DO NOT USE OBSERVATION FOR PROSTATE CANCER PATIENTS YOUNGER THAN 65 YEARS OF AGE

May 5, 2011 — Radical prostatectomy appears to be a wise choice for men with early-stage prostate cancer who are younger than 65 years, according to new data from a Swedish randomized clinical trial that compares surgery with "watchful waiting."
The study shows that, at 15 years, the cumulative incidence of death from prostate cancer was 14.6% among 347 men randomized to prostatectomy and 20.7% among 348 men being observed without treatment.
However, the survival benefit was confined to men younger than 65 years of age, according to the study authors, led by Anna Bill-Axelson, MD PhD, from the University Hospital in Uppsala, Sweden.
For men older than 65 years, survival was highly similar in the 2 groups.
The new data from the ongoing Scandinavian Prostate Cancer Group Study Number 4 (SPCG-4) appear in the May 5 issue of the New England Journal of Medicine.
It has been conducted in men with predominantly symptom-detected early prostate cancer. All the men had clinical stage T1 or T2 disease, well or moderately well differentiated histologic findings, and a prostate-specific antigen (PSA) level of below 50 ng/mL.
"This is the best information we have to date on the extent to which treatment will influence outcomes in men with early prostate cancer," said H. Ballentine Carter, MD, from Johns Hopkins University in Baltimore, Maryland. Dr. Carter was not involved with the study and was approached for comment by Medscape Medical News.
However, the results do not rule out the value of watchful waiting or active surveillance, said Dr. Carter.
"The study strongly supports the role of treatment and the role of surveillance," he said.
The results from this study indicate that a patient's age — and related life expectancy — are apparently pivotal to receiving benefit from watchful waiting in early prostate cancer, Dr. Carter explained.
He interpreted the study findings for clinicians and patients.
"If you are young and have a long life expectancy — 15 years or more — then you need to be treated for prostate cancer," he said, adding that this even applies to men with very-low- or low-risk prostate cancer.
"If you are an older man — 65 to 70 years old — and you have low- or very-low-risk disease, your first consideration should be whether or not treatment is necessary," he pointed out. Such men should "consider being monitored."
Dr. Carter described the randomized controlled trial as a "very, very important paper," saying it was "very carefully done" research.
The fact that Dr. Carter advocates for possible surveillance among certain older men is in keeping with what he knows from his own experience.
He is the senior author of a recently published study of 769 men enrolled initially in active surveillance in which there have been no known prostate-cancer-specific deaths after an average follow-up of about 3 years.
"This study offers the most conclusive evidence to date that active surveillance may be the preferred option for the vast majority of older men diagnosed with a very low-grade or small-volume form of prostate cancer," he said about his study.
Men With Low-Risk Disease Also Benefited From Treatment
SPCG-4 enrolled men from 1989 to 1999; they now have a median follow-up of 12.8 years, which allowed the authors to make 15-year estimates.
The study authors had previously shown that radical prostatectomy provided a survival benefit as well as a reduction in the risk for metastases (J Natl Cancer Inst. 2008;100:1144-1154). The updated data continue to show these benefits, but over a longer period of time.
The "most important new finding" from SPCG-4 is that a subgroup of men with low-risk disease received a survival benefit from radical prostatectomy, said Matthew Smith, MD, PhD, in an editorial accompanying the study. Dr. Smith is a radiation oncologist at the Massachusetts General Hospital Cancer Center in Boston.
Low risk was defined as a PSA level of less than 10 ng/mL and a tumor with a Gleason score of less than 7 or a World Health Organization grade of 1 in the preoperative biopsy specimens. There were a total of 124 men in the radical-prostatectomy group and 139 in the watchful-waiting group who qualified as low risk.
With respect to death from prostate cancer among these low-risk men, the absolute between-group difference at 15 years was 4.2% points (6.8% for the radical-prostatectomy group vs 11.0% for the watchful-waiting group). This corresponds to a relative risk of 0.53 (95% confidence interval, 0.24 to 1.14; P = .14), according to the authors.
This survival benefit for the low-risk men who received surgery might, however, not be "relevant" for many men who have low-risk prostate cancer detected today, Dr. Smith points out.
That is because most of the men in SPCG-4 had cancers detected on the basis of symptoms rather than by elevated PSA levels.
To illustrate what differences can arise out of these varying methods of detection, Dr. Smith notes that, in SPCG-4, the number needed to treat with prostatectomy to prevent 1 death at 15 years was 15. "The predicted number needed to treat is substantially greater for contemporary men with low-risk prostate cancers detected by PSA screening because the rates of death from prostate cancer are lower in this group," he writes.
Surgery Benefit Only in Younger Men: Novelty Questioned
The study authors say that their finding that only younger men benefited from surgery is novel in the literature. "The finding that the effect of radical prostatectomy is modified by age has not been confirmed in other studies of radical prostatectomy or external-beam radiation" they point out.
They suspect that, contrary to their findings to date, surgery might have some survival benefit for some older men.
"The apparent lack of effect in men older than 65 years of age should be interpreted with caution because, owing to a lack of power, the subgroup analyses may falsely dismiss differences," they write.
The data have hints that surgery has a positive effect in at least some older men, they say.
"At 15 years, there was a trend toward a difference between the 2 groups in the development of metastases," they write about the watchful-waiting and surgery groups.
The study stipulated that men treated with surgery who progressed should receive hormonal therapy (as opposed to observed men who progressed — they received surgery). That might have allowed some men to die from other diseases, say the authors. "Therefore, competing risks of death may blur the long-term effects of treatment," they write.
This study was supported by grants from the Swedish Cancer Society and the National Institutes of Health. One of the coauthors reports serving on the advisory board of Pfizer and receiving lecture fees from Astellas. The other authors have disclosed no relevant financial relationships.
N Engl J Med. 2011;364:1708-1717, 1770-1772. Bill-Axelson et al abstract, Smith abstract

