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The Clinical Benefit of Bevacizumab in Metastatic Colorectal Cancer
The utility of vascular endothelial growth factor (VEGF) inhibitors in colorectal cancer may be affected by mutations of the KRAS gene; patients with metastatic colorectal cancer who have the KRAS mutation have been found to not gain benefit anticipated with use of endothelial growth factor inhibitors. Researchers from Duke University, Durham, North Carolina, and Genentech, South San Francisco, California, sought to determine if the outcome of patients treated with bevacizumab, a VEGF inhibitor, is affected by KRAS mutation status.
The researchers analyzed the results of a phase III, placebo-controlled study of 812 patients with metastatic colorectal cancer that tested the efficacy of a regimen of fluorouracil, irinotecan, and leucovorin. Patients in the study group also received bevacizumab, whereas patients in the control group also received a placebo. Samples from the tumors of 230 patients were evaluable for KRAS status.
In patients with mutated KRAS genotypes, median progression-free survival was 9.3 months in those receiving bevacizumab, compared with 5.5 months in those receiving the control regimen (P = .0008). In those with wild-type KRAS, study group had a mean progression-free survival of 13.5 months compared with the control group’s median of 7.4 months (,i>P < .0001). In terms of overall survival, the median survivals were 19.9 months and 13.6 months, respectively for those with mutant KRAS samples ( = .26). For those with wild-type KRAS, the median overall survivals were 27.7 months and 17.6 months, respectively ( = .04).
The researchers concluded that KRAS status did not affect the benefit of bevacizumab treatment, even though patients with KRAS mutations experienced less benefit overall from treatment (both study and control). This means that KRAS testing in patients is unwarranted in patients who are candidates for bevacizumab treatment.
Hurwitz HI, Yi J, Ince W, et al: The clinical benefit of bevacizumab in metastatic colorectal cancer is independent of K-ras mutation status: Analysis of a phase III study of bevacizumab with chemotherapy in previously untreated metastatic colorectal cancer. Presented at the 2008 World Congress on Gastrointestinal Cancer, Zurich, Switzerland, July 1, 2008.
Once-Daily Dasatinib Associated with Better Efficacy and Tolerability in Chronic Myeloid Leukemia
In patients with chronic-phase chronic myelogenous leukemia (CML) whose treatment with imatinib did not produce the desired remission, dasatinib 70 mg twice daily has proven effective and is the approved dosage. However, this dose schedule is associated with toxicity, which is thought to be related to continuous inhibition of Bcr-Abl gene expression. Can less-frequent dosing result in similar efficacy but with fewer tolerability issues? A team of international researchers conducted a phase III trial to better understand if toxicity can be reduced with oncedaily administration and what might be the best once-daily dose.
In this open-label study, the investigators randomly assigned 670 patients with imatinib-resistant or intolerant chronic-phase CML to one of four dasatinib treatment groups: (1) 100 mg once daily, (2) 50 mg twice daily, (3) 140 mg once daily, or (4) 70 mg twice daily.
After a minimum follow-up of six months and a median treatment duration of eight months, the clinicians examined response rates for hematologic (complete, 86% to 92%) and cytogenetic (major, 54% to 59%; complete, 41% to 45%) parameters from the four groups. Similar time to and duration of cytogenetic response were noted, as well as progression-free survivals. Disease progression or death occurred in 8% to 11% of all patients.
Patients taking dasatinib 100 mg once daily, when compared with the approved 70 mg twice-daily course of therapy, had significantly lower rates of pleural effusion (all grades, 7% vs. 16%, respectively; = .024) and grade 3 to 4 thrombocytopenia (22% vs. 37%, respectively; = .004). Fewer patients needed dose interruption (51% vs. 68%, respectively), treatment discontinuation (16% vs. 23%, respectively) and dose reduction (30% vs. 55%, respectively).
The researchers concluded that dasatinib 100 mg once daily remains the efficacy of 70 mg twice daily, but with less toxicity. They believe that efficacy may be preserved and adverse events reduced by intermittent target inhibition with tyrosine kinase inhibitors.
