Purpose

This phase I study evaluated the safety, tolerability, pharmacokinetics and preliminary efficacy of the combination of decitabine with vorinostat.

Patients and methods

Patients with advanced solid tumors or non-Hodgkin's lymphomas were eligible. Sequential and concurrent schedules were studied.

Results

Forty-three patients were studied in 9 different dose levels (6 sequential and 3 concurrent). The maximum tolerated dose (MTD) on the sequential schedule was decitabine 10 mg/m2/day on days 1-5 and vorinostat 200 mg three times a day on days 6-12. The MTD on the concurrent schedule was decitabine 10 mg/m2/day on days 1-5 with vorinostat 200 mg twice a day on days 3-9. However, the sequential schedule of decitabine 10 mg/m2/day on days 1-5 and vorinostat 200 mg twice a day on days 6-12 was more deliverable than both MTDs with fewer delays on repeated dosing and it represents the recommended phase II (RP2D) dose of this combination. Dose-limiting toxicities during the first cycle consisted of myelosuppression, constitutional and gastrointestinal symptoms and occurred in 12/42 (29%) patients evaluable for toxicity. The most common ≥ grade 3 adverse events were neutropenia (49% of patients), thrombocytopenia (16%), fatigue (16%), lymphopenia (14%), and febrile neutropenia (7%). Disease stabilization for ≥ 4 cycles was observed in 11/38 (29%) evaluable patients.

Conclusion

The combination of decitabine with vorinostat is tolerable on both concurrent schedules in previously treated patients with advanced solid tumors or non-Hodgkin's lymphomas. The sequential schedule was easier to deliver. The combination showed activity with prolonged disease stabilization in different tumor types.

Aim

Gene amplification status of the epidermal growth factor receptor (EGFR) and the human epidermal growth factor receptor 2 (HER2) were analyzed and correlated with clinical outcome in patients with progressive malignant salivary glands tumors (MSGT) treated with the dual EGFR/Her2 tyrosine kinase inhibitor lapatinib

Methods

Fluorescence in situ hybridization (FISH) analysis for both EGFR and HER2 gene amplification was performed successfully in the archival tumor specimens of 20 patients with adenoid cystic carcinomas (ACC) and 17 patients with non-ACC, all treated with lapatinib.

Results

For ACC, no EGFR or HER2 amplifications were detected. For non-ACC, no EGFR gene amplifications were detected but 3 patients (18%) were HER2 amplified and all had stained 3+ for both EGFR and HER2 by immunohistochemistry (IHC) in their archival specimens. Two of these patients had time-to-progression (TTP) durations of 8.3 months and 18.4 months respectively. Interestingly, patients with low and high HER2/chromosome-specific centromeric enumeration probe (CEP) 17 ratio had a prolonged TTP than those with moderate ratios for both ACC and non-ACC subtypes.

Conclusions

HER2 to CEP17 FISH ratio may predict which patients with MSGT have an increased likelihood to benefit from lapatinib. The finding of HER2:CEP17 ratio as a predictive marker of efficacy to lapatinib warrants further investigation.

A systematic review was undertaken to determine whether interferon-alfa (IFN-α) is an effective treatment for patients with inoperable locally advanced or metastatic renal cell carcinoma (mRCC). MEDLINE, EMBASE, the Cochrane Library, guideline databases and relevant meeting proceedings were searched. Randomized clinical trials (RCTs) or meta-analyses comparing IFN-α-containing regimens to placebo or non-immunotherapy controls, and that reported response rate, survival, toxicity or quality of life data were eligible. Two systematic reviews and eight RCTs met the selection criteria. A Cochrane review updated in 2005 reported higher response rates and reduced one-year mortality based on 4 RCTs in patients who received IFN-α. Of the eight RCTs, three reporting objective response rate showed significant differences favouring IFN-α. Two of five trials reporting survival data showed longer median survival in the IFN-α group. Adverse effects of IFN-α were consistent across the trials with increased intensity and frequency concordant with increased IFN-α dose. Meta-analyses of seven RCTs for objective response and six RCTs for mortality favoured IFN-α: odds ratio 6.87 (95% Confidence Interval [CI], 3.29 to 14.35) and hazard ratio 0.79 (95% CI, 0.69 to 0.91), respectively. The effectiveness of IFN-α in mRCC has been subject to skepticism. As IFN-α has been used as a control arm in RCTs of new targeted therapies, therapies which not all patients may have access to, information about its effectiveness remains relevant. These data confirm genuine, if modest, effectiveness of IFN-α in mRCC.

Renal cell carcinoma (RCC) with rhabdoid features is an uncommon and highly aggressive malignancy. We report a case of adult clear-cell RCC with extensive rhabdoid features treated with the tyrosine kinase inhibitor sorafenib. A review of the literature summarizes important aspects of this malignancy. We discuss clinical and histological findings as well as the patient’s response to sorafenib therapy.

Objective

We performed a systematic review of randomized controlled trials (RCTs) to assess the efficacy of interleukin-2 (IL-2) for the treatment of patients with unresectable or metastatic renal cell carcinoma (RCC).

Methods

We searched the literature to identify RCTs or meta-analyses of RCTs comparing treatment regimens with IL-2 to those without. Outcomes of interest included overall or progression-free survival, response rate, toxicity and quality of life.

Results

We identified 36 RCTs, and 6 met the eligibility criteria (1098 patients). We studied IL-2 alone and in combination with other agents, including interferon-alpha (IFN-a), 5-fluorouracil (5-FU), and 13-cis-retinoic acid or tamoxifen. No trials comparing high-dose IL-2 to non-IL-2 regimens were identified. A meta-analysis of 1-year mortality data from the 6 trials did not show a difference between IL-2-based regimens and non-IL-2 controls. Two of the 6 trials detected statistically significant longer survival with IL-2 combined with IFN-a and 5-FU. Of the 4 trials that assessed progression-free survival, 3 reported significantly longer progression-free intervals with IL-2-based regimens. Five trials reported response rates; pooling the rates from these trials gave an overall weighted response rate of 13.3% (range 9%–39%) and 5.3% (range 0%–20%) for IL-2-containing regimens and non-IL-2 regimens, respectively. IL-2-based regimens were more toxic than were non-IL-2 controls; the most frequently reported grade 3–4 toxicities were hypotension (range 6%–68%), fever (2%–56%), nausea or vomiting or both (6%–34%), diarrhea (1%–28%) and cardiac toxicity (11%–25%). None of the trials reported health-related quality-of-life data.

Conclusion

Non-high-dose IL-2 containing regimens do not provide superior treatment efficacy over non-IL-2-based regimens, with added toxicity, and therefore should not be used as standard treatment for patients with unresectable or metastatic RCC. High-dose IL-2 should only be used by experienced physicians in the context of a clinical trial or investigative setting.