Dirk Schrijvers

Abiraterone in Metastatic Prostate Cancer without Previous Chemotherapy

BACKGROUND Abiraterone acetate, an androgen biosynthesis inhibitor, improves overall survival in patients with metastatic castration-resistant prostate cancer after chemotherapy. We evaluated this agent in patients who had not received previous chemotherapy. METHODS In this double-blind study, we randomly assigned 1088 patients to receive abiraterone acetate (1000 mg) plus prednisone (5 mg twice daily) or placebo plus prednisone. The coprimary end points were radiographic progression-free survival and overall survival. RESULTS The study was unblinded after a planned interim analysis that was performed after 43% of the expected deaths had occurred. The median radiographic progression-free survival was 16.5 months with abiraterone-prednisone and 8.3 months with prednisone alone (hazard ratio for abiraterone-prednisone vs. prednisone alone, 0.53; 95% confidence interval [CI], 0.45 to 0.62; P<0.001). Over a median follow-up period of 22.2 months, overall survival was improved with abiraterone-prednisone (median not reached, vs. 27.2 months for prednisone alone; hazard ratio, 0.75; 95% CI, 0.61 to 0.93; P=0.01) but did not cross the efficacy boundary. Abiraterone-prednisone showed superiority over prednisone alone with respect to time to initiation of cytotoxic chemotherapy, opiate use for cancer-related pain, prostate-specific antigen progression, and decline in performance status. Grade 3 or 4 mineralocorticoid-related adverse events and abnormalities on liver-function testing were more common with abiraterone-prednisone. CONCLUSIONS Abiraterone improved radiographic progression-free survival, showed a trend toward improved overall survival, and significantly delayed clinical decline and initiation of chemotherapy in patients with metastatic castration-resistant prostate cancer. (Funded by Janssen Research and Development, formerly Cougar Biotechnology; ClinicalTrials.gov number, NCT00887198.).

Docetaxel and cisplatin: an active regimen in patients with locally advanced, recurrent or metastatic squamous cell carcinoma of the head and neck. Results of a phase II study of the EORTC Early Clinical Studies Group.

BACKGROUND Docetaxel and cisplatin are among the most active antitumor agents in head and neck cancer, and phase I studies found the combination of the two drugs to be feasible. The EORTC ECSG performed a multicenter phase II study in patients with locally advanced, recurrent or metastatic squamous cell carcinoma of the head and neck to evaluate the antitumor efficacy and toxicity of this combination. PATIENTS AND METHODS Eligibility criteria included written informed consent, a WHO performance status < 2, life expectancy of > 12 weeks, and adequate bone marrow, liver and renal function. Neoadjuvant pretreatment with cisplatin-based chemotherapy or prior radiotherapy were allowed. Patients were ineligible if pretreated with taxoids, had CNS involvement, concurrent malignancy, peripheral neuropathy, or no measurable disease. Treatment consisted of docetaxel 100 mg/m2 (one-hour i.v. infusion), followed by cisplatin 75 mg/m2 (three-hour i.v. infusion), repeated every three weeks. Supportive care included hydration, 5HT3-antagonists, and corticosteroids. RESULTS Forty-four patients (median age 55 years, range 35-76) entered the trial; 41 patients were eligible, 164 cycles of treatment were evaluable for toxicity, and 31 patients for response. Fourteen patients had undergone prior surgery, 15 had received radiotherapy, and five had had chemotherapy. A median number of four treatment cycles (range 1-6) was given. Hematologic and non-hematologic toxicities were common, but hypersensitivity reactions and fluid retention were very infrequent due to corticosteroid prophylaxis. Four patients were taken off the study due to toxicity, and one toxic death occurred due to pneumonia. Among 41 eligible patients, objective responses as confirmed by independent review included six complete remissions and 16 partial remissions, resulting in an overall response rate of 53.7% (95% confidence interval: 37.4%-69.3%). Responses occurred in locally advanced, recurrent and metastatic disease, both in pre- and non-pretreated patients. Of 22 evaluable, non-pretreated patients with locally advanced or metastatic disease, five achieved complete responses, and 14 partial responses. Observed among nine evaluable pretreated patients with locally advanced or metastatic head and neck cancer were one complete response and two partial responses. CONCLUSION The combination of docetaxel and cisplatin is feasible and active in locally advanced, recurrent, and metastatic squamous cell carcinoma of the head and neck.

