- Pharmacotherapy. 2008 Nov;28(11):1354-73.
Dabigatran etexilate: an oral direct thrombin inhibitor for prophylaxis and treatment of thromboembolic diseases.
Baetz BE, Spinler SA.
Department of Pharmacy Practice and Pharmacy Administration, University of the Sciences in Philadelphia, PA 19104, USA.
As the only oral anticoagulation option available in the United States, warfarin use remains widespread. However, concerns of safety remain a substantial issue. Additional anticoagulation options include unfractionated heparin, low-molecular-weight heparins (e.g., enoxaparin, dalteparin, and tinzaparin), and the indirect-acting factor Xa inhibitor, fondaparinux. Direct thrombin inhibitors represent a newer class of anticoagulants used primarily in the treatment of heparin-induced thrombocytopenia and percutaneous coronary interventions. Three intravenous agents are currently available-lepirudin, bivalirudin, and argatroban-with an oral agent, dabigatran etexilate, undergoing clinical investigation. Dabigatran etexilate offers a rapid onset of action after oral administration, reaching peak plasma concentrations and onset of anticoagulant effect within 0.5-2 hours after administration. Studies have demonstrated linear pharmacokinetics, a linear relationship between ecarin clotting time and international normalized ratio, and no known clinically significant drug or food interactions. Dabigatran etexilate has been studied in clinical trials as prophylaxis for venous thromboembolism in patients undergoing total knee replacement or total hip replacement surgeries, as well as for stroke prevention in patients with atrial fibrillation. Dabigatran etexilate has demonstrated superiority and noninferiority to enoxaparin as prophylaxis for venous thromboembolism in patients undergoing orthopedic surgery, with the most frequent adverse effects being gastrointestinal complaints. Elevations in alanine aminotransferase concentrations were noted in small percentages of patients in both the dabigatran etexilate and enoxaparin groups, with no observed dose association. The overall rates of major bleeding were low, with minor bleeding commonly noted, often at surgical sites. Clinical trials of dabigatran etexilate in patients with atrial fibrillation are ongoing. Results of short-term efficacy and safety appear promising. Further research is needed regarding long-term safety and efficacy for other anticoagulation indications.
Σάββατο 20 Δεκεμβρίου 2008
TIME TO FORGET COUMAROL ANALOGUES? PRADAXA IS HERE
ALERT
Alert: A pharmacokinetic study shows that 10 out of 15 patients with moderate hepatic impairment and advanced solid tumours died during treatment or within 30 days of the last dose of erlotinib.
DIGOXIN AND BREAST CANCER
Digoxin Linked to Increased Risk of Breast Cancer
NEW YORK (Reuters Health) Dec 11 - Digoxin use appears to increase the risk of invasive breast cancer in postmenopausal women, according to results of a study published December 3rd online by Breast Cancer Research.
Dr. Thomas P. Ahern of Boston University in Boston, Massachusetts, and colleagues there and at Aarhus University Hospital in Denmark identified 5,565 postmenopausal women diagnosed with invasive breast cancer between 1991 and 2007, and matched them with 55,650 healthy controls.
The investigators estimated the odds ratio of breast cancer with digoxin use after adjusting for age, county of residence, use of anticoagulants, nonsteroidal anti-inflammatory agents (NSAIDs), aspirin, and hormone replacement therapy.
Dr. Ahern's team identified a history of digoxin use of at least one year's duration before the index date in 324 breast cancer cases (5.8%) and 2,546 controls (4.6%).
This translated to an adjusted odds ratio of 1.30 for breast cancer with digoxin use. The odds ratio "increased modestly with increasing duration of digoxin exposure," with an adjusted OR of 1.39 associated with 7-18 years of digoxin use.
"The association was robust to adjustment for age, receipt of hormone replacement therapy, co-prescribed drugs, and confounding by indication," the authors write.
Dr. Ahern and colleagues found no detection bias in screening mammography rates between cases and controls.
"While a number of laboratory studies of cardiac glycosides and female breast cancer have suggested protective effects, our results suggest that one specific cardiac glycoside, digoxin, moderately increases the incidence rate of breast cancer," Dr. Ahern and associates conclude.
GAP FROM SURGERY TO RADIOTHERAPY
Moderate Gap From Breast Cancer Surgery to Radiotherapy Advisable
NEW YORK (Reuters Health) Dec 11 - In women with early-stage breast cancer who are not receiving chemotherapy, intervals longer than 20 weeks from breast-conserving surgery to radiation therapy are associated with an inferior outcome, Canadian researchers report in an early on-line publication by the Journal of Clinical Oncology.
Dr. Ivo A. Olivotto of the British Columbia Cancer Agency - Vancouver Island Centre, Victoria, and colleagues studied data on more than 6400 women who had early stage breast cancer diagnosed between 1989 and 2003.
After a median follow-up of 7.5 years, the team found that various intervals ranging from 4 weeks up to a maximum of 20 weeks between surgery and radiation therapy had no significant effect on outcome.
However, the researchers report, "Participants who waited longer than 20 weeks had higher rates of local and distant recurrence and inferior breast cancer-specific survival compared with participants who started radiation therapy within 4 to 8 weeks of surgery."
On the other hand, say the investigators, "There is no evidence that hastening patients to start radiotherapy within 4 or even 12 weeks of breast-conserving surgery is necessary or helpful. At the same time, a cavalier attitude to the timing of radiotherapy is not appropriate or advocated."
Commenting on the findings, Dr. Olivotto told Reuters Health, "Women may be advised that they have time for the breast to heal and to gather information and make informed decisions, so they will be active partners in the cancer care planning."
A NEW FOLATE ANALOGUE
ASH 2008: Pralatrexate Shows Promise in Peripheral T-Cell Lymphoma
December 12, 2008 (San Francisco, California) — The investigational agent pralatrexate (Allos Therapeutics, Inc) shows promise in relapsed and refractory peripheral T-cell lymphoma, according to data presented here at the American Society of Hematology 50th Annual Meeting and Exposition. In this phase 2 trial, 27% of patients experienced either a complete or a partial response.
"Peripheral T-cell lymphomas are a particularly challenging form of non-Hodgkin's lymphoma," said lead author Owen A. O'Connor, MD, PhD, director of the Lymphoid Development and Malignancy Program and chief of the Lymphoma Service at the Herbert Irving Comprehensive Cancer Center at New York-Presbyterian Hospital and Columbia University Medical Center, in New York City.
"To date, combination conventional therapy regimens have fallen short and, more importantly, many patients receiving conventional therapy fail to respond," he explained. "So there is a need to develop new T-cell-centered therapy that will achieve remission and hopefully extend the life of these particular patients."
Peripheral T-cell lymphoma is an aggressive and relatively uncommon type of non-Hodgkin's lymphoma, with a generally poor prognosis. Thus far, there are no treatments approved the US Food and Drug Administration (FDA), either in the first-line or relapsed or refractory setting, and no consensus exists on the best therapeutic strategy for newly diagnosed or relapsed/refractory disease.
Pralatrexate, a folate analog inhibitor of dihydrofolate reductase, was granted orphan-drug designation and fast-track designation by the FDA for the treatment of patients with T-cell lymphoma, and was granted similar status in the European Union. It also recently received orphan-drug designation from the FDA for the treatment of diffuse large B cell and follicular lymphomas.
"Based on original work done by myself and colleagues at Memorial Sloan-Kettering Cancer Center and subsequently at Columbia University, we demonstrated in an early phase 1/phase 2 clinical trial that pralatrexate demonstrated efficacy in different types of non-Hodgkin's lymphomas and striking activity in patients with T-cell lymphoma," said Dr. O'Connor.
Responses Seen in Large Phase 2 Trial
Going forward with their preliminary data, an international phase 2 trial was designed to evaluate the safety and efficacy of pralatrexate in patients with relapsed or refractory peripheral T-cell lymphoma. PROPEL (Pralatrexate in Patients With Relapsed or Refractory Peripheral T-Cell Lymphoma) is the largest prospective study in patients with peripheral T-cell lymphoma, consisting of 115 patients. The single-group non-randomized open-label study was conducted in North America and Europe, and was developed under the FDA Special Protocol Assessment program.
All participants were heavily pretreated and had received a median of 3 previous systemic treatment regimens (range, 1–12); 18 patients (16%) had undergone an autologous stem-cell transplant.
Patients received weekly intravenous infusions of pralatrexate (30 mg/m2) for 6 or 7 weeks, along with vitamin B12 and folic acid supplementation, which has historically been shown to reduce the rate of adverse events associated with pralatrexate. The primary end point of the study was objective response rate, and secondary end points were duration of response, progression-free survival, and overall survival. Information on 109 patients was available for analysis.
Summary of Response Rates to Pralatrexate by Independent Central Review
| Best Response | n (%) |
| Complete response/partial response | 29 (27) |
| Complete response | 11 (10) |
| Partial response | 18 (17) |
| Stable disease | 23 (21) |
| Progressive disease | 40 (37) |
Of the patients who responded, 69% did so after receiving 1 cycle of therapy. The median duration of treatment in responding patients was 179 days at the time of this analysis, and the duration of response exceeded 3 months in 17 of 29 responders (59%), including 6 of the 17 patients who remain on treatment.
