Clinical Trial Reports: June 15, 2010

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â–º PHASE IV

Cancer Risks and Postmenopausal Hormone Link Confirmed

Overall health risks, including breast cancer, heart attacks, and related problems that outweighed the benefits of treatment with estrogen and progestin after menopause caused Women’s Health Initiative (WHI) researchers to abandon the trial six years ago, after a mean follow-up of 5.6 years. This landmark study changed how hormone-replacement therapy was prescribed, and researchers from the University of North Carolina, School of Public Health, Chapel Hill, reported some interesting findings based on their follow-up of the women who participated in that trial.

In the initial double-blind, placebo-controlled, randomized WHI study, 16,608 women aged 50 through 79 years received conjugated equine estrogens 0.625 mg/day plus medroxyprogesterone acetate 2.5 mg/day. The latest report, a postintervention follow-up that included 15,730 women, began in July 2002 and concluded in March 2005.

This follow-up to the WHI study found that the annualized risk of cardiovascular problems was 1.97% (343 events) in patients who received hormone-replacement therapy, compared with 1.91% (323 events) in the placebo group. Patients in the WHI’s active treatment group experienced approximately one-quarter greater risk of malignancies (and breast cancer risk) (Table). The researchers revealed a slight trend toward a lower hazard ratio for breast cancer during the follow-up period. Postmenopausal patients receiving hormonereplacment therapy also had a “somewhat” higher level of all-cause mortality than the placebo group. They noted that overall, there was no change in the risks or benefits than that seen in the original WHI study. The global risk for the women receiving hormone- replacement therapy was still 12% higher than for women in the placebo group.

Outcomes follow-up of women's health initiative (WHI)

Risk Category

WHI Intervention Group

Placebo Group

Hazard Ratio

Any Malignancy*

1.56%

1.26%

1.24

Breast Cancer*

0.42%

0.33%

1.27

All-Cause Mortality

1.20%

1.06%

1.15

* Annualized Incidence

Heiss G, Wallace R, Anderson GL, et al: Health risks and benefits 3 years after stopping randomized treatment with estrogen and progestin. JAMA 2008;299:1036-1045.

â–º PHASE III

Do Vitamins Protect Against Lung Cancer?

In the United States, lung cancer remains the leading cause of cancer-related deaths. Approximately one-half of the population takes supplemental multivitamins in order to help prevent chronic diseases or cancer. However, researchers from the University of Washington, Seattle, found that taking vitamin supplements, especially vitamins C, E, and folate, do not lower the risk of lung cancer; long-term use of high-dose vitamin E may in fact increase the risk.

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The researchers studied the 10-year vitamin intake habits of 77,721 subjects between the ages of 50 and 76 years. A total of 521 study participants developed lung cancer over a four-year follow-up. Using regression analysis, the investigators adjusted for age, sex, and smoking habits. They found that taking vitamin supplements did not confer protection from lung cancer. Patients using supplemental vitamin E experienced a slight increase for the risk of lung cancer (hazard ratio, 1.05 for every 100-mg/day increase in dose; = .033). That supplemental vitamin E risk, the clinicians noted, was mostly restricted to current smokers (hazard ratio, 1.11 for every 100-mg/ day increase in vitamin E dose; < .01). This association was most significant for the development of non—small cell lung cancer (hazard ratio, 1.07 for every 100-mg/day increase in dose; = .004).

Current smokers taking at least 215 mg/day of vitamin E over 10 years were 59% more likely to develop lung cancer than current smokers who did not take any vitamin supplement. Among all study participants, those who had a high rate of vitamin E, use had a lung cancer rate of 209 per 100,000 people, compared with 189 per 100,000 for nonusers.

The use of supplemental vitamins, vitamins C, E and folate were not related to a decreased risk of lung cancer, concluded the clinicians. They did point out that the risk of potential harm was greater from tobacco use alone than from vitamin E usage (even at high doses), with a current smoker being 24 times more likely to develop lung cancer than a nonsmoker.

Slatore CG, Littman AJ, Au DH, et al: Long-term use of supplemental multivitamins, vitamin C, vitamin E, and folate does not reduce the risk of lung cancer.

2008;177:470-471.

Am J Respir Crit Care Med

Longer Life Expectancy in Pancreatic Cancer When Gemcitabine Is Added to Chemotherapy

One of the deadliest malignancies, only 5% of patients with pancreatic cancer are expected to survive for five years. In a cancer in which a few extra months may make a difference, oncologists from the University of Maryland Medical Center, Baltimore, have found that gemcitabine added to an adjuvant chemotherapy and radiation after surgery can extend survival.