PAM50-ANOTHER GENOMIC TEST FOR BREAST CANCER PROGNOSIS

May 5, 2011 — Several genomic tests for use in breast cancer are now available, but how they compare and relate to one another remains a "clinical challenge for practicing physicians," according to a researcher who set out to evaluate 2 of these products in the same patients
"This is the first study to compare 2 standardized, readily available but conceptually different prognostic risk predictors," said Catherine Kelly, MD, from the Mater Misericordiae University Hospital, Dublin, Ireland.
The trial compared the widely used Oncotype DX test with the recently launched PAM50 test in a cohort of 119 breast cancer patients.
Presenting the results today at the IMPAKT Breast Cancer Conference in Brussels, Belgium, she said: "The results indicate that there is reasonably good agreement between the 2 methods for high and low prognostic risk assignment."
However, the intermediate-risk groups showed discordant results. About half of the patients who were categorized as intermediate risk by the Oncotype DX test were categorized as low risk by the PAM50 test.
This could save some women from undergoing chemotherapy, noted another expert. Speaking during a press briefing, Nadia Harbeck, MD, from the University of Cologne, Germany, who is executive chair of IMPAKT 2011, said that the intermediate-risk result from the Oncotype DX test "makes us feel insecure."
Clinicians use the Oncotype DX test to help them decide on treatment, she explained. When the test identifies a women as being at high risk for breast cancer recurrence, it is recommended that she undergo both chemotherapy and endocrine therapy; a low-risk result leads to treatment with endocrine therapy only. The intermediate-risk result presents a dilemma.
"Personally, I would rather treat than not treat these women, if they want maximum security from their breast cancer," Dr. Harbeck said.
However, these new results suggest that the second test, PAM50, could recategorize this intermediate group and identify women who are at low risk. "Maybe there is a role for combining these tests," she said. "They may complement one another."
Dr. Kelly cautioned, however, that there are no outcome data as yet, and that the PAM50 test has only recently been launched and is still undergoing validation.
"This new test potentially adds information, and this is interesting and potentially useful information, but we don't have outcome data," she emphasized. "Outcome data are required to show which test is getting it right."
Patients Who Present a Quandary
The study was conducted in breast cancer patients who would present a quandary for clinicians considering adjuvant therapy after surgery. All of the 119 patients were classified by researchers as having a "clinically intermediate" risk for recurrence on the basis of several criteria: a median tumor size of 1.5 cm; and estrogen-receptor-positive, HER2-negative, lymph-node-negative disease, most of which was grade 2.
"In other words, these patients would likely be a challenge in terms of whether they would benefit from chemotherapy or not," Dr. Kelly explained.
"In these situations, multigene assays can provide additional independent prognostic information," she added. Both tests were used on samples taken from all women (and were both conducted on paraffin-embedded tissue).
Oncotype DX measures the activity of 21 genes and generates a recurrence score that categorizes women into high-, intermediate-, and low-risk groups, depending on the risk for distant metastases.
PAM50 measures the activity of 50 genes and stratifies breast cancer into 5 subtypes: luminal A, luminal B, basal-like, HER2-enriched, and normal-like. The luminal A subtype is considered to be low risk for recurrence, and patients with this subtype and negative lymph nodes can forego chemotherapy, Dr. Kelly explained. In comparison, the luminal B subtype is at higher risk for recurrence, she added.
The results from the study showed that all patients who were categorized as high risk by the Oncotype DX test were categorized as the luminal B or basal-like subtype by the PAM50 test (both considered to be higher risk).
In addition, the majority of patients (83%) who were categorized as low risk by Oncotype DX were categorized as the luminal A subtype (low risk) by the PAM50 test.
However, half of the patients (51%) who were categorized as intermediate risk by Oncotype DX were categorized as the low-risk luminal A subtype on the PAM50 test.
There was other discordance between the tests. Not all of the cancers that were categorized by PAM50 as being of the luminal A subtype (hence, low risk) were categorized as low risk by Oncotype DX; this test determined that 70% were low risk but 30% were intermediate risk.
Commenting on the study, which he was not involved in, Roberto Labianca, MD, from the Ospedali Riuniti de Bergamo, Italy, said: "The data with PAM50 are very interesting, because they indicate that in the intermediate-risk group (as defined by the well-established Oncotype DX test), it is possible to exclude additional patients from adjuvant chemotherapy."
"However, a validation of these findings in a larger population is mandatory before they can be translated into clinical practice," he added.
IMPAKT Breast Cancer Conference: Abstract 82O. Presented May 5, 2011.

