Rucaparib or Physician's Choice in Metastatic Prostate Cancer.

BACKGROUND: In a phase 2 study, rucaparib, an inhibitor of poly(ADP-ribose) polymerase (PARP), showed a high level of activity in patients who had metastatic, castration-resistant prostate cancer associated with a deleterious BRCA alteration. Data are needed to confirm and expand on the findings of the phase 2 study. METHODS: In this randomized, controlled, phase 3 trial, we enrolled patients who had metastatic, castration-resistant prostate cancer with a BRCA1, BRCA2, or ATM alteration and who had disease progression after treatment with a second-generation androgen-receptor pathway inhibitor (ARPI). We randomly assigned the patients in a 2:1 ratio to receive oral rucaparib (600 mg twice daily) or a physician's choice control (docetaxel or a second-generation ARPI [abiraterone acetate or enzalutamide]). The primary outcome was the median duration of imaging-based progression-free survival according to independent review. RESULTS: Of the 4855 patients who had undergone prescreening or screening, 270 were assigned to receive rucaparib and 135 to receive a control medication (intention-to-treat population); in the two groups, 201 patients and 101 patients, respectively, had a BRCA alteration. At 62 months, the duration of imaging-based progression-free survival was significantly longer in the rucaparib group than in the control group, both in the BRCA subgroup (median, 11.2 months and 6.4 months, respectively; hazard ratio, 0.50; 95% confidence interval [CI], 0.36 to 0.69) and in the intention-to-treat group (median, 10.2 months and 6.4 months, respectively; hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001 for both comparisons). In an exploratory analysis in the ATM subgroup, the median duration of imaging-based progression-free survival was 8.1 months in the rucaparib group and 6.8 months in the control group (hazard ratio, 0.95; 95% CI, 0.59 to 1.52). The most frequent adverse events with rucaparib were fatigue and nausea. CONCLUSIONS: The duration of imaging-based progression-free survival was significantly longer with rucaparib than with a control medication among patients who had metastatic, castration-resistant prostate cancer with a BRCA alteration. (Funded by Clovis Oncology; TRITON3 ClinicalTrials.gov number, NCT02975934.).

Moving forward after cancer: successful implementation of a colorectal cancer patient-centered transitions program.

PURPOSE: Cancer survivors transitioning between academic comprehensive cancer systems and community general practice settings are vulnerable to discontinuity, inconsistency and variation in care, inappropriate surveillance testing, and a sense of isolation and loss. Though these issues have been well recognized for over a decade and a half in the survivorship, oncologic, and health services literature, there remains a dearth of positive examples of models that have been well received by both the transitioned patient and the providers on either side of the handoff. We herein describe a sustained positive example of a transitions program. This program centers on standardized and personalized survivorship care plans (SCP) to guide follow-up care and recovery. METHODS: Following the province-wide introduction of a transitions program for treated stages II and III colorectal cancer (CRC) patients, a post-implementation survey was mailed to transitioned patients with the primary outcome evaluated the patients' perception of improved continuity of care and the main instrument used the Patient Continuity of Care Questionnaire. This was compared against a previously published pre-implementation historical control. RESULTS: The data presented comparing pre- and post-implementation patient cohorts reflect significantly improved patient-reported perceptions regarding the enhanced continuity and coordination of their follow-up and survivorship care after the province-wide introduction of a formal transitions process. This SCP intervention has been sustained post implementation. CONCLUSIONS: Using, as a starting-point, a standardized electronically SCP, CancerCare Manitoba has successfully facilitated a jurisdiction-wide implementation of a scalable, reproducible, and adaptable transitions program. IMPLICATIONS FOR CANCER SURVIVORS: This intervention at the time of transition back to the community has enhanced CRC survivor perception of continuity and coordination of follow-up care.

A randomized phase 2 study of a HSP27 targeting antisense, apatorsen with prednisone versus prednisone alone, in patients with metastatic castration resistant prostate cancer.

Purpose Heat shock protein 27 (Hsp27) is implicated in prostate cancer progression. Apatorsen is a second generation phosphorothioate antisense inhibitor of Hsp27 expression. We evaluated apatorsen in patients with metastatic castration resistant prostate cancer (mCRPC). Experimental design Eligible patients were randomized 1:1 to receive intravenous apatorsen (3 loading doses of 600 mg within 5-9 days followed by weekly doses of 1000 mg) with oral prednisone 5 mg twice daily or prednisone alone. The primary endpoint was disease progression at 12 weeks. Crossover from prednisone alone was allowed after radiographic progression. Results 74 patients received apatorsen + prednisone (n = 36) or prednisone alone (n = 38). Twenty-five patients crossed-over to receive apatorsen + prednisone. Apatorsen treated patients received a median of 19 infusions. 50% of apatorsen + prednisone patients (95% CI: 32.9%, 67.1%) compared with 42% of prednisone patients (95% CI: 26.3%, 59.2%) did not have disease progression at week 12 (P = 0.33). A PSA decline of ≥50% was observed in 47% of apatorsen + prednisone and 24% of prednisone patients (P = 0.04), with a median duration of response of 24.1 weeks (95% CI: 12.0, 52) and 14.0 weeks (95% CI: 4.0, 44.4), respectively. A PSA decline of ≥50% was observed in 5 patients (20%) that received cross-over apatorsen. Infusion reactions were the most commonly reported adverse event occurring in 77% of apatorsen-treated patients. Conclusions Apatorsen + prednisone did not change the proportion of CRPC patients without disease progression at 12 weeks compared to prednisone but was associated with significant PSA declines. Further evaluation of Hsp27 targeting in prostate cancer is warranted.

