Clinical Trial Reports: June 16, 2010

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PHASE IV

Long-Term Aspirin Therapy Reduces Colorectal Cancer Risk

Much has been hinted at the possible benefit of nonsteroidal anti-inflammatory use to prevent colorectal cancer. A long-term, large prospective, nonrandomized study performed by researchers at Harvard Medical School, Boston, finally answers this question, and it seems that the protective effect may well be dose related.

The clinicians gathered data on aspirin use, risk factors, and diagnoses of colorectal cancer in 47,363 male health professionals who, when enrolled in 1986, were 40 to 75 years of age. Data on aspirin use were collected every two years.

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The investigators documented 975 cases of colorectal cancer over 761,757 person-years, during the 18 years of follow-up. After risk-factor adjustment, the researchers found that individuals who used aspirin regularly (≥ 2 times/wk) experienced a multivariate relative risk (RR) for colorectal cancer of 0.79 (95% confidence interval [CI], 0.69—0.90) compared with those who did not use aspirin regularly. This difference was not deemed statistically significant. However, study participants who used aspirin regularly for six to 10 years did have a significant risk reduction ( = 0.008). Within four years of discontinuing use, this benefit was no longer evident (multivariate RR, 1.00).

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They found that the preventive benefit was correlated with increasing cumulative average dose: Compared with men who did not use aspirin (RR, 1.0), the multivariate RRs for cancer were 0.94 for men who used 0.5—1.5 standard (325-mg aspirin tablets per week, 0.80 for 2–5 tablets/wk, 0.72 for 6–14 aspirin tablets/wk, and 0.30 for > 14 tablets/wk ( for trend = 0.004).

The risk of colorectal cancer among men is reduced by regular, long-term aspirin use, the researchers noted, although the benefit of aspirin therapy requires at least six years of consistent use with the maximal risk reduction at doses more than 14 tablets/week. No advantage was seen by taking aspirin for less than five years or the equivalent of less than 1.5 tablets/week.

However beneficial the high dosage seems in terms of colorectal cancer prevention, the authors warn, high aspirin intake can result in serious gastrointestinal side effects.

Aspirin Benefit in Colorectal Cancer

Aspirin Intake

Risk Reduction

No aspirin use

0%

162—487 mg/wk

6%

650—1,625 mg/wk

20%

1,950—4,450 mg/wk

28%

>4,450 mg/wk

70%

Chan AT, Giovannucci EL, Meyerhardt JA, et al: Aspirin dose and duration of use and risk of colorectal cancer in men.

2008;134:341-343.

Gastroenterology

PHASE III

Does Adding Cisplatin to Adjuvant Chemotherapy Improve Outcomes in Advanced Gastric Cancer?

Previous studies have suggested that mitomycin-C plus fluoropyrimidine (Mf) may improve the outcome of curatively resected advanced gastric cancer, although a debate remains about the role of adjuvant chemotherapy. In a randomized phase III trial, researchers have extended the administration of oral fluoropyrimidine to improve the adjuvant Mf chemotherapy while adding cisplatin to the Mf regimen (MFP) in order to determine whether that strategy could improve three-year relapse-free survival for patients who had undergone resection for advanced gastric cancer.

The trial group consisted of patients who had postoperative stage II—IV three to six weeks after undergoing surgery. They were randomized to receive either Mf or MFP chemotherapy. Individuals in the Mf group received an injection of mitomycin C 20 mg/m² and four weeks later, doxifluridine 460–600 mg/m²/day orally for three months. For patients in the MFP group, doxifluridine was continued for a total of 12 months; six bolus injections of monthly cisplatin 60 mg/m² were added to Mf chemotherapy.

