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Clinical Abstracts From OverseasSpain
Paclitaxel Improves Survival in Early Breast Cancer Though Hormone-Receptor Status not a Factor
Taxane drugs, when added to adjuvant chemotherapy, have been shown to increase survival in patients with metastatic breast cancer, but toxicity limits their utility. Spanish researchers from multiple centers tested whether paclitaxel added to standard adjuvant chemotherapy would improve outcomes in patients with early breast cancer and to determine whether a subset of patients could be identified in whom paclitaxel might be optimally effective.
A total of 1,246 women (median age, 50 yr) with early breast cancer who underwent surgical excision were randomized to receive either six 21-day cycles of fluorouracil, epirubicin, and cyclophosphamide (FEC) (632 pts) or FEC followed by weekly doses of paclitaxel (FEC-P), consisting of four 21-day cycles of FEC, three weeks of no treatment, and eight 1-week courses of paclitaxel (614 pts). All patients had at least one positive axillary lymph node of the minimum six removed during their primary curative surgery. Approximately 70% of both patient groups underwent radiation treatment. All patients with tumors positive for estrogen receptor, progesterone receptor, or both received tamoxifen therapy for five years after completion of their assigned regimens.
The investigators calculated the median relative dose intensities in the control and study groups to be at least 99%. Seventy-three women in the FEC-P group died compared with 95 in the FEC group. Their analysis revealed that patients administered paclitaxel had a 5-year disease-free survival of 78.5% compared with those receiving FEC who had a disease-free survival of 72.1% (P = .006). With multiple adjustments for such factors as lymph node involve, tumor size, age, histology, and others, they calculated a 23% reduced risk of relapse associated with paclitaxel use.
Although the researchers found that HER2 and hormone-receptor status was significantly associated with survival overall (HER2-positive patients had lower survival, hormone-receptor negatives had lower survival), they also found that the use of paclitaxel in patients with HER-2 amplification or hormone-receptor positivity did not predict greater survival. Therefore, a subset of patients in whom paclitaxel worked optimally could not be isolated based on these factors.
Martin M, Rodriguez-Lescure A, Ruiz A, et al: Randomized phase 3 trial of fluorouracil, epirubicin, and cyclophosphamide alone or followed by paclitaxel for early breast cancer
. J Natl Cancer Inst
Daily Multivitamin Use Associated With Greater Breast Density
A vitamin a day may be deemed beneficial by consumers, but a group of Canadian researchers fear that it may have a negative effect in terms of breast cancer risk. Breast density is considered to be a biomarker for increased breast cancer risk, and a link between vitamin use and greater breast tissue density may set off a few alarms, in light of the prevalence of multivitamin use.
The investigators recruited more than 1,600 pre- and post-menopausal women (split evenly) at the time of routine screening mammography to take part in the study, in which demographic characteristics were obtained, and lifestyle and behavioral habits were recorded during a telephone interview. Twenty-two percent of women reported multivitamin use (21% of premenopausal and 23% of postmenopausal women). When analyzing the data against the mammography results, the investigators found a trend for higher adjusted mean breast density among premenopausal women who were current multivitamin users ( = .009) compared with those who used them in the past or never used them. Duration of use did not seem to affect the findings.
The absolute difference in breast densities were relatively small (approximately 5 percentage points), but the evaluation revealed this to be a statistically significant difference. There is no information whether this degree of increased density is clinically significant, however. Furthermore, the researchers pointed out that no link between multivitamin use and breast tissue density could be found in post-menopausal women.
The authors recommend further study of this association before pre-menopausal women should be advised to stop taking multivitamins or that they should receive more frequent mammograms.
Berube S, Diorio C, Brisson J: Multivitamin- multimineral supplement use and mammographic breast density. Am J Clin Nutr
What an Effective Public Health Program Can Do
Regular prostate-specific antigen (PSA) screening for men in their 40s is recommended to enhance the early detection of prostate cancer. However, it is often not performed because of cost considerations, the worry that high PSA levels may result in false-positive tests and lead to unnecessary work-ups and biopsies, and simply because of patient noncompliance.
Austrian public health officials instituted a natural experiment in the state of Tyrol, providing free PSA screening to men between 45 and 75 years old, beginning in 1993. Throughout the country, PSA screening was encouraged and access increased. The researchers reported the results of a long-term follow-up, in which they compared the rates of prostate cancer in Tyrol with those of other Austrian states where the PSA screening was not free of charge.
The researchers found that 87% of all Tyrolean men had undergone at least one PSA screening since 1993. Until introduction of the program, only 11% of male residents underwent the screening test. Compared with cancer mortality rates from 1986 to 1990, they revealed the number of deaths from prostate cancer in the state were 54% lower than that extrapolated from the earlier analysis period. In contrast, the prostate cancer mortality in other Austrian states was 29% lower than expected ( = .001) (owing to the increased emphasis on PSA screenings, according to the researchers).,br>
They concluded the decline in prostate cancer deaths is most likely the result of earlier detection of tumors and effective treatment. They believe the removal of the cost barrier to obtaining screening, if it is readily available, will encourage many more men to take advantage of it.
Bartsch G, Horninger W, Klocker H, et al: Tyrol Prostate Cancer Demonstration Project: Early detection, treatment, outcome, incidence, and mortality.
Italy / Canada
Prostate Cancer Radiation Therapy and the Risk for New Tumors Locally
The use of beam radiation therapy for patients with early prostate cancer is considered a relatively safe approach in terms of harming other local organs. Previous reports of secondary tumors have been published, but not in a large study over a long follow-up. The results of a large multinational study indicate that suspicions of a higher risk of secondary tumors arising in these patients are confirmed, and it may have implications for continued surveillance of patients who have undergone external- beam radiation treatment.
