Phase II Study of Pegylated Arginine Deiminase for Nonresectable and Metastatic Hepatocellular Carcinoma

Purpose It is well known that hepatocellular carcinoma (HCC) is an arginine auxotroph due to argininosuccinate synthetase I deficiency. This study's purpose was to evaluate the effects of pegylated arginine deiminase (ADI) in terms of toxicity, tumor response, α-fetoprotein (AFP) levels, and serum arginine levels. Patients and Methods Eighty patients were randomly assigned to receive either 80 IU/m2 or 160 IU/m2 of ADI weekly for up to 6 months. Adverse events, serum arginine, AFP levels, and antibody production against ADI were measured on a regular basis. In addition, disease response and time to progression according to the Response Evaluation Criteria in Solid Tumors (RECIST) and survival rates were evaluated. Results Four patients were excluded from the survival analysis because they developed exclusion criteria after randomization, but before first treatment. The number of patients in the two cohorts were similar (n = 37 in the low-dose cohort, n = 39 in the high-dose cohort). Mean (±SE) survival for all subjects was 15.8 months (474 days ± 39 days) from time of diagnosis of unresectable disease. Arginine levels remained below baseline for 50 days while antibodies against ADI reached a plateau at approximately the same time. There were no deaths attributed to ADI treatment. Only two patients were withdrawn for immunogenic-related adverse events. Grade 2, 3, or 4 toxicities were recorded in 92, 19, and 0 patients, respectively. Conclusion Pegylated ADI is a promising drug that capitalizes on a significant enzymatic deficiency in HCC. It is safe, well tolerated, and may benefit patients with unresectable HCC.

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Impact of Baseline ALBI Grade on the Outcomes of Hepatocellular Carcinoma Patients Treated with Lenvatinib: A Multicenter Study

Cancers ◽

10.3390/cancers11070952 ◽

2019 ◽

Vol 11 (7) ◽

pp. 952 ◽

Cited By ~ 40

Author(s):

Kazuomi Ueshima ◽

Naoshi Nishida ◽

Satoru Hagiwara ◽

Tomoko Aoki ◽

Tomohiro Minami ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Liver Function ◽

Adverse Events ◽

Objective Response Rate ◽

Response Rate ◽

Objective Response ◽

Evaluation Criteria ◽

Treatment Discontinuation ◽

The Impact ◽

Group 1

Background: This study investigated the impact of baseline liver function according to the Child–Pugh score and ALBI (albumin-bilirubin) grade on the outcomes of patients with unresectable hepatocellular carcinoma treated with lenvatinib. Methods: A total of 82 lenvatinib treated patients were included. The correlations of baseline liver function according to the Child–Pugh score and ALBI grade with treatment outcomes, including objective response rate per mRECIST (modified Response Evaluation Criteria in the Solid Tumor), time to treatment failure, treatment duration, and likelihood of treatment discontinuation due to adverse events, were assessed in patients with hepatocellular carcinoma treated with lenvatinib. Patients were divided into four groups: (1) Child–Pugh score 5 and ALBI grade 1 (group 1), (2) Child–Pugh score 5 and ALBI grade 2 (group 2), (3) Child–Pugh score 6 (group 3), and (4) Child–Pugh score ≥7 (group 4). Univariate and multivariate analyses were performed to identify the factors contributing to the objective response rate and likelihood of discontinuation due to adverse events. Results: Among the 82 patients analyzed, group 1 had the highest objective response rate (57.1%) and the lowest likelihood of treatment discontinuation because of adverse events (11.1%) among the four groups (p < 0.05 and p < 0.05). Multivariate analysis identified ALBI grade 1 and baseline AFP level <200 ng/mL as the significant predictors of a high objective response rate (p < 0.05 and p < 0.01), and confirmed that patients with ALBI grade 1 had the lowest probability of treatment discontinuation due to adverse events (p < 0.01). Conclusions: Patients with Child–Pugh score of 5 and ALBI grade 1 predicted a higher response rate and lower treatment discontinuation due to adverse events by lenvatinib treatment.

