Avelumab in Men With Metastatic Castration-Resistant Prostate Cancer, Enriched for Patients Treated Previously With a Therapeutic Cancer Vaccine.

Therapeutic cancer vaccines including sipuleucel- T , a prostatic acid phosphatase (PAP) targeted vaccine that improves survival in metastatic castration-resistant prostate cancer (mCRPC), can produce immune responses that translate to clinical benefit. The effects of sequential checkpoint inhibitors after therapeutic vaccine on immune responses are unknown. Avelumab is an anti-programmed death ligand-1 monoclonal antibody evaluated in patients with mCRPC in the JAVELIN solid tumor phase 1 trial expansion cohort, enriched for patients with a previous therapeutic prostate cancer-targeted vaccine. mCRPC patients received intravenous avelumab 10 mg/kg every 2 weeks with imaging every 6 weeks. Peripheral blood T-cell responses to PAP and to PA2024, the peptide containing PAP utilized by the vaccine, were evaluated pre and posttreatment. Eighteen patients enrolled, and previous treatments included abiraterone or enzalutamide in 14 (78%), therapeutic cancer vaccine in 14 (78%), and chemotherapy in 4 (22%). Avelumab had a manageable safety profile. There were no sustained prostate specific antigen decreases. Of 17 patients evaluable for best overall response by RECISTv1.1, 12 had stable disease (SD) and 5 had progressive disease. Seven patients had SD for >24 weeks posttreatment. Fourteen patients had previously received therapeutic cancer vaccines. Eleven (79%) had SD as the best overall response. Of these 14 patients, 9 had previously received sipuleucel T . Analysis of antigen-specific T-cell responses pre and postavelumab treatment did not demonstrate changes in interferon-γ production or proliferation in response to PAP or PA2024. This unplanned analysis does not support the use of sequential therapeutic cancer vaccine therapy followed by programmed death ligand-1 inhibition in mCRPC.

Management Options for Biochemically Recurrent Prostate Cancer.

Prostate cancer is the most common solid tumor malignancy in men worldwide. Treatment with surgery and radiation can be curative in organ-confined disease. Unfortunately, about one third of men develop biochemically recurrent disease based only on rising prostate-specific antigen (PSA) in the absence of visible disease on conventional imaging. For these patients with biochemical recurrent prostate cancer, there is no uniform guideline for subsequent management. Based on available data, it seems prudent that biochemical recurrent prostate cancer should initially be evaluated for salvage radiation or prostatectomy, with curative intent. In selected cases, high-intensity focused ultrasound and cryotherapy may be considered in patients that meet very narrow criteria as defined by non-randomized trials. If salvage options are not practical or unsuccessful, androgen deprivation therapy (ADT) is a standard option for disease control. While some patients prefer ADT to manage the disease immediately, others defer treatment because of the associated toxicity. In the absence of definitive randomized data, patients may be followed using PSA doubling time as a trigger to initiate ADT. Based on retrospective data, a PSA doubling time of less than 3-6 months has been associated with near-term development of metastasis and thus could be used signal to initiate ADT. Once treatment is begun, patients and their providers can choose between an intermittent and continuous ADT strategy. The intermittent approach may limit side effects but in patients with metastatic disease studies could not exclude a 20% greater risk of death. In men with biochemical recurrence, large studies have shown that intermittent therapy is non-inferior to continuous therapy, thus making this a reasonable option. Since biochemically recurrent prostate cancer is defined by technological limitations of radiographic detection, as new imaging (i.e., PSMA) strategies are developed, it may alter how the disease is monitored and perhaps managed. Furthermore, patients have no symptoms related to their disease and thus many prefer options that minimize toxicity. For this reason, herbal agents and immunotherapy are under investigation as potential alternatives to ADT and its accompanying side effects. New therapeutic options combined with improved imaging to evaluate the disease may markedly change how biochemically recurrent prostate cancer is managed in the future.

Immunotherapies for bladder cancer: a new hope.

PURPOSE OF REVIEW: We review recent data on immunotherapies for bladder cancer and discuss strategies to maximize the antitumor effect of immunotherapy in solid tumors. RECENT FINDINGS: Anti-programmed death ligand 1 has shown promise in advanced bladder cancer. Clinical trials of immune checkpoint inhibitors as monotherapy or in combination are underway. Here we review strategies for enhancing antitumor immunity using immunomodulating agents or combination treatments that may increase tumor response. SUMMARY: Combining immune checkpoint inhibitors with other treatment modalities may lead to the development of new treatment strategies in advanced bladder cancer; however, identifying predictive biomarkers is essential for appropriate patient selection.

Recombinant human factor VIIa for alveolar hemorrhage following allogeneic stem cell transplantation.