Led by researchers from Canada, Italy, and the United States, data on 10,333 men with prostate cancer were retrospectively evaluated from an administrative database. Of these patients, 6,196 were treated with radical prostatectomy and 4,137 were given external-beam radiation therapy between 1983 and 2004.
Increased risk of secondary cancers related to external-beam radiation therapy compared with prostatectomyfor localized prostate cancer*
*Based on claims for surgical removals.
The rates of subsequent tumors in other organs were low in patients receiving radiation treatment, but it was significantly higher than in patients who underwent prostatectomy (Figure). The researchers revealed that 0.9% of patients undergoing radiation therapy had claims for cystectomy treatment for bladder cancer, 2.2% had surgery to remove colorectal cancers, and 0.8% had surgery to treat lung cancer. Compared with radical prostatectomy, the differences are all statistically significantly (P = .04, P = .02, and P = .02, respectively).
Although the use of pelvic beam radiation causing bladder or colorectal cancer is logical, why lung cancer should also be a risk is unknown. However, in light of these findings, it would not be unreasonable to consider external-beam radiation therapy in older patients with prostate cancer who are not good candidates for surgery, as their shorter life expectancy might render the possibility for new secondary tumors less of a risk than in younger patients.
Bhojani N, Jeldres C, Da Pozzo LF, et al: External- beam radiation therapy increases the rate of secondary malignancies relative to radical prostatectomy in men with prostate cancer. Presented at the 2008 annual meeting of the American Urological Association, Orlando, Florida, May 19, 2008.
Does Adding Cladribine Improve Low-Grade non-Hodgkin’s Lymphoma Outcomes
In patients not previously treated for low-grade B-cell non-Hodgkin’s lymphoma, usual chemotherapy includes cyclophosphamide, vincristine, and prednisone (CVP) (without rituximib and doxorubicin, which are ordinarily recommended as R-CHOP chemotherapy, for more aggressive forms). Polish researchers sought to improve patient outcomes by testing the use of cladribine, a product approved to treat hairy-cell leukemia in the United States, as part of the therapeutic regimen.
The investigators randomly assigned 197 patients to receive one of three chemotherapy options: (1) six monthly courses of cladribine therapy, (2) combined cladribine and cyclophosphamide treatment, or (3) the standard CVP regimen. This was not an intent-to-treat study; data from the 162 patients who completed the regimens were analyzed only.
The study results indicated that patients receiving the cladribine-only or cladribine—cyclophosphamide combination treatment were more likely to have an overall response than patients receiving CVP. Patients taking the cladribine–cyclophosphamide combination were 8.5 times more likely to have an overall response, and 14 times more likely to have a complete remission (Figure). Although progression- free survival was significantly improved (hazard ratio, 2.38; P < .0002) in patients taking cladribine- containing therapies, no significant differences could be ascertained for overall survival.
Comparing Three Regimens for the Treatment of Low-Grade non—Hodgkin’s Lymphoma
Cladribine + Cyclophosphamide
*Expressed as odds ratio of achieving, compared with CVP therapy.CVP = Cyclophosphamide, vincristine, and prednisone.
The cladribine and cyclophosphamide combination resulted in higher frequencies of neutropenia, anemia, and thrombocytopenia than those taking CVP, but this was not so for the cladribine-only group.
The researchers concluded that the use of cladribine or cladribine plus cyclophosphamide provided better treatment response rates than CVP in patients with low-grade non-Hodgkin’s lymphoma, and with acceptable toxicity.
Kalinka-Warzocha E, Wajs J, Lech-Maranda E, et al: Randomized comparison of cladribine alone or in combination with cyclophosphamide and cyclophosphamide, vincristine and prednisone in previously untreated low-grade B-cell non-Hodgkin lymphoma patients: Final report of the Polish Lymphoma Research Group. Cancer 2008; May 9 [Epub ahead of print].
Linking Arthritis Medications and Cancer
Recently, the Food and Drug Administration announced that it was investigating a possible link between tumor necrosis factor (TNF) inhibitors, such as etanercept or infliximab, used to treat rheumatoid arthritis or Crohn’s disease in children, with the development of cancer. The agency was focusing on approximately 30 reports of cancer in patients who had taken the drugs between 1998 and 2006. The fact that TNF inhibitors might theoretically result in cancer development, owing to their mechanism of action, is not truly surprising; however, a new report about one of the mainstays of arthritis treatments being associated with increased cancer development, did raise some eyebrows among the clinical community.
Methotrexate, a generically available agent that has been used in cancer treatment as well as a disease-modifying antirheumatic drug, has been also been linked with increased risk of cancer—this time in adults.
Researchers from Victoria, Australia, determined the risk of cancer in 459 patients with rheumatoid arthritis who received methotrexate before 1986 (when it was commonly used, before the approval of biologic agents). Comparing follow-up data obtained from the Victoria Cancer Registry for the period 1983 to 1998, for a total of 4,145 person-years of follow-up, the investigators found 73 malignancies during or after methotrexate therapy.
Statistical analysis revealed a 50% higher risk of malignancies compared with the general population, with a threefold risk of melanoma or lung cancer and a fivefold risk of non-Hodgkin’s lymphoma.
They conclude that patients receiving methotrexate for rheumatoid arthritis may be at higher relative risk for at least three types of cancer, and that increased screening efforts may be justified, particularly in Australia, where the risk for melanoma is relatively high among the general population.
Buchbinder R, Barber M, Heuzenroeder L, et al: Incidence of melanoma and other malignancies among rheumatoid arthritis patients treated with methotrexate.