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Transarterial chemoembolization for pulmonary or mediastinal metastases from hepatocellular carcinoma

British Journal of Radiology ◽

10.1259/bjr.20190407 ◽

2020 ◽

Vol 93 (1110) ◽

pp. 20190407 ◽

Cited By ~ 2

Author(s):

Atsushi Hori ◽

Ryosuke Ohira ◽

Tomoyuki Nakamura ◽

Yasushi Kimura ◽

Shota Ueda ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Overall Survival ◽

Adverse Events ◽

Objective Response ◽

Evaluation Criteria ◽

Reduction Rate ◽

End Point ◽

Promising Treatment ◽

Grade 3 ◽

Arterial Chemoembolization

Objective: To evaluate the feasibility, efficacy and safety of transcatheter arterial chemoembolization (TACE) with HepaSphere for patients with pulmonary or mediastinal metastases from hepatocellular carcinoma (HCC). Methods: Between June 2009 and January 2018, 14 patients with pulmonary or mediastinal metastases from HCC were treated with TACE with a combination of 1–3 chemotherapeutic drugs followed by HepaSphere embolization. As first end point, local tumor response and adverse events were evaluated after the first session of TACE, with Response Evaluation Criteria In Solid Tumors v. 1.1 and Common Terminology Criteria for Adverse Events v. 4 criteria, respectively. Overall survival was evaluated as secondary end point. TACE was repeated on-demand. Results: TACE with HepaSphere was well tolerated with acceptable safety profile and no 30 day mortality. 1 month objective response and disease control rate were calculated to be 7.1 and 100%, respectively. Mean tumor size reduction rate was 15.6±9.5% at the first month. Two Grade 3 cytopenia events were seen (14.3 %), however none of the Grade 2 or more post-embolization syndrome was observed. The median overall survival time was 15.0 months and the 1 year, 3 year and 5 year survival rate were, 57.1%, 28.6%, 19.1%, respectively. Conclusion: Early experience showed that the transarterial treatment with HepaSphere is safe and effective treatment for patients with pulmonary or mediastinal metastases from HCC. Advances in knowledge: Currently, the effects of molecular targeted drugs on HCC metastases are limited and side-effects are relatively frequent. In the present study, transarterial treatment might be a promising treatment for HCC metastasis.

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Enhancing Care of the Survivor of Gynecologic Cancer: Managing the Menopause and Radiation Toxicity

American Society of Clinical Oncology Educational Book ◽

10.1200/edbk_158676 ◽

2016 ◽

pp. e270-e275

Author(s):

Linda Van Le ◽

Mary McCormack

Keyword(s):

Early Stage ◽

Gynecologic Cancer ◽

Survival Rates ◽

Radiation Toxicity ◽

Gynecologic Cancers ◽

Number Of Patients ◽

Menopausal Women ◽

Endometrial Cancers ◽

To Receive ◽

Gender Specific

It is expected that there will be 290,000 cases of gynecologic cancers in 2016. Of these cancers, 60,000 will be endometrial and 22,000 will be ovarian—the two most common gynecologic cancers. Endometrial and ovarian cancers occur in menopausal women with mean ages of 60 and 63, respectively. The majority of endometrial cancers are early stage, and 5-year survival is considered good at upwards of 75%. For ovarian cancer, while survival rates have improved, the 5-year survival rate for the most common stage (stage III) is 40%. Thus, a substantial number of patients with gynecologic cancer are menopausal, and a significant number of patients are survivors, particularly of endometrial cancers. It will be important for survivors of gynecologic cancers to receive care tailored to their needs as women and to mitigate gender-specific side effects of their cancer treatment.

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Safety and feasibility of adding tumor debulking to palliative chemotherapy in multi-organ metastatic colorectal cancer: The ORCHESTRA trial.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.3553 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. 3553-3553

Author(s):

Elske C. Gootjes ◽

Eric P. van der Stok ◽

Lotte Bakkerus ◽

Tineke E Buffart ◽

Barbara M Zonderhuis ◽

...

Keyword(s):

