A randomized phase 2 study of temozolomide and bevacizumab or nab‐paclitaxel,carboplatin, and bevacizumab in patients with unresectable stage IV melanoma

BACKGROUND:

Increasing evidence shows chemotherapy in combination with vascular endothelial growth factor (VEGF) inhibition is a clinically active therapy for patients with metastatic melanoma (MM).

METHODS:

A phase 2 trial was conducted in chemotherapy‐naive patients with unresectable stage IV MM who were randomized to temozolomide (200 mg/m² on days 1 through 5) and bevacizumab (10 mg/kg intravenously on days 1 and 15) every 28 days (Regimen TB) or nab‐paclitaxel (100 mg/m², or 80 mg/m² post‐addendum 5 secondary to toxicity, on days 1, 8, and 15), bevacizumab (10 mg/kg on days 1 and 15), and carboplatin (area under the curve [AUC] 6 on day 1, or AUC 5 post‐addendum 5) every 28 days (Regimen ABC). Accrual goal was 41 patients per regimen. The primary aim of this study was to estimate progression‐free survival rate at 6 months (PFS6) in each regimen. A regimen would be considered promising if its PFS6 rate was > 60%.

RESULTS:

Ninety‐three eligible patients (42 TB and 51 ABC) were enrolled. The majority of patients had M1c disease (20 TB and 26 ABC). The median PFS and overall survival times with ABC were 6.7 months and 13.9 months, respectively. Median PFS time and median overall survival with TB were 3.8 months and 12.3 months, respectively. The most common severe toxicities (≥ grade 3) in both regimens were cytopenias, fatigue, and thrombosis. Among the first 41 patients enrolled onto each regimen, PFS6 rate was 32.8% (95% confidence interval: 21.1%‐51.2%) for TB and 56.1% (90% confidence interval: 44.7%‐70.4%) for ABC.

CONCLUSIONS:

The addition of bevacizumab to nab‐paclitaxel and carboplatin shows promising activity despite tolerability issues. Cancer 2013. © 2012 American Cancer Society.     

Tumor and liver determinants of prognosis in unresectable hepatocellular carcinoma: A case cohort study

Background and Aims:  A total of 967 patients with unresectable and untransplantable, biopsy-proven hepatocellular carcinoma (HCC) were prospectively evaluated at baseline and followed up till death.
Methods:  Survival was the end-point for all analyses.
Results:  We found in our overall analysis, that male gender, ascites, cirrhosis, portal vein thrombosis (PVT), elevated alpha-fetoprotein (AFP) or bilirubin or alkaline phosphatases were each statistically significant adverse prognostic factors. Patients with normal AFP survived longer than those with elevated AFP, in the presence of PVT, large or bilobar tumors or cirrhosis. We used a bivariate analysis to separate patient subgroups based on poor liver function and aggressive tumor characteristics. In subgroup analysis based on these subsets, there was clear discrimination in survival between subsets; in addition both cirrhosis and presence of PVT were significant, independent but modest risk factors. The results of this large dataset show that amongst nonsurgical HCC patients, there are clear subsets with longer survival than other subsets.
Conclusions:  This data also supports the concept of heterogeneity of HCC.     

Pembrolizumab use for the treatment of advanced melanoma

Introduction: Until recently, overall long term survival in patients with stage IV melanoma was lower than 10%. However, the treatment of melanoma has evolved rapidly over the last few years, with the advent of inhibitors of BRAF and MEK and of immunotherapeutic agents including ipilimumab, nivolumab, and pembrolizumab.

Areas covered: This is a comprehensive review of the literature on the role of pembrolizumab in melanoma. Pembrolizumab is a Programmed Death Receptor 1 (PD-1) directed monoclonal antibody which is approved by FDA and EMA for the treatment of patients with metastatic melanoma.

Expert opinion: Phase II and III trials demonstrated that pembrolizumab is superior to ipilimumab in previously untreated patients and to chemotherapy in ipilimumab pre-treated patients. Unfortunately, prospectively validated predictive markers are lacking. Immune-related adverse events are particularly interesting and should be managed per the published guidelines. There are still many issues that remain unresolved including: when to stop treatment, biomarkers for choosing a single agent or combination therapy, the optimal schedule of ipilimumab in combination with anti-PD1 monoclonal antibodies, optimal management of adverse events, the role of immunotherapy in specific populations, the optimal sequence of immunotherapy and the BRAF/MEK inhibitor combination in patients.     

Serum cytokine levels in response to hepatic cryoablation

BACKGROUND AND OBJECTIVES: Cryogenic treatment sometimes stimulates the immune system by releasing intracellular antigens. We evaluated anti-tumor immune response by analyzing alterations in serum cytokine levels. METHODS: Percutaneous cryosurgery was performed in 13 patients with unresectable tumors. Serum levels of interleukin (IL) -4, -6, and -10, tumor necrosis factor (TNF)-alpha, and interferon (IFN)-gamma were measured by enzyme-linked immunosorbent assay (ELISA). The Th1/Th2 ratio was estimated from the IFN-gamma/IL-4 ratio. RESULTS: Levels of serum factors in the immune reaction (IR) group, in which tumor necrosis was identified not only in the treated area but also away from the treated area, were compared with those in the local effect (LE) group. Serum amyloid A (SAA), C-reactive protein (CRP), and IL-6 levels were increased in both groups after three treatments. The serum IL-10 level tended to increase with the number of treatments. Pretreatment IL-10 levels in the LE group were significantly greater than those in the IR group, and the maximum value in the LE group (59.5 +/- 13.2 pg/ml) was greater than that in the IR group (47.0 +/- 15.0 pg/ml). The TNF-alpha level was increased in the IR group. Pretreatment TNF-alpha levels and maximum levels in response to treatment were significantly greater in the IR group than in the LE group (P = 0.0313). The Th1/Th2 ratio was increased in the IR group, and the maximum ratio was significantly greater in the IR group than in the LE group. CONCLUSION: It might be possible to evaluate the appearance of immune responses to cryosurgery by monitoring serum cytokine levels.     