Taxanes in the treatment of head and neck cancer

Purpose of review This review presents new data on the role of paclitaxel and docetaxel in the management of squamous cell carcinoma of the head and neck. Recently both agents have been tested in squamous cell carcinoma of the head and neck in combination with other chemotherapeutic agents, targeted drugs, and radiotherapy in in-vitro experiments and in the clinic as first-line treatment of patients with metastatic/recurrent and locally advanced squamous cell carcinoma of the head and neck. Recent findings The combination of taxanes with standard or accelerated radiotherapy is feasible and induction chemotherapy followed by chemoradiation is active and feasible without excessive toxicity in patients with locally advanced squamous cell carcinoma of the head and neck. The use of low-dose fractionated radiotherapy shows promising in-vitro and clinical results and is further explored. Summary Both docetaxel and paclitaxel can be combined with chemotherapeutic agents and radiotherapy, but phase III studies are needed to prove the superiority of these approaches compared to standard treatment. The final results of the combination study of cisplatin and 5-fluorouracil with or without docetaxel may change the standard chemotherapeutic regimen for induction chemotherapy in patients with locally advanced squamous cell carcinoma of the head and neck.

Evaluation of the Groningen Frailty Indicator and the G8 questionnaire as screening tools for frailty in older patients with cancer

OBJECTIVE In this study, we evaluated the Groningen Frailty Indicator (GFI) and the G8 questionnaire as screening tools for a Comprehensive Geriatric Assessment (CGA) in older patients with cancer. PATIENTS AND METHODS Eligible patients with various types and stages of cancer were evaluated for frailty before treatment. Patients were categorized as patients with a normal CGA and abnormal CGA (≥2 impaired tests). The diagnostic performance of the screening tools was evaluated against the CGA with Receiver Operating Characteristic analysis. RESULTS In total, 170 patients (79 women) with median age 77years old (range 66-97years) were included. Sixty-four percent of patients had an abnormal CGA while according to the GFI (GFI≥4) and G8 questionnaire (G8≤14) 47% and 76% of patients had an abnormal screening test, respectively. Overall, there was no significant difference (p=0.97) in diagnostic performance between the two screening tools. The Area Under the Curve was 0.87 for both tools. For the GFI and G8 questionnaire the sensitivity was respectively 66% (95% CI: 56-75%), 92% (95% CI: 85-96%); the negative predictive value (NPV): 59% (95 CI%: 49-69%), 78% (95% CI: 63-88%); and the specificity: 87% (95% CI: 76-94%), 52% (95% CI: 39-65%). CONCLUSION In this study, we showed that overall both the GFI and the G8 questionnaire were able to separate older patients with cancer with a normal and abnormal CGA. For the G8 questionnaire, an adequate sensitivity and NPV were demonstrated, however at the expense of the specificity. For the GFI, we suggest to lower the threshold with one point to GFI ≥3 to screen patients for a CGA.

Improvements in Radiographic Progression-Free Survival Stratified by ERG Gene Status in Metastatic Castration-Resistant Prostate Cancer Patients Treated with Abiraterone Acetate