Four hundred thirty-six patients were randomized to receive Mf and 435 received MFP. More than three-quarters of the patients were in postoperative stages II or IIIA. The researchers did not find any difference in three-year relapsefree survival between the two groups after a median follow-up of 31 months (66% for Mf patients and 64% for MFP patients). Differences in overall survival after three years was not significant: 75% in the Mf group and 73% in MFP group. Both groups tolerated the treatments well, but more of the Mf group completed the treatment (93%) than did the MFP group (72%). Grade 3 or 4 neutropenia was more frequent in the MFP group (34%) than in the Mf group (9%). The MFP group also experienced more vomiting (≥ grade 2) than the Mf group (23% vs. 12%, respectively). No treatment related deaths were seen.

Although the addition of cisplatin to doxifluridine and mitocycin-C chemotherapy was well tolerated, the researchers acknowledged, this regimen did not demonstrate improved treatment outcomes for patients who underwent curative resection in advanced gastric cancer.

Kang Y, Chang H, Min Y, et al: A randomized phase III trial comparing mitomycin-C plus short-term doxifluridine (Mf) versus mitocycin-C plus longterm doxifluridine plus cisplatin (MFP) after curative resection of advanced gastric cancer (AMC 0201). Presented at the ASCO Gastrointestinal Cancers Symposium, January 25—27, 2008, Orlando, Florida.

FOLFIRI Plus Bevacizumab Provides Better Survival Than Other Irinotecan-Containing Regimen in First-Line Colorectal Cancer

For patients with colorectal cancer, first-line treatment with irinotecan-based chemotherapy has been proven relatively effective, delaying disease progression and improving survival (median overall survival, 23 mo with a regimen of irinotecan, and infused 5-fluorouracil and leucovorin [FOLFIRI]). The addition of bevacizumab to the regimen seems to provide additional benefit, according to researchers from multiple centers.

In an update to their original analysis, which was first published in October in the Journal of Clinical Oncology, the investigators reported updated survival data based on the inclusion of bevacizumab to the FOLFIRI regimen.

Survival advantage for FOLFIRI and bevacizumabcompared with mIFL and bevacizumab

FOLFIRI+ Bevacizumab

mIFL+ Bevacizumab

Overall Survival, Median

28.0 mo

19.2 mo

One-year Survival

87%

61%

FOLFIRI = Folinic acid, fluorouracil, and irinotecan;

MIFL = bolus FU/LV

In period 1 of the initial investigation, patients underwent treatment with either FOLFIRI, irinotecan plus bolus FU/LV (mIFL), or irinotecan plus oral capecitabine (CapeIRI). A median progression-free survival (PFS) of 7.6 months was attained for FOLFIRI, 5.9 months for mIFL (P = 0.004 for the comparison with FOLFIRI) and 5.8 months for CapeIRI (P = 0.015). The median overall survival was 23.1 months for individuals in the FOLFIRI group, 17.6 months for mIFL (P = 0.09) and 18.9 months for CapeIRI (P = 0.27).

In period 2 of the trial, denoted by the addition of bevacizumab, the median survival time had not yet been reached for the FOLFIRI+Bev arm, but it was recorded as 19.2 months for mIFL+Bev (P = 0.007). The updated overall survival data revealed by the researchers involved 117 individuals randomly assigned to receive either FOLFIRI+Bev (57) or mIFL+Bev (60). They detected significantly improved median overall survival (28.0 mo), by a median follow-up period of 34.4 months in the FOLFIRI+Bev group compared with the mIFL+Bev group (19.2 mo; P = 0.037). At one year, 87% of subjects receiving FOLFIRI+Bev survived compared with 61% in the mIFL+Bev group.

As with the earlier findings of the trial, the clinicians noted, FOLFIRI+bev offered a significant survival benefit when compared with mIFL+bev.

Fuchs CS, Marshall J, Barrueco J: Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: Updated results from the BICC-C study (letter).

2008; 26:689-690.