Shah NP, Kantarjian HM, Kim DW, et al: Intermittent target inhibition with dasatinib 100 mg once daily preserves efficacy and improves tolerability in imatinib-resistant and -intolerant chronic-phase chronic myeloid leukemia.
J Clin Oncol
New Mechanism Shows Promise in Patients With Non-Small Cell Lung Cancer
A new testing program is just getting underway to test the viability of another class of agents that address blood vessel supply to tumors. This class is distinct from an angiogenesis inhibitor, which tries to prevent tumors from growing new blood vessels; instead, a tumor-vascular disrupting agent will destroy blood vessels already created by the tumor.
ASA404, a product that has already undergone small phase II studies, is the subject of two phase III trials called Antivascular Targeted Therapy: Researching ASA404 in Cancer Treatment (ATTRACT). The ATTRACT-1 study will include roughly 1,200 patients who will be randomized to receive ASA404 1,800 mg/m2 plus carboplatin and cisplatin chemotherapy or placebo plus the standard chemotherapy as first-line treatment for non—small cell lung cancer (NSCLC). ATTRACT-2 will comprise approximately 900 patients, who will also be randomized to receive ASA404 plus docetaxel or placebo plus docetaxel for the second-line treatment of NSCLC.
The promise of this agent was seen in phase II trials, which indicated a median overall survival advantage of more than 5 months for patients with squamous-cell NSCLC taking first-line ASA404 plus chemotherapy compared with those receiving chemotherapy. Median time to tumor progression was improved by four months. Patients with squamous-cell history obtained more survival and time-to-progression benefit with ASA404 than did patients with non—squamous-cell tumors.
McKeage J, Jameson MB, AS1404-201 Study Group Investigators: Comparison of safety and efficacy between squamous and non-squamous non—small cell lung cancer (NSCLC) patients in phase II studies of DMXAA (ASA404). Presented at the 2008 annual meeting of the American Society of Clinical Oncology, Chicago, May 30–June 3, 2008. ASA404 programme to expand with new pivotal trial in lung cancer (press release). July 17, 2008
ASA404 programme to expand with new pivotal trial in lung cancer (press release). July 17, 2008.
Erectile Dysfunction Response to Androgen Deprivation Therapy for Prostate Cancer
Erectile dysfunction (ED) may be a common consequence of prostate cancer treatment with androgen deprivation therapy (ADT). Libido and sexual function can be altered because of ADT-induced changes in serum testosterone. Researchers from the University of Tennessee Health Science Center, Memphis, sought to quantify the incidence of patient-reported ED as well as their response to treatment for ED through the use of a retrospective database analysis.
Data from patients at the University who received ADT between January 1989 to July 2005 for prostate cancer were reviewed for ED reporting, libido changes, and ED therapy initiation (surgical or medical). The researchers analyzed the charts of 395 patients (mean age, 71.7 yr; 59% African—American, 41% Caucasian/ other, at ADT initiation). Treatment for ED in these subjects included phosphodiesterase type-5 (PDE-5) inhibition monotherapy (72%), prostaglandin E1 analogues alone (11%), vacuum erection devices alone (7%), inflatable penile prosthesis (2%), or a combination of treatments (9%).
Erectile dysfunction was reported in 57 (14.4%) of the individuals during the mean follow-up period of 87.4 months. Of those men, 40 (70%) had new-onset ED and 17 (30%) experienced ED before ADT. Medical therapy response rates were 33% to 80% (depending on therapy used—44% who were treated with PDE-5 inhibitor monotherapy responded).
Interestingly, the researchers revealed that patients younger than 70 years of age ( < .001) were more likely to report ED than their older counterparts. Furthermore, multivariate analysis revealed that patients who did not have diabetes ( = .024) were more likely to report ED after ADT. Both of these results could relate to the fact that patients older than 70 years and those with diabetes are in general more likely to have ED at baseline and therefore would not report a change.
Variable degrees of ED have been observed in men who are given ADT for prostate cancer, the researchers admitted. They believe that the best chance for a positive ED outcome may be through the use of multimodal therapy.
