Among the articles provided in this issue are topics presented at the 43rd annual meeting of the American Society of Clinical Oncology: 1) Spain: When Two "Mabs" Are Better Than One 2) United Kingdom: Evidence Mounts Against Use of Adjuvant External Beam Radiotherapy in Endometrial Cancer 3) Norway: Clinical Data Suggest Potential Versatility of Pemetrexed for Injection (Alimta)-Based Regimens in Lung Cancer 4) Germany: An Anti-Inflammatory Approach to Inducing Remission in Metastatic Prostate Cancer
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â–º ASCO SPOTLIGHT
Spain When Two “Mabs” Are Better Than One
Investigators from multiple centers in Europe have combined trastuzumab with an investigational agent to treat late-stage breast cancer, with encouraging results.
The HER-dimerization inhibitor pertuzumab was given to patients with HER2-positive breast cancer that had advanced despite treatment with trastuzumab and other chemotherapy. Pertuzumab works by antagonizing the pairing of HER2 protein with other HER receptors. The mechanism of action of pertuzumab may complement that of trastuzumab, leading to the hypothesis that it may be effective in combination.
The study was a phase II trial but not randomized. Each of 33 patients assessed to date had received up to three courses of chemotherapy in addition to trastuzumab before experiencing progression. Once enrolled into this investigation, patients received intravenous pertuzumab 420 mg every three weeks (after a 840-mg loading dose) and trastuzumab 2 mg/kg weekly or 6 mg/kg every three weeks.
The researchers noted a complete response in one patient and partial response in five patients. Seven additional patients experienced disease stabilization.
Also of note, 11 patients received a total of 39 cycles of combined treatment. Five patients experienced leftventricular systolic dysfunction, which resolved in three patients after discontinuation of treatment.
A response rate of 18% is “striking” according to lead author, Jose Baselga, MD, Vall d’Hebron University Hospital, Barcelona, Spain, “and this is potentially good news for patients whose HER2-positive breast cancer is not responding to current treatments.” Larger studies are needed to confirm these results, however.
In related news, a phase III study of the effect of trastuzumab used as neoadjuvant treatment (when combined with chemotherapy) in patients with HER2-positive breast cancer demonstrated that it can contribute to greater use of breast-conserving surgery. When used before surgery, Italian investigators found that trastuzumab plus chemotherapy completely eradicated the tumor in 43% of the 115 patients studied compared with chemotherapy, which eradicated the tumor in 23% of 113 patients. Furthermore, the researchers found that a greater percentage of patients in the trastuzumab group had complete eradication of tumor from the lymph nodes than chemotherapy alone (38% vs. 20%, respectively).
Baselga J, et al: Objective response rate in a phase 2 multicenter trial of pertuzumab, a HER2 dimerization inhibiting monoclonal antibody, in combination with trastuzumab in patients with HER2-positive metastatic breast cancer which had progressed during trastuzumab therapy. Presented at ASCO, June 3, 2007.
Gianni L, et al: Neoadjuvant trastuzumab in locally advanced breast cancer (NOAH): Antitumor and safety analysis. Presented at ASCO, June 3, 2007.
â–º ASCO SPOTLIGHT
United Kingdom Evidence Mounts Against Use of Adjuvant External Beam Radiotherapy in Endometrial Cancer
Does adjuvant external beam radiotherapy (EBRT) improve survival in women with endometrial cancer? This therapy has been used for years without a great deal of evidence to support its use. Two study centers, in Canada and the United Kingdom, merged their investigations to obtain convincing data that EBRT after surgery does not affect overall survival.
The study pooled results from 905 women with stage 1 endometrial cancer, of whom 453 were randomized to not receive ERBT, with or without brachytherapy (51% received brachytherapy); 452 were randomized to receive ERBT, and just more than half also had brachytherapy. The study recruited patients from 1996 to 2005.
Nearly all of the patients had World Health Organization performance status of 0 to 1 before treatment. Eighty-three percent of patients demonstrated endometroid histology.