"Toxicities were what we had expected, based on prior clinical experience, and included mucositis and thrombocytopenia," said Dr. O'Connor. "There was very little grade 4 toxicity."
The most common grade 3 or 4 adverse events were thrombocytopenia (in 32% of patients), mucosal inflammation (in 21% of patients), neutropenia (in 20% of patients), and anemia (in 18% of patients).
Dr. O'Connor emphasized that 1 criterion of the study was that there was no limit on previous therapy. "Our results show that the drug has activity, and response was seen irrespective of the number of prior therapies," he said. "This suggests a lack of cross resistance between pralatrexate and other agents."
The patients in this study will continue to be followed and, on the basis of these results, pralatrexate-based combinations might provide a novel platform for future upfront T-cell treatment programs.
Data Early But Promising
"The data are early, as this is only a phase 2 trial, but there was a strong enough response to move it forward," commented Janet Burns, MD, professor of medicine in the Division of Hematology, Oncology, and Transplantation, at the University of Minnesota, in Minneapolis. "But this isn't quite a home run, and Dr. O'Connor knows that he will need to combine pralatrexate with other therapies."
However, it is exciting to see a potential new agent come on the market for peripheral T-cell lymphoma, she told Medscape Oncology. "We are learning more about the genetic signatures of T-cell lymphoma, and hopefully we can begin to develop therapies specific to this lymphoma subtype."
NEOADJUVANT TRASTUZUMAB
SABCS 2008: Neoadjuvant Trastuzumab Should Be a Standard for Locally Advanced Breast Cancer
December 12, 2008 (San Antonio, Texas) — Neoadjuvant use of trastuzumab (Herceptin, Roche) with chemotherapy for locally advanced HER2-positive breast cancer should become a new standard of treatment, say researchers presenting new data from a large phase 3 clinical trial here at the 31st Annual San Antonio Breast Cancer Symposium.
This would represent a new use for trastuzumab; so far it is approved for use only in the adjuvant setting. Physicians are already using trastuzumab before surgery, even though this is an off-label use, because there were dramatic results showing a benefit in the neoadjuvant setting from a previous smaller trial carried out at the MD Anderson Cancer Center, in Houston, Texas (J Clin Oncol. 2005;23:3676-3685).
This latest study is a phase 3 trial in 228 patients, partly funded by the manufacturer, and the results will likely be used in the submission for regulatory approval for a new indication. The final results of the trial, known as NOAH (Neo-Adjuvant Herceptin), were presented at the meeting by Luca Gianni, MD, from the Istituto Nazionale Tumori Milano, in Milan, Italy.
An Unmet Medical Need
Locally advanced breast cancer, which includes inflammatory breast cancer, is an area of unmet medical need, Dr. Gianni commented. It is a particularly aggressive form of the disease, with a prognosis of 3 to 6 years, compared with more than 10 years for other forms of breast cancer.
In the NOAH study, adding trastuzumab to chemotherapy containing an anthracycline and a taxane administered before surgery significantly improved event-free survival, Dr. Gianni reported. At a median follow-up of 3 years, event-free survival with the combination was 70%, compared with 53% for chemotherapy alone, so the relative risk for recurrence was almost halved (hazard ratio, 0.56; P = .006).
In addition, trastuzumab plus chemotherapy produced a complete pathologic response in nearly twice as many patients as chemotherapy alone (39% vs 20%; P = .002). The overall response rate was also significantly increased, to 89% with the combination vs 77% with chemotherapy alone (P = .02). There was a trend toward increased overall survival for the combination group, but this was not significant, and longer follow-up is needed, Dr. Gianni said.
All subgroups of patients benefited from the addition of trastuzumab, Dr. Gianni noted. The combination was superior to chemotherapy alone in patients with inflammatory breast cancer and in those with noninflammatory breast cancer, in those who were hormone-receptor positive and those who were hormone-receptor negative, and in those who had or did not have a complete pathologic response.
The combination of trastuzumab with chemotherapy in the neoadjuvant setting was well tolerated, with acceptable cardiac safety, Dr. Gianni commented.
"These data establish preoperative trastuzumab with chemotherapy as a standard treatment option in women with locally advanced HER2-positive breast cancer," Dr. Gianni concluded.
"It is a very reasonable alternative, I would say, for these patients," said Carlos Arteaga, MD, from Vanderbilt University, in Nashville, Tennessee, who moderated a press conference during the meeting. Physicians are already using trastuzumab in the neoadjuvant setting, he said. There are some patients who are treated with chemotherapy alone before surgery, and then have trastuzumab added on after surgery, but these are a minority. The previous study from the MD Anderson Cancer Center showed a 65% complete pathologic response rate with neoadjuvant trastuzumab and chemotherapy, which "is not too far from these latest results," he said. That result was so dramatic that the study was stopped early, he told Medscape Oncology.THIAZIDES AND DIABETES RISK
Potassium Changes Mediate Thiazide-Induced Diabetes
NEW YORK (Reuters Health) Dec 05 - The increased risk for diabetes in patients taking thiazide diuretics appears to be mediated by changes in serum potassium levels, according to a report in the December issue of Hypertension.
"It has been speculated for some time that potassium loss from the body due to diuretic use could lead to diabetes," lead author Dr. Tariq Shafi, from Johns Hopkins University, Baltimore, told Reuters Health. In the current study, "loss of potassium from the body with resulting lowering of potassium levels in blood explained most of the risk of diabetes from thiazides."
The results also indicated that if a patient does not develop diabetes within 1 year of starting thiazide therapy, then diabetes that develops afterward is likely not thiazide-induced.
The study featured an analysis of data on 3790 nondiabetic subjects enrolled in the Systolic Hypertension in Elderly Program, a randomized trial involving treatment with chlorthalidone or placebo. Diabetes was defined by use of antidiabetic agents, self report, fasting glucose of 126 mg/dL or higher, or a random glucose of 200 mg/dL or higher.
During 1 year of follow-up, chlorthalidone use doubled the risk of diabetes. After accounting for the change in potassium levels, the risk was markedly reduced, which supports a mediating effect.
Each 0.5-mEq/L drop in serum potassium was independently linked to a 45% increase in diabetes risk (p <>
As noted, beyond 1 year, chlorthalidone use was not significantly associated with diabetes risk, the report shows.
"Thiazide diuretics are very effective for control of blood pressure," Dr. Shafi emphasized. "Clinicians have been reluctant to use it for treatment of hypertension because of the risk of diabetes among other things. Our study suggests that taking adequate amounts of potassium, either in diet or as supplements, might prevent diabetes and will allow the use of these cheap and highly effective medications."
Nonetheless, data from randomized trials are needed to determine if, in fact, preventing potassium loss can cut the risk of diabetes, he said.
STEM CELL TRANSPLANT AND T-CELL LYMPHOMA
Stem Cell Transplant Effective Against Peripheral T-Cell Lymphomas
NEW YORK (Reuters Health) Dec 15 - Myeloablative therapy and autologous stem-cell transplantation may offer an effective strategy for the treatment of patients with peripheral T-cell lymphomas (PTCLs), German researchers report in an advance on-line publication in the Journal of Clinical Oncology.
"Early -- upfront - high-dose therapy with support of autologous stem cells is a promising approach for the rare and aggressive group of PTCLs," lead investigator Dr. Peter Reimer told Reuters Health.
Dr. Reimer of Wurzburg University Clinic and colleagues note that conventional chemotherapy leads to poor outcomes in these patients and no standard therapy for most PTCLs has yet been defined.
To investigate further, the researchers enrolled 83 PTCL patients who underwent 4 to 6 cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone. The patients who achieved complete or partial remission underwent myeloablative chemoradiation therapy and stem-cell transplantation.
Mainly because of progressive disease, only 55 of the 83 patients underwent autologous stem-cell transplant. At last follow-up, 23 of the 28 of the patients who did not undergo transplant had died.
After autologous stem-cell transplant, 48 of 55 patients had a complete response and 7 had a partial response. This gave an overall response rate in intention-to-treat analysis of 66%.
The estimated 3-year survival rate was 71% in patients who underwent autologous stem-cell transplant, compared with only 11% in patients who did not.
Despite these promising results, Dr. Reimer concludes that "the impact of this strategy can only be determined by a randomized trial that has to be done in cooperation with many other centers."
STEM CELL TRANSPLANT AND T-CELL LYMPHOMA
Stem Cell Transplant Effective Against Peripheral T-Cell Lymphomas
NEW YORK (Reuters Health) Dec 15 - Myeloablative therapy and autologous stem-cell transplantation may offer an effective strategy for the treatment of patients with peripheral T-cell lymphomas (PTCLs), German researchers report in an advance on-line publication in the Journal of Clinical Oncology.
"Early -- upfront - high-dose therapy with support of autologous stem cells is a promising approach for the rare and aggressive group of PTCLs," lead investigator Dr. Peter Reimer told Reuters Health.
Dr. Reimer of Wurzburg University Clinic and colleagues note that conventional chemotherapy leads to poor outcomes in these patients and no standard therapy for most PTCLs has yet been defined.
To investigate further, the researchers enrolled 83 PTCL patients who underwent 4 to 6 cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone. The patients who achieved complete or partial remission underwent myeloablative chemoradiation therapy and stem-cell transplantation.