卡培他滨联合适形放疗对不能手术的老年胃癌患者的治疗效果

目的:探讨卡培他滨联合三维适形放疗(three-dimensionalconformalradiotherapy,3DCRT)治疗不能手术的老年胃癌患者的疗效。方法:从2007年1月至2009年l0月,32例不能手术切除、年龄超过65岁的老年胃癌患者,卡培他滨片1250 mg/m2,每天两次,1-14天,21天重复;同时联合3DCRT,处方剂量45Gy,1.8Gy/次,5次/周。用Kaplan-Meier法分析患者的生存率。结果:10例患者获得完全缓解(31.3%),15例患者部分缓解(46.9%);17例出现症状的患者中15例患者症状缓解(88.2%)。中位生存期为11.4个月。治疗过程中的不良反应可以接受。结论:卡培他滨联合3DCRT对不能手术的年龄大于65岁的老年患者有较好的治疗效果。     

The GOFURTGO Study: AGITG phase II study of fixed dose rate gemcitabine-oxaliplatin integrated with concomitant 5FU and 3-D conformal radiotherapy for the treatment of localised pancreatic cancer

Background:

Locally advanced inoperable pancreatic cancer (LAPC) has a poor prognosis. By increasing intensity of systemic therapy combined with an established safe chemoradiation technique, our intention was to enhance the outcomes of LAPC. In preparation for phase III evaluation, the feasibility and efficacy of our candidate regimen gemcitabine–oxaliplatin chemotherapy with sandwich 5-fluorouracil (5FU) and three-dimensional conformal radiotherapy (3DCRT) needs to be established.

Methods:

A total of 48 patients with inoperable LAPC without metastases were given gemcitabine (1000 mg m⁻² d1 + d15 q28) and oxaliplatin (100 mg m⁻² d2 + d16 q28) in induction (one cycle) and consolidation (three cycles), and 5FU 200 mg m⁻² per day over 6 weeks during 3DCRT 54 Gy.

Results:

Median duration of sustained local control (LC) was 15.8 months, progression-free survival (PFS) was 11.0 months, and overall survival was 15.7 months. Survival rates for 1, 2, and 3 years were 70.2%, 21.3%, and 12.8%, respectively. Global quality of life did not significantly decline from baseline during treatment, which was associated with modest treatment-related toxicity.

Conclusion:

Fixed-dose gemcitabine and oxaliplatin, combined with an effective and safe regimen of 5FU and 3DCRT radiotherapy, was feasible and reasonably tolerated. The observed improved duration of LC and PFS with more intensive therapy over previous trials may be due to patient selection, but suggest that further evaluation in phase III trials is warranted.     

Living-related liver transplantation with removal of inferior vena cava for unresectable hepatoblastoma

We report a case of a two-yr-old boy with hepatoblastoma resectable only by total hepatectomy including the vena cava. Successful LTx was performed with a living donor segment without vena cava reconstruction. The tumor was located in the bilateral lobe, surrounding the IVC. In spite of the high-dose chemotherapy, the tumor did not become resectable. LTx was performed using left lateral segment after removal of the IVC combined with total hepatectomy. Because the collaterals were well developed, the patient tolerated the procedure well. The serum AFP level decreased from 186 699 to 8 ng/mL in 11 months after LTx without local recurrence or distant metastasis.     

Survival benefits of adjuvant chemotherapy with oral doxifluridine (5'-DFUR) following radiotherapy in patients with unresectable pancreatic cancer.

BACKGROUND AND OBJECTIVES: The combination of 5-fluorouracil and radiotherapy is thought to be the most effective treatment for locally unresectable pancreatic carcinoma. The outcomes, however, are far from acceptable from the viewpoint of long-term survival. We assessed the survival benefits of oral adjuvant chemotherapy with doxifluridine (5'-DFUR) following radiotherapy for patients with the disease. METHODS: Thirty-five consecutive patients who underwent bypass surgery and radiotherapy for localized advanced unresectable adenocarcinoma of the pancreas head were retrospectively reviewed in regard to disease progression and survival. Ten of the 35 patients underwent adjuvant chemotherapy with 5'-DFUR after radiotherapy in an outpatient setting. RESULTS: The 1-year survival for patients treated with radiotherapy alone was 29%. The 1-, 2-, and 3-year survivals for patients treated with the adjuvant chemotherapy after radiotherapy were 50, 40, and 30%, respectively (P = 0.0069, log-rank test). The elevation of tumor markers was delayed (P = 0.0346) and local control rate was improved (P = 0.0475) in patients with chemotherapy. Multivariate analysis demonstrated that the adjuvant chemotherapy with 5'-DFUR was a significant independent prognostic factor as well as tumor size. CONCLUSIONS: The adjuvant chemotherapy with 5'-DFUR following radiotherapy led to a significant prolongation of the survival for patients with unresectable localized pancreatic cancer.