The researchers found that after a mean 51 months of follow-up that treatment-related morbidity was higher in the ERBT arm (56% vs. 24%), though grade 3 toxicity or higher was rare. Five-year survival for both groups was 84%, and the recurrence-free survival for both groups was 87%. A statistically significant difference in isolated vaginal or pelvic recurrence favored ERBT treatment, but this difference was only three percentage points, and did not seem to affect the overall survival.
Orton J, et al: Adjuvant external beam radiotherapy (EBRT) in the treatment of endometrial cancer: Results of the randomised MRC ASTEC and NCIC CTG EN.5 trial. Presented at ASCO, June 5, 2007.
â–º ASCO SPOTLIGHT
Norway Clinical Data Suggest Potential Versatility of Pemetrexed for Injection (Alimta)-Based Regimens in Lung Cancer
According to results from a Phase III study presented at ASCO, pemetrexed for injection (Alimta) showed additional utility in the treatment of the most diagnosed type of cancer. Study results suggest that a first-line Alimta-based regimen may deliver less toxicity than a commonly used therapy in advanced non-small cell lung cancer (NSCLC).
A prospective, randomized, multicenter Phase III study was conducted to compare pemetrexed for injection plus carboplatin with the commonly used regimen of gemcitabine HC1 for injection (Gemzar) plus carboplatin. The study, conducted by the Norwegian Lung Cancer Group, enrolled 446 chemonaive patients with either stage IIIB or IV NSCLC. The primary purpose of the study was to evaluate if the Alimta-carboplatin combination provided increased quality-of-lifebenefits while offering comparable survival data. As such, the primary endpoint was quality of life(defined in the study as nausea/vomiting; dyspnea or a difficulty in breathing; and fatigue) and the secondary endpoint was overall survival.
To date, 384 patients have been analyzed for toxicity and there were fewer patients in the Alimta arm who experienced Grade 3/4 thrombocytopenia or a low platelet level (48 vs. 107, < .001); leukopenia or a lowering of leukocyte white blood cells (44 vs. 89, P < .001); and granulocytopenia or a lowering of granulocyte white blood cells (78 vs. 98, = .02). More patients in the Gemzar arm received transfusion of platelets (5 vs. 19, = .02). At this point, no difference in survival has been observed.
“The patients in this study received a comparable quality-of-lifebenefit whether they received Alimta and carboplatin or Gemzar and carboplatin,” said Bjorn Henning Gronberg, MD of St. Olavs University Hospital in Norway and the study’s principal investigator. “Patients on the Alimta arm also appeared to benefit from a lower toxicity profile.”
Additional data from a Phase II, open-label, non-randomized trial will report on an International Oncology Network Study evaluating the safety of a triplet therapy in which bevacizumab (Avastin) was added to the combination of Alimta plus oxaliplatin (Eloxatin) in patients with advanced NSCLC. Previous research has indicated that oxaliplatin and Alimta, as single agents, have shown activity in NSCLC, and Alimta has shown synergistic effects when combined with platinum-based drugs. This preliminary study was conducted to evaluate the efficacy and safety of the combination as first-line treatment for NSCLC.
Alimta plus cisplatin for the first-line treatment of NSCLC is also being studied. In the first quarter of 2007, a study of Alimta plus cisplatin versus Gemzar plus cisplatin met its primary endpoint of non-inferiority relative to overall survival. Utilizing these data, Lilly plans to submit Alimta for an indication for the first-line treatment of NSCLC to the European Medicines Agency (EMEA) later this year.
BH Grønberg, et al. Pemetrexed + carboplatin versus gemcitabine + carboplatin in the treatment of stage IIIB/IV non-small cell lung cancer. Presented at ASCO June 2, 2007.
â–º ASCO SPOTLIGHT
Germany An Anti-Inflammatory Approach to Inducing Remission in Metastatic Prostate Cancer
Hormone-refractory metastatic prostate cancer remains a difficult clinical challenge. German researchers have investigated a different approach to this problem, and found that they could obtain remission in some patients.