Purpose: Gene fusions leading to androgen receptor–modulated ERG overexpression occur in up to 70% of metastatic castration-resistant prostate cancers (mCRPC). We assessed the association between ERG rearrangement status and clinical benefit from abiraterone acetate. Experimental Design: COU-AA-302 is a phase III trial comparing abiraterone acetate and prednisone versus prednisone in chemotherapy-naïve mCRPC. ERG status was evaluated by FISH on archival tumors. End points included radiographic progression-free survival (rPFS), time to PSA progression (TTPP), rate of ≥50% PSA decline from baseline, and overall survival (OS). Cox regression was used to evaluate association with time-to-event measures and Cochran–Mantel–Haenszel for PSA response. Results: ERG status was defined for 348 of 1,088 intention-to-treat patients. ERG was rearranged in 121 of 348 patients with confirmed ERG status (35%). Cancers with an ERG fusion secondary to deletion of 21q22 and increased copy number of fusion sequences (class 2+ Edel) had a greater improvement in rPFS after abiraterone acetate and prednisone [22 vs. 5.4 months; HR (95% confidence interval, CI), 0.31 (0.15–0.68); P = 0.0033] than cancers with no ERG fusion [16.7 vs. 8.3 months; 0.53 (0.38–0.74); P = 0.0002] or other classes of ERG rearrangement. There was also greater benefit in this subgroup for TTPP. Conclusions: Both ERG-rearranged and wild-type cancers had a significant improvement in rPFS with abiraterone acetate and prednisone in the COU-AA-302 trial. However, our data suggest that 2+ Edel cancers, accounting for 15% of all mCRPC patients and previously associated with a worse outcome, derived the greatest benefit. Clin Cancer Res; 21(7); 1621–7. ©2015 AACR.

A phase I study of bendamustine hydrochloride administered once every 3 weeks in patients with solid tumors.

The present phase I trial was planned to assess the maximum tolerated dose, the dose-limiting toxicity and the pharmacokinetics of bendamustine hydrochloride in a once every 3 weeks schedule, and to recommend a safe dose for future phase II studies. Included were patients with refractory solid tumors. Bendamustine hydrochloride was administered as a short intravenous infusion over 30 min. The starting dose was defined at 160 mg/m2 and dose escalation used increments of 20 mg/m2. Plasma and urine samples were analyzed using validated high-pressure liquid chromatography/fluorescence assays. Twenty-six patients (14 men, 12 women) were enrolled for the study. At 280 mg/m2, one out of four patients developed a thrombocytopenia grade 4, two experienced grade 3 fatigue and three experienced cardiac toxicity (grade 2). The latter toxicity was considered dose limiting also and further dose escalation was stopped. Plasma pharmacokinetics parameters of bendamustine hydrochloride and its metabolites were assessed in 15 patients. Mean pharmacokinetic parameters of bendamustine hydrochloride were a tmax of 32.3 min, a t1/2 of 37.8 min, a volume of distribution of 14.2 l/m2 and a clearance of 287.8 ml/min/m2. No dose dependency of bendamustine hydrochloride was observed within the used dose range. The metabolites comprised only 23% of the overall area under the concentration–time curve. The maximum tolerated dose of bendamustine hydrochloride on day 1 q 3 weeks is 280 mg/m2. Fatigue and cardiac toxicity were dose limiting. The plasma pharmacokinetics data of bendamustine and its metabolites were in accordance with previous reports. The recommended dose for future trials is 260 mg/m2 every 3 weeks.

Activated oxazaphosphorines are transported predominantly by erythrocytes

PURPOSE Oxazaphosphorines are metabolised by a variety of pathways, one of which leads to activation and the formation of alkylating compounds. However, the transport forms conveying activated oxazaphosphorines to the tumour cell have not been fully characterised. There is increasing recognition of the importance of the erythrocyte as a carrier of compounds in the circulation, and we have recently described higher concentrations of 4-hydroxycyclophosphamide within the erythrocyte compartment compared to plasma. We have now determined the concentrations of ifosfamide and seven of its metabolites in the plasma and erythrocytes of patients receiving a six-hour intravenous infusion of ifosfamide. PATIENTS AND METHODS Red cells from five patients, receiving a total of eight cycles of ifosfamide, were separated from plasma using the MESED instrument, and analysis of red cells and plasma performed using Gas Chromatography-Mass Spectrometry (GC/MS). RESULTS The concentration of all compounds in the erythrocyte compartment was higher than or equal to those in plasma, and isophosphoramide mustard and carboxyifosfamide showed a particular affinity for the erythrocyte. The red cell fraction can contain as much as 77% of the total blood concentration of isophosphoramide mustard. CONCLUSIONS Erythrocyte associated isophosphoramide mustard is an important transport form of activated ifosfamide. Red cells may have a role in the delivery of activated oxazaphosphorines to tissues.