Mainly because of progressive disease, only 55 of the 83 patients underwent autologous stem-cell transplant. At last follow-up, 23 of the 28 of the patients who did not undergo transplant had died.
After autologous stem-cell transplant, 48 of 55 patients had a complete response and 7 had a partial response. This gave an overall response rate in intention-to-treat analysis of 66%.
The estimated 3-year survival rate was 71% in patients who underwent autologous stem-cell transplant, compared with only 11% in patients who did not.
Despite these promising results, Dr. Reimer concludes that "the impact of this strategy can only be determined by a randomized trial that has to be done in cooperation with many other centers."
AI SOMEWHAT BETTER THAN TAMOXIFEN
SABCS 2008: AIs "Somewhat Better" Than Tamoxifen as Adjuvant Therapy for ER-Positive Breast Cancer
December 17, 2008 (San Antonio, Texas) — More evidence suggesting that aromatase inhibitors (AIs) have better efficacy than tamoxifen as adjuvant therapy for postmenopausal women with estrogen-receptor-positive breast cancer was presented here at the 31st Annual San Antonio Breast Cancer Symposium (SABCS). However, although the survival data are very similar, the toxicity profiles are quite distinct, and there is an enormous difference in the cost of the 2 approaches, experts pointed out.
"Tamoxifen is a very good drug, it just appears that the aromatase inhibitors are somewhat better," commented James Ingle, MD, director of the Breast Cancer Specialized Program of Research Excellence at the Mayo Clinic Cancer Center, in Rochester, Minnesota. He was presenting data from a new meta-analysis involving nearly 20,000 patients on behalf of the Aromatase Inhibitors Overview Group.
Both drug approaches reduce estrogen, but in different ways. Tamoxifen is a selective estrogen-receptor modulator that prevents estrogen from interacting with its receptor, whereas AIs act by inhibiting an enzyme involved in the synthesis of estrogen, and hence reduce levels of the hormone. Three AIs are currently marketed — anastrozole (Arimidex, AstraZeneca), exemestane (Aromasin, Pfizer), and letrozole (Femara, Novartis).
Both approaches have been shown to significantly reduce the rate of relapse in women with estrogen-receptor-positive breast cancer when used as adjuvant therapy, but evidence suggesting that AIs may be more effective than tamoxifen is mounting, as previously reported by Medscape Oncology.
"The aromatase inhibitors are usually a few percent better, especially for preventing relapse," when you consider all the data, Hyman Muss, MD, from the Vermont Cancer Center, in Burlington, who cochaired the session, commented to Medscape Oncology. This includes data both from head-on comparator trials and studies in which patients were switched over from one drug to another, he added.
"But when you look at the survival data, even in this huge meta-analysis, then the difference is very small," Dr. Muss pointed out. There are some concerns about the interpretation of the mortality data, he said, adding: "We don't know enough yet about mortality with the aromatase inhibitors."
Significant Reduction in Relapse of Breast Cancer
The meta-analysis that Dr. Ingle presented at the meeting was split into 2 parts:
- Cohort 1 consisted of data from monotherapy clinical trials that directly compared an AI to tamoxifen (9586 patients with a median follow-up of 5.9 years).
- Cohort 2 consisted of data from "switching" trials in which the patients on tamoxifen were switched to an AI after 2 or 3 years (9015 patients with a median follow-up of 3.9 years).
AIs produced significantly lower recurrence rates than tamoxifen in both cohorts, Dr. Ingle reported. The proportional reduction was 23% in cohort 1 and 29% in cohort 2. The absolute gains were 2.9% at 5 years and 3.9% at 8 years in cohort 1, and 3.1% at 3 years and 3.5% at 6 years in cohort 2.
In cohort 1, the proportional reductions were similar in the first 2 years and the last 3 years of treatment; there were further reductions beyond 5 years, but these were not significant, Dr. Ingle noted. In cohort 2, there were significantly greater reductions during the first 3 years of treatment than there were beyond the 3 years, he added.
"These findings raise the issue of value for longer AI therapy," he commented
There was no significant difference in breast cancer mortality between the 2 therapies in cohort 1 (there was a 1.1% benefit for AIs at 5 years, and 0.5% at 8 years). There was a significant reduction in breast cancer mortality for the AIs in cohort 2 (0.7% at 3 years and 1.6% at 6 years from treatment divergence), but as Dr. Ingle and several physicians in the audience pointed out, the gains were very small.
The fact that nonbreast cancer mortality and overall mortality were not higher with the AIs in either cohort is reassuring regarding their overall safety.
Dr. Ingle said the fact that nonbreast cancer mortality and overall mortality were not higher with the AIs in either cohort is "reassuring regarding their overall safety."
He also said that any efficacy gain had to be balanced against tolerability in each individual patient.
During the discussion period, a British doctor questioned the cost-effectiveness of using AIs instead of tamoxifen in light of the very small gain in mortality that was seen. Tamoxifen is now available as a generic, so is much cheaper than the branded AIs. In the United States, it's the difference between $5 and $300, Dr. Muss pointed out to Medscape Oncology.
Concerns Over Survival Data
In an interview, Dr. Muss elaborated on some of the concerns surrounding the mortality data, which he said were "not clean."
First, there is CYP2D6, Dr. Muss said, the enzyme that metabolizes tamoxifen to its active form. Between 5% and 10% of white women are deficient in this enzyme and are poor metabolizers of tamoxifen, and there is research to suggest that the drug is not effective in this patient population, as reported by Medscape Oncology.
So, in all the clinical trials, it could be that between 5% and 10% of women taking tamoxifen were not metabolizing it and the drug was ineffective, Dr. Muss said. Conversely, some of the women who were high metabolizers and who were responding to tamoxifen might have come off the drug early because of adverse effects. Both of these effects could introduce bias into the results, he pointed out.
There is the question of patient compliance with the 2 different approaches, Dr. Muss continued. He pointed at that in another presentation at the same session, results from the Tamoxifen Exemestane Adjuvant Multinational (TEAM) study reported noncompliance in 29% of women taking tamoxifen and in 19% of women taking AIs. This trial was just being reported, so data from it were not included in the meta-analysis, but there may be a similar issue with compliance in the other trials. "When you are looking at a difference of 10% between compliance with these drugs, and a difference of only 1% in survival, that may be due to chance," he commented. An intention-to-treat analysis would not take into account the patients who dropped out, he said.
AIs May Be a Better Choice
Overall, Dr. Muss said that he feels that AIs "may be a better choice," than tamoxifen, particularly for older patients, but he would be influenced more by toxicity than by efficacy.
Tamoxifen has 2 major adverse effects — blood clots and uterine cancer, Dr. Muss said. Thromboembolism is a major concern, because most women with breast cancer are older and have comorbidities, such as hypertension and vascular problems. Neither of these adverse effects are seen with AIs, although these drugs have their own problems, he commented. In particular, AIs are associated with aches and pains in the joints, which can be severe and pose major problems. "Some women say they are unable to walk," he noted, "and there is not much that can be done, [other than] maybe change to another aromatase inhibitor."
AIs also carry the risk for osteoporosis, but this can be monitored and countered with bisphosphonates, he pointed out. "Oncologists have become very good bone doctors . . . since these drugs have been around," Dr. Muss commented. Also, there is now some research suggesting that these drugs also have an effect on the breast cancer itself, he noted. (New data suggesting the bisphosphonate zoledronic acid has a direct anti-tumor effect was presented at the SABCS meeting, as recently reported by Medscape Oncology.)
AIs should be a part of the treatment for every postmenopausal woman, Dr. Muss said, as laid out in the American Society of Clinical Oncology guidelines. "But from where we sit today, it is not, to me, totally convincing that you have to start every patient on an aromatase inhibitor as initial endocrine adjuvant therapy."
"However, I would say that at some stage in the course of treatment, maybe 2 years later, and there are data for 5 years later, an aromatase inhibitor should be used as part of the patient's treatment," he said. The switching data show that there may be some survival advantage, he added.
A major question than remains, however, is how long such treatment should be continued, Dr. Muss said. "The overview analysis shows that most women who are treated with tamoxifen relapse after 5 years, so it may be that you have to continue women on endocrine therapy for many, many years to do the best you can." These studies are currently in progress, comparing 5 years of therapy with 10, and 10 years of therapy with 15, he noted.
IF YOU USE TAC USE 6 CYCLES
SABCS 2008: Six Cycles of Adjuvant Concurrent TAC Seems Optimal
December 18, 2008 (San Antonio, Texas) — In women with operable node-positive breast cancer, 6 cycles of concurrent therapy with docetaxel (Taxotere), doxorubicin (Adriamycin), and cyclophosphamide (TAC) seems optimal, based on the results of 2 studies presented here at the 31st Annual San Antonio Breast Cancer Symposium.
One of the studies, from the Breast Cancer International Research Group (BCIRG), led by Wolfgang Eiermann, MD, from the Red Cross Women's Hospital, in Munich, Germany, showed that 6 cycles of concurrent TAC was equivalent to 8 cycles of sequential adjuvant treatment with the same agents (AC-T) for disease-free survival, the primary end point of the study.
The other study, the National Surgical Adjuvant Breast and Bowel Project (NSABP), found that 4 cycles of concurrent TAC was inferior to sequential AC-T for overall survival and disease-free survival.
