March 2008 Clinical Trial Reports

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PHASE III

Central Nervous System Stimulant for Brain Tumors

Brain radiation can have a number of negative effects on patients while treating brain tumors. This includes adversely affected quality of life (QOL) and impairment of neurocognitive function. However, it is difficult to understand whether these effects are not also caused by the cancer itself. Researchers from Wake Forest School of Medicine, Winston—Salem, North Carolina, recently tested a compound that acts as a central nervous system stimulant, to evaluate its effects on QOL and cognitive function in patients with brain cancer who undergo radiation therapy.

The study group comprised 68 subjects with primary or metastatic brain tumors. They were randomly assigned to receive D-threo-methylphenidate hydrochloride (D-MPH) or placebo. The initial dose of D-MPH was 5 mg bid, which was increased by 5 mg bid to a maximum of 15 mg bid. The placebo was given as one pill bid and could be escalated to three pills bid.

Fatigue was the primary outcome measure. The investigators assessed the patients at baseline, at the conclusion of radiation therapy, and four, eight, and 12 weeks after radiation therapy was complete. Patients were evaluated through the use of the Functional Assessment of Cancer Therapy with brain and fatigue (FACIT- F) subscales in addition to the Center for Epidemiologic Studies Scale and Mini-Mental Status Exam.

At baseline, the mean scores for the D-MPH group and the placebo group were not significantly different. However, eight weeks after the brain RT was completed, no difference was still noted in fatigue between the two patient groups.

The quality of life was not improved by using prophylactic D-MPH in patients with brain tumors who are undergoing radiation therapy, the researchers concluded.

Butler JM Jr, Case LD, Atkins J, et al: A phase III, double-blind, placebo-controlled prospective randomized clinical trial of d-threo-methylphenidate HCl in brain tumor patients receiving radiation therapy.

2007;69:1496-1501.

Int J Radiat Oncol Biol Phys

Paclitaxel and Carboplatin Treatment for Patients With Lung Cancer

The efficacy and safety of weekly paclitaxel combined with carboplatin given every four weeks has been compared with the standard regimen of paclitaxel and carboplatin every three weeks for treating individuals with advanced non— small-cell lung cancer (NSCLC). This has been examined by researchers from multiple cancer centers from around the United States.

Patients with previously untreated stage IIIB/ IV NSCLC were randomly assigned to receive either paclitaxel 100 mg/m² weekly for three of four weeks with carboplatin 6 mg/mL-min on day 1 of each four-week cycle (arm 1, 223 patients) or paclitaxel 225 mg/m² and carboplatin 6 mg/mL-min on day 1 of each three-week cycle (arm 2, 221 patients). The 444 patients in both treatment groups were eligible, after four cycles of treatment, to continue weekly paclitaxel (70 mg/m², 3 of 4 wk) as maintenance therapy until disease progression or unacceptable toxicity.

Participants in the weekly paclitaxel arm had an objective response rate of 27.6% compared with 19.2% for those in the every-three-week arm. Median time to progression was 18.4 weeks for arm 1 and 16.7 weeks for arm 2, and the median survival was 38.6 weeks and 42.9 weeks, respectively. Grade 3 or 4 anemia was seen more frequently in the weekly treatment arm, but grade 2 or 3 neuropathy and arthralgia were less common. The two groups were similar with regard to other toxicities.

Weekly vs. Q3wk Paclitaxel in combination chemotherapy for non—small cell lung cancer

Criteria

Weekly Treatment

Every-3-Week Treatment

Object response rate

27.6%

19.2%

Median time to

progression

18.4 wk

16.7 w

The two treatment groups had similar efficacy parameters, the authors noted. However, they added, the weekly treatment arm demonstrated a favorable nonhematologic toxicity profile, and therefore, this should be considered an acceptable alternative to the standard every-three-week therapy for patients with advanced NSCLC.