J Clin Oncol

PHASE II

Single-Agent Activity of Sunitinib in Refractory Non-Small Cell Lung Cancer

Lung cancer is the most common cancer worldwide, but it is associated with low survival in comparison with other cancers. Prognosis for advanced lung cancer remains dismal. Previous studies have shown that abnormal activity of epithelial and platelet-derived growth factor is involved in the pathogenesis of the disease. The efficacy and safety of sunitinib malate, an oral, multikinase inhibitor, which blocks both types of growth factor receptors, for treating refractory patients with advanced non—small cell lung cancer (NSCLC) was recently studied in a phase II, multicenter, single-arm trial.

The study group comprised 64 subjects with previously treated, advanced NSCLC (nonsquamous and squamous) who received only sunitinib 50 mg/day once daily for four consecutive weeks, followed by two weeks off treatment. Sixty percent of these patients were heavily pretreated with two or more prior systemic therapies. Overall confirmed objective response rate, considered to be the percentage of patients with confirmed complete responses or partial responses, was the primary study endpoint. Safety, progression-free survival (PFS), and overall survival were also evaluated as secondary endpoints.

Confirmed partial responses were attained in seven (11%) of the 63 patients who were evaluable. Stable disease (≥ 8 wk) was noted in 18 individuals, and the median duration of response was 21 weeks. Eighteen patients (29%) experienced stable disease for at least eight weeks.

The researchers noted that a median overall survival of 23 weeks was attained. The median PFS was 12 weeks and a one-year survival of 20.2% was recorded in these patients with advanced NSCLC.

Adverse events were generally regarded as grade 1 or 2, the most common being fatigue, nausea, pain, and stomatitis. The researchers believe that future studies should build on these findings, and sunitinib should be tried in combination with other agents for the treatment of NSCLC.

Socinski MA, Novello S, Brahmer JR, et al: Multicenter, phase II trial of sunitinib in previously treated, advanced non-small-cell lung cancer.

2008;26:650-656.

J Clin Oncol

The Importance of Targeting Androgen Receptor Signaling for Prostate Cancer Response Rate

Earlier phase I clinical trial results of abiraterone acetate demonstrated promising potency in patients with prostate cancer. Data from two ongoing phase II clinical trials of this steroidal enzyme 17-alpha-hydroxylase/ C17,20 lyase inhibitor were recently presented by researchers from Great Britain at a U.S. symposium.

The first trial included patients with medical castration—refractory prostate cancer who had not received other chemotherapy. These individuals had progressive disease even though they had previously been treated with luteinizing hormone-releashing gene analogues as well as other hormone therapies. All of the 44 evaluable patients had radiological evidence of metastatic disease. In addition, 31 (70%) had evidence of bone metastases.

After administering a regimen of abiraterone once daily, the researchers found a greater than 50% decline in prostate-specific antigen (PSA) levels in 27 participants (61%). Eleven patients experienced a decline of greater than 90%. Treatment with abiraterone in 21 evaluable patients with measurable tumors lesions produced partial radiological responses in 12 patients (57%). Seven displayed stable disease and three experienced regressing bone metastases. Improvement in pain and a reduction of opioid use was also noted. Progression in PSA score occurred after a median of 8.4 months. Treatment side effects were not reported in this presentation.

In the second phase II trial, which is ongoing in various locations in the United States and the United Kingdom, clinicians studied the effect of abiraterone in patients with advanced prostate cancer who failed to respond to treatment with androgen-deprivation therapy and first-line docetaxel-based chemotherapy.

Reid A: Selective CYP17 inhibition with abiraterone acetate result in a high response rate in castration-resistant prostate cancer (CRPC), confirming the continued importance of targeting androgen receptor signaling (COU-AA-001 and COU-AA-003). Presented at the 2008 ASCO Genitourinary Cancers Symposium, Los Angeles, February 14, 2008.

Improving Survival in Gastrointestinal Stromal Tumor

Individuals with high-risk primary gastrointestinal (GI) stromal tumor had a two-year overall survival of approximately 50% until tyrosine-kinase inhibitors became available. One of the first tyrosinekinase inhibitors, imatinib, demonstrated clinical benefits in the majority of patients with metastatic GI stromal tumor but who did not undergo surgery. Researchers from the U.S. Intergroup phase II trial Z9000 conducted their single-arm, open-label, multicenter study to determine whether imatinib would exert similar clinical benefits in the adjuvant setting after resection of localized, primary GI stromal tumor.

