Clinical Trial Reports: June 10, 2010

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PHASE III

Second-Line Pemetrexed Does Not Provide Survival Advantage in Malignant Pleural Mesothelioma

Pemetrexed seems to be one of the few therapies to exert positive effects in patients with malignant pleural mesothelioma (MPM). Researchers from Poland, Germany, Italy, and the United States conducted a controlled, phase III study to determine whether second-line treatment with pemetrexed in patients with advanced MPM improved their overall survival.

The study group comprised 123 patients who after first-line chemotherapy experienced relapsed MPM. They were randomly assigned to receive treatment with pemetrexed 500 mg/m² plus best supportive care (BSC) every 21 days. Their progress was compared against a control group of 120 patients who received BSC alone.

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The investigators did not find any significant differences in the primary outcome measure, median overall survival, between the two treatment groups (8.4 mo for the pemetrexed + BSC group and 9.7 mo for the BSC group). However, they did reveal that the combination of pemetrexed and BSC led to significantly better progression-free survival and time-to-tumor progression. Although the overall survival did not favor the second-line pemetrexed group, those receiving the combination attained a 19% rate of partial response compared with only 2% in the BSC-only group ( < .0001). The disease control rate (partial response and stable disease) was noted in 59% of the pemetrexed group and 19% of the BSC group ( < .0001).

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Interestingly, the investigators found that subjects who received BSC treatment only had significantly greater use of postdiscontinuation chemotherapy than the pemetrexed group (52% vs. 28%, respectively; = .0002) with 18.3% of patients in the BSC group being given pemetrexed versus 3.3% in the pemetrexed group ( = .0001). Chemotherapy was well tolerated in both groups, with 4% to 7% grade 3 and 4 hematologic toxicities.

Measure

P+BSC

BSC only

Median Overall Survival

8.4 mo

9.7 mo

Partial Response

18.7%

1.7%

Partial Response + Stable Disease

59.3%

19.2%

P = Pemetrexed; BSC = best supportive care.

An overall survival improvement rate was not found in this study, concluded the researchers, because of a difference in the use of post-discontinuation chemotherapy between the two treatment groups. Those using second-line pemetrexed and BSC had better tumor response and longer-delayed disease progression compared with only BSC use in patients with advanced MPM, the researchers commented.

Jassem J, Ramlau R, Santor A, et al: Phase III trial of pemetrexed plus best supportive care compared with best supportive care in previously treated patients with advanced malignant pleural mesothelioma.

2008;26:1698-1704.

J Clin Oncol

PHASE III

Colon Cancer Risk Reduced Dramatically by Two-Drug Combination

The risk of colon cancer may be decreased by more than 90% in high-risk patients, according to researchers from the University of Arizona who presented their findings at the American Association for Cancer Research annual meeting in San Diego. They found that the use of a synthetic amino acid that interferes with cancer development but is highly toxic at regular doses can be given with a nonsteroidal antiinflammatory drug (NSAID) but at greatly reduced doses, reduced the risk of colorectal adenomas, without significant toxicity.

The study group comprised 375 patients with a history of colorectal polyps within the past five years. The enrollees were randomly assigned to receive either a combination of difluoromethylornithine (DFMO) 500 mg/day plus sulindac 150 mg/day or a placebo.

After a three-year follow-up period, the risk of a recurrent polyp was 41.1% in the placebo group but only 12.3% with the combination treatment, a 70% reduction. Patients with a history of advanced polyps who took the active drug combination saw their risk of recurrent polyps drop 92%.

The rate of polyp reappearance in patients with multiple previous adenomas was 13.2% in the placebo group and 0.7% in the group receiving the DFMO—sulindac combination treatment (95% reduction). The lead researcher pointed out that 17 patients in the placebo group experienced regrowth of at least one adenoma, compared with only one patient in the treatment group.

The study was halted early by the trial’s Data Safety and Monitoring Board because the rate of risk reduction was so high. No differences were noted, the clinicians added, between individuals receiving treatment and placebo in terms of gastrointestinal or cardiovascular side effects as well as temporary hearing loss or side effects that required hospitalization.

Meyskens FL: Marked efficacy of difluoromethylornithine plus sulindac in reducing recurrent colorectal adenomas in patients with prior adenomas: Results of a randomized, placebo-controlled, double-blind Phase III trial.

Presented at the 99th annual meeting of the American Association for Cancer Research, San Diego, California,

April 21—16, 2008.

PHASE III

Perioperative Chemotherapy With FOLFOX4 Versus Surgery Alone for Patients With Metastatic Colorectal Cancer

Within two years of surgical resection of primary colorectal tumors, more than half of patients will experience metastasis to the liver. In patients with liver metastases from colorectal cancer, surgical excision of the metastases is the standard of care. However, this standard therapy does not yield good outcomes; relapse frequently occurs, leading to poor prognoses. Oncologists and surgeons from multiple European centers decided to evaluate whether the use of perioperative chemotherapy can affect the progression-free survival (PFS) and overall survival in these patients compared with surgical excision alone.