The randomized, controlled study took place at 164 United States and Canadian institutions. Two hundred thirty patients with pancreatic cancer received chemotherapy with fluorouracil (continuous infusion of 250 mg/m²/day) and 221 individuals were treated with chemotherapy plus gemcitabine (30-minute infusion of 1,000 mg/m² once weekly) for three weeks before starting chemoradiation therapy and for 12 weeks after the therapy. All of the subjects received radiation (50.4 Gy) as well as a continuous infusion of fluorouracil (250 mg/m²/day).

Tumors in the pancreatic head were found in 388 out of 451 patients. In these specific patients, the addition of gemcitabine was associated with a five-month gain in median survival and a 40% improved three-year survival rate. However, owing to how the study was powered statistically, this outcome indicated a positive trend but one that was not significantly different (hazard ratio, 0.82; P = .09). No survival benefit was revealed for the other patients receiving gemcitabine who had tumors in other areas of the pancreas.

The principal toxicity that was associated with gemcitabine was hematologic, as 14% of those receiving the intervention experienced grade 4 toxicity compared with only 1% of patients who received fluorouracil in the control group (P < .001). The use of gemcitabine did not affect the ability of the patient to complete the chemotherapy or radiation therapy regimen; the rate was more than 85% in both groups.

Adding gemcitabine to adjuvant fluorouracil-based chemoradiation was related to survival benefits for patients with resected pancreatic cancer, the researchers stated, although it was a statistically insignificant trend.

Regine WF, Winter KA, Abrams RA, et al: Fluorouracil vs gemcitabine chemotherapy before and after fluorouracil-based chemoradiation following resection of pancreatic adenocarcinoma: A randomized controlled trial.

2008;299:1019-1026.

JAMA

Outcomes Improve With Letrozole Treatment in Women With Early-Stage Breast Cancer

Previous pivotal trials of the use of an aromatase inhibitor given after five years of adjuvant tamoxifen therapy definitively showed that it was beneficial in patients with early-stage breast cancer. In the main trial (National Cancer Institute of Canada Clinical Trials Group MA.17), once the study was unblinded, women were allowed to start letrozole therapy if desired. Researchers from Canada, the United States, and Scotland, evaluated the follow-up results of the women who switched to the aromatase inhibitor treatment from the placebo group of the initial study—representing a considerable lapse of time during which active therapy was provided&mdash; compared with those who did not choose to start letrozole therapy.

All of the postmenopausal women in the trial completed five years of adjuvant tamoxifen therapy. Only events (recurrences, toxicity, and death) that happened after unblinding were reported.

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A total 1,579 women (median time from completion of 5-yr of tamoxifen treatment, 2.8 yr) elected to begin letrozole treatment and 804 women decided not to continue with the new therapy. Women in the letrozole group tended to be younger and had superior performance status and were more likely to have had node-positive disease and axillary dissection than women in the control group. With those differences considered, women using letrozole obtained better disease- free survival at the median follow-up of 5.3 years ( <.0001). With regards to adverse events, women who received letrozole reportedly had more new diagnoses of osteoporosis and significantly more clinical fractures ( = .02).

Even after a nearly three-year break from active adjuvant therapy, the researchers concluded, disease-free survival can be improved with letrozole treatment in women who were diagnosed with early-stage disease and who completed a five-year course of tamoxifen therapy.

Goss PE, Ingle JN, Pater JL, et al: Late extended adjuvant treatment with letrozole improves outcome in women with early-stage breast cancer who complete 5 years of tamoxifen.

2008; 26: 1948-1955.

J Clin Oncol

Pemetrexed vs. Docetaxel for Non—Small Cell Lung Cancer Treatment

A large, randomized phase III trial involving patients with advanced non—small cell lung cancer (NSCLC) who had been treated previously, demonstrated that pemetrexed had similar efficacy to docetaxel but a better toxicity profile. The following study, for which updated results should be available later in 2008, suggests that pemetrexed may have improved efficacy in patients with nonsquamous tumors.

Researchers from the United States, Korea, Germany, and Italy studied patients who received either intravenous pemetrexed 500 mg/m² (with vitamin B12 injections and oral folic acid) (283 patients) or intravenous docetaxel 75 mg/m² every 21 days (288 patients).