"This result, combined with the results from the Eiermann study, has huge implications for the length of treatment with this regimen," said NSABP B-30 principal investigator Sandra Swain, MD, from the Washington Cancer Institute, in Washington, DC.
"If you are going to use TAC, use 6 cycles," she summarized.
“The NSABP B30 study is important. . . . Giving TAC for 4 cycles was part of the experimental nature of this study, and these results indicate once again that duration matters within the context of each regimen we use — that you cant ‘skimp’ on the number of cycles,” said Kathy Albain, MD, from the Loyola University Chicago Cardinal Bernardin Cancer Center, in Illinois.
Dr. Swain explained the choice of TAC in the NSABP B-30 trial. "We chose TAC because it was being used [successfully] in metastatic disease at the time of the study design and was just being brought into the adjuvant setting." She also commented on the prominence of doxorubicin and docetaxel in the study, which was designed in 1997. "The idea was to combine the 2 most effective agents. And these were the 2 we thought to be most effective."
“The other important advance that TAC gave us historically was that it seems to be equally active in estrogen-receptor-positive and estrogen-receptor-negative disease,” added Dr. Albain.
Dr. Eiermann noted that because taxanes are already established as effective treatments in this patient population, the BCIRG, NSABP B-30, and a number of other studies are "second-generation" trials of taxanes to establish the optimal scheduling of the agents.
Interestingly, the NSABP B-30 trial is the "last major study" in breast cancer to use overall survival as a primary end point, said Dr. Swain.
"Survival as a primary end point doesn't happen anymore. It takes a lot longer and disease-free survival gives you a quicker answer," she said.
These 2 studies also serve as a reminder of the continuing importance of adjuvant chemotherapy treatment, said Dr. Swain. "Chemotherapy is very effective and we can't abandon it. This is especially true in younger women. We know for sure that chemotherapy is 1 of the factors in their increased survival [in multiple studies]."
AC-T: Higher Dose Density and 8 Cycles Not Enough
BCIRG involved 3298 women with axillary lymph-node-positive HER2-normal breast cancer who were evenly randomized to either TAC (75/50/500 mg/m2 every 3 weeks for 6 cycles), or AC (60/600 mg/m2 every 3 weeks for 4 cycles) followed by T (100 mg/m2 every 3 weeks for 4 cycles).
The study design consisted of 3 groups:
- AC-T: sequential therapy of doxorubicin and cyclophosphamide for 4 cycles, followed by docetaxel for 4 cycles
- AT: concurrent therapy of doxorubicin and docetaxel for 4 cycles
- TAC: concurrent therapy of docetaxel, doxorubicin, and cyclophosphamide for 4 cycles.
The disease-free survival between the TAC and AC-T groups was nearly identical. Followed for a median of 63 months, the 1649 women receiving TAC had 352 events and the 1649 women receiving AC-T had 356 events (hazard ratio [HR], 1.002; 95% confidence interval [CI], 0.86 - 1.16). Disease-free probability at 60 months was 78.9% for TAC and 78.6% for AC-T.
Overall survival, which was a secondary end point, slightly favored AC-T. There were 202 deaths among the 1649 women receiving TAC and 187 deaths among the 1649 women receiving AC-T (HR, 0.91; 95% CI, 0.75 - 1.11). Survival probability at 60 months was 88.9% for TAC and 88.1% for AC-T.
"Despite delivering higher dose density for each of the 3 agents and requiring 8 cycles, AC-T was not more effective than TAC," concluded Dr. Eiermann.
In terms of hematological adverse events, TAC had significantly more febrile neutropenia (17.9 vs 8.3%; P < .0001) and thrombocytopenia (2.5% vs 1.3%; P = .01). However, neutropenic infection (9.7% vs 8.5%; P = .25) and anemia (2.9% vs 2.0%; P = .25) were comparable.
“[TAC] does yield greater neutropenic events and infections, so when we use it (as I commonly do for many women with high-risk breast cancer), many choose to prophylactically give pegfilgrastim to support the white blood cell counts and prevent neutropenic events,” said Dr. Albain.
In terms of nonhematologic events, AC-T had significantly more neuropathy sensory (42.8% vs 27.5%; P < .0001), nail changes (44.5% vs 50.9%; P < .0001), and myalgia (50.9% vs 35.8%; P < .0001). For both regimens, the incidence of stomatitis was about 63%, and the incidence of nausea and vomiting (grade 3/4) was about 4%.
Baseline characteristics in BCIRG were well balanced, said Dr. Eiermann. A total of 47% of patients were younger than 50 years; 61% had 1 to 3 nodes; 82% had hormone-receptor-positive tumors; and 58% had tumors larger than 2 cm. For TAC, 93.5% of patients received the planned 6 cycles; for AC-T, 90.5% received the 8 cycles.
Half of All Women With Breast Cancer
The NSABP B-30 study population consisted of women of any menopausal status with stage I, II, or IIIA breast cancer and positive axillary lymph nodes. "These women represent about half of all women with breast cancer," noted Dr. Swain.
In this multicenter study, 5351 women were randomized to 1 of the 3 groups and followed for a median of 73 months:
- AC-T: doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 every 3 weeks for 4 cycles, followed by docetaxel 100 mg/m2 every 3 weeks for 4 cycles
- AT: doxorubicin 50 mg/m2 and docetaxel 75 mg/m2 every 3 weeks for 4 cycles
- TAC: doxorubicin 50 mg/m2, docetaxel 75 mg/m2, and cyclophosphamide 500 mg/m2 every 3 weeks for 4 cycles.
All patients with estrogen-receptor-positive and/or progesterone-receptor-positive tumors received hormonal therapy after completing chemotherapy.
There were a total of 803 deaths during the study. In terms of overall survival, mortality with AC-T was significantly decreased by 17%, compared with AT (P = .034), and was decreased by 14%, compared with TAC (P = .034), which is a marginal benefit, Dr. Swain commented. AT and TAC were comparable in terms of overall survival (P = .67).
There were a total of 1313 recurrences, and more than half were distant recurrences. "The fact that most were distant recurrences is typical of a study of this size and length. It's expected," said Dr. Swain.
In terms of disease-free survival, events with AC-T were significantly decreased by 17%, compared with TAC (P = .006), and were also significantly decreased by 20%, compared with AT (P = .001). AT and TAC were comparable in terms of disease-free survival (P = .58).
The women were also stratified according to the number of positive nodes (1 to 3, 4 to 9, or at least 10), sequential tamoxifen or anastrozole administration (yes or no), and type of prior surgery or radiotherapy plan (mastectomy with no local or regional radiotherapy; mastectomy with local and/or regional radiotherapy; lumpectomy with local radiotherapy; or lumpectomy with local and regional radiotherapy).
In an analysis of these stratifications with regard to disease-free survival, AC-T was superior to TAC and AT in every stratification category.
The most common toxicity was febrile neutropenia, affecting 22% of patients receiving AC-T, 16% receiving TAC, and 13% receiving AT. Other statistically significant toxicities were stomatitis (5% for AC-T, 1% for AT, and 2% for TAC) and infection (8% for AC-T, 6% for AT, and 6% for TAC). There were a total of 24 treatment-related deaths, and 12 of those were in the TAC group.
A very high percentage of women completed all of their cycles — 97% in both the AT and TAC groups. However, in the AC-T group, although 99% completed all cycles in the AC portion of the sequential regimen, only 86% completed the T portion.
There were somewhat more postmenopausal women (about 53%) than peri- or premenopausal women (about 46%) in the study; only 1% were of unknown menopausal status. Notably, 75% of the women were estrogen-receptor positive. Also, 66% had 1 to 3 positive nodes, 26% had 4 to 9, and 8% had 10 or more. With regard to surgery and radiation, 49% had lumpectomy, 51% mastectomy, and 24% local/regional radiotherapy. The mean tumor size was 2.5 cm.
Amenorrhea Improves Survival
The NSABP B-30 study also shows that women who have treatment-induced amenorrhea for 6 months or more have improved overall and disease-free survival, regardless of the regimen. "It's been thought for years that stopping the ovaries' production of estrogen improved survival. However, this is the first time that a study of this size prospectively evaluated menstrual history and showed this improved survival," explained Dr. Swain.
As part of the study, 2366 women had their menstrual history assessed before randomization, on day 1 of course 4, and at 6, 12, 18, and 24 months. Amenorrhea was defined as a cessation of menses for 6 or more months during this 24-month evaluation period at the front of the longer study.
Of the 1868 women with amenorrhea, 247 died (risk ratio, 0.76); of the 475 women with no amenorrhea, 103 died. The difference was statistically significant.
In terms of disease-free survival, of the 1868 women with amenorrhea, 424 experienced recurrence (risk ratio, 0.70). Of the 475 women with no amenorrhea, 173 experienced recurrence. The difference was statistically significant.
Dr. Swain suggested that clinicians who have patients receiving chemotherapy who do not have amenorrhea of 6 months or longer should seek a clinical trial. "The SOFT and TEXT trials are evaluating whether ovarian ablation, with either an aromatase inhibitor or tamoxifen, is beneficial," she said.