The mortality rate of alveolar hemorrhage (AH) after allogeneic hematopoietic stem cell transplantation is greater than 60% with supportive care and high-dose steroid therapy. We performed a retrospective cohort analysis to assess the benefits and risks of recombinant human factor VIIa (rFVIIa) as a therapeutic adjunct for AH. Between 2005 and 2012, 57 episodes of AH occurred in 37 patients. Fourteen episodes (in 14 patients) were treated with steroids alone, and 43 episodes (in 23 patients) were treated with steroids and rFVIIa. The median steroid dose was 1.9 mg/kg/d (interquartile range [IQR], 0.8 to 3.5 mg/kg/d; methylprednisolone equivalents) and did not differ statistically between the 2 groups. The median rFVIIa dose was 41 µg/kg (IQR, 39 to 62 µg/kg), and a median of 3 doses (IQR, 2 to 17) was administered per episode. Concurrent infection was diagnosed in 65% of the episodes. Patients had moderately severe hypoxia (median PaO2/FiO2, 193 [IQR, 141 to 262]); 72% required mechanical ventilation, and 42% survived to extubation. The addition of rFVIIa did not alter time to resolution of AH (P = .50), duration of mechanical ventilation (P = .89), duration of oxygen supplementation (P = .55), or hospital mortality (P = .27). Four possible thrombotic events (9% of 43 episodes) occurred with rFVIIa. rFVIIa in combination with corticosteroids did not confer clear clinical advantages compared with corticosteroids alone. In patients with AH following hematopoietic stem cell transplantation, clinical factors (ie, worsening infection, multiple organ failure, or recrudescence of primary disease) may be more important than the benefit of enhanced hemostasis from rFVIIa.

Radiation exposure from diagnostic procedures following allogeneic stem cell transplantation--how much is acceptable?

BACKGROUND: Frequent diagnostic radiology procedures in allogeneic stem cell transplantation (SCT) recipients raise concern about the potential harm from incidental radiation. OBJECTIVES: To determine the cumulative radiation dose from diagnostic studies in allogeneic SCT and its impact on clinical outcome. PATIENTS AND METHODS: This retrospective cohort study was conducted to determine the cumulative radiation dose from diagnostic studies following SCT. Sixty-four consecutive patients with hematological malignancies in a single tertiary care institution underwent total body irradiation (TBI)-based myeloablative conditioning followed by six of six human leukocyte antigen (HLA)-identical sibling allogeneic SCT. The median follow-up was 3 years. The cumulative effective dose in mSv from diagnostic radiological studies in the peri-transplant period from day -30 to day +200 was calculated for each patient and its impact on overall survival and non-relapse mortality was determined. RESULTS: The median cumulative radiation exposure from diagnostic radiological procedures was 92 mSv (range 1.2-300), representing about 30× the normal annual background radiation for the population and 10% of the 1200 cGy TBI dose used in conditioning. Sixty-five percent of the cumulative radiation exposure was delivered between day +1 and day 100 and computed tomography scans contributed 88%. In multivariate analysis, diagnostic procedures did not significantly impact clinical outcomes. CONCLUSIONS: While radiation exposure from diagnostic procedures did not impact clinical outcomes the risk of secondary cancers in long-term survivors is likely to be increased. Our results indicate that patients who are acutely ill for prolonged periods can receive clinically significant radiation doses during their hospital care. Our findings should prompt attempts to limit radiation exposure from diagnostic procedures in post-SCT recipients.

The role of consolidation treatment in locally advanced unresectable NSCLC.

Concurrent chemotherapy and radiation therapy remains the standard-of-care treatment in patients with unresectable stage III non-small-cell lung cancer. Most regimens include low doses of radiosensitizing agents. Because of concern for the presence of micrometastatic disease and the high rate of systemic failure, many trials have addressed the role of additional consolidation chemotherapy. Only a few of these studies have been performed in a randomized setting on a large number of patients, and the rest are smaller phase I and phase II trials that explore the safety and efficacy of different chemotherapy regimens. More recently, targeted agents have also been evaluated in such regimens, although molecular and histologic markers have not been fully incorporated in these studies. In this review, we discuss these trials and compare the different sequences and regimens of systemic doses of chemotherapy when delivered in addition to concurrent chemotherapy and radiation therapy.

Clinical and histological significance of atypical glandular cell on Pap smear.

BACKGROUND: Atypical glandular cell (AGC) on Pap smear is uncommon but may represent a variety of benign and malignant lesions. AIM: The aim of this study was to evaluate the association between AGC on Pap smear and significant pathological finding to tailor management protocols. METHODS: Between 2002 and 2005, 60 women with AGC on Pap smears were referred to our colposcopy clinic. Forty-one women underwent colposcopy-directed biopsy, endocervical curettage, endometrial sampling and cervical conisation to determine the cytological and histological correlations of AGC on Pap smears. RESULTS: The mean age of the patients was 46.9 +/- 11.5 years (range, 23-80 years). Of these patients 13 patients (31.7%) were postmenopause and 28 patients (68.2%) were in reproductive age. We found eight (19.5%) significant pathological findings including four (9.7%) high-grade squamous intraepithelial lesion, one (2.4%) adenocarcinoma of uterus, one (2.4%) adenocarcinoma of cervix, one (2.4%) squamous cell carcinoma of cervix and one (2.4%) papillary serous tumour of ovary. CONCLUSION: AGC on Pap smear was associated with a clinically significant diagnosis in approximately 20% of our cases. The women with a diagnosis of AGC on cervicovaginal smear are needed to be evaluated at least with colposcopy, endocervical and endometrial curettage. Clinicians should be careful about the significance of AGC on Pap smears.