Costantine Albany

Randomized, Double-Blind, Placebo-Controlled, Phase III Cross-Over Study Evaluating the Oral Neurokinin-1 Antagonist Aprepitant in Combination With a 5HT3 Receptor Antagonist and Dexamethasone in Patients With Germ Cell Tumors Receiving 5-Day Cisplatin Combination Chemotherapy Regimens: A Hoosier Oncology Group Study

PURPOSE Aprepitant, a 5-HT3 receptor antagonist (5HT3-RA), and dexamethasone are standard antiemetic therapy for prevention of single-day, cisplatin-induced nausea and vomiting. We conducted a double-blind, placebo-controlled phase III cross-over study that compared aprepitant to placebo combined with standard antiemetic prophylaxis (a 5HT3-RA and dexamethasone) in patients receiving 5 days of cisplatin combination chemotherapy for testicular cancer. PATIENTS AND METHODS Patients receiving two consecutive identical courses of a 5-day cisplatin-based chemotherapy were randomly assigned to aprepitant 125 mg on day 3 and 80 mg per day on days 4 through 7 or to placebo with the initial course and crossover to the opposite treatment with the second course. The primary objective was complete response (CR). Secondary end points were emetic episodes (acute and delayed), nausea measurement based on a visual analog scale (VAS), and patient-stated preference after the second study cycle. RESULTS In all, 71 patients were screened for the study and 69 were evaluable. Thirty-five patients were randomly assigned to receive aprepitant and 34 to receive placebo for the first course. Forty-two percent achieved CR with aprepitant compared with 13% with placebo (P < .001). Eleven patients (16.2%) had at least one emetic episode during the aprepitant cycle versus 32 patients (47.1%) with placebo. Thirty-eight patients preferred the aprepitant cycle whereas 11 preferred placebo (P < .001). There was no statistical difference in VAS for nausea, but it was numerically superior with aprepitant. There was no toxicity with aprepitant compared with placebo. CONCLUSION There was a significant improvement in CR rate with aprepitant combined with a 5HT3-RA and dexamethasone. Patient preference strongly favored the aprepitant cycle.

Extragonadal germ cell tumors: Clinical presentation and management

Purpose of review The extragonadal germ cell tumors (EGCTs) represent a unique entity, and as such require specialized management. This review article will discuss the diagnosis, prognosis and treatment modalities for EGCTs. Recent findings The anterior mediastinal germ cell tumors (GCTs) are the most common EGCT. These tumors originate in the anterior mediastinum without any testis primary. Mediastinal nonseminomatous GCTs carry a poor prognosis with 40–50% overall survival and should be treated with cisplatin-based chemotherapy followed by surgical resection of the residual tumor. At Indiana University, we recommend etoposide (VP-16), ifosfamide and cisplatin (VIPx4) instead of bleomycin, etoposide and platinum (BEPx4) to prevent pulmonary complications, as these patients require extensive thoracic surgical resection. Patients who relapse have a dismal outcome with only 10% long-term survival. Our preferred treatment option is surgery for localized relapse; if surgery is not feasible, then high-dose chemotherapy with stem cell transplant in an experienced center is a reasonable approach. Retroperitoneal GCT should be treated in a similar fashion to primary testis cancer. Summary The utilization of cisplatin-based chemotherapy is associated with the best chance of cure for EGCTs. This should be followed by surgical resection of residual tumor in nonseminomatous GCT.

Epigenetics in Prostate Cancer

Prostate cancer (PC) is the most commonly diagnosed nonskin malignancy and the second most common cause of cancer death among men in the United States. Epigenetics is the study of heritable changes in gene expression caused by mechanisms other than changes in the underlying DNA sequences. Two common epigenetic mechanisms, DNA methylation and histone modification, have demonstrated critical roles in prostate cancer growth and metastasis. DNA hypermethylation of cytosine-guanine (CpG) rich sequence islands within gene promoter regions is widespread during neoplastic transformation of prostate cells, suggesting that treatment-induced restoration of a “normal” epigenome could be clinically beneficial. Histone modification leads to altered tumor gene function by changing chromosome structure and the level of gene transcription. The reversibility of epigenetic aberrations and restoration of tumor suppression gene function have made them attractive targets for prostate cancer treatment with modulators that demethylate DNA and inhibit histone deacetylases.