Participants underwent a complete gross resection of the tumor because of an expected high risk of recurrence (tumor size ≥ 10 cm, tumor rupture, or > 5 peritoneal metastases). A regimen of imatinib 400 mg/ day was prescribed for one year. The study’s primary endpoint was overall survival (OS).

Between September 2001 and September 2003, 107 patients (median age, 58 yr; range, 19—79 yr) were enrolled in the trial. Imatinib treatment was initiated at a median of 59 (range 25–84) days after surgery. Resected tumors were a median 13 cm in diameter.

The researchers reported excellent OS (≥ 97%) after a median follow-up of four years. When given at a daily oral dose of 400 mg for one year, they concluded imatinib prolongs recurrence-free survival in patients undergoing GI stromal tumor resection, and is associated with improved OS compared with historical controls.

Overall survival in patients with resected gastrointestinal stromal tumors given imatinib therapy

Measure

Rate

1-yr overall survival

99%

2-yr overall survival

97%

3-yr overall survival

97%

DeMatteo RP, Owzar K, Antonescu CR, et al: Efficacy of adjuvant imatinib mesylate following complete resection of localized, primary gastrointestinal stromal tumor (GIST) at high risk of recurrence: The U.S. Intergroup phase II trial ACOSOG Z9000. Presented at the ASCO Gastrointestinal Cancers Symposium, January 25—27, 2008, Orlando, Florida.

Improving Overall Survival in Patients With Hormone-Resistant Prostate Cancer

The endothelin A (ETA) receptor signaling has been linked with mechanisms involved in the progression of cancer. A double-blind phase II study was recently conducted by researchers at the Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, to determine the efficacy and safety of ZD4054, a specific ETA receptor antagonist, in patients with hormone-resistant prostate cancer and bone metastases who were either pain free or had mild pain symptoms.

The study participants were randomized to receive the oral agent once-daily (10 or 15 mg) or a placebo. The oncologists evaluated progression- free survival (PFS) primarily. A group of blinded radiologists reviewed bone scans, which were collected at baseline and at therapy discontinuation.

A total of 312 patients were enrolled. At the first planned analysis, no significant difference was seen for the primary outcome, PFS. At the second analysis, overall survival, a secondary outcome, in the intent-to-treat population was improved for those receiving ZD4054. Although not considered statistically significant, some decrease in the development of new bone metastases compared with placebo was seen with ZD4054 10 mg but not the higher dose (5% fewer in higher dose group, 14% fewer in the lower-dose group). Common adverse events included nasal congestion, headache, and peripheral edema, few of which were considered grade 3 or above.

The researchers commented that improvement in overall survival for patients with metastatic hormone-resistant prostate cancer who were asymptomatic or mildly symptomatic for pain was associated with ZD4054, although PFS was not improved. These results, they added, also suggest a possible beneficial effect of this ETA-receptor antagonist on bone metastasis, which should be studied further.

Dawson N, Phung D, Morris T, et al: Impact of the specific endothelin A receptor antagonist ZD4054 on overall survival and bone metastasis in patients with hormone-resistant prostate cancer: Results of a phase II trial. Presented at the 2008 ASCO Genitourinary Cancers Symposium, Los Angeles, February 14, 2008.

Breast Cancer Stem Cells Decreased With Neoadjuvant Lapatinib

Tumorigenic breast cancer cells (CD44+/CD24-/ low) have previously been shown to resist conventional chemotherapy. These stem cells, which help maintain tumor size and growth even in very low numbers, were the target of a clinical trial of neoadjuvant therapy with lapatinib, performed by researchers at Baylor College of Medicine, Houston.