A NEW TUMOR SUPPRESSOR GENE
PTPRD a Strong Candidate for New Human Tumor Suppressor Gene
December 16, 2008 — A study of genes that contribute to glioblastoma multiforme (GBM) has found deletions in protein tyrosine phosphatase, receptor type D (PTPRD), in 14% of the GBM tumor samples. PTPRD mutations were also demonstrated in 12% of melanoma tumor samples. Published online December 15 in Cancer Research, the findings suggest that PTPRD fits the criteria for a tumor suppressor gene whose inactivation underlies many human cancers.
Cyclin-dependent kinase inhibitor 2A (CDKN2A) has been recognized as a tumor suppressor gene for more than a decade. However, although loss of heterozygosity on chromosome 9p has been reported in about 60% of melanomas, fewer than 10% of these demonstrated CDKN2A mutations. This raised the possibility that another tumor suppressor gene is also located on chromosome 9p. The present study found frequent PTPRD mutations or deletions in GBM tumor samples, making PTPRD a likely candidate for the "other" 9p tumor suppressor gene.
Senior author Todd Waldman, MD, PhD, associate professor of oncology, Lombardi Comprehensive Cancer Center, Georgetown University School of Medicine, Washington, DC, told Medscape Pathology & Lab Medicine in an email: "[W]e didn't start out looking for the 'other' tumor suppressor gene telomeric to CDKN2A/B. Rather, we started out looking for new tumor suppressors in GBM and found this one, which fits the criteria for the 'other' 9p tumor suppressor gene."
Using a panel of 58 GBM tumor samples, the investigators screened for alterations in gene copy numbers. Focal deletions (<10>CDKN2A/B (78% of samples) and CDKN2C (16% of samples) and were next most prevalent in PTPRD (14% of samples). Large-scale chromosomal loss (>10 Mb) of PTPRD occurred in 33% of the GBM tumor samples, second only to large-scale loss of PTEN in 55% of samples.
Because the "other" tumor suppressor gene on chromosome 9p had been proposed in studies of malignant melanoma, the investigators extended their study of PTPRD to melanoma tumor samples. Among 47 tumor samples, 7 samples showed PTPRD mutations (8 somatic missense mutations and 2 somatic nonsense mutations). The 12% mutation frequency for PTPRD is one of the higher rates reported for specific genes in melanoma. In addition, PTPRD mutations have recently been reported in lung and colon cancers.
For a functional assessment, viral vectors were used to restore expression of PTPRD protein in cultures of GBM and melanoma cells that had PTPRD mutations or deletions. Restoration of PTPRD expression resulted in lowered viability and growth inhibition in the tumor cells. The authors point out: "These are the first reported data indicating that PTPRD has growth-suppressive properties when expressed in human cancer cells, supporting the hypothesis that PTPRD is a bona fide human tumor suppressor gene."
Asked whether a similar restoration of function could work in a clinical setting, Dr. Waldman replied: "One of the major challenges in cancer biology is how to 'target' a loss of function event like mutation of PTPRD with new drugs, since most pharmacology is focused on designing inhibitors."
He continued, "Probably the most fruitful future strategy will be to identify a downstream 'gain of function' in the PTPRD pathway that we can then use for drug development efforts for the design of novel inhibitors. In an effort to identify such targets, we are now actively looking for the substrates of the PTPRD tyrosine phosphatase activity."
Victor Velculescu, MD, PhD, associate professor of oncology, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, also talked with Medscape Pathology & Lab Medicine by telephone about therapeutic approaches.
"PTPRD is a phosphatase," said Dr. Velculescu. "For every phosphatase, there has to be a complementary kinase — a kinase has to put a phosphate on a particular target molecule, and the phosphatase removes that phosphate. And so if the tyrosine phosphatase is being inactivated, that means that the phosphate remains on that molecule and the pathway is perhaps active more often."
Dr. Velculescu added, "You can imagine inhibiting the kinase because that must have an activating effect, as opposed to the inactivating effect of the phosphatase. So that could be a therapeutic modality which could result in the same effect that you saw with respect to reintroduction of PTPRD [in the cell cultures]. But it would be through the kinase," he said.
MYC ONCOGENE AND OVARIAN CANCER
Silencing MYC Oncogene Has Therapeutic Potential in Ovarian Cancer
NEW YORK (Reuters Health) Dec 15 - For growth and proliferation, ovarian cancer cells are "addicted" to a family of proteins produced by the oncogene MYC, according to research reported at the 48th annual meeting of the American Society for Cell Biology underway in San Francisco.
Importantly, lead researcher Dr. Tulsiram Prathapam told Reuters Health: "Our results suggest that inhibition of MYC and MYC family members will have significant therapeutic value in the treatment of ovarian cancer."
The MYC oncogene is amplified in 30% to 60% of human ovarian tumors, usually in the presence of extra copies of the MYC gene. In studying the role of MYC in ovarian cancer, Dr. Prathapam, cell biologist from University of California, Berkeley, and colleagues observed that MYC-amplified ovarian cancer cell lines are dependent on MYC expression for continued proliferation, whereas MYC non-amplified ovarian cancer cell lines are dependent on expression of MYC family members for continued proliferation.
"Strikingly," the team wrote in their meeting abstract, inhibition of MYC using RNA interference inhibited ovarian tumor cell proliferation only in MYC-amplified cell lines, and not in MYC non-amplified cell lines.
Further investigation revealed that MYC non-amplified ovarian tumor cells displayed elevated expression of other MYC isoforms (such as L-MYC and N-MYC) that rendered their proliferation independent of MYC.
The use of small-interfering RNA (siRNA) to silence all MYC isoforms led to growth arrest in the MYC non-amplified ovarian cancer cells, Dr. Prathapam and colleagues observed.
They also observed that blocking the MYC family of proteins in a culture of normal ovarian surface epithelial cells did not affect their ability to grow.
A logical next step, Dr. Prathapam noted, would be to see if MYC siRNAs block tumor cell growth in a mouse model of ovarian cancer.
GEMCITABINE AND CORONARY VASOSPASM
Med Princ Pract. 2009;18(1):76-80. Epub 2008 Dec 4. Related Articles, LinkOut
Gemcitabine-induced acute coronary syndrome: a case report.
Ozturk B, Tacoy G, Coskun U, Yaman E, Sahin G, Buyukberber S, Yildiz R, Kaya AO, Topal S, Ozdemir M, Benekli M.
Department of Medical Oncology, Gazi University Medical School, Ankara, Turkey.
OBJECTIVES: To report a case of metastatic leiomyosarcoma, in which a patient developed chest pain accompanied by acute left bundle-branch block (LBBB) after gemcitabine infusion. CLINICAL PRESENTATION AND INTERVENTION: A 59-year-old woman admitted with bilateral pulmonary nodules had classic risk factors for coronary heart disease and coronary stenosis as demonstrated by previous coronary angiography. She was treated with gemcitabine infusion, and 30 min later she experienced severe chest pain accompanied by acute LBBB confirmed by ECG. We suspected gemcitabine-induced coronary vasospasm exacerbated by the preexisting coronary artery disease as the cause of the acute coronary syndrome. The patient was subsequently treated with antianginal therapy and percutaneous coronary intervention. Her chest pain resolved and LBBB disappeared. She was discharged 2 days later without any further cardiac events. No additional cancer therapy was given and she died 5 months later, due to disease progression. CONCLUSION: This case showed that chemotherapeutic agents must be administered with intensive cardiac monitoring especially in patients with cardiac disease and well-known risk factors to prevent the development of cardiac complications, despite an agent not being known to be 'cardiotoxic'. Copyright 2008 S. Karger AG, Basel.
PROCALCITONIN AND ANTIBIOTIC USE
Procalcitonin to Guide Antibiotic Use in Primary Care
Summary
Respiratory tract infections (RTIs) are among the most common reasons for antibiotic prescription in primary care. A test that can differentiate between bacterial and viral RTIs could help to reduce antibiotic use. Procalcitonin (PCT) levels have been used as a marker for bacterial infection in hospitalized patients but have not been evaluated in the primary care setting. In a recent randomized trial, investigators in Switzerland (1 of whom received research support from the maker of the PCT assay used in the study) compared a PCT-guided approach with standard care among adult outpatients who had acute RTIs. All participants were believed — consistent with evidence-based guidelines — to require antibiotic treatment.
When PCT-arm patients had PCT levels >0.25 µg/L, a bacterial infection was considered likely, and antibiotic prescription was recommended; for lower levels, antibiotic prescription was discouraged. When antibiotics were withheld, a second PCT level was obtained within 6 to 24 hours. If the level was then >0.25 µg/L or had increased by >50% with no clinical improvement, antibiotics were recommended. In addition, all patients prescribed antibiotics based on PCT levels were reassessed after 3 days, and antibiotics were discontinued if the level was ≤0.25 µg/L. The primary outcome measure was the number of days in the first 2 weeks during which daily activities were restricted by an RTI.
Of 458 patients randomized, 455 were evaluated at 2 weeks. The antibiotic-prescription rate was significantly lower in the PCT arm than in the standard-care arm (25% vs. 97%). The number of RTI-restricted days and the rate of ongoing or relapsing infection at 28 days were similar between arms.