Targeting Androgen Receptor and DNA Repair in Metastatic Castration-Resistant Prostate Cancer: Results From NCI 9012

Purpose To determine whether cotargeting poly (ADP-ribose) polymerase-1 plus androgen receptor is superior to androgen receptor inhibition in metastatic castration-resistant prostate cancer (mCRPC) and whether ETS fusions predict response. Patients and Methods Patients underwent metastatic site biopsy and were stratified by ETS status and randomly assigned to abiraterone plus prednisone without (arm A) or with veliparib (arm B). Primary objectives were: confirmed prostate-specific antigen (PSA) response rate (RR) and whether ETS fusions predicted response. Secondary objectives were: safety, measurable disease RR (mRR), progression-free survival (PFS), and molecular biomarker analysis. A total of 148 patients were randomly assigned to detect a 20% PSA RR improvement. Results A total of 148 patients with mCRPC were randomly assigned: arm A, n = 72; arm B, n = 76. There were no differences in PSA RR (63.9% v 72.4%; P = .27), mRR (45.0% v 52.2%; P = .51), or median PFS (10.1 v 11 months; P = .99). ETS fusions did not predict response. Exploratory analysis of tumor sequencing (80 patients) revealed: 41 patients (51%) were ETS positive, 20 (25%) had DNA-damage repair defect (DRD), 41 (51%) had AR amplification or copy gain, 34 (43%) had PTEN mutation, 33 (41%) had TP53 mutation, 39 (49%) had PIK3CA pathway activation, and 12 (15%) had WNT pathway alteration. Patients with DRD had significantly higher PSA RR (90% v 56.7%; P = .007) and mRR (87.5% v 38.6%; P = .001), PSA decline ≥ 90% (75% v 25%; P = .001), and longer median PFS (14.5 v 8.1 months; P = .025) versus those with wild-type tumors. Median PFS was longer in patients with normal PTEN (13.5 v 6.7 months; P = .02), TP53 (13.5 v 7.7 months; P = .01), and PIK3CA (13.8 v 8.3 months; P = .03) versus those with mutation or activation. In multivariable analysis adjusting for clinical covariates, DRD association with PFS remained significant. Conclusion Veliparib and ETS status did not affect response. Exploratory analysis identified a novel DRD association with mCRPC outcomes.

High-Dose Chemotherapy and Autologous Peripheral-Blood Stem-Cell Transplantation for Relapsed Metastatic Germ Cell Tumors: The Indiana University Experience

Purpose Patients with relapsed metastatic germ cell tumor (GCT) can be cured with second-line and even third-line regimens. We report survival outcomes of patients treated with high-dose chemotherapy (HDCT) and peripheral-blood stem-cell transplantation (PBSCT) at Indiana University between 2004 and 2014. Patients and Methods We conducted a retrospective analysis of 364 consecutive patients with GCT who progressed after cisplatin-based combination chemotherapy and were subsequently treated with HDCT and PBSCT. Three hundred forty-one patients received two consecutive courses of HDCT consisting of 700 mg/m2 carboplatin and 750 mg/m2 etoposide, each for 3 consecutive days, and each followed by PBSCT. Twenty-three patients received only a single course of HDCT because of progressive disease or toxicity. Cox proportional hazards models were used to test predictors of disease progression. Results The median age was 32 years (range, 17 to 70 years). With a median follow-up of 3.3 years, the 2-year progression-free survival (PFS) was 60% (95% CI, 55% to 65%) and the 2-year overall survival was 66% (95% CI, 60% to 70%). Three hundred three patients received HDCT as second-line therapy with a 2-year PFS of 63% (95% CI, 57% to 68%), and 61 patients received HDCT as third-line or later therapy with a 2-year PFS of 49% (95% CI, 36% to 61%). In a multivariable analysis, factors associated with disease progression included use of HDCT as third-line or later therapy, platinum-refractory disease, mediastinal primary tumor site, nonseminoma histology, intermediate- or poor-risk disease at the time of GCT diagnosis, and human chorionic gonadotropin ≥ 1,000 mIU/mL at initiation of HDCT. There were nine treatment-related deaths. Secondary leukemia developed in five patients. Conclusion This large single-institution study demonstrates that patients with relapsed metastatic GCT are curable by HDCT plus PBSCT even when used in third-line or later therapy.

Management of stage I testicular germ cell tumours

Clinical stage I testicular germ cell tumours (TGCT) are highly curable neoplasms. The treatment of stage I testicular cancer is complex and requires a multidisciplinary approach. Standard options after radical orchiectomy for seminoma include active surveillance, radiation therapy or 1–2 cycles of carboplatin, and options for nonseminoma include active surveillance, retroperitoneal lymph node dissection (RPLND) or 1–2 cycles of bleomycin plus etoposide plus cisplatin (BEP). All the options should be discussed with each patient and treatment choices should be made by shared decision making as virtually all patients with clinical stage I TGCT can be cured of their disease. Long-term survival of men with stage I disease is ∼99% and care must be taken to limit the long-term risks of treatment. Orchiectomy is curative in the majority of patients. The management of clinical stage I TGCT remains controversial among experts at high-volume centres throughout the world. The main controversy is whether to overtreat a substantial number of patients with stage I disease to prevent relapse, or to observe and treat only patients who experience disease relapse as adjuvant treatment and surveillance strategy both bring curative outcome. Thus, a summary of the available evidence in stage I disease and recommendations for disease management from a high-volume centre such as Indiana University might be of interest to treating clinicians.