Belani CP, Ramalingam S, Perry MC, et al: Randomized, phase III study of weekly paclitaxel in combination with carboplatin versus standard every-3-weeks administration of carboplatin and paclitaxel for patients with previously untreated advanced non—small-cell lung cancer.

2008;26:468-473.

J Clin Oncol

The 100-Month Analysis of the ATAC Trial

In women with early-stage breast cancer, little data are available regarding the effect of more than five years of adjuvant treatment with an aromatase inhibitor. The Arimidex, Tamoxifen, Alone or in Combination (ATAC) Trialists’ Group released long-term results of their study comparing anastrozole with tamoxifen.

The study group comprised a total intent-to-treat population of 6,241 patients (3,125 received anastrozole; 3,116 received tamoxifen) and a hormone-receptor— positive subgroup, in whom, stated the research group, endocrine treatment is now known to be effective (2,618 given anastrozole; 2,598 given tamoxifen).

The primary endpoint for this study of postmenopausal women with localized invasive breast cancer was disease-free survival. Secondary endpoints included incidence of new contralateral breast cancer, time to recurrence, time to distant recurrence, overall survival, and death after recurrence.

After a median follow-up of five years, significant improvements were seen in both the intent-to-treat and hormonereceptor—positive groups for disease-free survival, time to recurrence, time to distant recurrence, and incidence of new contralateral breast cancer (Figure).

Hazard ratios for selected end points: Long-term results of anastrozole vs. tamoxifen for early breast cancer in hormone receptor—positive women.

Disease-free survival

0.85 (P = .003

Time to recurrence

0.76 (P = .0001)

Time to distant

recurrence

0.84 (P = .022)

Incidence of new

contralateral breast

cancer

0.60 (P = .004)

P

P

Over time, the absolute differences in time to recurrence increased, in favor of the aromitase inhibitor (at 5 yr, recurrence was seen in 9.7% of the anastrozole group vs. 12.5% of the tamoxifen group; at 9 yr, recurrence was observed in 17.0% of the anastrozole vs. 21.8% of the tamoxifen group). After completing the treatment, rates of recurrence were still significantly lower with anastrozole than with tamoxifen (hazard ratio, 0.75; = .01). However, fewer deaths after recurrence was not statistically significant (anastrozole, 245 vs. tamoxifen, 269; = .2). In addition, no effect for overall survival was found.

P

While receiving active treatment, patients given with anastrozole experienced higher fracture rates than those who received tamoxifen (number [annual rate]: 375 [2.9%] vs. 234 [1.9%]; incidence rate ratio, 1.55; < .0001). However, after treatment was completed, the difference was no longer significant (incidence rate ratio, 1.03). No significant difference was noted for the risk of cardiovascular morbidity or mortality between the anastrozole and tamoxifen groups.

As an initial adjuvant treatment for postmenopausal women with hormone-sensitive, early breast cancer, anastrozole’s long-term safety and efficacy have been confirmed by this study, the researchers concluded.

The Arimidex, Tamoxifen, Alone or in Combination (ATAC) Trialists’ Group Forbes JF, Cuzik J, Buzdar A, et al: Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 100-month analysis of the ATAC trial.

2008;9:45-53.

Lancet Oncol

Radical Nephrectomy not as Beneficial as Partial Nephrectomy for Small Renal Tumors in Younger Populations

In patients with small renal masses, what is the surgical approach that results in better overall survival? Using a patient registry, researchers from the Department of Urology Mayo Medical School and Mayo Clinic, Rochester, Minnesota, compared overall survival in patients with PT1a tumors treated with radical and partial nephrectomy.

The subjects of this study comprised patients who had sporadic, unilateral, solitary and localized renal masses of no greater than 4 cm in diameter who underwent radical or partial nephrectomy between 1989 and 2003. A total of 229 of whom had had radical nephrectomy and 358 had partial nephrectomy.