Comment
Using PCT level to guide antibiotic therapy for outpatients with RTIs dramatically reduced antibiotic use without increasing the risk for adverse outcomes. These results are even more striking considering that the study enrolled only patients who were believed to need antibiotics by physicians in a country where antibiotic-prescription rates are much lower than in the U.S. As an editorialist notes, wide adoption of this approach requires development of a rapid, accurate, and inexpensive office-based PCT test.
METRONOMIC CHEMOTHERAPY IN BREAST CANCER
- J Clin Oncol. 2008 Oct 20;26(30):4899-905. Epub 2008 Sep 15.
-
Metronomic cyclophosphamide and capecitabine combined with bevacizumab in advanced breast cancer.
Medical Senology Research Unit and Division of Medical Oncology, Department of Medicine, European Institute of Oncology, Milan, Italy.
PURPOSE: Metronomic chemotherapy has shown efficacy in patients with metastatic breast cancer. When used in association with targeted antiangiogenic drugs, it was more active than metronomic therapy alone in preclinical and clinical studies. PATIENTS AND METHODS: Patients with advanced breast cancer were candidates to receive metronomic oral capecitabine (500 mg thrice daily) and cyclophosphamide (50 mg daily) plus bevacizumab (10 mg/kg every 2 weeks). RESULTS: In 46 assessable patients, we observed one complete response (CR; 2%), 21 partial responses (PR; 46%), 19 patients (41%) with stable disease (SD), and five patients (11%) with progressive disease, for an overall response rate of 48% (95% CI, 33% to 63%). Additional long-term disease stabilization (SD > or = 24 weeks) occurred in eight patients, for an overall clinical benefit (CR + PR + SD > or = 24 weeks) of 68% (95% CI, 51% to 81%). Median time to progression was 42 weeks (95% CI, 26 to 72 weeks). Toxicity was generally mild. Grade 3 or 4 nonhematologic adverse effects included hypertension (n = 8), transaminitis (n = 2), and nausea/vomiting (n = 2). Higher baseline circulating endothelial cells (CECs) were correlated with overall response (P = .02), clinical benefit (P = .01), and improved progression-free survival (P = .04). CONCLUSION: Treatment with metronomic capecitabine and cyclophosphamide in combination with bevacizumab was effective in advanced breast cancer and was minimally toxic. The number of baseline CECs significantly correlated with response and outcome, therefore supporting further studies on this surrogate marker for the selection of patients to be candidates for antiangiogenic treatments.
PLERIXAFOR FOR STEM CELL MOBILIZATION
FDA Approves Plerixafor to Improve Stem Cell Mobilization for Autologous Transplantation
December 17, 2008 — The US Food and Drug Administration has approved plerixafor (Mozobil, Genzyme), a novel small-molecule CXCR4 chemokine antagonist that enhances mobilization of stem cells for autologous transplantation in patients with non-Hodgkin's lymphoma (NHL) and multiple myeloma (MM). Genzyme, the manufacturer, anticipates that the drug will be available in the United States in 2009.
"Mozobil is an important advancement in the treatment of patients with certain types of cancer who require a stem cell transplant," John F. DiPersio, MD, PhD, a professor at Washington University in St. Louis, Missouri, said in a news release. "This product should become an integral part of the treatment regimen for transplantation because of the benefits it offers to patients, physicians and transplant centers."
Plerixafor injection, which has also been granted orphan drug designation, is intended for use in combination with granulocyte-colony stimulating factor (G-CSF) to mobilize hematopoietic stem cells to the bloodstream, where they can be collected.
Autologous transplantation requires at least 2 million stem cells per kilogram of body weight, which may take 3 or 4 hours during multiple days in some patients, and other patients are not able to reach this goal.
"For many cancer patients, moving on to a transplant is their only hope for remission or a cure," Dr. DiPersio said.
Pivotal phase 3 trials showed that the number of stem cells mobilized for collection was significantly increased in patients receiving plerixafor vs current standard of care, and that the time needed for patients to mobilize sufficient numbers of stem cells for autologous transplantation was decreased.
The target number of at least 5 million stem cells/kg body weight in 4 or fewer apheresis sessions was achieved in 59% percent of patients with NHL who received plerixafor and G-CSF vs 20% of patients who received placebo. The median number of days to reach this target stem cell count was 3 days for patients receiving plerixafor and was not evaluable in the placebo group.
The target number of at least 6 million stem cells/kg of body weight collected in 2 or fewer apheresis sessions was achieved in 72% of patients with MM who received plerixafor and G-CSF compared with 34% of those who received placebo. The median number of days to reach this target cell count was 1 vs 4 days, respectively. At 12-month follow-up, the plerixafor plus G-CSF and placebo plus G-CSF groups had comparable graft durability rates.
By decreasing the number of apheresis days, plerixafor may also provide economic benefits for transplant centers. Plerixafor may also decrease the number of patients needing a second mobilization procedure because of failure to mobilize sufficient numbers of stem cells with G-CSF alone.
Additional therapeutic indications for plerixafor under development may include mobilization of hematopoietic stem cells in allogeneic stem cell transplants and tumor sensitization in adult myeloid leukemia and other hematological cancer.
Treatment with plerixafor should begin after the patient has received G-CSF once daily for 4 days, approximately 11 hours before starting apheresis, for up to 4 consecutive days. The recommended dose is 0.24 mg/kg body weight by subcutaneous injection. The dose should not exceed 40 mg/day, based on increasing exposure with increasing body weight. If creatinine clearance is 50 mL/min or less, the plerixafor dose should be decreased by one third to 0.16 mg/kg.Potential adverse effects of plerixafor may include tumor cell mobilization in leukemia patients, increased circulating leukocytes and decreased platelet counts, splenic enlargement, and fetal harm when given in pregnancy. Adverse reactions that were reported in more than 10% of patients who received plerixafor plus G-CSF and that occurred more often than in patients who received placebo were diarrhea, nausea, fatigue, injection site reactions, headache, arthralgia, dizziness, and vomiting.
COLONOSCOPY LEADS TO FEWER DEATHS
Colonoscopy May Be Associated With Fewer Colorectal Cancer Deaths
December 17, 2008 — Colonoscopy as performed in usual practice is associated with fewer deaths from colorectal cancer (CRC), primarily because of fewer deaths from cancer developing in the left side of the colon, according to the results of a population-based, case-control study reported in the December 15 Early Release issue of the Annals of Internal Medicine.
"Colonoscopy is advocated for screening and prevention of...CRC, but randomized trials supporting the benefit of this practice are not available," write Nancy N. Baxter, MD, PhD, from Li Ka Shing Knowledge Institute, St. Michael's Hospital; University Health Network and University of Toronto in Toronto, Ontario, Canada, and colleagues. "The accuracy of colonoscopy done in the real world is unknown but may be substantially less than that in published reports."
The goal of this study was to examine the association between colonoscopy and CRC deaths in a cohort from Ontario, Canada, of persons aged 52 to 90 years who were diagnosed with CRC from January 1996 to December 2001 and who died of CRC by December 2003. For each case patient, 5 control subjects were randomly selected, matched by age, sex, geographic location, and socioeconomic status.
Using administrative claims data, the investigators identified exposure to any colonoscopy and complete colonoscopy (to the cecum) from January 1992 to an index date 6 months before diagnosis in each case patient and the same assigned date in the matched control subjects. Conditional logistic regression controlling for comorbid conditions compared exposures in case patients (n = 10,292) and control subjects (n = 51,460), and secondary analyses determined whether associations differed by site of primary CRC, age, or sex.
Colonoscopy was performed in 719 case patients (7.0%) and 5031 control subjects (9.8%), with adjusted conditional odds ratio (OR) of having undergone any attempted colonoscopy of 0.69 for case patients vs control subjects (95% confidence interval [CI], 0.63 - 0.74; P < .001). For complete colonoscopy, adjusted conditional OR was 0.63 (95% CI, 0.57 - 0.69; P < .001).
Complete colonoscopy was strongly associated with fewer deaths from left-sided CRC (adjusted conditional OR, 0.33; 95% CI, 0.28 - 0.39). However, complete colonoscopy was not linked to fewer deaths from right-sided CRC (adjusted conditional OR, 0.99; 95% CI, 0.86 - 1.14).
"In usual practice, colonoscopy is associated with fewer deaths from CRC," the study authors write. "This association is primarily limited to deaths from cancer developing in the left side of the colon."
Limitations of this study were that screening could not be differentiated from diagnostic procedures, confounding by factors inadequately controlled for by matching or adjustment, inability to assess family history, inability to detect exposure to colonoscopy before 1991, and overall rate of colonoscopy low in case patients and control subjects.
"Although randomized, controlled trials with cancer death as the outcome are the gold standard for evaluating cancer screening, no such trial of screening colonoscopy is currently under way," the study authors conclude. "In an Ontario-wide sample, colonoscopy is associated with a reduced risk for death from CRC arising from the left colon but not from the right colon. Although improvements in the quality of screening colonoscopy may narrow this difference, differences in tumor biology may limit the potential to prevent right-sided colon cancer deaths with current endoscopic technology."
In an accompanying editorial, David F. Ransohoff, MD, from the University of North Carolina at Chapel Hill, suggests that unrealistic goals regarding prevention of CRC deaths with colonoscopy may lead to risks if they cause overuse of colonoscopy.