In their small, multicenter, phase II study, 36 consecutive patients with metastatic hormone-refractory prostate cancer received both an anti-inflammatory and angiostatic regimen (low-dose chemotherapy with capecitabine 1g bid for 14 days every 3 wk, 15+; cyclo-oxygenase- 2 blockade with etoricoxib 60 mg/day, day 1+; combined with two transcription modulators, pioglitazone 60 mg/day, day 1+, plus dexamethasone 1 mg daily for 14 days, every 3 wk, day 15+) until disease progression.
Twenty-two patients had not received chemotherapy previously. Fourteen had, with a mean of 2.1 regimens. The researchers found objective responses in 10 cases, with prostate-specific antigen (PSA) (and C-reactive protein) level reductions better than 50%. The median time to PSA response was 2.4 months (range, 1.0—7.3 mo). Two patients who had PSA below 4 ng/mL achieved complete remission after nine and 16 months. Stable disease was attained in 16 cases, but the cancer progressed in five patients. The investigators reported a median progression- free survival (PFS) of 3.6 months (range, 0.5–28.5 mo) and median overall survival (OS) of 14.4 months (range, 0.6–37.2 mo).
The researchers, led by Albrecht Reichle, MD, PhD, of the University of Regenstadt, Germany, concluded that this is the first study demonstrating continuous complete remissions in hormone-refractory prostate cancer using a “biomodulatory therapy approach.”
Reichle A, et al: Induction of complete remission in metastatic hormone-refractory prostate cancer: A combined anti-inflammatory therapy approach. Presented at ASCO, June 3, 2007.
The NetherlandsGene Therapy in Esophageal Cancer: Which Adenoviruses Are Most Reliable?
The use of adenoviruses continues to hold promise in the transference of therapeutic genetic material to intended tissue. As therapeutic genes are actively being developed, work continues on how we deliver these genes to their intended targets. Gastroenterologists from the University Academic Medical Center, Amsterdam, The Netherlands, tested adenovirus subtypes to determine whether certain adenoviruses can better transfer their genetic material into esophageal cancer cells.
Transduction efficacy was assessed using flow cytometry. The GFP gene was used as a marker of transduction. Chimeras of adenoviral subtype 5, 16, 35, 40, and 50 were utilized for this test.
The investigators found that overall, transduction was efficiently achieved; however, serotype 16 and 50 revealed improved transduction. When attempting to do the same with cells affected by Barrett’s esophagus, the researchers found that transduction was limited.
They concluded that some specific adenoviral serotypes can be more effective than others in transmitting genetic material to target cells. This can have important implications for gene therapy for esophageal cancer.
Marsman WA, Wesseling JG, El Bouch A, et al: Adenoviral serotypes in gene therapy for esophageal Carcinoma
. J Surg Res
AustraliaNanotechnology a Better Way to Delivery Cancer Chemo to Target Cells?
In the 1980s, the leading edge of research on targeted drug delivery was the monoclonal antibody. In this decade, the leading edge seems to be nanotechnology, and this is now being applied to cancer therapeutics.
A Sydney, Australia firm, EnGenelC Ltd, has discovered a method of forcing bacteria to divide in such a way as to produce buds of encapsulated cytoplasm, into which different drugs can be packaged. Dubbed EnGenelC Delivery Vehicles or EDVs, they are able to selectively target tissues, linked to antibodies that attach to the cancer cell’s surface, such as the HER2 receptor. At 400 nm in size, the EDVs penetrate the tumor membrane. According to Himanshu Brahmbhatt, co-inventor, “within two hours of intravenous administration, greater than 30% of the dose ends up in the tumor microenvironment.”
Once incorporated into the tumor, the EDVs are broken down, releasing the attached drug. The researchers have tested the treatment using doxorubicin within the EDV in mice that were xenografted with human breast, leukemia, and ovarian tumors. The result were significant inhibition of tumor growth and progression compared with mice given intravenous doxorubicin.