Colorectal Cancer ◽

Adverse Events ◽

Palliative Chemotherapy ◽

Survival Rates ◽

Local Treatment ◽

Standard Of Care ◽

Serious Adverse Events ◽

Term Survival ◽

Number Of Patients ◽

Tumor Debulking

3553 Background: For selected patients with oligometastatic colorectal cancer (mCRC), local treatment of metastases is standard of care based on retrospective reports showing long term survival rates. Local treatment of metastases is technically feasible in an increasing number of patients with multi-organ mCRC. It is unknown if patients with extensive disease will benefit from tumor debulking when added to first line palliative chemotherapy. The ORCHESTRA trial (NCT01792934) was designed to prospectively evaluate overall survival (OS) benefit from tumor debulking in patients with multi-organ mCRC. Methods: Patients with multi-organ mCRC were eligible if > 80% tumor debulking was deemed feasible by resection, radiotherapy and/or thermal ablative therapy. All patients received oxaliplatin based chemotherapy ± bevacizumab. In case of stable disease or response at first evaluation (9 weeks), patients were randomized to continuation of chemotherapy or tumor debulking followed by chemotherapy. Adverse events were reported. If patient withdrawal after randomization was < 10%, the study was deemed feasible. Study continuation was based on the interim report on safety and feasibility after inclusion of 100 (of 478) patients. Results: Patients were randomized to the standard (N = 43) or intervention arm (N = 45). No patients withdrew after randomization. In 6.8% of patients debulking was not performed due to progressive disease (N = 5) or death (N = 1) prior to local treatment. Two patients had no lesions left to treat, 37 patients underwent tumor debulking. In 15 patients (40%) 21 serious adverse events related to debulking were reported, 83.7% of patients had no SAEs or recovered within 30 days. Postoperative 90-day mortality was 2.7% (N = 1). Chemotherapy was resumed in 86.5% of patients, median time to restart was 12.7 weeks (SD 5.6) and 78.4% completed ≥24 weeks of chemotherapy. Conclusions: Tumor debulking is feasible and safe and does not prohibit administration of palliative chemotherapy in the majority of patients with multi-organ mCRC. The ORCHESTRA trial will continue accrual to determine whether the aim of > 6 months OS benefit from tumor debulking will be achieved. Clinical trial information: NCT01792934.

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Comparison of the frequency of adverse events requiring interventions determined by telephone follow up in hepatocellular carcinoma patients treated with sorafenib and lenvatinib.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.4_suppl.507 ◽

2020 ◽

Vol 38 (4_suppl) ◽

pp. 507-507

Author(s):

Koki Morishita ◽

Hidetaka Suzuki ◽

Junko Tauchi ◽

Misaki K Takeno ◽

Kohei Hayashi ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Adverse Events ◽

Treatment Withdrawal ◽

Cancer Center ◽

First Line ◽

Sorafenib Treatment ◽

Number Of Patients ◽

Center Hospital ◽

Hand Foot Syndrome

507 Background: The REFLECT trial demonstrated that lenvatinib is non-inferior to sorafenib for first-line treatment of unresectable hepatocellular carcinoma (uHCC). However, no comparison of the frequency of adverse events (AEs) requiring interventions has been reported yet between uHCC patients receiving sorafenib and those receiving lenvatinib. At the National Cancer Center Hospital East, Japan, pharmacists conduct telephone follow-up (TF) during the first month after the start of treatment with sorafenib or lenvatinib in uHCC patients, for the purpose of detecting and treating AEs early. The aim of this study was to reveal the frequency of AEs requiring interventions between patients receiving sorafenib and those receiving lenvatinib, based on TF. Methods: The characteristics, AEs and contents of intervention by TF of 56 uHCC patients who had been started on treatment with sorafenib and lenvatinib were reviewed retrospectively. The study subjects were 33 patients initiated on sorafenib treatment and monitored by TF from March 2017 to March 2018 (Group S) and 23 patients initiated on lenvatinib treatment and monitored by TF from March 2018 to March 2019 (Group L). Results: The total numbers of TFs in Group S and Group L were 91 and 48, respectively. The rate of AEs requiring interventions was significantly higher in Group S as compared to Group L (Group S, 17.6% (16/91); Group L, 4.2% (2/48); p = 0.032). The frequencies of the interventions, including use of supportive treatments (A), withdrawal of sorafenib or lenvatinib (B), and medical examination (C), differed between the two groups (A/B/C: Group S, 8/5/3 times vs. Group L, 2/0/0 times). The most frequently observed AE that necessitated intervention in Group S was the hand-foot syndrome (HFS) (75.0%, 12/16). Conclusions: The frequency of interventions for AEs appears to be higher in uHCC patients receiving sorafenib than in those receiving lenvatinib. Although a great number of patients taking sorafenib had symptomatic AEs, such as HFS, early detection of the symptoms through TF contributed to prevention of treatment withdrawal on account of AEs.