PRTON BASED RADIOTHERAPY PROVIDES LOCAL CURE FOR OSTEOSRACOMA

NEW YORK (Reuters Health) Apr 29 - Proton-based radiotherapy provides local control for 5 years in nearly three-quarters of patients with unresectable or incompletely resected osteosarcoma, according to a report in the March 29th online Cancer.
"Osteosarcomas arising in the axial spine, pelvis, or skull have traditionally been very difficult to treat," Dr. Thomas F. DeLaney from Massachusetts General Hospital, Boston, told Reuters Health in an email. "They require high radiation doses for local tumor control. Protons, with no exit radiation dose beyond the tumor, allow high-dose radiation, in combination with chemotherapy, while sufficiently sparing normal tissue to control some of the challenging osteosarcomas."
The cost of proton-based radiotherapy, Dr. DeLaney said, "is higher in the short term, but may be less expensive than IMRT photons in the long run because of fewer treatment-associated late effects, i.e., cardiac, second tumors, etc."
Dr. DeLaney and colleagues reviewed their entire series of 55 patients who were treated with proton therapy for osteosarcoma between 1983 and 2009.
The median age of the patients was 29 years, and the median follow-up was 27 months.
Twenty-seven patients (49.1%) underwent surgery and had positive surgical margins, and surgeon's notes indicated that five other patients (9.1%) had residual disease. The remaining 23 patients had surgery consisting of biopsy only or minor resection with residual gross tumor.
Twenty-two patients (40%) received proton-based radiotherapy doses between 60 Gy and 70 Gy, and 28 patients (50.1%) received total doses of 70 Gy or more. Five patients (9.1%) received doses below 60 Gy.
Local control rates were 82% at 3 years and 72% at 5 years, and there were no relapses in the 12 patients with grade 1 disease.
Ten patients failed within the treatment field, including eight of 22 patients with osteosarcoma of the bones of the skull. Eleven patients experienced distant failure (10 of these had grade 2 or higher disease).
Disease-free survival was 68% at 2 years and 65% at 5 years, and overall survival was 84% at 2 years and 67% at 5 years.
Twelve patients experienced grade 1 toxicity, 12 patients experienced grade 2 toxicity, and 17 patients experienced grade 3 or 4 toxicity. Two patients died from treatment-related malignancies 1.5 years and nearly 16 years after successful treatment of their osteosarcoma.
"Proton therapy is especially suitable for young patients with osteosarcoma, in whom reductions in the integral dose to nontarget tissue is important to minimize the risk to normal tissue development and of secondary malignancies," the researchers note.
As far as alternatives to proton-based radiotherapy, Dr. DeLaney said, "Patients could get 3D or IMRT (intensity-modulated radiotherapy) photons, which would likely be associated with higher acute and late morbidity, especially in young patients who are the majority of osteosarcoma patients. There is also some experience with radioisotopes such as samarium, but usually not curative."