P

P

The researchers reported that, based on the last evaluation, 502 individuals were alive (median follow-up, 7.1 yr), and 146 patients had died of any cause. Radical nephrectomy was not significantly associated with death from any cause compared with partial nephrec tomy for all patients (relative risk, 1.12; = .52). When the investigators stratified the analysis based on the median age of 65 years, they found that in the 327 younger patients radical nephrectomy was significantly associated with death from any cause compared with partial nephrectomy (relative risk, 2.16; = .02). Even after adjusting for multiple other factors, the increased risk of death persisted.

Compared with partial nephrectomy, radical nephrectomy is associated with a decrease in the overall survival rate of younger patients with small renal masses, the clinicians concluded.

Thompson RH, Boorjian SA, Lohse CM, et al: Radical nephrectomy for pT1a renal masses may be associated with decreased overall survival compared with partial nephrectomy.

2008;179:468-471.

J Urol

Combination Therapy Reduces Prostate Cancer Death Rates

Long-term death rates in patients with severe prostate cancer may be reduced with a controversial treatment. This approach does not seem to be associated with a markedly higher risk of heart problems, which some opponents had worried might appear.

This combination of neoadjuvant testosterone-lowering drugs and external beam radiation therapy seemed to lower the odds of dying of severe prostate cancer over a 10-year period from 36% to 23% in patients compared with patients who did not receive both therapeutic modalities.

Researchers from the University of California, San Francisco, examined the effects of combined goserelin and flutamide, which lowers testosterone levels, plus radiation therapy. They studied the long-term effects of this treatment in 456 patients with large prostate tumors (stage T2-T4) who enrolled between 1987 and 1991.

Of the 456 patients (average age, 70 yr), some received radiation alone while the second group underwent radiation in addition to four months of goserelin 3.6 mg every four weeks and flutamide 250 mg tid for two months before and concurrent with radiotherapy. The patients in the dual-treatment group did better in several areas, commented the researchers. That group was more likely to survive without signs of the disease (11% vs. 3% for the radiation alone group) and more likely to avoid the spread of cancer to distant parts of the body (35% vs. 47%, respectively). It also took longer for many in the combination-treatment group to develop cancer in their bones. No statistically significant difference was found in the risk of fatal heart problems between the two groups.

The researchers concluded that the addition of four months of testosterone-lowering chemotherapy with goserelin and flutamide results in improvements over multiple long-term endpoints, without increased cardiac risk.

10-year outcomes in patients with severe prostate cancer

Treatment

10-yr OS

MS

DSM

DM

DFS

Combination Therapy

43%

8.7 yr

23%

35%

11%

Radiation Alone

34%

7.3 yr

36%

47%

3%

OS = Overall survival; MS = mean survival; DSM = disease-specific mortality; DM =

distant metastasis; DFS = disease-free survival.

Roach III M, Bae K, Speight J, et al: Short-term neoadjuvant androgen deprivation therapy and external-beam radiotherapy for locally advanced prostate cancer: long-term results of RTOG 8610.

2008;26:585-591.

J Clin Oncol

Bortezomib Produced Significant Complete Remission Rates in Front-Line Multiple Myeloma Trial

Autologous stem cell transplantation is considered the standard of care for younger patients with multiple myeloma. The benefit of stem cell transplantation is at least partly related to an increase in complete remission plus very good partial remission rate. One way to increase the complete remission rate is to improve the induction treatment prior to stem cell transplantation. Several phase II studies with Velcade (bortezomib) in combination as induction treatment yielded promising complete remission rates.

P

In one study the results from a 482 patient, multi-center, randomized Phase III clinical trial, comparing Velcade and dexamethasone (VcD) to vincristine, adriamycin and dexamethasone (VAD) demonstrated that (as induction therapy prior to stem cell transplantation) the VcD arm had a complete remission (complete remission, including immunofixation positive and negative) rate of 21% compared to 8% with VAD ( < 0.0001).