Antitumor activity of brentuximab vedotin in CD30 positive refractory germ cell tumors.

327 Background: Brentuximab Vedotin (BV) is a novel antibody drug conjugate that combines the agent mono-methyl auristatin E (MMAE) to a CD-30 specific monoclonal antibody by a protease-cleavable linker. It is approved by the FDA for treatment of relapsed Hodgkin lymphoma (HL) and systemic anaplastic large cell lymphoma (ALCL). In addition to HL and ALCL, CD-30 expression has been reported on malignant tumors of non-lymphoid origin including testicular embryonal carcinoma (EC). Here we report our initial experience in three heavily pre-treated patients with CD30-positive EC who were treated as part of an ongoing phase 2 open-label multicenter study designed to evaluate the antitumor activity of BV in patients with CD30-positive non-lymphomatous malignancies. METHODS Three men with relapsed or refractory, histologically confirmed CD-30 positive testicular cancer received BV until progression or toxicity. CD-30 expression was assessed by immunohistochemistry. All 3 patients were dosed at 1.8 mg/kg IV every 21 days and followed for response at cycles 2, 4. RESULTS Three patients were enrolled at 2 sites in the US. Median age was 26 years (range 24-33). All 3 patients progressed after high dose chemotherapy with peripheral blood stem cell transplant. Two patients received BV as 4th line and 1 patient as 3rd line therapy. Tumor sites included lungs, liver, retroperitoneal, mediastinal and supraclavicular lymph nodes. The first patient baseline hCG was 5571. After 2 cycles of therapy, hCG nadir was 45 with a radiologic partial response (PR) by RESICT that lasted 2 months. He then had serologic and radiographic progression in the liver while on therapy. Patient 2 was serologic marker negative and had a radiographic PR by RECIST in lung and mediastinum after cycle 2 and continues on therapy. Patient 3 had a baseline hCG of 10400, with nadir at 110 after 2 doses and continues to have serologic response. By RECIST he currently has stable disease. The treatment was well tolerated in all 3 patients with no grade 3-4 toxicities. CONCLUSIONS All 3 patients with heavily pretreated CD-30 positive EC had clinical benefit after treatment with brentuximab vedotin. The treatment was well tolerated. The enrollment is ongoing in this Phase 2 study. CLINICAL TRIAL INFORMATION NCT01461538.

Clinical Correlates of Benefit From Radium-223 Therapy in Metastatic Castration Resistant Prostate Cancer

We sought to identify potential clinical variables associated with outcomes after radium‐223 therapy in routine practice.

Refractory testicular germ cell tumors are highly sensitive to the second generation DNA methylation inhibitor guadecitabine

Testicular germ cell tumors (TGCTs) are the most common cancers of young males. A substantial portion of TGCT patients are refractory to cisplatin. There are no effective therapies for these patients, many of whom die from progressive disease. Embryonal carcinoma (EC) are the stem cells of TGCTs. In prior in vitro studies we found that EC cells were highly sensitive to the DNA methyltransferase inhibitor, 5-aza deoxycytidine (5-aza). Here, as an initial step in bringing demethylation therapy to the clinic for TGCT patients, we evaluated the effects of the clinically optimized, second generation demethylating agent guadecitabine (SGI-110) on EC cells in an animal model of cisplatin refractory testicular cancer. EC cells were exquisitely sensitive to guadecitabine and the hypersensitivity was dependent on high levels of DNA methyltransferase 3B. Guadecitabine mediated transcriptional reprogramming of EC cells included induction of p53 targets and repression of pluripotency genes. As a single agent, guadecitabine completely abolished progression and induced complete regression of cisplatin resistant EC xenografts even at doses well below those required to impact somatic solid tumors. Low dose guadecitabine also sensitized refractory EC cells to cisplatin in vivo. Genome-wide analysis indicated that in vivo antitumor activity was associated with activation of p53 and immune-related pathways and the antitumor effects of guadecitabine were dependent on p53, a gene rarely mutated in TGCTs. These preclinical findings suggest that guadecitabine alone or in combination with cisplatin is a promising strategy to treat refractory TGCT patients.

Heat shock and other apoptosis-related proteins as therapeutic targets in prostate cancer.

Defects within apoptotic pathways have been implicated in prostate cancer (PCa) tumorigenesis, metastatic progression and treatment resistance. A hallmark of cancers is the ability to derail apoptosis by inhibiting the apoptotic signal, reducing the expression of apoptotic proteins and/or amplifying survival signals through increased production of antiapoptotic molecule. This review describes associations between heat shock proteins (HSPs) and the human androgen receptor (AR), the role of HSPs and other stress-induced proteins in PCa development and emerging strategies in targeting these protective proteins to treat PCa.