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• Breast Cancer
• Anticancer Benefit from Zoledronic Acid
• Lung Cancer
• Pemetrexed Approved for Front-Line Therapy of NSCLC
• Gefitinib Trials
• Phase III Study of Gefitinib Versus Docetaxel in Previously Treated Japanese Patients with NSCLC
• ESMO 2008 Presidential Symposium
• NCI Clinical Trial on Biomarkers and Lung Cancer
• Vitamin C Supplements and Interaction with Chemotherapy
• Quick Poll

Breast Cancer

Anticancer Benefit from Zoledronic Acid
Zoledronic acid (Zometa^® [ZA]) has been shown to not only be therapeutic for bone density, but also has been suggested to have anticancer effects. At the 2008 European Society for Medical Oncology (ESMO) Annual Meeting in Stockholm, Sweden, 3 separate trials were discussed that showed that ZD reduced the risk of both local and distant recurrence in premenopausal and postmenopausal women with early breast cancer. As also reported at the 2008 American Society of Clinical Oncology^® (ASCO) Annual Meeting, the ABCSG-12 trial found a 33% reduction in the risk of disease-free survival events in patients who received ZA versus those who did not receive bisphosphonate therapy. This trial was confined to premenopausal women. Patients received a gonadotropin-releasing hormone (GnRh) agonist and were randomly assigned to either tamoxifen or anastrozole, and then were again randomized to either ZA or no bisphosphonate therapy. The phase III Z-FAST and ZO-FAST trials that randomized postmenopausal patients with estrogen receptor (ER)–positive breast cancer to letrozole with immediate ZA versus delayed ZA also demonstrated a significant drop in local and metastatic recurrences for patients who received up-front ZA (3.6% vs 5.5% at 24 months). A third pilot trial of 45 women assessed the effect of ZA on disseminated cancer cells in the bone marrow. At a median of 2 years, 71% of evaluable patients had a decrease in disseminated cancer cells (P = .01). A specific trial designed to evaluate ZA in a larger cohort of patients is the AZURE trial that has randomized 3360 women with early breast cancer to standard therapy +/- ZA for 5 years. Presentation of outcome data from the AZURE trial is anticipated.

Gnant M, Mlineritsch B, Schippinger W, et al. Zoledronic acid improves disease-free and recurrence-free survival in premenopausal women with early breast cancer (ERBC) receiving adjuvant endocrine therapy: multivariate analysis of efficacy data from ABCSG-12. Ann Oncol. 2008;19(Suppl 8). Abstract 69O.

Frassoldati A, Brufsky A, Bundred N, et al. The effect of Zoledronic acid on aromatase inhibitor associated bone loss in postmenopausal women with early breast cancer (EBC) receiving adjuvant letrozole: 24 months integrated follow-up of the Z-FAST/ZO-FAST trials. Ann Oncol. 2008;19(Suppl 8). Abstract 185PD.

Lin AY, Park JW, Scott J, et al. Adjuvant zoledronic acid therapy decreases the prevalence of disseminated tumor cells in bone marrow of patients with early-stage breast cancer: 2-year results. J Clin Oncol. 2008;26(May 20 Suppl). Abstract 559.

ClinicalTrials.gov. Chemotherapy and/or hormone therapy with or without zoledronate in treating women with stage II or stage III breast cancer. Available at: www.clinicaltrials.gov/ct2/show/NCT00072020?term=azure&rank=1. Accessed October 27, 2008.

Lung Cancer

Pemetrexed Approved for Front-Line Therapy of NSCLC
The US Food and Drug Administration (FDA) approved pemetrexed (Alimta^®) for use in combination with cisplatin therapy for the initial treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer (NSCLC). This approval was based on a phase III trial of 1725 patients with stage IIIB/IV NSCLC who were randomized to pemetrexed plus cisplatin or gemcitabine (Gemzar^®) plus cisplatin. In patients with nonsquamous cell NSCLC, the median survival was 11.0 months vs 10.1 months for the pemetrexed versus gemcitabine-randomized arms, respectively. Patients with squamous cell histology had a worse outcome if they were randomized to treatment with pemetrexed. The most common adverse reactions in patients receiving pemetrexed plus cisplatin were nausea (56%), fatigue (43%), vomiting (40%), anemia (33%), neutropenia (29%), anorexia (27%), and constipation (21%). Single-agent pemetrexed was approved in 2004 for previously treated NSCLC.