"Although colonoscopy is generally safe, it is still an invasive procedure with a 0.2% rate of serious complications — 10 times higher than for any other commonly used, cancer screening test," Dr. Ransohoff writes. "Colonoscopy is an effective intervention, but, as Baxter and colleagues suggest, we must realize that current evidence is indirect and does not support a claim of 90% effectiveness. Until we have better data, we can be grateful and optimistic to have a useful intervention to offer our patients, but we should be realistic and cautious when talking with them about the magnitude of both benefits and risks."
RADIOTHERAPY AND LYMPHADENECTOMY FOR EARLY ENDOMETRIAL CANCER
Pelvic Lymphadenectomy, Radiotherapy Should Not Be Used Routinely for Early Endometrial Cancer
December 16, 2008 — In women with early endometrial cancer, pelvic lymphadenectomy or external-beam radiotherapy provide no survival benefit and should not be used routinely, according to 2 studies reported in the December 13 Online First issue of The Lancet. One study showed no benefit of pelvic lymphadenectomy in overall or recurrence-free survival for women with early endometrial cancer, and the second study showed that adjuvant external-beam radiotherapy cannot be recommended as part of routine treatment for women with intermediate-risk or high-risk early-stage endometrial cancer with the aim of improving survival.
"Hysterectomy and bilateral salpingo-oophorectomy (BSO) is the standard surgery for stage I endometrial cancer," write H. Kitchener, from the University of Manchester, School of Cancer and Imaging Sciences in Manchester, United Kingdom, and colleagues from the writing committee of the Medical Research Council A Study in the Treatment of Endometrial Cancer (MRC ASTEC) study group. "Systematic pelvic lymphadenectomy has been used to establish whether there is extra-uterine disease and as a therapeutic procedure; however, randomised trials need to be done to assess therapeutic efficacy. The ASTEC surgical trial investigated whether pelvic lymphadenectomy could improve survival of women with endometrial cancer."
This trial, which took place at 85 centers in 4 countries, enrolled 1408 women with histologically proven endometrial carcinoma thought before surgery to be confined to the uterine corpus. With use of a minimization method, participants were randomly assigned 1:1 to undergo standard surgery (hysterectomy and BSO, peritoneal washings, and palpation of para-aortic nodes) or standard surgery plus pelvic lymphadenectomy (n = 704).
Overall survival was the main study endpoint, and analysis was by intent-to-treat. Median follow-up was 37 months (interquartile range, 24 - 58 months).
Women who had early-stage disease at intermediate or high risk for recurrence were randomly assigned, independent of lymph-node status, into the ASTEC radiotherapy trial, to control for postsurgical treatment.
Of 191 deaths at follow-up, 88 were in the standard surgery group and 103 in the lymphadenectomy group. Hazard ratio (HR) was 1.16 (95% confidence interval [CI], 0.87 - 1.54; P = .31) favoring standard surgery. Absolute difference in 5-year overall survival was 1% (95% CI, –4 to 6).
Of 251 women who died or had recurrent disease, 107 were in the standard surgery group and 144 in the lymphadenectomy group, yielding an HR of 1.35 favoring standard surgery (95% CI, 1.06 - 1.73; P =.017). Absolute difference in 5-year recurrence-free survival was 6% (95% CI, 1 - 12).
HR was 1.04 for overall survival (95% CI, 0.74 - 1.45; P = .83) and 1.25 for recurrence-free survival (95% CI, 0.93 - 1.66; P = .14), after adjustment for baseline characteristics and pathologic details.
"Our results show no evidence of benefit in terms of overall or recurrence-free survival for pelvic lymphadenectomy in women with early endometrial cancer," the study authors write. "Pelvic lymphadenectomy cannot be recommended as routine procedure for therapeutic purposes outside of clinical trials."
Limitations of this study were that the lymphadenectomy specified in the protocol was not comprehensive and did not include all pelvic and para-aortic nodes, and there was a possible failure to report mild lymphoedema (moderate and severe lymphoedema were worse in the lymphadenectomy group).
"The balance of risks and benefits for systematic lymphadenectomy does not favour this intervention, with no clear evidence of benefit in terms of overall or recurrence-free survival and increased risk of lymphoedema," the study authors conclude. "Although the results do not invalidate the use of lymphadenectomy for surgical staging to identify the need for adjuvant treatment, our results suggest that lymphadenectomy in itself has no therapeutic effect and is therefore not justified as a therapeutic procedure in its own right."
The second report was a systematic review and meta-analysis of pooled trial results from the ASTEC and EN.5 studies regarding adjuvant external-beam radiotherapy in the treatment of endometrial cancer.
"External beam radiotherapy added to surgery has been investigated in several small trials, which have mainly included women at intermediate risk of recurrence," write P. Blake, from Royal Marsden Hospital in London, United Kingdom, and colleagues. "In these trials, postoperative radiotherapy has been shown to reduce the risk of isolated local recurrence but there is no evidence that it improves recurrence-free or overall survival. We report the findings from the ASTEC and EN.5 trials, which investigated adjuvant external beam radiotherapy in women with early-stage disease and pathological features suggestive of intermediate or high risk of recurrence and death from endometrial cancer."
ASTEC (n = 789) and EN.5 (n = 116) enrolled 905 women with intermediate-risk or high-risk early-stage disease from 112 centers in the United Kingdom, Canada, Poland, Norway, New Zealand, Australia, and the United States. Between July 1996 and March 2005, participants were randomly assigned after surgery to observation (n = 453) or to external-beam radiotherapy (n = 452). The radiotherapy protocol specified a target dose of 40 to 46 Gy in 20 to 25 daily fractions to the pelvis, with treatment 5 times per week. Overall survival was the primary outcome measure, and all analyses were by intent-to-treat. Median follow-up was 58 months.
Of 135 deaths at follow-up, 68 were from the observation group and 67 were from the external-beam radiotherapy group. Overall survival was no better with external-beam radiotherapy vs observation (HR, 1.05; 95% CI, 0.75 - 1.48; P = .77). In both groups, 5-year overall survival was 84%. A meta-analysis of trials combining data from ASTEC and EN.5 confirmed that there was no benefit of external radiotherapy on overall survival (HR, 1.04; 95% CI, 0.84 - 1.29). In addition, the meta-analysis ruled out an absolute benefit of external-beam radiotherapy at 5 years of more than 3%.
At 5 years, the local recurrence rate in the observation group was 6.1%. It should be noted that in ASTEC and EN.5, brachytherapy was used in 53% of women.
"Adjuvant external beam radiotherapy cannot be recommended as part of routine treatment for women with intermediate-risk or high-risk early-stage endometrial cancer with the aim of improving survival," the study authors write. "The absolute benefit of external beam radiotherapy in preventing isolated local recurrence is small and is not without toxicity....Brachytherapy is a more convenient treatment than external beam radiotherapy and might be associated with less toxicity."
Limitations of the study include lack of central pathology review of specimens in ASTEC, and inability to draw firm conclusions about any possible interaction of lymphadenectomy and postoperative adjuvant external radiotherapy.
In an accompanying editorial, Michael Höckel and Nadja Dornhöfer, from the University of Leipzig in Leipzig, Germany, note that "less may be more" for most patients with early-stage endometrial cancer, and that "different may be better" for patients with high-risk tumors.
"Appropriate studies need to explore whether locoregional tumour control can be improved and distant metastases prevented by better surgery and different systemic therapies," Drs. Höckel and Dornhöfer write. "These could include first, for all cases, modified THBSO [total hysterectomy and bilateral salpingo-oophorectomy], including resection of the vaginal cuff with techniques that minimise tumour dissemination and endopelvic secondary healing. Second, for the preoperatively and intraoperatively identified high-risk cases, modified pelvic lymph-node dissection on the basis of embryologically defined pelvic visceroparietal compartmentalisation and complete inframesenteric and supramesenteric periaortic lymph-node dissection with resection of the infundibulopelvic ligaments."
"Third, for the postoperatively established high-risk cases, adjuvant chemotherapy. Paclitaxel-carboplatin seems to be an appropriate candidate combination," Drs. Höckel and Dornhöfer conclude. "Another important avenue of research should be the identification of high-risk cases in early-stage disease by molecular markers or gene signatures."
DIABETES AND CANCER MORTALITY
Preexisting Diabetes Boosts Risk for Mortality in Cancer Patients
December 16, 2008 — Cancer patients with preexisting diabetes at the time of their cancer diagnosis have an increased risk for death vs patients without diabetes. According to a meta-analysis reported in the December 17 issue of the Journal of the American Medical Association, diabetes was associated with an increased mortality hazard ratio (HR) of 1.41 across all cancer types.
December 16, 2008 — Cancer patients with preexisting diabetes at the time of their cancer diagnosis have an increased risk for death vs patients without diabetes. According to a meta-analysis reported in the December 17 issue of the Journal of the American Medical Association, diabetes was associated with an increased mortality hazard ratio (HR) of 1.41 across all cancer types.
Additional subanalysis of the data showed that preexisting diabetes was significantly associated with increased long-term, all-cause mortality for cancers of the endometrium (HR, 1.76), breast (HR, 1.61), and colorectum (HR, 1.32). The authors also found an association between diabetes and a nonsignificant increase in the risk for prostate, gastric, hepatocellular, lung, and pancreatic cancer.
