William Proctor Harris

Androgen deprivation therapy: progress in understanding mechanisms of resistance and optimizing androgen depletion

Androgen deprivation therapy remains a critical component of treatment for men with advanced prostate cancer, and data support its use in metastatic disease and in conjunction with surgery or radiation in specific settings. Alternatives to standard androgen deprivation therapy, such as intermittent androgen suppression and estrogen therapy, hold the potential to improve toxicity profiles while maintaining clinical benefit. Current androgen deprivation strategies seem to incompletely suppress androgen levels and androgen-receptor-mediated effects at the tissue level. Advances in the understanding of mechanisms that contribute to castration-resistant prostate cancer are leading to rationally designed therapies targeting androgen metabolism and the androgen receptor. The results of large trials investigating the optimization of primary androgen deprivation therapy, including evaluation of intermittent androgen suppression and phase III studies of novel androgen synthesis inhibitors, such as abiraterone acetate, are eagerly awaited.

Phase Ib Study of PEGylated Recombinant Human Hyaluronidase and Gemcitabine in Patients with Advanced Pancreatic Cancer

Purpose: This phase Ib study evaluated the safety and tolerability of PEGylated human recombinant hyaluronidase (PEGPH20) in combination with gemcitabine (Gem), and established a phase II dose for patients with untreated stage IV metastatic pancreatic ductal adenocarcinoma (PDA). Objective response rate and treatment efficacy using biomarker and imaging measurements were also evaluated. Experimental Design: Patients received escalating intravenous doses of PEGPH20 in combination with Gem using a standard 3+3 dose-escalation design. In cycle 1 (8 weeks), PEGPH20 was administrated twice weekly for 4 weeks, then once weekly for 3 weeks; Gem was administrated once weekly for 7 weeks, followed by 1 week off treatment. In each subsequent 4-week cycle, PEGPH20 and Gem were administered once weekly for 3 weeks, followed by 1 week off. Dexamethasone (8 mg) was given pre- and post-PEGPH20 administration. Several safety parameters were evaluated. Results: Twenty-eight patients were enrolled and received PEGPH20 at 1.0 (n = 4), 1.6 (n = 4), or 3.0 μg/kg (n = 20), respectively. The most common PEGPH20-related adverse events were musculoskeletal and extremity pain, peripheral edema, and fatigue. The incidence of thromboembolic events was 29%. Median progression-free survival (PFS) and overall survival (OS) rates were 5.0 and 6.6 months, respectively. In 17 patients evaluated for pretreatment tissue hyaluronan (HA) levels, median PFS and OS rates were 7.2 and 13.0 months for “high”-HA patients (n = 6), and 3.5 and 5.7 months for “low”-HA patients (n = 11), respectively. Conclusions: PEGPH20 in combination with Gem was well tolerated and may have therapeutic benefit in patients with advanced PDA, especially in those with high HA tumors. Clin Cancer Res; 22(12); 2848–54. ©2016 AACR.

mTORC1 and FGFR1 signaling in fibrolamellar hepatocellular carcinoma

Fibrolamellar hepatocellular carcinoma, or fibrolamellar carcinoma, is a rare form of primary liver cancer that afflicts healthy young men and women without underlying liver disease. There are currently no effective treatments for fibrolamellar carcinoma other than resection or transplantation. In this study, we sought evidence of mechanistic target of rapamycin complex 1 (mTORC1) activation in fibrolamellar carcinoma, based on anecdotal reports of tumor response to rapamycin analogs. Using a tissue microarray of 89 primary liver tumors, including a subset of 10 fibrolamellar carcinomas, we assessed the expression of phosphorylated S6 ribosomal protein (P-S6), a downstream target of mTORC1, along with fibroblast growth factor receptor 1 (FGFR1). These results were extended and confirmed using an additional 13 fibrolamellar carcinomas, whose medical records were reviewed. In contrast to weak staining in normal livers, all fibrolamellar carcinomas on the tissue microarray showed strong immunostaining for FGFR1 and P-S6, whereas only 13% of non-fibrolamellar hepatocellular carcinomas had concurrent activation of FGFR1 and mTORC1 signaling (P<0.05). When individual samples were stratified according to staining intensity (scale 0–4), the average score in fibrolamellar carcinomas was 2.46 for FGFR1 and 3.77 for P-S6, compared with 0 and 0, respectively, in non-tumor liver. Immunoblot analyses of fibrolamellar carcinomas revealed high mTORC1 activities relative to AKT activities accompanied by reduced TSC2 expression, which was not observed in non-fibrolamellar hepatocellular carcinomas. Our findings provide evidence for mTORC1 activation and FGFR1 overexpression in human fibrolamellar carcinoma, and support the use of FGFR1 inhibitors and rapamycin analogs in the treatment of patients with unresectable fibrolamellar carcinoma.