A multivariable model of clinical variables predicts advanced fibrosis in chronic hepatitis C.

BACKGROUND: A noninvasive method to identify advanced hepatic fibrosis (AHF) in chronic hepatitis C (CHC) could preclude the need for routine liver biopsy. Recent evidence suggests that obesity may contribute to hepatic fibrosis in hepatitis C virus infection. GOALS: To determine whether clinical variables, including body mass index (BMI), can predict risk of AHF. STUDY: Retrospective review of untreated CHC patients evaluated between 1993 and 2002 without clinical or physical evidence of end-stage liver disease. Liver biopsies were scored for fibrosis, steatosis, and inflammation. Multivariable analysis was used to derive and internally validate a prediction equation. A clinical index was created from the equation by assigning points for each variable. The risk of AHF was measured for each risk category. RESULTS: Two hundred eighty-six satisfied inclusion criteria, of which 86 (30%) had AHF. In the derivation subgroup (N=190), 5 factors were independently associated with AHF: diabetes mellitus, platelets count <150,000, aspartate aminotransferase > or =65 IU/mL, international normalized ratio > or =1.1, and bilirubin > or =0.85 mg/dL. The corresponding risk index contained 3 categories: low-risk (score of 0), intermediate risk (scores of 1 to 3), and high risk (scores of > or =4), in which the respective risks of AHF were 9%, 34%, and 92%. Inclusion of BMI did not improve model performance. CONCLUSIONS: A model for estimating AHF risk in CHC performed well in this population. BMI had no effect on the risk of AHF. If this model can be validated in other patient cohorts, it could preclude the need for liver biopsy in patients with scores of 0 or > or =4.

Targeting the EGFR pathway for cancer therapy.

Clinical studies have shown that HER-2/Neu is over-expressed in up to one-third of patients with a variety of cancers, including B-cell acute lymphoblastic leukemia (B-ALL), breast cancer and lung cancer, and that these patients are frequently resistant to conventional chemo-therapies. Additionally, in most patients with multiple myeloma, the malignant cells over-express a number of epidermal growth factor receptors (EGFR)s and their ligands, HB-EGF and amphiregulin, thus this growth-factor family may be an important aspect in the patho-biology of this disease. These and other, related findings have provided the rationale for the targeting of the components of the EGFR signaling pathways for cancer therapy. Below we discuss various aspects of EGFR-targeted therapies mainly in hematologic malignancies, lung cancer and breast cancer. Beside novel therapeutic approaches, we also discuss specific side effects associated with the therapeutic inhibition of components of the EGFR-pathways. Alongside small inhibitors, such as Lapatinib (Tykerb, GW572016), Gefitinib (Iressa, ZD1839), and Erlotinib (Tarceva, OSI-774), a significant part of the review is also dedicated to therapeutic antibodies (e.g.: Trastuzumab/Herceptin, Pertuzumab/Omnitarg/rhuMab-2C4, Cetuximab/Erbitux/IMC-C225, Panitumumab/Abenix/ABX-EGF, and also ZD6474). In addition, we summarize, both current therapy development driven by antibody-based targeting of the EGFR-dependent signaling pathways, and furthermore, we provide a background on the history and the development of therapeutic antibodies.

Approach to the complications of treatment for acute leukemia in the elderly.

Acute leukemia is common in the elderly and, due to the aging population and poorer prognosis, represents a major challenge. Elderly acute leukemia patients have been arbitrarily defined as >or=55 to 65 years of age and are underrepresented in clinical trials. There are physiologic differences between elderly and non-elderly patients. A comprehensive understanding of these differences allows the development of a systematic approach to assessing the risks for treatment-related complications. Use of a comprehensive geriatric assessment (CGA), initially developed and validated in the general geriatric population, may allow more accurate assessment of the likelihood of chemotherapy-induced complications and allow for proactive risk minimization. Once complications to therapy develop, aggressive treatment is essential. Treatment related to common complications that arise from therapy will be reviewed. Further research directed at this population is required.

Phosphorylation of thymidine and AZT in heart mitochondria: elucidation of a novel mechanism of AZT cardiotoxicity.

Antiretroviral nucleoside analogs used in highly active antiretroviral therapy (HAART) are associated with cardiovascular and other tissue toxicity associated with mitochondrial DNA depletion, suggesting a block in mitochondrial (mt)-DNA replication. Because the triphosphate forms of these analogs variably inhibit mt-DNA polymerase, this enzyme has been promoted as the major target of toxicity associated with HAART. We have used isolated mitochondria from rat heart to study the mitochondrial transport and phosphorylation of thymidine and AZT (azidothymidine, or zidovudine), a component used in HAART. We demonstrate that isolated mitochondria readily transport thymidine and phosphorylate it to thymidine 5'-triphosphate (TTP) within the matrix. Under identical conditions, AZT is phosphorylated only to AZT-5'-monophosphate (AZT-MP). The kinetics of thymidine and AZT suggest negative cooperativity of substrate interaction with the enzyme, consistent with work by others on mitochondrial thymidine kinase 2. Results show that TMP and AZT-MP are not transported across the inner membrane, suggesting that AZT-MP may accumulate with time in the matrix. Given the lack of AZT-5'-triphosphate (AZT-TP), it seems unlikely that the toxicity of AZT in the heart is mediated by AZT-TP inhibition of DNA polymerase gamma. Rather, our work shows that AZT is a potent inhibitor of thymidine phosphorylation in heart mitochondria, having an inhibitory concentration (IC)(50) of 7.0 +/- 0.9 microM. Thus, the toxicity of AZT in some tissues may be mediated by disrupting the substrate supply of TTP for mt-DNA replication.