The study included 30 patients with locally advanced, HER2—overexpressing breast cancers. For the first six weeks of the trial, the subjects received lapatinib, which is a epithelial growth factor/HER2 tyrosine-kinase inhibitor as a single agent, followed by a combination of weekly trastuzumab and thrice-weekly docetaxel for 12 weeks before primary surgery. After neoadjuvant therapy, the pathologic response in the surgical specimens was assessed. At the time of diagnosis and after week 6 of lapatinib, seqential core biopsies of the primary cancers were taken and evaluated for the presence of tumorigenic CD44+/CD24-/low stem cells. An analysis of global gene expression differences between cancer cells bearing CD44+/CD24-/low cells and all other sorted cells was also conducted.

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After six weeks of single-agent lapatinib administration, significant tumor regression in the product of bidimensional tumor measure- ments was seen, with a median decrease of —60.8% ( = .001) in primary tumors. Treatment with lapatinib reduced the percentage of tumorigenic CD44+/CD24-/low breast cancer cells in tumor tissue from 10.6% before treatment to 4.7% after treatment. The researchers also found that with the reduced concentration of stem cells in residual tumor, the ability of the tumor to spread was reduced ( = .01).

The pathologic complete response rate (63%) after lapatinib and trastuzumab/docetaxel therapy was greater than expected by the researchers.

This study has shown for the first time, the researchers pointed out, that lapatinib decreases tumorigenic breast cancer stem cells in the primary breast cancers of women given neoadjuvant treatment. Specific signaling inhibitors of the pathways responsible for stem-cell self-renewal, they added, could present a therapeutic strategy for eradicating tumorigenic cells in order to obtain long-term remission of breast cancer.

Li X, Creighton C, Wong H, et al: Decrease in tumorigenic breast cancer stem cells in primary breast cancers with neoadjuvant lapatanib. Presented at the San Antonio Breast Cancer Symposium, Dallas, December 16, 2007.

PHASE I / II

Patients With Recurrent Glioblastoma May Benefit From Implant Combinations

The options for effective treatment for patients with recurrent glioblastoma multiforme (GBM) are limited. Patient survival is usually less than one year, highlighting the need for novel treatment approaches. Researchers from the University of Cincinnati Medical Center noted that when used individually, localized adjunct treatment with carmustine (BCNU) wafers or permanent, low-activity ¹²⁵I seed implants have previously demonstrated some effectiveness for GBM. They decided to assess the efficacy and safety of these therapies when used in combination following tumor resection.

A total of 34 individuals with recurrent GBM were initially enrolled in this trial. Treatment consisted of maximal tumor resection, followed by implantation of BCNU wafers and permanent ¹²⁵I seeds into the tumor cavity. Patients were followed up every three months through clinical evaluations and magnetic resonance imaging studies. The primary study endpoints were progression-free survival (PFS) and overall survival (OS).

The researchers reported that 27 patients experienced local disease progression, resulting in 23 deaths. The median OS after resection and implantation was 69 weeks, and the median PFS was 47 weeks. Survival was calculated as 66% at 12 months, 37% at 18 months, and 23% at 24 months. PFS figures were 32% at 12 months, 20% at 18 months, and 13% at 24 months.

Patients who experienced extended survival were more likely to be younger (age < 60 yr), have a Karnofsky Performance Scale score of at least 70, and have ¹²⁵I seed activity ≥ 0.8 mCi/cm³ of tumor cavity. Eight patients who developed brain necrosis were successfully treated with surgery or hyperbaric oxygen therapy. Although brain necrosis was manageable and did not affect survival, they added, the incidence of the necrosis seemed to be higher than that expected with either treatment alone.

Although far from optimal, the authors believe that the combination of adjunct therapy of BCNU wafers and permanent ¹²⁵I seeds does seem to show an advantage for this approach.

Darakchiev BJ, Albright RE, Breneman JC, et al: Safety and efficacy of permanent iodine-125 seed implants and carmustine wafers in patients with recurrent glioblastoma multiforme.

2008;108:236-242.

Neurosurg