Targeting the Tumor Stroma: the Biology and Clinical Development of Pegylated Recombinant Human Hyaluronidase (PEGPH20)

The tumor stroma is increasingly recognized as a key player in tumorigenesis through its effects on cell signaling, immune responses, and access of therapeutic agents. A major component of the extracellular matrix is hyaluronic acid (HA), which raises the interstitial gel fluid pressure within tumors and reduces drug delivery to malignant cells, and has been most extensively studied in pancreatic ductal adenocarcinoma (PDA). Pegylated recombinant human hyaluronidase (PEGPH20) is a novel agent that degrades HA and normalizes IFP to enhance the delivery of cytotoxic agents. It has demonstrated promising preclinical results and early clinical evidence of efficacy in the first-line treatment of metastatic PDA with acceptable tolerability. Moreover, intratumoral HA content appears to be a predictive biomarker of response. Phase 2 and 3 trials of PEGPH20 plus chemotherapy are ongoing in metastatic PDA, and it is also being evaluated in other malignancies and in combination with radiation and immunotherapy.

HALO 202: Randomized Phase II Study of PEGPH20 Plus Nab-Paclitaxel/Gemcitabine Versus Nab-Paclitaxel/Gemcitabine in Patients With Untreated, Metastatic Pancreatic Ductal Adenocarcinoma

Purpose Metastatic pancreatic ductal adenocarcinoma is characterized by excessive hyaluronan (HA) accumulation in the tumor microenvironment, elevating interstitial pressure and impairing perfusion. Preclinical studies demonstrated pegvorhyaluronidase alfa (PEGPH20) degrades HA, thereby increasing drug delivery. Patients and Methods Patients with previously untreated metastatic pancreatic ductal adenocarcinoma were randomly assigned to treatment with PEGPH20 plus nab-paclitaxel/gemcitabine (PAG) or nab-paclitaxel/gemcitabine (AG). Tumor HA levels were measured retrospectively using a novel affinity histochemistry assay. Primary end points were progression-free survival (PFS; overall) and thromboembolic (TE) event rate. Secondary end points included overall survival, PFS by HA level, and objective response rate. An early imbalance in TE events in the PAG arm led to a clinical hold; thereafter, patients with TE events were excluded and enoxaparin prophylaxis was initiated. Results A total of 279 patients were randomly assigned; 246 had HA data; 231 were evaluable for efficacy; 84 (34%) had HA-high tumors (ie, extracellular matrix HA staining ≥ 50% of tumor surface at any intensity). PFS was significantly improved with PAG treatment overall (hazard ratio [HR], 0.73; 95% CI, 0.53 to 1.00; P = .049) and for patients with HA-high tumors (HR, 0.51; 95% CI, 0.26 to 1.00; P = .048). In patients with HA-high tumors (PAG v AG), the objective response rate was 45% versus 31%, and median overall survival was 11.5 versus 8.5 months (HR, 0.96; 95% CI, 0.57 to 1.61). The most common treatment-related grade 3/4 adverse events with significant differences between arms (PAG v AG) included muscle spasms (13% v 1%), neutropenia (29% v 18%), and myalgia (5% v 0%). TE events were comparable after enoxaparin initiation (14% PAG v 10% AG). Conclusion This study met its primary end points of PFS and TE event rate. The largest improvement in PFS was observed in patients with HA-high tumors who received PAG. A similar TE event rate was observed between the treatment groups in stage 2 of the trial.