In the squamous and nonsquamous groups who received docetaxel, efficacy did not differ greatly, the researchers noted, but pemetrexed seemed to be more effective for nonsquamous than for the squamous group of patients. Patients with nonsquamous histology in the pemetrexed therapy group had a higher median overall survival (9.3 mo) compared with docetaxel (8.0 mo). In the squamous tumor group, patients receiving pemetrexed had an overall survival of 6.2 months versus 7.4 months in the docetaxel group. Median progression-free survival did not vary significantly among the groups, but the likelihood for recurrence was substantially higher in the squamous tumor group receiving either medication, based on hazard ratio analysis.

Peterson P, Park K, Fossella F, et al: Is pemetrexed more effective in patients with non-squamous histology? A retrospective analysis of a phase III trial of pemetrexed vs. docetaxel in previously treated patients with advanced non—small cell lung cancer (NSCLC). Presented at the 14th annual European Cancer Conference (ECCO), Barcelona, SpainSeptember 23–27, 2007.

â–º PHASE II

Talactoferrin-Alfa Treatment for Non-Small Cell Lung Cancer

Systemic chemotherapy is the current standard of care for patients with non—small cell lung cancer (NSCLC), but in the United States, the five-year survival rate in patients with advanced disease is less than 3%. Clinicians from the National Cancer Institute, Bethesda, Maryland, recently presented results of a phase 2 trial of talactoferrin alfa for treating NSCLC that provided some optimism.

In this double-blind, placebo-controlled trial, 100 patients with stage IIIB/IV NSCLC whose disease was refractory to previous chemotherapy were enrolled. Forty seven were randomly assigned to receive oral talactoferrin 1.5 g bid, and 53 were given a placebo twice daily. Although supportive care was given, no one received any other anticancer treatment while participating in the study. Treatment was given in 14-week cycles (12 wk receiving treatment, 2 wk without treatment) for up to three cycles or until the disease progressed.

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Median overall survival for the intent-totreat population was found to be 65% higher in the talactoferrin group compared with the placebo group (6.1 vs. 3.7 mo; hazard ratio, 0.68; P = .04). A significant difference in six-month survival for the full intent-to-treat population was noted in the talactoferrin group (49%) compared with the placebo group (28%) ( = .03).

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Oral talactoferrin was well tolerated in the study group, the researchers noted, with generally mild adverse events. Patients in the talactoferrin group had 26% fewer adverse events and registered 48% fewer grade 3—5 adverse events compared with the placebo group ( = .004 and = .002, respectively), they added.

Giaccone G: Oral talactoferrin alfa improves overall survival in patients with refractory non-small cell lung cancer: Final phase 2 study results presented at the 8th annual Targeted Therapies for the Treatment of Lung Cancer meeting. Santa Monica,California February 26, 2008.

Advanced Carcinoid Systemic Therapy

For patients with advanced carcinoid tumors, treatment with octreotide and alfa-interferon may not prevent disease progression. Researchers from Texas and Maryland evaluated the use of bevacizumab compared with pegylated interferon alfa-2B, in a phase II study of patients with metastatic or unresectable carcinoid tumors.

All of the 44 study participants were receiving stable doses of octreotide. They were randomly assigned to 18 weeks of treatment with either bevacizumab or PEG interferon alfa-2b. The effect on tumor blood flow was measured by functional computer tomography (CT) scans.

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Four patients in the bevacizumab group (18%) attained a confirmed partial response; 17 (77%) experienced stable disease. One patient suffered disease progression. Of the patients who received pegylated interferon, the disease stabilized in 15 (68%) and the disease progressed in six (27%). After 18 weeks of treatment, progression-free survival was 95% in the bevacizumab group versus 68% in the pegylated interferon group. Tumor blood flow at day 2 and at week 18, the clinicians noted after comparing paired baseline measurements on functional CT scans, decreased 49% ( < .01) and 28% ( < .01), respectively, for patients who were given bevacizumab therapy. In contrast, tumor blood flow changes were not observed after pegylated interferon therapy.

Pegylated interferon therapy was associated with a significant decrease in plasma basic fibroblast growth factor concentration as well as a significant increase in plasma interleukin-18 levels, reported the researchers, whereas significant changes in either plasma level were not found after bevacizumab therapy.

The clinicians concluded that patients who were treated with bevacizumab had reduced tumor blood flow, better objective responses, and longer progression-free survival than those individuals treated with pegylated interferon.

Yao JC, Phan A, Hoff PM, et al: Targeting vascular endothelial growth factor in advanced carcinoid tumor: A random assignment phase II study of depot octreotide with bevacizumab and pegylated interferon alfa-2b.

2008;26:1316-1323.

J Clin Oncol