FINDING OVARIAN CANCER FAST MAY NOT HELP SURVIVAL

NEW YORK (Reuters Health) May 03 - Once a woman begins experiencing symptoms of ovarian cancer, getting diagnosed and treated quickly may not help her survive longer, according to a new study of Australian women.
The finding is discouraging, researchers say, especially because doctors have believed that catching more cases of ovarian cancer early may help extend how long women live after diagnosis.
Ovarian cancer kills the majority of women with the disease within 5 years.
The results, published in the Journal of Clinical Oncology online May 2 "do not mean that women who have persistent symptoms that might be due to ovarian cancer should not seek immediate medical attention," Dr. Christina Nagle, the study's lead author from the Queensland Institute of Medical Research in Australia, told Reuters Health.
"Presenting promptly will help ensure that they are appropriately referred and can then make informed choices about their treatment," she said in an email.
Dr. Nagle and her colleagues followed almost 1,500 Australian women who were diagnosed with ovarian cancer between 2002 and 2005. The researchers interviewed the women about their symptoms and when they first went to the doctor and were diagnosed with cancer, then continued to track the participants for the next 5 years.
Most of the women had symptoms before they were diagnosed -- in the others, cancer was caught at a routine check-up or during surgery for a different condition.
In women with symptoms, about 40% went to their doctors and were examined and diagnosed with ovarian cancer within 2 months of when the symptoms started. Within 3 months, about 60% of women had been diagnosed, and 6 months after symptoms began, 80% had been diagnosed.
Women whose cancer was picked up before symptoms started survived longer than those who had symptoms. For example, in all women with late-stage cancer, those without symptoms lived an average of 4 years after their diagnosis, compared to 3 years in women with symptoms.
But among those who did have invasive, symptomatic cancer, survival didn't depend on how soon they saw their doctor.
Fifty-two percent of women who were diagnosed within 1 month of their first symptoms survived for the next 5 years, compared to 53% of women who took more than a year to be diagnosed.
Dr. Nagle said that her team suspects that once cancer is advanced enough to cause symptoms, it may be too late for treatment to help most patients live longer.
According to the National Cancer Institute, about 22,000 new cases of ovarian cancer were diagnosed last year.

EXENTERATION AS ALTERNATIVE TO CHEMORADIATION FOR LOCALLY ADVANCED CERVICAL CANCER?

NEW YORK (Reuters Health) May 04 - In certain patients with locally advanced cervical cancer, exenteration is an effective primary treatment, German researchers report in an April 7th online paper in the American Journal of Obstetrics and Gynecology.
"Exenteration can be an alternative to radiotherapy in cases of advanced cervical carcinoma. Especially when the tumor has not yet spread to the local lymph nodes, long term results are very good and patients should be offered this alternative therapy," Dr. Dirk Michael Forner told Reuters Health by email.
Dr. Forner and Dr. Bjoern Lampe of Florence Nightingale Hospital, Dusseldorf, note that although exenteration is an established approach in recurrent cervical carcinoma, it's not often performed for primary locally advanced cervical cancer.
Opinions are divided on its value, and they point out that a recent study showed that about half of surveyed German physicians would consider such use -- far more than was true of their US counterparts.
To gain more information, the team retrospectively studied data on all 35 patients who underwent a pelvic exenteration for primary cervical cancer at their institution over a period of 10 years. All operations were performed by the authors.
In 20 patients, pelvic lymph nodes were involved, and in six of these, metastatic tissue had reached the para-aortal nodes. Patients with positive lymph nodes received adjuvant radiochemotherapy.
After surgery, 34 patients (97%) were macroscopically free of tumor. This was confirmed microscopically in 30 patients (86%).
After a median follow-up of more than 5 years, median disease-free survival was 21 months and overall survival was 30 months. The probability of 5-year survival was 43%.
Median survival was greater in patients who underwent complete resection compared to those who did not (47% versus less than 10%).
Prognosis was also significantly better in patients with negative lymph nodes. Median overall survival was 44 months compared to 15 months in positive patients. Their probability of 5-year survival was 70% compared to 15%.
Pelvic lymph node involvement, the researchers observe, was the only factor significantly affecting overall survival.
"Pelvic exenteration is a treatment option that shows good long-term results and an acceptable perioperative risk," they conclude.
"When the tumor can be fully resected and there is no spread to lymph nodes or distant metastases," the investigators add, the results "are at least equivalent to those of chemoradiation."