Tivantinib for second-line treatment of MET-high, advanced hepatocellular carcinoma (METIV-HCC): a final analysis of a phase 3, randomised, placebo-controlled study

BACKGROUND Tivantinib (ARQ 197), a selective, oral MET inhibitor, improved overall survival and progression-free survival compared with placebo in a randomised phase 2 study in patients with high MET expression (MET-high) hepatocellular carcinoma previously treated with sorafenib. The aim of this phase 3 study was to confirm the results of the phase 2 trial. METHODS We did a phase 3, randomised, double-blind, placebo-controlled study in 90 centres in Australia, the Americas, Europe, and New Zealand. Eligible patients were 18 years or older and had unresectable, histologically confirmed, hepatocellular carcinoma, an Eastern Cooperative Oncology Group performance status of 0-1, high MET expression (MET-high; staining intensity score ≥2 in ≥50% of tumour cells), Child-Pugh A cirrhosis, and radiographically-confirmed disease progression after receiving sorafenib-containing systemic therapy. We randomly assigned patients (2:1) in block sizes of three using a computer-generated randomisation sequence to receive oral tivantinib (120 mg twice daily) or placebo (twice daily); patients were stratified by vascular invasion, extrahepatic spread, and α-fetoprotein concentrations (≤200 ng/mL or >200 ng/mL). The primary endpoint was overall survival in the intention-to-treat population. Efficacy analyses were by intention to treat and safety analyses were done in all patients who received any amount of study drug. This study is registered with ClinicalTrials.gov, number NCT01755767. FINDINGS Between Dec 27, 2012, and Dec 10, 2015, 340 patients were randomly assigned to receive tivantinib (n=226) or placebo (n=114). At a median follow-up of 18·1 months (IQR 14·1-23·1), median overall survival was 8·4 months (95% CI 6·8-10·0) in the tivantinib group and 9·1 months (7·3-10·4) in the placebo group (hazard ratio 0·97; 95% CI 0·75-1·25; p=0·81). Grade 3 or worse treatment-emergent adverse events occurred in 125 (56%) of 225 patients in the tivantinib group and in 63 (55%) of 114 patients in the placebo group, with the most common being ascites (16 [7%] patients]), anaemia (11 [5%] patients), abdominal pain (nine [4%] patients), and neutropenia (nine [4%] patients) in the tivantinib group. 50 (22%) of 226 patients in the tivantinib group and 18 (16%) of 114 patients in the placebo group died within 30 days of the last dose of study medication, and general deterioration (eight [4%] patients) and hepatic failure (four [2%] patients) were the most common causes of death in the tivantinib group. Three (1%) of 225 patients in the tivantinib group died from a treatment-related adverse event (one sepsis, one anaemia and acute renal failure, and one acute coronary syndrome). INTERPRETATION Tivantinib did not improve overall survival compared with placebo in patients with MET-high advanced hepatocellular carcinoma previously treated with sorafenib. Although this METIV-HCC trial was negative, the study shows the feasibility of doing integral tissue biomarker studies in patients with advanced hepatocellular carcinoma. Additional randomised studies are needed to establish whether MET inhibition could be a potential therapy for some subsets of patients with advanced hepatocellular carcinoma. FUNDING ArQule Inc and Daiichi Sankyo (Daiichi Sankyo Group).

Multidisciplinary perspective of hepatocellular carcinoma: A Pacific Northwest experience.

Hepatocellular carcinoma (HCC) is the most rapidly increasing type of cancer in the United States. HCC is a highly malignant cancer, accounting for at least 14000 deaths in the United States annually, and it ranks third as a cause of cancer mortality in men. One major difficulty is that most patients with HCC are diagnosed when the disease is already at an advanced stage, and the cancer cannot be surgically removed. Furthermore, because almost all patients have cirrhosis, neither chemotherapy nor major resections are well tolerated. Clearly there is need of a multidisciplinary approach for the management of HCC. For example, there is a need for better understanding of the fundamental etiologic mechanisms that are involved in hepatocarcinogenesis, which could lead to the development of successful preventive and therapeutic modalities. It is also essential to define the cellular and molecular bases for malignant transformation of hepatocytes. Such knowledge would: (1) greatly facilitate the identification of patients at risk; (2) prompt efforts to decrease risk factors; and (3) improve surveillance and early diagnosis through diagnostic imaging modalities. Possible benefits extend also to the clinical management of this disease. Because there are many factors involved in pathogenesis of HCC, this paper reviews a multidisciplinary perspective of recent advances in basic and clinical understanding of HCC that include: molecular hepatocarcinogenesis, non-invasive diagnostics modalities, diagnostic pathology, surgical modality, transplantation, local therapy and oncological/target therapeutics.