Gefitinib Trials Reported
Elderly patients with NSCLC are frequently treated with single-agent chemotherapy when they develop advanced disease. The INVITE trial is a randomized phase II trial that enrolled 190 previously untreated patients with stage IIIB/IV NSCLC who were ≥ 70 years of age. The patients either received gefitinib (Iressa^®) 250 mg/day orally or vinorelbine (Navelbine^®) 30 mg/m² IV on days 1 and 8 of a 21-day cycle. Patients received a maximum of 6 cycles. Both gefitinib and vinorelbine resulted in similar progression-free survival (PFS) and overall survival (OS) rates. Median PFS for gefitinib was 2.7 months, and the median PFS for vinorelbine was 2.9 months (hazard ratio [HR] = 1.19; 95% confidence interval [CI], 0.85 to 1.65; P = .31). At 4 months, PFS rates for gefitinib and vinorelbine were 27.0% and 39.8%; at 6 months, PFS rates were 14.9% and 23.6%, respectively. Median OS for gefitinib was 2.8 months, and median OS for vinorelbine was 2.5 months (HR = 0.98; 95% CI, 0.66 to 1.47). At 6 months, OS rates for gefitinib and vinorelbine were 49.2% and 54.0%; at 12 months, OS rates were 33.9% and 33.2%, respectively. Although gefitinib and vinorelbine resulted in similar rates of improvement of lung cancer and pulmonary symptoms, quality of life scores were better for the gefitinib compared to vinorelbine. Unexpectedly, there was a paradoxical relationship between epidermal growth factor receptor (EGFR) copy number and benefit from gefitinib versus vinorelbine. In patients whose disease was EGFR-positive, treatment with vinorelbine resulted in an improved PFS and OS than for those who received gefitinib. In the group of patients who received gefitinib, patients whose disease was EGFR-positive had a worse outcome than patients whose disease was EGFR-negative. The opposite was found to be true for the patients who received vinorelbine.

Crinò L, Cappuzzo F, Zatloukal P, et al. Gefitinib versus vinorelbine in chemotherapy-naive elderly patients with advanced non-small-cell lung cancer (INVITE): a randomized, phase II study. J Clin Oncol. 2008;26(26):4253-4260.

Phase III Study of Gefitinib Versus Docetaxel in Previously Treated Japanese Patients with NSCLC
Due to suggestions that gefitinib may offer a survival benefit in Asian patients with refractory NSCLC, this phase III trial was performed to compare docetaxel (Taxotere^®) to gefitinib in Japanese patients with previously treated metastatic NSCLC. The trial evaluated 489 patients who were randomly assigned to receive gefitinib 250 mg/day or docetaxel 60 mg/m² every 3 weeks. The primary statistical endpoint was OS, and the trial was designed to show noninferiority of gefitinib to docetaxel. At a median follow-up of 21 months, the overall mortality was 62.6%. Noninferiority in OS for gefitinib was not established, and there was not a difference in OS (P = .33). Progression-free survival was 2.0 months for both groups and median survival was 11.5 months vs 14 months with a 1-year survival of 47.8% vs 53.7% for gefitinib versus docetaxel, respectively. Surprisingly, there were significantly better overall response rates with gefitinib vs docetaxel (22.5% vs 12.8%). Contrary to the previously reported study, patients in both arms had a better PFS if their tumors were EGFR-positive.

ESMO 2008 Presidential Symposium

During the 2008 ESMO Presidential Symposium, 2 lung cancer presentations occurred. The first was the report of the IPASS (Iressa Pan Asia Study), which is a phase III trial comparing gefitinib versus paclitaxel (Taxol^®)/carboplatin chemotherapy in untreated Asian patients with adenocarcinoma and who were either nonsmokers or “light” smokers. The statistical endpoint was noninferiority of gefitinib versus the chemotherapy regimen for PFS. This endpoint was met with an HR of 0.741, and a surprising superiority of gefitinib for PFS. Response rates and quality of life were also improved in the gefitinib arm. The presence of the EGFR mutation (EGFR-positive) was predictive of PFS and response to gefitinib. The absence of the mutation was predictive of benefit from paclitaxel and carboplatin.

