hypoalbuminaemia and paclitaxel coadministration. Neurotoxicity >grade 1 (11% of patients) was associated with prior chemotherapy and paclitaxel coadministration. Symptomatic hearing loss occurred in 15% with anaemia as the predisposing factor. We conclude that weekly high-dose cisplatin administered in hypertonic saline is a feasible treatment regimen.

Cross-resistance between taxanes and new hormonal agents abiraterone and enzalutamide may affect drug sequence choices in metastatic castration-resistant prostate cancer.

INTRODUCTIONnTreatment options for patients with metastatic castration-resistant prostate cancer (mCRPC) have expanded in recent years with the introduction of cabazitaxel, abiraterone and enzalutamide. With new systemic therapies available, the optimal treatment sequence of these drugs in mCRPC becomes increasingly important. As shown recently, patients who had previously been treated with abiraterone showed impaired responses to docetaxel, suggesting clinical cross-resistance [1]. In the present study, we aimed to identify cross-resistance between taxanes (docetaxel and cabazitaxel) and the new hormonal agents abiraterone and enzalutamide. As a potential mechanism for cross-resistance, we investigated the effects on androgen receptor (AR) nuclear translocation of these compounds.nnnMETHODSnTo identify cross-resistance, we determined the effects of docetaxel, cabazitaxel, abiraterone and enzalutamide on cell viability in prostate cancer cell lines with acquired resistance to abiraterone and enzalutamide. Time-lapse confocal microscopy was used to study the dynamics of AR nuclear translocation.nnnRESULTSnWe observed impaired efficacy of docetaxel, cabazitaxel and enzalutamide in the abiraterone-resistant cell line, compared to the non-resistant cell line, providing evidence for in vitro cross-resistance. Impaired efficacy of docetaxel, cabazitaxel and abiraterone was observed in the enzalutamide-resistant cell line. Furthermore, docetaxel and cabazitaxel inhibited AR nuclear translocation, which was also observed for abiraterone and enzalutamide.nnnCONCLUSIONSnIn conclusion we found substantial preclinical evidence for cross-resistance between the taxanes docetaxel and cabazitaxel, and AR targeting agents abiraterone and enzalutamide. Since these compounds all interfere with AR-signalling, this strongly suggests a common mechanism of action, and thus a potential mechanism for cross-resistance in mCRPC.

Survival and PSA response of patients in the TAX 327 study who crossed over to receive docetaxel after mitoxantrone or vice versa

BACKGROUNDnThe TAX 327 study compared 3-weekly docetaxel, weekly docetaxel or 3-weekly mitoxantrone, each with prednisone, for 1006 patients with metastatic hormone-refractory prostate cancer. Survival and symptom control were superior following 3-weekly docetaxel as compared with mitoxantrone. At progression, many patients were treated with the other drug. Here, we provide a retrospective report of survival and prostate-specific antigen (PSA) response after second-line therapy.nnnMETHODSnThe TAX 327 database provided information about treatment after progression on first-line therapy, and survival has been updated. Investigators were asked to provide information about crossover treatment and serial PSA values.nnnRESULTSnWe identified 232 crossover patients. Median survival after crossover was 10 months and did not depend on direction of crossover. Data on PSA response are available for 96 patients: PSA response (> or =50% reduction) occurred in 15% of 71 men receiving mitoxantrone after docetaxel and in 28% of 25 men receiving docetaxel after mitoxantrone. Median PSA progression-free survival was 3.4 months for mitoxantrone after docetaxel and 5.9 months for docetaxel after mitoxantrone.nnnCONCLUSIONSnOne quarter of men received crossover therapy and survival was similar in the crossover groups. The PSA response rate to docetaxel after mitoxantrone was higher than that for mitoxantrone after docetaxel.

Phase II study of weekly gemcitabine in patients with metastatic breast cancer relapsing or failing both an anthracycline and a taxane

A phase II study was performed to investigate the efficacy and tolerability of gemcitabine as third-line chemotherapy for patients with metastatic breast cancer, previously treated with both an anthracycline - and taxane-containing regimen. Twenty-three patients were treated with gemcitabine 1200u2009mg/m2 in a 30-min infusion on day 1, 8 and 15 of a 28 day cycle. Seventy-four percent of the patients had visceral metastases. No complete or partial responses were observed. Six patients (26%) had stable disease with a median duration of 4.0 months. The median time to progression was 1.9 months and the median survival time was 7.8 months. Neutropenia grade 3 and 4 was observed in four patients (18%). Non-hematological toxicity grade 3 included nausea and vomiting in 14%, skin toxicity in 9% and elevation of transaminases in 23% of the patients. Gemcitabine is ineffective as third-line single agent therapy in patients failing anthracycline and taxane treatment for metastatic breast cancer.