Three hundred sixty-four patients with proven colorectal cancer and up to four liver metastases (which were considered resectable) were included in the study. They were randomly assigned to standard surgery alone (N = 182) or to treatment with FOLFOX4 (oxaliplatin injection combined with 5-fluorouracil/ leucovorin) six cycles before and six cycles after surgery (N = 182). A hazard ratio (HR) of 0.71 or less would denote a 40% increased PFS in this phase III study and was denoted as the objective.

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Eighty-three percent of the patients in the perioperative chemotherapy group received a median of six preoperative cycles and underwent surgical resection, with 115 (63%) receiving a median six postoperative cycles. In the surgery-only group, 152 (84%) of patients were resected. At three years, the absolute increase in the PFS rate was only 7.3 percentage points (from 28.1% to 35.4%; HR, 0.79; = .06) for randomized patients (patients who were randomized to participate but were not necessarily resected). The increase in PFS rate for all patients undergoing resection was 9.2 points (from 33.2% to 42.4%; HR, 0.73; = .025). The researchers noted that fewer patients in the perioperative chemotherapy group died (64) compared with the surgery-only group (75) over the three-year follow- up, and that perioperative mortality was below 1% in both groups.

Serious adverse events associated with preoperative FOLFOX4 chemotherapy included grade 3/4 neutropenia (18%), grade 3 diarrhea (8%), grade 3 stomatitis and pharyngitis (6%), and grade 3/4 leucopenia (6%). When given postoperatively, the following significant adverse events occurred: grade 3/4 neutropenia (35%), grade 3 leucopenia (12%), grade 3 miscellaneous neurologic toxicity (12%), grade 3 sensory neuropathy (10%), and grade 3 thrombocytopenia (7%).

Although the use of FOLFOX4 therapy perioperatively was not associated with the 40% PFS advantage sought by the investigators, they did find that it does improve survival. The evaluation for overall survival is ongoing and will be reported in another paper.

Nordinger B, Sorbye H, Glimelius B, et al: Perioperative chemotherapy with FOLFOX4 and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC Intergroup trial 40983): A randomised controlled trial.

Lancet 2008;371:1007-1016.

PHASE II

Can a COX-2 Inhibitor Inhibit Oral Cancer?

In preclinical models, inhibition of cyclooxygenase- 2 (COX-2) curbs carcinogenesis and is considered a potential approach for the prevention of oral cancer. These agents have been available in the United States for a number of years, and it has been hypothesized that celecoxib might be useful in this role. Researchers from multiple centers around the United States participated in a pilot study of the safety and efficacy of celecoxib in patients with oral premalignant lesions (OPL).

In the main portion of the study, which was randomized and controlled, 18 patients received placebo, 17 were given celecoxib 100 mg twice daily, and 15 received celecoxib 200 mg twice daily for 12 weeks. In an unblinded extension of the trial, six other patients received celecoxib 400 mg twice daily. All study participants had at least one histologically confirmed early OPL (atypical hyperplasia, atypical hyperkeratosis, or mild dysplasia) or advanced OPL (moderate to severe dysplasia). Biopsies were taken at baseline and at week 12.

Efficacy analyses were available for 49 patients (46 of 50 randomized and 3 of 6 open-label). Although the therapy was well tolerated, the differences among response rates in the control and placebo groups were not statistically significant: 33.3% (6 of 18) in the placebo group, 41.2% (7 of 17) in the celecoxib 100 mg twice daily group, and 20.0% (3 of 15) in the celecoxib 200 mg twice daily group and were not considered statistically significant differences. Only two of the six patients receiving celecoxib 400 mg twice daily responded. An increased risk of disease progression within three months was seen in patients with higher baseline COX-2 messenger ribonucleic acid levels.

Oral premalignant lesions were not effectively controlled by treatment with celecoxib at either 100 or 200 mg twice daily regimens, acknowledged the clinicians. Owing to the cardiovascular toxicity found in other randomized, controlled clinical trials of the COX-2 inhibitors and the lack of efficacy demonstrated in this pilot trial, the researchers acknowledge that these agents probably do not have a role in the prevention of oral cancer.

Papadimitrakopoulou VA, William WN Jr, Dannenberg AJ, et al: Pilot randomized phase II study of celecoxib in oral premalignant lesions.

2008;14:2095-2101.

Clin Cancer Res

PHASE II

Small-Cell Lung Cancer Survival Not Improved By High-Dose Chemotherapy

The ability to attain the intended dose intensity and duration of chemotherapy is sometimes limited by the patient tolerance to treatment and the need for supportive therapy. Often, a patient’s negative response to chemotherapy is attributed to this limitation.

In patients with small-cell lung cancer (SCLC), does the ability to receive a sufficiently intense dose contribute to the response to the regimen? Researchers from multiple centers throughout Europe evaluated the use of three times the normal dose intensity of a chemotherapy regimen to see if it affects survival in patients with SCLC, which is subject to frequent recurrence and therapy resistance.

Patients with limited or extensive SCLC (≤ 2 metatastic sites) received either the standard dose of ifosfamide, carboplatin, and etoposide (ICE) or the high dose, supported with blood stem-cell transfusions (which were harvested after treatment with filgrastim). The primary outcome was survival after a three-year period.

