LITTLE FALLS, N.J., June 19 — Certain compounds in green tea may slow the progression of prostate cancer, researchers say.

Men with prostate cancer who consumed polyphenon E — a polyphenol found in green tea — had a significant reduction in biomarkers of cancer progression, James A. Cardelli, PhD, of Louisiana State University, and colleagues reported in the July issue of Cancer Prevention Research.

“These findings support a potential role for polyphenon E in the treatment or prevention of prostate cancer,” the researchers said.

Some studies have shown that green tea may be tied to a reduced incidence of prostate cancer, and its polyphenols have been regarded as a potential cancer therapy.

• Explain that men in a small phase II study who consumed a polyphenol found in green tea had a significant reduction in biomarkers of cancer progression, including VEGF and HGF.

But epidemiological data on green tea consumption are still inconclusive: some studies show possible benefits and others find no effects on risk ratios for cancer, the researchers said.

Last year said FDA announced that the evidence for green tea benefits was inconclusive, because people consume relatively small quantities.

So the researchers conducted an open-label, single-arm phase II clinical trial to determine the effects of short-term supplementation with active compounds in green tea on serum biomarkers in patients with prostate cancer.

The biomarkers included hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF), and prostate specific antigen (PSA).

They assessed 26 men, ages 41 to 68, who had been diagnosed with prostate cancer and were scheduled for radical prostatectomy.

The men consumed four capsules containing polyphenon E every day until the day before surgery. Four capsules are equivalent to about 12 cups of green tea, the researchers said.

They found a significant reduction in serum levels of the three biomarkers (P<0.03).

A total of 10 of 25 patients had more than a 25% decrease in HGF levels, and six of 25 had a greater than 25% decrease in their VEGF levels.

The researchers said that in vitro, EGCG (the main catechin in polyphenon E) rapidly blocked the production of HGF, and the block “seems to be at the level of transcription.”

EGCG also blocked the production of VEGF, which plays a critical role in the angiogenic process in cancer-associated fibroblasts, they said.

And age, race, and time on drug did not have a significant effect on the changes in serum biomarkers.

Some case studies have suggested that high doses of EGCG may have adverse effects on liver function.

But this study found that all markers of liver dysfunction decreased, five of them significantly: total protein, albumin, aspartate aminotransferase, alkaline phosphatase, and amylase.

“The doses that we used seem to be safe,” Dr. Cardelli said.

This raises a strictly practical question. The patients got results from taking concentrated active ingredients equal to 12 cups of tea daily.

“Does that translate to ‘If I drink 12 cups of green tea a day, will that work?’” Dr. Cardelli asked. “You can speculate, but I don’t know.”

Still, the researchers concluded that the data “support a potential role for polyphenon E in the treatment or prevention of prostate cancer.”

They said that the findings need to be “verified by larger, placebo-controlled clinical trials. The effects of different doses, long-term administration, and combination with other drugs remain to be seen.”

Polyphenon Pharma supplied the polyphenon E used in the trial. The researchers reported no conflicts of interest.

Primary source: Cancer Prevention Research

Source reference:
McLarty J, et al “Tea polyphenols decrease serum levels of prostate-specific antigen, hepatocyte growth factor, and vascular endothelial growth factor in prostate cancer patients and inhibit production of hepatocyte growth factor and vascular endothelial growth factor in vitro” Cancer Prev Res 2009; 2(7).

WASHINGTON, June 19 — Almost two-thirds of patients with advanced thyroid cancer benefited from treatment with the tyrosine kinase inhibitor sorafenib (Nexavar), data from a small clinical trial showed.

• Explain to patients that targeted therapy led to objective response or stable disease in a majority of patients with advanced thyroid cancer that could not be treated by conventional means.
• Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.

Of the 26 patients in the study, 19 (62%) had partial responses or stable disease during 26 weeks of treatment, Karen Heemstra, MD, of Leiden University in the Netherlands, and colleagues reported here at the Endocrine Society meeting.

Median progression-free survival exceeded a year, and 14 patients remained alive after a median follow-up of 63 weeks.

“Sorafenib halts tumor progression in non-iodine avid advanced thyroid cancer,” the investigators concluded. “Response is not related to histology. Response is worse in patients with bone metastases. There is no reinduction of iodine uptake.”

As a multitargeted tyrosine kinase inhibitor, the investigators postulated that sorafenib might have value in the treatment of differentiated thyroid cancer. Moreover, in vitro studies showed decreased radioiodine uptake after treatment with sorafenib, they said.

Dr. Heemstra presented data from a phase 2 clinical trial involving 31 patients, median age 65, who had differentiated thyroid cancer that could not be treated with surgery or radioiodine ablation.

All patients received sorafenib 400 mg twice a day for a maximum of 26 weeks, and response was assessed at baseline and at 26 weeks by CT scan and thyroglobulin measurement.

Patients who completed the study could remain on treatment during an open-ended extension phase.

Median time from diagnosis was three years. Only one patient had localized disease. Papillary and follicular histology accounted for 90% of the cases.

Of the 13 patients with papillary disease, 12 had the BRAFV600E mutation and one had NRAS mutation. Among the 14 patients with follicular histology, 10 had Hurtle-cell metaplasia and one had mutated NRAS.

At the end of 26 weeks, five patients had withdrawn because of adverse events. An additional four patients had progressive disease.

Of the 22 patients who entered the open-phase extension, six had progressive disease and two withdrew because of adverse events.

Eight patients had partial responses and 11 others had stable disease, resulting in a total clinical benefit of 62% (19 of 26).

No patient had reinduction of iodine uptake.

When grouped according to presence of bone metastases, patients in whom the cancer had not spread were significantly more likely to have objective responses or stable disease (P=0.04).