Neutrophil-to-lymphocyte ratio as a prognostic biomarker for men with metastatic castration-resistant prostate cancer receiving first-line chemotherapy: data from two randomized phase III trials

BACKGROUNDnThe neutrophil-to-lymphocyte ratio (NLR), a marker of host inflammation, has been associated with poor outcome in several solid tumors. Here, we investigated associations of the derived NLR (dNLR) and duration of initial androgen deprivation therapy (ADT) with survival of men with metastatic castration-resistant prostate cancer (mCRPC) receiving first-line chemotherapy.nnnPATIENTS AND METHODSnData from the multinational randomized phase III studies VENICE and TAX327 included a total of 2230 men with mCRPC randomized to receive first-line chemotherapy, and were used as training and validation sets, respectively. Associations of dNLR and duration of initial ADT with overall survival (OS) were evaluated by multivariable Cox regression analysis in the training set stratified for performance status and treatment arm. The model was then tested in the validation set. Subsequently, we investigated the treatment effect of docetaxel on OS in subgroups according to dNLR and duration of initial ADT.nnnRESULTSnIn the training set, both dNLR ≥median (2) and duration of initial ADT <median (15 months) were associated with increased risk of death [hazard ratio (HR) 1.29; 95% confidence interval (CI) 1.11-1.50, P < 0.001 and HR 1.41; 95% CI 1.21-1.64, P < 0.001, respectively] after adjustment for age, alkaline phosphatase, hemoglobin, and pain at baseline. In the validation set, dNLR remained an independent prognostic factor for OS (HR 1.43; 95% CI 1.20-1.70, P < 0.001), whereas duration of initial ADT was not (HR 1.16; 95% CI 0.97-1.37, P = 0.10). In subgroup analyses of the TAX327 study, docetaxel improved OS irrespective of dNLR and duration of initial ADT.nnnCONCLUSIONnThe dNLR was prognostic for OS in men with mCRPC receiving first-line chemotherapy in two randomized phase III trials. A high dNLR (≥2) was associated with shorter survival irrespective of the received treatment. This readily available biomarker may serve for risk stratification in future clinical trials and could be incorporated into prognostic nomograms.nnnCLINICAL TRIALS NUMBERnNCT00519285.

The influence of prior novel androgen receptor targeted therapy on the efficacy of cabazitaxel in men with metastatic castration-resistant prostate cancer

INTRODUCTIONnThe treatment armamentarium for metastatic castration-resistant prostate cancer (mCRPC) has expanded with the introduction of several new therapies. In this treatment continuum, it is unclear whether the efficacy of cabazitaxel is affected by prior novel androgen receptor targeted therapies (ART) such as abiraterone and enzalutamide. In this study, we investigated the influence of prior ART on the efficacy of cabazitaxel in men with mCRPC.nnnPATIENTS AND METHODSnData from an ongoing multicentre, phase II trial were used comprising 114 men with mCRPC treated with cabazitaxel in the post-docetaxel setting. The primary endpoints of the current analysis were prostate-specific antigen (PSA) response (⩾ 50%), and overall survival (OS). Univariate and multivariable analyses were conducted to investigate the influence of prior ART on the efficacy of cabazitaxel.nnnRESULTSnFrom the 114 patients included in this analysis, 44 men received prior ART and 70 men did not receive prior ART before treatment with cabazitaxel. PSA response rates while on cabazitaxel treatment were similar in patients with and without prior ART (34% versus 40%, respectively, P = 0.53). Likewise, median OS was not significantly different between men with and without prior ART (13.0 versus 14.0 months, respectively, logrank P = 0.65). In multivariable analysis, the only variables significantly associated with OS were performance status, serum albumin and alkaline phosphatase.nnnCONCLUSIONnOur study showed that prior treatment with ART may not influence the efficacy of cabazitaxel in men with mCRPC. With emerging evidence of cross-resistance in the treatment of mCRPC, cabazitaxel provides a good treatment option irrespective of prior ART.

When to start cytotoxic therapy in asymptomatic patients with hormone refractory prostate cancer

Until the publication of two pivotal trials, there were no treatment options available that did prolong the overall survival in men with hormone refractory prostate cancer (HRPC). Currently, docetaxel-based cytotoxic treatment is considered as a standard of care in all the patients with progressive metastatic HRPC. The use of this treatment regimen renders an equal survival benefit in all the subgroups of patients; however, there is a substantial difference in the overall survival between the subgroups. This review addresses the optimal timing of the cytotoxic treatment in asymptomatic patients with HRPC.