P

Of the 404 patients who proceeded to stem cell transplantation, the VcD arm demonstrated a post-transplantation complete remission (including immunofixation positive and negative) rate of 41% compared to 29% with VAD ( = 0.0089).

“The very high complete and near complete remission rate of 21% with this induction therapy significantly improved post-transplantation complete remission rates. This led to a decrease in patients requiring a second transplant,” said Jean-Luc Harousseau, MD, Hospital Hotel- Dieu Nantes and Principal Investigator of the trial. “Historically, regimens used as induction therapy prior to stem cell transplantation produced low complete remission rates and offered minimal incremental benefit post-transplantation.”

Patients in the VcD arm received four cycles of Velcade at 1.3 mg/m2 on days 1, 4, 8 and 11 of a 21-day cycle. Patients also received dexamethasone at 40 mg on days 1 through 4 during cycles one through four and on days 9 through 12 during cycles one and two only. The patients in the VAD arm were treated for four 28-day cycles with vincristine at 0.4 mg/ m² on days 1 through 4; adriamycin at 9 mg/ m² on days 1 through 4; and dexamethasone 40 mg on days 1 through 4, days 9 through 12 during cycles one through four and on days 17 through 20 during cycles one and two only. VcD was well tolerated with the incidence of grade 3 and grade 4 adverse events similar in each arm.

Harousseau JL, Mathiot C, Attal M, et al. Velcade/dexamethasone versus VAD as induction treatment prior to autologous stem cell transplantation in newly diagnosed multiple myeloma. Presented at the American Society of Hematology, Atlanta, GA, December 10, 2007.

PHASE II

Subcutaneous Amifostine Treatment for Head and Neck Carcinoma

The use of intravenous amifostine in patients who received chemotherapy with head and neck cancer has been studied in the past, but outcomes data are not generally available for the use of the subcutaneous form of the agent. Therefore, researchers from the Geisinger Medical Center, Danville, Pennsylvania, conducted a prospective, nonrandomized trial of adult patients who have squamous cell carcinoma of the head and neck (SCCHN), using subcutaneous amifostine.

Patients in this trial had previously untreated stage III or IV SCCHN. Every patient received subcutaneous amifostine 500 mg 30 to 60 minutes before radiotherapy (accompanied by antihistamines and antiemetics). All were given fractionated radiotherapy 1.8-2.0 Gy/day five days per week, to a total dose of 70-71 Gy. In addition, they received weekly intravenous administration of paclitaxel 40 mg/m² and carboplatin 100 mg/m² for six weeks.

Twenty patients (median age, 55 yr) were eligible for the study. The incidence of grade 2 xerostomia was 42% at 12 months and 29% at 18 months. Grade 3 or 4 xerostomia was not observed in any of the patients. Thirty percent of subjects experienced grade 3 or 4 mucositis, with a median time to resolution of 12.5 weeks (range, 5-17 wk). Estimates of survival were 95% at one year and 71% at two years. The researchers observed grade 2 weight loss in all of the individuals. Seven patients experienced mild (grade 1 or 2) nausea or vomiting. No grade 3 or 4 amifostine-related adverse events were reported.

The researchers concluded that subcutaneous amifostine was well tolerated by the subjects, and it seems to be better tolerated than intravenous amifostine, if these results are compared with earlier trials.

The incidence of xerostomia and mucositis inpatients receiving subcutaneous amifostinewith radiotherapy for head and neck cancer

Xerostomia

Grade 2

42% (12 mo)

29% (18 mo)

Grade 3 or 4

0

Mucositis

Grade 3 or 4

30%

Law A, Kennedy T, Pellitteri P, et al: Efficacy and safety of subcutaneous amifostine in minimizing radiation-induced toxicities in patients receiving combined-modality treatment for squamous cell carcinoma of the head and neck

2007;69:1361-1368.

. Int J Radiat Oncol Biol Phys