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Pegylated Arginine Deiminase Treatment of Patients With Unresectable Hepatocellular Carcinoma: Results From Phase I/II Studies

Journal of Clinical Oncology ◽

10.1200/jco.2004.11.120 ◽

2004 ◽

Vol 22 (10) ◽

pp. 1815-1822 ◽

Cited By ~ 156

Author(s):

Francesco Izzo ◽

Paolo Marra ◽

Gerardo Beneduce ◽

Giuseppe Castello ◽

Paolo Vallone ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Polyethylene Glycol ◽

Phase I ◽

Progressive Disease ◽

Hepatocellular Cancer ◽

Complete Response ◽

Arginine Deiminase ◽

Lower Plasma ◽

Plasma Arginine ◽

To Receive

Purpose Recently, we reported that a large number of human hepatocellular cancer (HCC) cell lines were auxotrophic for arginine. Here we report the results obtained with the amino acid–degrading enzyme arginine deiminase (ADI) conjugated to polyethylene glycol (ADI-SS PEG 20,000 mw) as a means of lowering plasma arginine to treat HCC. The study was a cohort dose-escalation phase I/II study. Patients and Methods Pharmacodynamic studies indicated an ADI-SS PEG 20,000 mw dose level of 160 U/m2 was sufficient to lower plasma arginine from a resting level of approximately 130 μmol/L to below the level of detection (< 2 μmol/L) for more than 7 days, a dose later defined as the optimal biologic dose. All patients were to receive three cycles at the optimum biologic dose. Results This therapy was well tolerated, even in patients who had no detectable plasma arginine for 3 continuous months of therapy. Of the 19 patients enrolled, two had a complete response, seven had a partial response, seven had stable disease, and three had progressive disease. The median survival for the 19 patients enrolled on this study was 410 days, with four patients still alive at present (> 680 days). Conclusion Elimination of all detectable plasma arginine in patients with HCC was well tolerated and seemed to be effective in the treatment of some patients with HCC. Further testing of ADI-SS PEG 20,000 mw in a larger population of individuals with HCC as well as other human tumors auxotrophic for arginine is warranted.

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Safety and Pharmacokinetics of Isavuconazole as Antifungal Prophylaxis in Acute Myeloid Leukemia Patients with Neutropenia: Results of a Phase 2, Dose Escalation Study

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.04569-14 ◽

2015 ◽

Vol 59 (4) ◽

pp. 2078-2085 ◽

Cited By ~ 67

Author(s):

Oliver A. Cornely ◽

Angelika Böhme ◽

Anne Schmitt-Hoffmann ◽

Andrew J. Ullmann

Keyword(s):

Acute Myeloid Leukemia ◽

Adverse Events ◽

Dose Escalation ◽

Myeloid Leukemia ◽

Low Dose ◽

High Dose ◽

Dose Escalation Study ◽

Once Daily ◽

Dose Cohort ◽

Acute Myeloid

ABSTRACTIsavuconazole is a novel broad-spectrum triazole antifungal agent. This open-label dose escalation study assessed the safety and pharmacokinetics of intravenous isavuconazole prophylaxis in patients with acute myeloid leukemia who had undergone chemotherapy and had preexisting/expected neutropenia. Twenty-four patients were enrolled, and 20 patients completed the study. The patients in the low-dose cohort (n= 11) received isavuconazole loading doses on day 1 (400/200/200 mg, 6 h apart) and day 2 (200/200 mg, 12 h apart), followed by once-daily maintenance dosing (200 mg) on days 3 to 28. The loading and maintenance doses were doubled in the high-dose cohort (n= 12). The mean ± standard deviation plasma isavuconazole areas under the concentration-time curves for the dosing period on day 7 were 60.1 ± 22.3 μg · h/ml and 113.1 ± 19.6 μg · h/ml for the patients in the low-dose and high-dose cohorts, respectively. The adverse events in five patients in the low-dose cohort and in eight patients in the high-dose cohort were considered to be drug related. Most were mild to moderate in severity, and the most common adverse events were headache and rash (n= 3 each). One patient in the high-dose cohort experienced a serious adverse event (unrelated to isavuconazole treatment), and two patients each in the low-dose and high-dose cohorts discontinued the study due to adverse events. Of the 20 patients who completed the study, 18 were classified as a treatment success. In summary, the results of this analysis support the safety and tolerability of isavuconazole administered at 200 mg and 400 mg once-daily as prophylaxis in immunosuppressed patients at high risk of fungal infections. (This study is registered at ClinicalTrials.gov under registration number NCT00413439.)