SURGERY AND RADIATION FOR ANORECTAL MELANOMA

NEW YORK (Reuters Health) Apr 29 - A sphincter-sparing local excision plus hypofractionated radiation therapy is well tolerated and effective for patients with rare anorectal melanomas, according to doctors who recently reported on 2 decades of using this approach.
The "vast majority" of patients with anorectal melanoma die of distant metastasis within 2 to 3 years of diagnosis - but in the authors' series of 54 patients, nearly two-thirds were alive at 2 years and a third were still alive at 5 years, according to a March 28th online report in Cancer.
Lead author Dr. Patrick Kelly and colleagues from The University of Texas MD Anderson Cancer Center in Houston had previously reported initial success with their combination of sphincter-sparing wide local excision plus adjuvant hypofractionated radiation therapy for localized anorectal melanoma. In this report, they update their 20-year experience with this approach in 54 patients.
"It is our clinical practice to recommend adjuvant radiation therapy after patients undergo negative-margin surgical resection of a primary anorectal melanoma," the researchers say.
By the time of final analysis, 39 patients (72%) had relapsed and 42 (78%) had died, with a median overall survival of 29 months.
The actuarial disease-specific survival rates were 60% at 2 years and 32% at 5 years, and the actuarial overall survival rates were 59% at 2 years and 30% at 5 years.
On multivariate analysis, the only factor that significantly predicted worse disease-specific survival and overall survival was lymph node involvement, which was also the only significant predictor of distant metastasis.
The local disease control rate was 85% at 2 years and 82% at 5 years. Only two patients required a permanent colostomy.
Although the actuarial rate of lymph node relapse was 12% at 2 years, no patient experienced an isolated lymph node relapse. All lymph node relapses occurred in association with local recurrence or distant relapse.
Treatment was generally well tolerated, and surgical complications were uncommon. Nearly half the patients (26 patients, 48%) had late complications associated with radiation therapy (16 mild, 9 moderate, 1 severe).
"Because the outcome for patients with anorectal melanoma is determined by distant disease recurrence, further progress in the care of these patients likely will come from improved systemic therapies that address the risk of distant disease," the investigators conclude.

NO PROTECTION OF LHRHa ON OVARIAN FUNCTION FOR BREAST CANCER PATIENTS RECEIVING CHEMOTHERAPY

J Clin Oncol. 2011 May 2. [Epub ahead of print]

Effect of Luteinizing Hormone-Releasing Hormone Agonist on Ovarian Function After Modern Adjuvant Breast Cancer Chemotherapy: The GBG 37 ZORO Study.

Gerber B, von Minckwitz G, Stehle H, Reimer T, Felberbaum R, Maass N, Fischer D, Sommer HL, Conrad B, Ortmann O, Fehm T, Rezai M, Mehta K, Loibl S.

Source

University of Rostock, Rostock; German Breast Group, Neu-Isenburg; Vinzenz-von-Paul-Kliniken, Marienhospital, Stuttgart; Klinikum Kempten Oberallgäu, Kempten; Universitätsklinikum Schleswig-Holstein, Campus Kiel, Kiel; Universitätsklinikum Schleswig-Holstein, Campus Lübeck, Lübeck; Klinikum der Ludwig-Maximilians-Universität, Women's Hospital Maistrasse, Munich; Kassel Elisabeth Krankenhaus, Breast Centre, Kassel; University of Regensburg, Regensburg; University Women's Hospital, Tübingen; and Luisenkrankenhaus, Düsseldorf, Germany.

Abstract

PURPOSE Observational studies suggested that luteinizing hormone-releasing hormone agonists (LHRHa) might prevent premature ovarian failure resulting from adjuvant chemotherapy in premenopausal patients. We aimed to test the efficacy of ovarian function preservation with the LHRHa goserelin in patients with breast cancer. PATIENTS AND METHODS In a prospective, randomized, open-label, controlled multicenter study, 60 patients younger than age 46 years with hormone-insensitive breast cancer were allocated to receive anthracycline/cyclophosphamide (with or without taxane) -based neoadjuvant chemotherapy with or without goserelin. The first goserelin injection was administered at least 2 weeks before the first chemotherapy cycle, continuing at 3.6 mg subcutaneously every 4 weeks until the end of the last cycle. The primary objective was the reappearance of normal ovarian function, defined as two consecutive menstrual periods within 21 to 35 days at 6 months after end of chemotherapy. Results Fifty-three patients (88.3%) experienced temporary amenorrhea (93.3% with v 83.3% without goserelin). No significant difference was observed regarding the reappearance of menstruation at 6 months after chemotherapy (70.0% with v 56.7% without goserelin; difference of 13.3%; 95% CI, -10.85 to 37.45; P = .284). All but one evaluable patient reported regular menses at 2 years after chemotherapy. Time to restoration of menstruation was 6.8 months (95% CI, 5.2 to 8.4) with goserelin and 6.1 months (95% CI, 5.3 to 6.8) without goserelin (P = .304). Chemotherapy resulted in a decreased ovarian reserve measured by inhibin B and anti-Müllerian hormone during follow-up, supporting the other findings. CONCLUSION Premenopausal patients with breast cancer receiving goserelin simultaneously with modern neoadjuvant chemotherapy did not experience statistically significantly less amenorrhea 6 months after end of chemotherapy compared with those receiving chemotherapy alone.