A rare occurrence of hepatocellular carcinoma metastasis to the mandible: report of a case and review of the literature.

Hepatocellular carcinoma (HCC) is the sixth most common cancer globally, with 626,000 new cases per year, and is the third leading cause of global cancer-related mortality, with 598,000 deaths per year. In the United States, HCC is the ninth leading cause of cancer-related deaths. From 2001 through 2006, 48,596 cases of HCC were reported in the United States according to the Surveillance, Epidemiology and End Results Program from the Centers for Disease Control and Prevention. The incidence f HCC is estimated to be 3 per 100,000 individuals, ith an expectation for increasing numbers in comng years because of the higher incidence of hepaitis C infection during the 1960s through the 990s. Distant metastasis has been reported in 10% to 20% of patients with HCC. Metastatic disease to the orofacial region, however, is a rare occurrence. The objective of this article was to review the relevant body of literature and report a clinical case of metastatic disease to the mandible as the initial presenting symptom of HCC in a 72-year-old man.

Postembolization Syndrome after Hepatic Transarterial Chemoembolization: Effect of Prophylactic Steroids on Postprocedure Medication Requirements

PURPOSE To evaluate the impact of prophylactic use of dexamethasone and scopolamine on analgesic and antiemetic agent requirements after transarterial chemoembolization. MATERIALS AND METHODS A total of 148 patients underwent 316 rounds of chemoembolization for hepatocellular carcinoma at a single institution over a 17-month period. Patient charts were retrospectively reviewed for demographic data, procedural technique, and use of analgesic and antiemetic medications. Patients were grouped into three categories: group A received steroid prophylaxis before and after the procedure, group B received steroid prophylaxis before the procedure only, and group C received no steroid prophylaxis. RESULTS Analysis was performed on 125 patients undergoing 252 procedures. Demographics were similar among groups. Overall, 86 (68.8%) were male, and mean age was 62 years (range, 39-82 y). Ninety-one patients (75%) had Child-Pugh class A cirrhosis and 25% had Child-Pugh class B cirrhosis. Dexamethasone was not significantly associated with decreased analgesic agent use (P = .6). Group A patients used significantly fewer antiemetic agents (Δ = 0.89; P = .007) compared with group C. A transdermal scopolamine patch was not associated with reduced use of antiemetic agents (P = .3). Age was inversely associated with analgesic (P <.001) and antiemetic agent use (P = .004). Men received significantly fewer antiemetic agents than women (P = .002), whereas there was no significant difference in analgesic agent use (P = .7). CONCLUSIONS The use of steroids did not affect analgesic agent use and had a minor effect on antiemetic requirements. The use of a scopolamine patch was not associated with reduced antiemetic agent use.

Nonresponse to neoadjuvant chemotherapy for muscle-invasive urothelial cell carcinoma of the bladder.

BACKGROUND Cisplatin-based neoadjuvant chemotherapy (NC) is commonly used in the treatment of muscle-invasive urothelial cell carcinoma of the bladder (UC) and has been shown to improve survival. However, not all patients respond to NC, thus delaying the interval to potentially curative surgical therapy, risking disease progression and subjecting patients to potential morbidity from NC. In this study, we perform a retrospective analysis of patients who received NC prior to cystectomy to identify factors associated with nonresponse. PATIENTS AND METHODS We identified 80 patients with clinical T2 to T4, N0 to N1 UC of the bladder who received NC and underwent radical cystectomy. Nonresponse was defined as patients with higher pathologic T stage than clinical stage or patients with nodal involvement identified on final pathology. RESULTS Overall, 20% of patients were considered nonresponders. In multivariate analysis, age was predictive of nonresponse (P(trend) < .05). Compared with those < 60 years of age, those aged 60 to 69 years (odds ratio [OR], 2.9; 95% CI, 0.7-12) and those aged ≥ 70 (OR, 5.0; 95% CI, 0.9-28) had higher odds of nonresponse. Patients who received gemcitabine-carboplatin had higher odds of nonresponse compared with those who received gemcitabine-cisplatin (OR, 4.4; 95% CI, 0.8-21). CONCLUSION A subset of patients receiving NC prior to cystectomy will experience disease progression. Future study will need to better identify methods to distinguish individuals more likely to benefit from NC and those that should receive upfront cystectomy.