Current position of 5HT3 antagonists and the additional value of NK1 antagonists; a new class of antiemetics

The advent of the 5HT3 receptor antagonists (5HT3 antagonists) in the 1990u2009s and the combination with dexamethasone has resulted in acute emesis protection in 70% of patients receiving highly emetogenic chemotherapy. Despite complete protection in the acute phase, however, 40% of patients as yet have symptoms in the delayed phase. 5HT3 antagonists and dexamethasone are only modestly effective in this delayed phase. Moreover, the antiemetic protection over repeated cycles is not sustained. Neurokinine 1 receptor antagonists (NK1 antagonists) belong to a new class of antiemetic agents that specifically target the NK1 receptor, which is involved in both the acute and, particularly, the delayed phase of emesis. Clinical studies have demonstrated that the addition of NK1 antagonists to dual therapy with a 5HT3 antagonist plus dexamethasone improves the acute emesis protection by a further 10–15%. In the delayed phase, the proportion of patients remaining free of emesis increases by even 20–30%. Since the effectiveness of this triplet combination was found to be sustained over six cycles of chemotherapy, the chance for an individual patient to remain completely protected during both the acute and the delayed phase over six chemotherapy cycles is nearly doubled.The advent of the 5HT3 receptor antagonists (5HT3 antagonists) in the 1990u2009s and the combination with dexamethasone has resulted in acute emesis protection in 70% of patients receiving highly emetogenic chemotherapy. Despite complete protection in the acute phase, however, 40% of patients as yet have symptoms in the delayed phase. 5HT3 antagonists and dexamethasone are only modestly effective in this delayed phase. Moreover, the antiemetic protection over repeated cycles is not sustained. Neurokinine 1 receptor antagonists (NK1 antagonists) belong to a new class of antiemetic agents that specifically target the NK1 receptor, which is involved in both the acute and, particularly, the delayed phase of emesis. Clinical studies have demonstrated that the addition of NK1 antagonists to dual therapy with a 5HT3 antagonist plus dexamethasone improves the acute emesis protection by a further 10–15%. In the delayed phase, the proportion of patients remaining free of emesis increases by even 20–30%. Since the effectiveness of this triplet combination was found to be sustained over six cycles of chemotherapy, the chance for an individual patient to remain completely protected during both the acute and the delayed phase over six chemotherapy cycles is nearly doubled.

Second-line chemotherapy with long-term low-dose oral etoposide in patients with advanced breast cancer

SummaryIn a phase II study, 27 patients with metastatic breast cancer were treated with oral etoposide as second-line chemotherapy at a dose of 50 mg/m2/day for 21 days, which courses were repeated every 4 weeks. Twenty-one patients were evaluable for response, and twenty-five for toxicity. In two (10%) patients a partial response was observed with a duration of 60 and 122 weeks respectively, and seven patients (33%) showed stable disease. Gastrointestinal toxicity was usually mild, though relatively frequent. Anemia grade II and III was observed in 20% of all courses (< 10% of all measurements), and leukopenia grade III and IV was observed in 22% of all courses (< 10% of all measurements). There was one toxic death.Reviewing the literature we calculated a response rate of intravenous etoposide treatment of 8% in 276 patients with metastatic breast cancer from 7 studies (response rates ranging between 0–14%), while (chronic) oral treatment caused a response rate of 19% in 145 patients from 8 different studies (response rates ranging between 0–35%).

Analysis of docetaxel therapy in elderly (⩾70 years) castration resistant prostate cancer patients enrolled in the Netherlands Prostate Study

BACKGROUNDnProstate cancer truly is an age-associated disease. Due to the increased life expectancy and more sensitive diagnostic techniques in the Western world, prostate cancer is diagnosed more frequently and with rapidly increasing incidence and prevalence rates. However, age above 65 or 70 years has been an exclusion criterion in clinical trials for decades and the knowledge about chemotherapy tolerance in elderly is limited.nnnMETHODSnWe performed a retrospective analysis of data acquired from the recently published Netherlands Prostate Study (NePro) to evaluate the influence of advanced age on docetaxel therapy in elderly men (>70 years) with castration resistant prostate cancer (CRPC) and bone metastases. Statistical analyses were performed stratified for age into four categories: <70 (n=315), 70-74 (n=150), 75-79 (n=85), and ≥80 years old (n=18).nnnRESULTSnWe analysed 568 patients (median age 68.1 years, range 46-89 years, 44.5% aged ≥70 years). There was no relation between dosage and age (p=0.60). We found no significant differences between the number of dose reductions, time to progression (TTP), overall survival, chemotherapy tolerance and toxicity up to the age of 80 years. However, when compared to younger men, men aged 80 years or above more frequently experienced grade 3/4 toxicity and were five times less likely to complete the first three treatment cycles at the intended dose (Odds ratio (OR) 5.34, p=0.0052) and showed decreased overall survival (15.3 months versus 24.5 months in <80 years group, p=0.020).nnnCONCLUSIONnIn CRPC patients up to the age of 80 years, docetaxel chemotherapy is well tolerated, with toxicity levels and TTP comparable to those of younger patients. For chemotherapeutic treatment of patients above the age of 80 years an individual assessment should be made.