GEMCITABINE ADDED TO CISPALTIN CHEMORADIOTHERAPY FOR CERVICAL CANCER IMPROVES SURVIVAL

May 4, 2011 — Adding gemcitabine to cisplatin chemoradiotherapy, compared with the current standard of care, improves survival outcomes for patients with locally advanced cervical cancer, according to the results of a large international trial.
Among patients who received gemcitabine, a statistically significant benefit was observed for the 3 main survival end points: progression-free survival at 3 years, overall progression-free survival, and overall survival.
The results of this study were initially presented at the 2009 meeting of the American Society of Clinical Oncology (ASCO), and were reported by Medscape Medical News at that time. The study was published in the May 1 issue of the Journal of Clinical Oncology.
In an accompanying editorial, Gillian Thomas, MD, from the Sunnybrook Odette Cancer Centre, University of Toronto, Ontario, Canada, says that this trial is an important addition to the field. She also congratulates the researchers on completing the study "undoubtedly under some difficult circumstances," as it was conducted in 8 developing nations (Argentina, Bosnia and Herzegovina, India, Mexico, Pakistan, Panama, Peru, and Thailand).
"This study represents clear evidence that large phase 3 randomized controlled trials can be conducted in a rapid fashion in the developing world if sufficient commitment, expertise, and financial support is available in countries where the disease is so rampant," Dr. Thomas notes.
It also highlights the importance of using therapies that are accessible and affordable in the developing world, she explains.
Limitations and Unanswered Questions
Although the results of this study are encouraging, with the authors reporting a 9% improvement in progression-free survival at the fixed time point of 3 years of follow-up, Dr. Thomas points out that there are limitations.
"It is impossible to understand the actual impact of this more intense and toxic therapy on long-term overall survival from the data provided," she notes. It is also unclear whether the treatment in the study group "simply delayed recurrence or cured more patients."
She points out that since accrual was completed 6 years ago, sufficient time has elapsed that if further follow-up had been conducted, an accurate assessment of overall survival rates could have been reported.
"The trial does not explain the possible mechanisms by which the observed gain in progression-free survival was achieved," she adds.
Dr. Thomas cites a number of questions raised by this study. Can patients with stage IIB and stage III disease also benefit from this combination therapy? Is the contribution of gemcitabine specifically unique, or could agents with less toxicity also be considered?
"It is currently unclear whether this new treatment, specifically with gemcitabine and cisplatin, will be widely implemented without confirmatory studies to determine the magnitude and relative benefits of intensifying pelvic treatment and adding further systemic therapy," she writes.
Improved Survival End Points
In this study, led by Alfonso Dueñas-González, MD, PhD, a cancer researcher at the National Cancer Institute of Mexico and the Instituto of Biomedical Research UNAM in Mexico City, 515 chemotherapy- and radiotherapy-naive patients with stage IIB to IVA disease were randomly assigned to 1 of 2 study groups.
Patients in the gemcitabine group received cisplatin 40 mg/m² and gemcitabine 125 mg/m² weekly for 6 weeks with concurrent external-beam radiotherapy 50.4 Gy in 28 fractions, followed by brachytherapy 30 to 35 Gy in 96 hours, and then 2 adjuvant 21-day cycles of cisplatin 50 mg/m² on day 1, plus gemcitabine 1000 mg/m² on days 1 and 8).
Patients in the standard-therapy group received cisplatin and concurrent external-beam radiotherapy followed by brachytherapy only (dosing was the same as in the gemcitabine group).
At 3 years, progression-free survival was 74.4% with gemcitabine and 65.0% with standard therapy (P = .029).
The authors also observed that patients in the gemcitabine group had improved overall progression-free survival, compared with the standard-therapy group (hazard ratio [HR], 0.68; P = .0227), and improved overall survival (HR, 0.68; P = .0224). Time to disease progression was also superior in the gemcitabine group (HR, 0.54; P = .0012).
The tumor response rate was 95.8% in the gemcitabine group and 93.4% in the standard-therapy group; the between-treatment difference was not statistically significant (P = .249).
Higher Toxicity
The incidence of grade 3/4 toxicities was significantly higher in the gemcitabine group than in the standard-therapy group (86.5% vs 46.3%). In the gemcitabine group, 2 patients died of causes that were probably related to their treatment; in the standard-therapy group, no patients died.
"As expected, the addition of a second therapeutic agent increased hematologic and nonhematologic toxicities," said Dr. Dueñas-González during his presentation at ASCO. "However, the rates of grade 3/4 events were low overall and considered to be clinically acceptable and manageable."
"Further studies are required to define optimal patient selection for this combination and to delineate the specific contributions of multiagent chemoradiotherapy and adjuvant chemotherapy phases to survival outcomes," the authors conclude.
The study was funded by Eli Lilly. Several of the authors report a financial relationship with Eli Lilly, as noted in the paper.
J Clin Oncol. 2011;29:1654-1656, 1678-1685. Thomas full text, Dueñas-González et al abstract