DiBlassio CJ, Malcolm JB, Derweesh IH, et al: Patterns of sexual and erectile dysfunction and response to treatment in patients receiving androgen deprivation therapy for prostate cancer.
Motesanib Shows Potential For Thyroid Cancer Treatment
Although the value of using vascular endothelial growth factor (VEGF) inhibitors to halt cancer spread has not generally met expectations, angiogenesis inhibitors may have a role in extending life in patients with advanced cancer and poor prognosis. Researchers from the University of Texas M.D. Anderson Cancer Center and colleagues in 10 countries found that thyroid cancer metastasis was slowed in some patients by treatment with the VEGF inhibitor motesanib diphosphate.
This open-label, single-group trial enrolled subjects with progressive, locally advanced or metastatic, differentiated thyroid cancer that proved resistant to radioiodine therapy. Fifty-seven of the 93 participants (61%) had papillary thyroid carcinoma. An independent radiographic review (with magnetic resonance imaging or computed tomography) determined whether patients met the primary endpoint of having an objective response. Treatment comprised motesanib 125 mg given orally once a day for 48 weeks or until the disease progressed or side effects became unacceptable.
Of the 93 initial enrollees, 32 (34%) completed the entire 48-week treatment period. The therapy was halted in 35 patients because of disease progression and in 12 patients because of adverse events related to the treatment. Nine individuals withdrew from the study for various reasons and five patients died. An objective partial response to motesanib diphosphate was attained by 13 patients (14%). Stable disease occurred in 62 patients (67%) and durable stable disease was maintained by 33 of those individuals (35%) for 24 weeks or more. Seven patients (8%) had progressive disease without any improvement or period of stability. No response information could be obtained for 11 patients (12%), because radiographic scans were incomplete or could not be interpreted.
A genetic evaluation of 25 patients by the researchers revealed that patients with the BRAF V600E mutation in their tumor tissue demonstrated better objective response rates, but the patient numbers were too low to yield significantly different figures.
The median duration to response, as estimated by Kaplan—Meier survival analysis, was 32 weeks. The median progression-free survival was estimated to be 40 weeks. Thyroglobulin analysis was performed on 75 subjects, and 81% demonstrated a decrease in serum thyroglobulin concentrations when compared with baseline levels.
Treatment-related adverse events occurred in 87 patients (94%) with the most common being diarrhea (59%), hypertension (56%), fatigue (46%), and weight loss (40%).
The clinicians stated that patients with progressive advanced or metastatic differentiated thyroid cancer can achieve a partial response with motesanib diphosphate treatment, even though only a small percentage of all patients with the disease survive for 10 years. They suggested more research to better define the role of the BRAF V600E gene mutation as a marker of increased probability for success.
Sherman SI, Wirth LJ, Droz JP, et al: Motesanib diphosphate in progressive differentiated thyroid cancer.
N Engl J Med
For Melanoma Patients, Recurrence-Free Survival Improves With Pegylated Interferon Therapy
The use of adjuvant pegylated interferon alfa-2b for resected stage III melanoma results in significant improvement in recurrence- free survival, according to investigators from Erasmus University Medical Center, Rotterdam, Netherlands and other European researchers for the EORTC Melanoma Group. These results were based on a randomized phase III trial involving more than 1,250 patients.
The study participants were randomly assigned to receive an induction dose of pegylated interferon alfa-2b (N = 627) 6 μg/kg/ week for eight weeks followed by a maintenance dose of 3 μg/kg/week, with the intent to treat for up to five years. A total of 629 patients were assigned to the observation group (controls).
Patients were treated with pegylated interferon alfa-2b for a median of 12 months. Individuals in the interferon group experienced 328 melanoma recurrences by a median of 3.8 years of follow-up compared with 368 recurrences in the observation group (hazard ratio, 0.82; 95% CI, 0.71-0.96; = .01); the recurrence-free survival at four years was calculated to be 45.6% and 38.9%, respectively. No difference in the overall survival was observed between the two groups.