Update on the taxoids and other new agents in head and neck cancer therapy.

Both paclitaxel and docetaxel have shown activity when used as a single agent in patients with squamous cell carcinoma of the head and neck (SCCHN). Combinations of both drugs with platinum derivatives and antimetabolites have been tested in patient populations with encouraging results, but some have exhibited considerable toxicity. It is unknown as yet whether such combinations are in any way superior to the standard platinum-based regimens. Intensive weekly schemes of taxoids and platinum compounds alone or in combination seem possible and deserve further study. Other agents such as vinorelbine, ifosfamide, thymetaq, trimetrexate, gemcitabine and topotecan showed variable activity in patients with SCCHN, but their role is still questionable. Following the optimistic view on the role of chemoradiation, combinations of paclitaxel (with or without carboplatin) with radiotherapy were studied, and the results seem feasible and promising.

Intensity-modulated radiotherapy in patients with head and neck cancer: a European single-centre experience

OBJECTIVE The purpose of this study was to analyse retrospectively the intensity-modulated radiotherapy (IMRT) results in patients with head and neck cancer (HNC) treated between November 2003 and June 2007. METHODS Patients with early and locoregionally advanced HNC were treated with inverse-planned step-and-shoot IMRT. The prescribed dose varied from 66 Gy to 70 Gy in those receiving IMRT as definitive treatment and from 60 Gy to 70 Gy in the post-operative setting. IMRT was given alone, after induction chemotherapy (ICT), with concomitant chemotherapy (CRT) or with both. Acute and late toxicities are reported; locoregional control (LRC), locoregional relapse-free survival (LRRFS) and overall survival (OS) were calculated from the start of radiation. RESULTS IMRT was used in 78 patients (48 as definitive treatment, 30 post-operatively), of whom 20 also received ICT and 35 CRT. Three patients stopped IMRT early, one for toxicity (mucosa). Acute toxicity scoring revealed 5 cases (6%) of severe skin toxicity and 65 cases (83%) of severe mucosal toxicity. After a median follow-up of 18.7 months, late toxicities included xerostomia (44%), loss of taste (14%) and fibrosis of the neck (9%). 16 patients had died, of whom 10 due to tumour recurrence/progression and 2 due to treatment (but not IMRT related). The LRC, LRRFS and OS at 3 years are 66.1%, 48.5% and 60.3% in the definitive IMRT group and 85.4%, 82.5% and 85.9% in the post-operative setting, respectively. CONCLUSION We consider IMRT for locoregional HNC feasible not only as a single modality but also after surgery, after induction chemotherapy and concurrently with chemotherapy.

Psychomotor Changes in Major Depressive Disorder during Sertraline Treatment

Background: There is a relative scarcity of studies on major depressive disorder that use objective assessment methods to explore the psychomotor effects of antidepressants. Striatal dopaminergic disturbances are known to be involved in the pathogenesis of major depressive disorder that is associated with psychomotor retardation. Because of its additional dopaminergic mechanism, the psychomotor effects of the selective serotonin reuptake inhibitor sertraline merit further exploration. Methods: In 19 patients diagnosed with a current major depressive episode, clinical variables and graphic motor activity were assessed applying digitized figure copying tasks during a 6-week regimen of sertraline. Patients’ baseline and weekly psychomotor performance was compared with the outcomes of 22 healthy, unmedicated controls. Results: Patients’ psychomotor slowing had improved after 6 weeks on sertraline as reflected by reductions in initiation and movement times on the simple line and figure copying tasks and decreased initiation times for the complex figure copying task relative to their baseline outcomes. Conclusions: The current study found evidence pointing to potential beneficial effects of sertraline after a 6-week treatment period in the lower-order cognitive and motor components involved in the graphic motor performance of depressed patients. The present findings are discussed in terms of the mechanism of action of sertraline.