Sixty-nine patients were randomly assigned to receive high-dose chemotherapy. Standard-dose chemotherapy with ICE was given to 71 subjects. Treatment intensity in the high-ICE group of patients was almost three times greater than in the standard- ICE group (293% median relative dose intensity for high-ICE group compared with the standard chemotherapy group; range, 174%—392%). At three years the survival rates were 18% in the high-ICE group and 19% for patients receiving standard-ICE treatment. Nor were there any differences found between the therapies for overall tumor response or complete response. Subgroup analysis did not reveal any outcome benefit from greater dose intensity. The standard-ICE group of patients experienced substantial hematologic toxicity (grade ≥3) including 49 individuals with neutropenia (70%), 17 with thrombopenia (25%), and 17 with anemia (25%) while three patients (4%) died from toxicity. Severe myelosuppression was associated with high-ICE treatment and five (8%) of those patients died from toxicity.

Increasing the dose intensity of ICE chemotherapy did not improve the long-term outcome of patients with SCLC, admitted the researchers, and the toxicities were severe. They do not recommend intense ICE therapy for the treatment of SCLC in the future.

Leyvraz S, Pampallona S, Martinelli G, et al: A threefold dose intensity treatment with ifosfamide, carboplatin, and etoposide for patients with small cell lung cancer: A randomized trial.

2008; 100:520-521.

J Natl Cancer Inst

PHASE II

Gastrointestinal Cancer Treatment With Prophylactic Chlorhexidine And Cryotherapy

Oral mucositis is a common side effect of cancer chemotherapy, which can result in discontinuation of therapy, poor nutrition, and negative outcomes. Danish researchers presented results of a phase II trial evaluating possible prevention of oral mucositis (OM) using chlorhexidine or placebo and oral cooling (cryotherapy) during chemotherapy in patients with gastrointestinal (GI) cancer.

Of the 225 patients initially randomized, 206 answered a questionnaire and reported the duration and severity of oral mucositis. Seventy members of the study group, all of whom were receiving bolus 5-FU/leucovorin chemotherapy (Arm A) received chlorhexidine mouthrinse three times/ day for three weeks. Sixty-four patients were given double-blind placebo (normal saline) with the same dose and frequency (Arm B), and 63 patients received cryotherapy with crushed ice for 45 minutes during chemotherapy (Arm C).

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The three study groups were similar with regard to age, sex, diagnoses, smoking habits, stage, and performance status. The clinicians reported that patients in Arm B (33%) experienced grade 3 or 4 mucositis more often than those in Arm A (13%; < .01) and Arm C (11%; < .005). A significantly longer duration was noted in Arm B than in both Arm A ( = .035) and Arm C ( = .003).

By utilizing prophylactic chlorhexidine or cryotherapy, the frequency and duration of OM were significantly improved, the clinicians stated, although cryotherapy has limited use, because it is drug- and schedule-dependent even though it is easy and inexpensive. In fact, many therapies are available for the prevention of OM, ranging from artificial saliva to over-thecounter medications and rinses. They suggest that the role for chlorhexidine for preventing OM should be further evaluated.

Sorensen JB, Skovsgaard T, Bork E, et al: Double-blind, placebo-controlled randomized study of chlorhexidine prophylaxis for 5-fluorouracil-based chemotherapy-induced oral mucositis with non-blinded randomized comparison to oral cooling (cryotherapy) in gastrointestinal malignancies.

2008;112:1600-1606.

Cancer

PHASE II

Systemic Inflammation Linked With Poor Survival in Bladder Cancer

A simple prognostic test may be useful for oncologists and patients who are deciding on late-stage therapeutic management for bladder cancer. Poor survival in various malignancies has increasingly been associated with systemic inflammatory responses, and Japanese researchers have found that response of C-reactive protein (CRP) levels in patients with muscle-invasive bladder cancer seems to predict survival following chemoradiotherapy.

The researchers reviewed the records of 88 patients with bladder cancer who had been treated with external beam radiotherapy (40 Gy) and two cycles of cisplatin (50—150 mg) at three-week intervals.

Nineteen of the 88 study participants died as a result of their cancer during the follow-up period (median, 33 mo). A 73% five-year cancerspecific survival was observed overall. Ten subjects with a high CRP level (≥ 0.5 mg/dL) before undergoing treatment had survivals that were significantly lower than patients with lower CRP levels (P = .003). C-reactive protein level was found to be an independent prognostic indicator for cancer-specific survival.< br>

The investigators found that six of the 10 patients who had initially high CRP levels before chemoradiotherapy reverted to normal levels. Five of these six patients were still living at the end of the follow-up, without metastasis or recurrence. However, the four patients whose CRP levels remained high after treatment had died within two years.

The researchers believe that this is the first study to show high levels of CRP are associated with poor survival in patients with muscleinvasive bladder cancer. In addition, they concluded survival is extremely poor for patients whose CRP levels remain elevated after chemoradiotherapy.

Yohisda S, Saito K, Koga F, et al: C-reactive protein level predicts prognosis in patients with muscleinvasive bladder cancer treated with chemoradiotherapy.

2008;101:978-981.

BJU Int