CONTROVERSY FOR SCREENING MAMMOGRAPHY BETWEEN 40-49 CONTINUES

May 4, 2011 (Washington, DC) — Breast tumors that are detected on screening mammography in women between 40 and 49 years of age are smaller and are less likely to have nodal metastases compared with tumors found on physical examination. Results of a study showing this were presented here at the American Society of Breast Surgeons (ASBrS) 12th Annual Meeting.
Paul Dale, MD, from the University of Missouri, Columbia, and colleagues found that breast tumors detected on screening mammography in women between the ages of 40 and 49 years were significantly smaller, at approximately 2 cm, compared with breast tumors identified by physical exam, at approximately 3 cm (P < .0001). Sentinel lymph nodes were also positive in only 25% of tumors detected on screening mammography compared with 56% of tumors detected on clinical examination (P < .0001).
At 5 years, 94% of women whose breast cancer was detected on screening mammography were still free of disease compared with 71% of those whose tumors were not detected by mammography, whereas overall survival (OS) at 5 years was also higher, at 97% in the mammographically detected tumor group compared with 78% for the nonmammographically detected group.
"The revised Preventative Service Task Force [USPSTF] mammography guidelines exclude women between 40 and 49 from routine mammography and will potentially result in later disease diagnosis and poorer survival rates for this age group of women," Dr. Dale said at a press conference here. "Our study found that tumors identified through mammography generally had better outcomes after treatment than those found through clinical exams."
Systematically Reviewed
For the study, investigators identified women between the ages of 40 and 49 years who were treated for breast cancer at their tertiary care center between 1998 and 2008. Women were divided into those who had mammographically detected cancers or cancers that were detected clinically, not by mammographic screening. Of some 1581 women treated for breast cancer at the tertiary center during the 10-year study interval, 320 women, or 20% overall, were between the ages of 40 to 49 years, as Dr. Dale pointed out.
Nine patients were excluded from the study because of incomplete records, leaving 145 women who had mammographically detected cancers and 166 women who had nonmammographically detected cancers.
Table.

	Mammographically Detected Cancers (n = 145)	Nonmammographically Detected Cancers (n = 166)
Tumor size (mm)	20.68	30.38
SLN positive	24.7%	55.9%
5-year DFS	94%	71%
5-year OS	97%	78%

Related Study
In a related study, Sharon Lum, MD, from the Loma Linda University School of Medicine in California, identified 46,691 patients between the ages of 40 and 74 years who were diagnosed with ductal carcinoma in situ (DCIS) or early invasive breast cancer (T1N0) between 2004 and 2008. Both DCIS and T1N0 breast tumors are more likely to be detected on screening mammography, as Dr. Lum pointed out. All patients had records in the California Cancer Registry.
Of this large cohort, 22.6% of patients were between the ages of 40 to 49 years, whereas 77.4% were between the ages of 50 to 74 years, "meaning that nearly one quarter of women in our study population would have been excluded from screening mammography [because of their age]," Dr. Lum added.
Results showed that women between the ages of 40 and 49 years who had DCIS were more likely to have hormone receptor–positive breast cancer compared with women between the ages of 50 and 74 years.
Younger women with T1N0 also were more likely to have hormone receptor–positive tumors compared with older women, as well as to be HER-2 positive than older women and to have triple-negative disease. Dr. Lum also observed that younger women with DCIS were more likely to be of Hispanic and Asian/Pacific Islander race or ethnicity, whereas those with early invasive tumors were also more likely to be from a Hispanic, non-Hispanic black, or Asian/Pacific Islander background.
Odds Ratios for Women Aged 40 to 49 Years vs Women Aged 50 to 74 Years

	DCIS	TIN0
Hormone receptor positive	1.85	1.43
HER-2 positive	NA	1.46
Triple negative	NA	1.67
Hispanic	1.62	1.82
Asian/Pacific Islander	1.50	1.66