The second trial reported was the final report of the AVAiL (Avastin in Lung Cancer) trial. This was a phase III randomized trial comparing gemcitabine/cisplatin with or without bevacizumab (7.5 mg/kg or 15 mg/kg every 3 weeks) in patients with stage IIIB/IV nonsquamous NSCLC. At the ASCO 2007 Annual Meeting, study investigators reported significant improvement in PFS for the low-dose bevacizumab arm vs the control arm (6.8 months vs 6.2 months). However, the final overall survival as presented at the ESMO 2008 meeting showed no improvement with the addition of bevacizumab to the gemcitabine/cisplatin chemotherapy regimen. Median OS times were 13.1 months, 13.6 months, and 13.4 months for the control group, the low-dose bevacizumab, and the high-dose bevacizumab groups, respectively. It was noted that the AVAiL trial did not support the findings of ECOG 1599, which showed a significant (20%) improvement when bevacizumab was added to paclitaxel and carboplatin. A discussion was led regarding the divergent results of these trials, but the conclusion was stated that in treating patients with NSCLC with gemcitabine/cisplatin, there is no benefit to adding bevacizumab.

NCI Clinical Trial on Biomarkers and Lung Cancer 

The NCI has launched a large clinical trial to validate biomarkers targeting EGFR and establishing whether specific therapy can be directed based on biomarker findings. The MARVEL trial (Marker Validation for Erlotinib in Lung Cancer) will enroll 1200 patients with lung cancer who will be tested for the presence of EGFR and will then be randomly assigned to treatment based on the results. Both patients whose disease is EGFR-positive and EGFR-negative will receive either of the chemotherapy drugs erlotinib (Tarceva^®) or pemetrexed (Alimta^®) after they have received their initial, standard chemotherapy. The hypothesis is that erlotinib will be superior in patients whose disease is EGFR-positive and pemetrexed will be superior in patients whose disease is EGFR-negative. In addition to testing for EGFR, tumor specimens will also be studied for multiple additional genetic studies to help identify other potential targets or predictive factors for toxicity. The trial is being led by the North Central Cancer Treatment Group (NCCTG) and many other clinical trial groups will cosponsor the study. The trial is being described as an outcome of a unique collaboration called the Oncology Biomarkers Qualification Initiative (OBQI) between the National Cancer Institute (NCI), the FDA, and the Centers for Medicare and Medicaid Services. The OBQI was developed to qualify biomarkers for use in clinical trials in order to develop more targeted and appropriate therapy for patients with cancer. For information about the trial, please access the following website: http://www.clinicaltrials.gov/ct2/show/NCT00738881?id=N0723&rank=1#desc

Vitamin C Supplements and Interaction with Chemotherapy

In the October 1, 2008, issue of Cancer Research, Heaney et al from the Memorial Sloan-Kettering Cancer Center evaluated the interaction between multiple chemotherapy drugs and vitamin C in cell cultures and in an animal model system. The cell culture studies evaluated drugs that work by producing reactive oxygen, and those that work by other mechanisms. They found that every chemotherapy drug evaluated and the targeted agent imatinib mesylate (Gleevec^®) caused less cancer cell death when the tumor cells were pretreated with vitamin C. This was then verified in the animal model system. Rather than neutralizing oxygen-free radicals, which was the suspected mechanism of interaction, the dehydroascorbic acid (DHA) restored viability to the cancer cells’ mitochondria. Dehydroascorbic acid is the form of vitamin C that gets into cells, and once inside the cell is converted to ascorbic acid and is trapped there. Dr Heaney’s group suggested that all anticancer drugs eventually have some interaction in disrupting the cell’s mitochondria that can then lead to cancer cell death. They also suggested that while vitamin C should be part of a healthy diet with foods that include the vitamin, large doses of over-the-counter vitamin C should be used with caution, especially by patients who are receiving antitumor agents.

Heaney ML, Gardner JR, Karasavvas N, et al. Vitamin C antagonizes the cytotoxic effects of antineoplastic drugs. Cancer Res. 2008;68(19):8031-8038.

What's Next?

The next issue of OncoFacts™ will be in December 2008 and then monthly throughout the year.

OncoFacts™ Editor:

Christy Russell, MD

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