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Initial Experience of Atezolizumab Plus Bevacizumab for Advanced Hepatocellular Carcinoma in Clinical Practice

Cancer Diagnosis & Prognosis ◽

10.21873/cdp.10012 ◽

2021 ◽

Vol 1 (2) ◽

pp. 83-88

Author(s):

TEIJI KUZUYA ◽

NAOTO KAWABE ◽

SENJU HASHIMOTO ◽

RYOJI MIYAHARA ◽

TAKUJI NAKANO ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Clinical Practice ◽

Adverse Events ◽

Response Rate ◽

Objective Response ◽

Evaluation Criteria ◽

Advanced Hepatocellular Carcinoma ◽

Response Evaluation ◽

Modified Recist ◽

Grade 3

Background/Aim: The aim of this study was to investigate the outcomes of atezolizumab plus bevacizumab in patients with advanced hepatocellular carcinoma (HCC), including those with disease refractory to lenvatinib, in clinical practice. Patients and Methods: Of 34 patients treated with atezolizumab plus bevacizumab, a total of 23, including 16 with lenvatinib failure, were enrolled in this retrospective study. The adverse events, changes in liver function and antitumor responses at 6 weeks after starting therapy were evaluated. Results: The incidence of grade 3 adverse events was low, at 13.0%. Albumin–bilirubin scores did not worsen at 3 and 6 weeks compared to baseline. The objective response rate and disease control rate at 6 weeks were 17.4% and 78.3% according to Response Evaluation Criteria in Solid Tumors (RECIST), and 30.4% and 78.3% according to modified RECIST, respectively. Conclusion: Our results suggest that atezolizumab plus bevacizumab might have potential therapeutic safety and efficacy in patients with advanced HCC, including those with disease refractory to lenvatinib. Further studies are needed to confirm the outcomes of atezolizumab plus bevacizumab after lenvatinib failure.

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A Study of the Use of the Thromboxane A2 Antagonist, Sulotroban, in Combination with Streptokinase for Local Thrombolysis in Patients with Recent Peripheral Arterial Occlusions: Clinical Effects, Platelet Function and Fibrinolytic Parameters

Thrombosis and Haemostasis ◽

10.1055/s-0038-1651563 ◽

1993 ◽

Vol 69 (02) ◽

pp. 103-111 ◽

Cited By ~ 8

Author(s):

Robert J Lonsdale ◽

Stan Heptinstall ◽

John C Westby ◽

David C Berridge ◽

Peter W Wenham ◽

...

Keyword(s):

Platelet Function ◽

Low Dose ◽

High Dose ◽

Clinical Effects ◽

Thromboxane Receptor ◽

Number Of Patients ◽

Peripheral Arterial ◽

Thromboxane Receptor Antagonist ◽

Fibrinolytic Parameters ◽

To Receive

SummaryIn peripheral thrombolysis adjuvant anti-platelet therapy may help to lyse otherwise resistant thrombus, thereby increasing the number of patients successfully treated and reducing the “time to lysis”. If continued after lysis it may help to prevent early rethrombosis. In this pilot study 21 patients undergoing peripheral thrombolysis with streptokinase were randomised to receive the thromboxane receptor antagonist sulotroban or placebo. The dose of sulotroban given was 2 mg/min (four patients), 4 mg/min (five patients) or 8 mg/min (four patients), eight patients received placebo. The clinical and laboratory effects of the treatment were monitored.Thrombolysis was achieved more quickly in patients receiving sulotroban, however, there was no difference between groups in the number of patients in whom recanalisation was achieved (six of eight receiving placebo and eight of 13 receiving sulotroban) or in the number of cases of early rethrombosis. During lysis there was an increase in plasma beta-thromboglobulin with similar levels being found in patients receiving sulotroban and streptokinase and those receiving streptokinase alone. No other major changes in platelet function during lysis were seen in patients receiving streptokinase alone. Sulotroban significantly reduced platelet aggregtion and 14C-5HT release in response to several platelet agonists. With the thromboxane mimetic U46619 the degree of inhibition of aggregation and 14C-5HT release depended on the dose of sulotroban used. High levels of inhibition were associated with an excess of haemorrhagic complications especially in combination with a low plasma fibrinogen level.We conclude that the use of low dose sulotroban in combination with streptokinase merits further study and may have a role in accelerating lysis. However, the combination of high dose sulotroban with streptokinase causes an increased incidence of bleeding. Monitoring platelet function during such therapy may identify patients likely to bleed.

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