Two hundred forty-six patients (40%) were found to have grade 3 adverse events in the treatment group compared with 60 (10%) in the control group. Grade 4 adverse events occurred in 32 (5%) and 14 (2%), respectively. For the patients in the interferon group, fatigue (97 patients, 16%), hepatoxicity (66, 11%), and depression (39, 6%) were the most common grade 3 or 4 adverse events. Treatment was halted in 191 (31%) of patients because of toxicity.
Although the absolute difference in recurrence- free survival is not large, it does represent a significant and sustained effect for patients with stage III melanoma by treatment with adjuvant pegylated interferon alfa-2b, acknowledged the researchers. However, they did note the relatively high rate of grade 3 adverse events in patients taking this treatment.
Eggermont AM, Suciu S, Santinami M, et al: Adjuvant therapy with pegylated interferon alfa-2b versus observation alone in resected stage III melanoma: Final results of EORTC 18991, a randomised phase III trial.
Induction Therapy for Patients With Anal Canal Carcinoma
Most patients with anal canal cancer who have large squamous cell tumors and lymph node involvement have a poor prognosis. American researchers from multiple centers have conducted a noncontrolled, nonrandomized trial to determine the safety and efficacy of an induction fluorouracil (FU)-based chemotherapy regimen with concurrent radiation.
Subjects with previously untreated T3 or T4 anal canal cancers, widespread nodal involvement, or both were given two 28-day cycles of induction therapy with infused FU plus cisplatin and then two 28-day cycles of FU plus mitomycin C with concurrent splitcourse radiation. Patients with persistent primary site disease or bulky N2 or N3 disease upon presentation received a third cycle of FU plus cisplatin with radiation boost.
Protocol therapy was given to 45 patients considered assessable. Generally, individuals tolerated the treatment well. The most common toxicities were gastrointestinal and hematologic. Eight complete and 21 partial responses were achieved with induction chemotherapy. A complete response occurred in 37 of the 45 high-risk patients (82%) after induction, combined-modality, and boost therapy.
The oncology researchers noted that after a follow-up period of four years, 68% of the patients are still alive, 61% are disease-free, and 50% are disease-free and not using a colostomy. The majority of patients with poor-prognosis anal canal cancer achieved disease control using this combined-modality approach.
Meropol NJ, Niedzwiecki D, Shank B, et al: Induction therapy for poor-prognosis anal canal carcinoma: A phase II study of the cancer and leukemia group B (CALGB 9281).
J Clin Oncol
Ovarian Cancer Treatment With Imatinib Mesylate
Does imatinib, which is highly effective for chronic myelogenous leukemia, also have a role in the treatment of other cancers? Researchers from the Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, have tested the activity and tolerance of imatinib in patients being treated for recurrent or persistent epithelial ovarian or primary peritoneal carcinoma.
In this noncontrolled experiment, the investigators evaluated the six-month progression-free survival (PFS) associated with imatinib monotherapy, and performed mutational analysis of several molecular markers related to imatinib targets to determine if any predicted tumor response to treatment.
Of the 56 patients who were evaluated, nine (16%) did not demonstrate any disease progression after six months progression-free, and one patient (2%) was considered a complete responder. However, median PFS was 2 months, with an overall median survival of 16 months. Common grade 3 and 4 adverse events included pain, GI, dermatologic effects, neutropenia, and electrolyte disturbances.
All tumors expressed at least one imatinib target (platelet-derived growth factor [PDGFR]-alpha, PDGFR-beta, or KIT); all three receptors were expressed by a majority of the tumors. Shorter PFS was related to greater p-AKT and PDGFR-beta expression.
Also associated with worse outcomes were higher pretreatment concentrations of vascular endothelial growth factor and PDGF-alpha and -beta. The investigators found none of the markers to predict positive outcomes with imatinib.
The researchers concluded that imatinib has only minimal single-agent activity in patients with recurrent ovarian or primary peritoneal cancer.
Schilder RJ, Sill MW, Lee RB, et al: Phase II evaluation of imatinib mesylate in the treatment of recurrent or persistent epithelial ovarian or primary peritoneal carcinoma: A Gynecologic Oncology Group Study.
J Clin Oncol