All patients with progressive disease had bone metastases.

Progression-free survival was 69 weeks without bone metastases and 47 weeks in patients who had bone metastases.

Toxicity was common. A majority of patients had hand-foot syndrome, weight loss, diarrhea, alopecia, and rash/mucositis, and almost half had treatment-emergent hypertension and hypocalcemia. Almost 60% of patients required temporary sorafenib dose reductions.

None of the investigators reported potential conflicts of interest.

Primary source: The Endocrine Society

Source reference:
Heemstra K, et al “Sorafenib in patients with progressive differentiated thyroid carcinoma: a phase 2 trial” ENDO 2009; Abstract OR21-4.

WASHINGTON, June 19 — Two investigational therapies for acromegaly achieved substantial reductions in growth hormone and insulin-like growth factor-1 (IGF-1) with no safety issues in studies reported here.

• Explain to patients that two drugs developed for treatment of acromegaly showed activity in preliminary clinical studies.
• Note that the studies involved relatively few patients and that neither drug is available yet.
• Note, too, that these studies were published as abstracts and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.

Somatostatin is a native growth hormone inhibitory hormone. A new class of agent that targets dopamine and somatostatin receptors reduced growth hormone levels by as much as 74% but had only a modest effect on IGF-1 levels, according to data from a small phase II study presented here at the Endocrine Society meeting.

Half the patients reported adverse events, but all resolved without treatment.

“From this preliminary study, we can say that BIM 23A760 appears safe and is active on somatostatin and dopamine receptors,” said Catherine Lesage, PhD, of Ipsen Innovation in Les Ulis, France. “The activity we observed suggests this compound should be effective in normalizing the hormonal profiles of patients with acromegaly.”

A second phase II study showed that a third of patients given the new-generation somatostatin analog pasireotide achieved growth hormone levels of 2.5 µg/L or below and normal IGF-1 levels. The spectrum of growth hormone suppression ranged as high as 89%, reported Mike Hu, PhD, of Novartis Pharmaceutical Corp. in Florham Park, N.J.

Acromegaly arises from persistent hypersecretion of growth hormone and almost always is caused by a somatotroph adenoma of the pituitary. Excess growth hormone stimulates hepatic secretion of insulin-like growth factor-I (IGF-I), which causes most of the clinical manifestations of acromegaly.

Somatostatin analogs have formed the basis for treatment, but normalize growth hormone levels in only about half of patients.

Evidence of a synergistic functional interaction between dopamine and somatostatin receptors expressed by pituitary tumors suggested that targeting both receptors might be more effective than focusing on one, said Dr. Lesage.

That observation provided a rationale for development of BIM 23A760, a chimeric compound that contains structural elements of somatostatin analogs and dopamine agonists.

BIM 23A760 was evaluated in seven men and four postmenopausal women with acromegaly. Five patients received a single 1-mg subcutaneous dose and the rest received 4 mg. All patients have been followed for two to three weeks. The 4-mg dose had a half-life of 6.5 days, suggesting that weekly administration would be appropriate, said Dr. Lesage.

The 1-mg cohort had a baseline growth hormone level of 5.1 µg/L compared with 29.1 µg/L in the 4-mg cohort. The lower dose achieved a maximum growth hormone suppression that averaged 66.4%, and the higher dose reduced baseline levels of growth hormone by an average of 74%.

Nine of 11 patients had growth hormone suppression greater than 50%, and the time to maximum growth suppression averaged 48 to 49 hours with both doses.

IGF-1 levels remained elevated throughout follow-up, but all patients in both groups had reductions from baseline, said Dr. Lesage.

Six patients had a total of 12 treatment-emergent adverse events, five of which were considered drug-related — two cases of mild hypotension and one each of abdominal distension, diarrhea, and injection-site erythema. All adverse effects were mild or moderate in severity, and none led to withdrawal from the study.

Dr. Hu presented data from a randomized, open-label, crossover study of pasireotide, a multireceptor ligand somatostatin analog. The study involved 60 patients with active acromegaly.

All patients self-injected octreotide 100 µg tid for 28 days to permit assessment of response to standard therapy. The patients were then randomized to pasireotide 200, 400, or 600 µg bid for 28 days, repeated until all patients received all three doses.

Pharmacokinetic steady state was reached within two weeks, and maximum concentrations occurred about one hour after administration.

Of 58 patients evaluable for efficacy analysis, 20 (34.5%) achieved growth hormone values of 2.5 µg/L or less and age/sex-normalized IGF-1 values during one or more pasireotide treatment periods.

Responders had significantly greater growth hormone suppression compared with nonresponders (88.8% versus 69.2%, P<0.001). Responders also had greater reductions in IGF-1 levels (P<0.001).

Nonresponders tended to have higher baseline levels of growth hormone, suggesting higher doses might be required for some patients, said Dr. Hu.

The BIM 23A760 study was supported by Ipsen, and the pasireotide study was supported by Novartis. Dr. Lesage and all co-investigators of the BIM 23A760 study are employees of Ipsen. Dr. Hu and all co-investigators in the pasireotide study are either employees of Novartis or have financial relationships with Novartis. Co-investigator Stephan Petersenn also disclosed relationships with Ipsen and Pfizer.

Primary source: The Endocrine Society

Source reference:
Lesage C, et al “A phase 2 exploratory study of BIM 23A760 in acromegalic patients: preliminary results of safety and efficacy after a single-dose administration” ENDO 2009; Abstract P3-673.

Additional source: The Endocrine Society

Source reference:
Hu K, et al “Pasireotide (SOM230) provides biochemical control in patients with active acromegaly: pharmacokinetic/pharmacodynamic (PK/PD) results from a randomized, multicenter, phase II trial” ENDO 2009; Abstract P3-677.