At this time, it is difficult to speculate why diabetes has a higher association with all-cause death in certain cancers. "There are many possible reasons, and it's hard to say which one for each cancer," said senior author Frederick L. Brancati, MD, MHS, director of the Division of General Internal Medicine at Johns Hopkins Bloomberg School of Public Health in Baltimore, Maryland. "We're digging down into each cancer now to try to find out."
For clinicians, Dr. Brancati offers 2 suggestions. "Make certain that you're giving the most appropriately aggressive treatment you can, even in the presence of diabetes," he said. "And make sure the primary care physician stays engaged during and after cancer treatment to tend to diabetic control."
Possible Explanations for the Increased Risk
The researchers did offer several potential explanations for the association between increased all-cause mortality and preexisting diabetes in cancer patients. One was that a physiologic environment of hyperinsulinemia and hyperglycemia might cause greater tumor cell proliferation. A second possibility is that there may be differences in cancer treatment between patients with and without diabetes. Diabetic patients often have accompanying comorbidities, including ischemic heart disease, chronic kidney disease, and neuropathy, and these may influence clinical decisions regarding treatment.
A third reason, the researchers hypothesize, is that patients with preexisting diabetes may have a poorer response to cancer therapies, such as an increased risk for infection and intraoperative mortality. Fourth, individuals with preexisting diabetes might present with cancer at a more advanced stage because of suboptimal cancer screening practices. However, they note that in their analysis, stage at diagnosis did not appear to be a major explanatory factor.
A fifth reason could be that the diagnosis and treatment of cancer might distract both the patient and practitioner from the appropriate management of diabetes, such as controlling hyperglycemia, lipid levels, and blood pressure. Appropriate control of these factors has been proven to lower morbidity and mortality rates in adults with diabetes. Finally, the authors note that it is entirely possible that the excess mortality risk associated with diabetes is completely independent of cancer and accompanying cancer therapy.
"We embarked on the study because we were most concerned about diabetes care deteriorating during cancer treatment," Dr. Brancati told Medscape Oncology. "But after our systematic review, I think the other explanations are equally likely."
Additional Research Needed
It is estimated that 20 million Americans, or approximately 7% of the adult population, have diabetes. Previous studies have shown that some malignant tumors, including cancers of the breast, colorectum, endometrium, liver, and pancreas, occur more commonly in individuals with diabetes. In addition, there is a high prevalence of diabetes in newly diagnosed cancer patients, with estimates ranging from 8% to 18%.
However, the association of preexisting diabetes with long-term, all-cause death in cancer patients has not been systematically assessed. Dr. Brancati and colleagues identified 48 articles that met criteria for the study and included 23 studies in their meta-analysis, and studies reporting cumulative survival rates were summarized qualitatively.
The pooled data across 23 studies of various types of cancer showed that preexisting diabetes was associated with a higher risk for all-cause mortality vs patients without diabetes. Their estimate was robust across sensitivity analyses that took into account population source, diabetes and mortality ascertainment, and statistical adjustment.
Additional research is needed to determine the relative importance of the different pathways leading to the increased mortality risk associated with diabetesRADIATION FOR PROSTATE CANCER
Radiation With ADT Halves Deaths in Older Men With Prostate Cancer
December 16, 2008 — The first trial to show an overall survival advantage for radiotherapy in the primary treatment of prostate cancer has been published online December 16 in the Lancet. It also shows that for older men with locally advanced prostate cancer, adding radiation to androgen-deprivation therapy halves their risk of dying from the disease.
December 16, 2008 — The first trial to show an overall survival advantage for radiotherapy in the primary treatment of prostate cancer has been published online December 16 in the Lancet. It also shows that for older men with locally advanced prostate cancer, adding radiation to androgen-deprivation therapy halves their risk of dying from the disease.
The 10-year prostate-cancer-specific mortality in men treated with endocrine therapy alone was 11.9%, compared with 23.9% in men who received only endocrine therapy. The relative risk for cancer-specific death was 0.44 (P < .0001).
There was also a significant reduction in 10-year overall mortality: 29.6% in the combined-therapy group vs 39.4% in the endocrine-therapy group. The relative risk for overall death was 0.68 (P = .004).
These results come from the Scandinavian Prostate Cancer Group Study 7 (SPCG-7), also known as the Swedish Association for Urological Oncology-3 (SFUO-3) trial. The authors, headed by Anders Widmark, MD, professor of radiation oncology at Umeå University, in Sweden, say that endocrine therapy plus radiation should be the new standard of care for such patients.
The authors of an accompanying editorial agree. "Long-term hormonal therapy has long been regarded as the mainstay of treatment for men with locally advanced prostate cancer," write editorialists Chris Parker, MD, and Alex Tan, MD, from the Institute of Cancer Research, in Surrey, United Kingdom. "These results should change clinical practice," they say, so that long-term hormonal therapy plus radical radiotherapy becomes the new standard.
These results were first presented a few months ago at the American Society for Therapeutic Radiology and Oncology (ASTRO), as reported by Medscape Oncology. At the time, incoming president of ASTRO, Anthony Zietman, MD, from Massachusetts General Hospital, in Boston, predicted that these results would change clinical practice.
"At present, there is a bit of a fatalistic attitude toward locally advanced prostate cancer, as it is generally considered to have already quietly spread elsewhere," he commented. This attitude may be more common in Europe, but it is also prevalent in the United States. As a result, older men at this stage of the disease are often offered only hormonal therapy, he explained.
The thinking is that the cat is already out of the bag.
"The thinking is that the cat is already out of the bag," Dr. Zietman commented, but "the results from this trial prove that this is not the case."
Significant Superiority of Combination
The published results are exactly the same as those presented at the meeting, but now there are more details, plus an independent commentary.
The trial was conducted in 875 men at 47 centers in Norway, Sweden, and Denmark. The results are reported for a median follow-up of 7.6 years (range, 0.2 - 11.9 years). From these figures, the authors calculated cumulative incidence at 7 and 10 years.
Scandinavian Prostate Cancer Group Study 7: Comparison of Treatments
| Cause of death | Radiotherapy plus endocrine treatment | Endocrine treatment alone |
| Prostate cancer | 37/436 (8.5%) | 79/439 (18.0%) |
| Something other than cancer | 56/436 (12.8%) | 52/439 (11.8%) |
"The present study indicates a significant superiority of endocrine plus radiotherapy treatment compared with endocrine alone in patients with locally advanced prostate cancer," the authors conclude.
This is a "pivotal trial," the editorialists comment, adding that it is "the first to show an overall survival advantage for radiotherapy in the primary treatment of cancer."
More Adverse Effects With Combination
Patients who received the combination therapy had more adverse effects that were judged by physicians to be moderate or severe. At 5-year follow-up, significantly more patients who received both radiation and endocrine therapy had urinary incontinence, urgency, urethral stricture, and erectile dysfunction. In addition, patient-reported diarrhea was significantly more frequent at 4 years.
"Patient acceptability was high (over 85%) and the side effects of adding radiotherapy are acceptable in comparison to the survival gain achieved," Dr. Widmark and colleagues comment.
Hormone Therapy Used Was Unconventional
All patients were given endocrine treatment and total androgen blockade with the lutenizing hormone-releasing hormone agonist leuprorelin (Procren depot, Abbott) and the oral anti-androgen flutamide (Eulexin, Schering-Plough) for 3 months. After that, that flutamide was continued until progression or death. If anti-androgen adverse effects became evident, flutamide was stopped and then restarted at a lower dose; if this failed, patients were switched to bicalutamide.
"The hormonal therapy used in the trial is unconventional," the editorialists state, and there are no published data to show the efficacy of the regimen that was used, they point out. Standard hormonal therapy is with androgen deprivation alone, and bicalutamide monotherapy is generally regarded as an acceptable alternative.
"However, the regimen was the same in both groups of the trial, and one would envisage that the benefits seen for radiotherapy [in this trial] would also apply to patients on standard hormonal treatment," they add. This very issue is being examined in an ongoing trial, the National Cancer Institute of Canada Clinical Trials Group PR3 and Medical Research Council PR07 (NCIC PR3/MRC PRO7), and these results "will now be eagerly awaited."
Results Could Be Even Better With Modern Radiotherapy
According to the study authors, half of the patients were randomized to also receive radiation, administered by a standard 3-dimensional radiotherapy technique. A prescribed central dose (of 50 Gy) was applied to the prostate and seminal vesicles, and a sequential boost of at least 20 Gy was added to the prostate.
The trial was not blinded, which raises the possibility of bias, the editorialists comment. "It is at least plausible, though unlikely, that the investigators underplayed the toxic effects for patients in the radiotherapy group, treated them more intensively on relapse, and were less likely to attribute their deaths to prostate cancer."
"Although the physician-reported data for toxic effects must be viewed with caution," they continue, "there is no disguising the fact that radiotherapy led to improved overall survival, which is not just an important observation, but also an objective one."
"Indeed, it is possible that the trial could underestimate the true benefit of radiotherapy," the editorialists comment. The radiotherapy technique used was routine when the study was designed, they note, but "contemporary treatment with better methods of normal tissue avoidance, and thus higher doses to the prostate and pelvic lymph nodes, might be still more effective.
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