It is hoped that use of these “bio-robots” will enable far lower doses of chemotherapy, with dramatically less toxic effects to healthy cells.
Geddes L: Mini-cells could stop side effects of chemotherapy. www.newscientist.com, May 7, 2007.
ItalyLenalidomide Combination Therapy May Improve Outcomes in Multiple Myeloma in Elderly Patients
The use of lenalidomide appears to be a promising addition to melphalan and prednisone therapy in older patient populations with multiple myeloma; but it may be limited by the occurrence of hepatotoxicities, cautioned investigators from the University of Torino, Italy.
After a single course of the triple combination therapy in elderly patients, the response rate was 53% compared with 48% after six courses of melphalan and prednisone alone. If the number of therapeutic cycles could be drastically reduced, the researchers believe that the incidence of adverse events in elderly treatment populations could be lowered.
This open-label trial comprised only 54 patients (median age, 71 yr). Patients received nine cycles of lenalidomide 5—10 mg/day for 21 days, combined with melphalan 0.18–0.25 mg/kg for four days and prednisone 2 mg/ kg for four days (q4–6wk). After completion, maintenance therapy with lenalidomide alone, at a dose of 10 mg/day was continued for 21 days every month. All patients took aspirin 100 mg/day to prevent thromboembolism.
After one year of taking the maximum tolerated dose of lenalidomide, researchers found partial responses in 82% of the subjects, including 48% who had at least a “very good partial remission” and 24% who demonstrated complete response. The reported one-year event-free and overall survivals were 92% and 100%, respectively.
At a median total follow-up of 22 months, the event-free survival rate for the triple therapy was 95%. However, these results were not without important adverse events. Among grade 3/4 adverse events were hematological toxicity (70%), nonhematological febrile neutropenia (9%), cutaneous rash (7%), and thromboembolism (6%)—two thirds of the thromboembolism events occurred after the patient discontinued aspirin prophylaxis.
The investigators concluded that these data must be confirmed by larger controlled investigations, but the preliminary data are very positive. Despite the high adverse effect rate, none of the patients in the trial suffered early death, and the response rate was very encouraging.
Palumbo A, et al: Oral melphalan, prednisone, and lenalidomide for elderly newly diagnosed myeloma patients. Presented at the 12th Congress of the European Hematology Society (EHA), Vienna, June 11, 2007.
GermanyCountering Evidence for Cognitive Deficit From Chemotherapy
Recently, reports of a “chemotherapy fog” have surfaced, in which patients with breast cancer complained of difficulty in performing cognitive tasks. A new study from Germany counters this assertion, performing cognitive tests before the start of chemotherapy and after chemotherapy was completed.
The investigators from Ludwig Maximillan University, Munich, Germany, tested 101 women with breast cancer who received neoadjuvant chemotherapy with epirubicin, paclitaxel, and cyclophosphamide. Each patient also received supportive therapy with darbepoetin.
Interestingly, the researchers found that cognitive decline occurred in 27% of patients but cognitive improvement was seen in 28% at the end of the chemotherapy cycles. Only one of 12 tests indicated any significant deterioration. Furthermore, the patients scored below test norms on five of 12 cognitive tests before beginning chemotherapy, as well as significantly higher than test norms on one test. The researchers cannot speculate as to whether the disease itself may predispose patients to cognitive difficulty, but the existence of such difficulties before administering chemotherapy may help explain the previous findings. They indicated that neither age, intelligence, nor other confounding factors might account for the change.
Based on these results, the link between chemotherapy for breast cancer and cognitive effects cannot be supported at this time, but further studies (including long-term investigations) will be needed before this question can be put to rest.
Hermelink K, Untch M, Lux MP, et al: Cognitive function during neoadjuvant chemotherapy for breast cancer: Results of a prospective, multicenter, longitudinal study