"Excluding 40- to 49-year-old women from screening could impact on the early diagnosis of hormone receptor–positive, HER-2, and triple-negative breast cancer and potentially lead to lost opportunities for targeted therapies in early-stage disease," Dr. Lum emphasized. "[A]nd the adoption of these recommendations would disproportionally affect nonwhite women and potentially lead to a more advanced stage [of] disease at the time of presentation."
In commenting on both studies, American Society of Breast Surgeons' Spokesperson Deanna Attai, MD, from the Center For Breast Care, Inc, in Burbank, California, told Medscape Medical News that society cannot ignore the fact that women between the ages of 40 and 49 years develop breast cancer at a not-insignificant rate.
"We are not talking of 1 or 2 patients here, we are talking about a fair number of patients. What was striking was that investigators really did show that women who did not undergo mammography had larger tumors, were more likely to have positive lymph nodes, and had poorer overall survival," she said.
"I think this is important news, and we are going to see more and more studies coming out that will continue to show the benefit of screening mammography in younger women," Dr. Attai said.
The American Cancer Society, the American College of Surgeons, and the American Society of Breast Surgeons all continue to recommend routine screening mammography for women older than 40 years.
Despite this, a study to be presented at the American Roentgen Ray Society 2011 Annual Meeting has found that the USPSTF recommendations have already begun to affect the number of yearly mammograms done in women between 40 and 49 years of age. Compared with the previous year, Lara Hardesty, MD, from the University of Colorado in Denver, counted 205 fewer women in the 40- to 49-year age group who underwent screening mammography in the 9 months after the USPSTF guidelines.
"We must continue to get the message out to our patients and make sure that referring providers understand our recommendations because they are the ones who are influencing patients in that age group," Dr. Hardesty said in a news release.
Partial support for Dr. Lum's study came from the National Cancer Institute. Dr. Dale, Dr. Lum, and Dr. Attai have disclosed no relevant financial relationships.
American Society of Breast Surgeons (ASBrS) 12th Annual Meeting: Abstracts 1670 and 1754. Presented April 29, 2011.

NILOTINIB BETTER THAN DASATINIB FOR CML?

Curr Med Res Opin. 2011 Apr 28. [Epub ahead of print]

Comparative efficacy of nilotinib and dasatinib in newly diagnosed chronic myeloid leukemia: a matching-adjusted indirect comparison of randomized trials.

Signorovitch JE, Wu EQ, Betts KA, Parikh K, Kantor E, Guo A, Bollu VK, Williams D, Wei LJ, Deangelo DJ.

Source

Analysis Group , Boston, MA , USA.

Abstract

Abstract Objective: Nilotinib and dasatinib have not been directly compared in a randomized trial for the treatment of newly diagnosed chronic myeloid leukemia in the chronic phase (CML-CP). The purpose of this study was to indirectly compare rates of major molecular response (MMR), progression-free survival (PFS) and overall survival by month 12 with nilotinib and dasatinib treatment of newly diagnosed CML-CP. Methods: Individual patient data from a randomized trial of nilotinib vs. imatinib (ENESTnd) and published summary data from a separate randomized trial of dasatinib vs. imatinib (DASISION) were utilized. A matching-adjusted indirect comparison was conducted by weighting individual patients treated with nilotinib to match baseline characteristics reported for dasatinib-treated patients, including age, gender, ECOG performance status and hematology lab values. After matching, efficacy outcomes were compared for patients treated with nilotinib 300 mg twice daily vs. dasatinib 100 mg once daily. Patients randomized to imatinib 400 mg once daily in each trial were used to assess the adequacy of the matching. Results: Before matching, patients randomized to nilotinib in ENESTnd (n = 273) were older, with a lower median platelet count and more favorable performance status compared to patients randomized to dasatinib in DASISION (n = 259). After matching, all baseline characteristics were balanced across treatment groups. Matched patients treated with nilotinib vs. dasatinib experienced significantly higher rates of MMR (56.8 vs. 45.9%, p = 0.014) and overall survival (99.5 vs. 97.3%, p = 0.046) and numerically higher rates of PFS (98.8 vs. 96.5%). Matched imatinib arms showed no statistically significant or clinically meaningful differences in these outcomes. Limitations: Baseline measures unavailable in one or both trials could not be matched. Adverse event rates were not formally compared across trials due to differences in reporting. Conclusion: Nilotinib was associated with significantly higher rates of MMR and overall survival compared with dasatinib by month 12 in the treatment of newly diagnosed CML-CP.