USE THE RIGHT DOSE FOR ELDERLY PATIENTS

Lung Cancer. 2009 Jan 24. [Epub ahead of print]

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Dose intensity correlates with survival in elderly patients treated with chemotherapy for advanced non-small cell lung cancer.

Luciani A, Bertuzzi C, Ascione G, Di Gennaro E, Bozzoni S, Zonato S, Ferrari D, Foa P.

Medical Oncology Unit, S. Paolo Hospital, Milan, Italy.

INTRODUCTION: In elderly patients treated with chemotherapy for advanced non-small cell lung cancer (NSCLC), frequently an adequate dose intensity (DI) is difficult to be delivered. We therefore performed in this population a study to assess the delivered DI and its impact on clinical outcome. PATIENTS AND METHODS: Inclusion criteria were: age equal or greater than 70 years; cytological or histological diagnosis of NSCLC; stage IIIB or IV; no previous chemotherapy for advanced disease. Total relative dose intensity (RDI) was taken into account for the analysis. An RDI less than 80% was considered as suboptimal for tumor shrinkage. A survival comparison between subgroups (more or less than 80% RDI) was done. RESULTS: 107 patients were eligible for the analysis. Mean age was 74.3 years. PS was 0-1 in 92.5% of subjects. Mean number of comorbidities was 1.86. The most frequently chemotherapy regimens used were single agent vinorelbine and single agent gemcitabine. Overall mean RDI was 68%; 36% of patients received a RDI>80% of the originally planned one. The objective response rate (RR) was 55.2% and 33.3% respectively for patients receiving more or less than 80% of the RDI (p<0.01); style="background: transparent none repeat scroll 0% 0%; cursor: pointer; -moz-background-clip: -moz-initial; -moz-background-origin: -moz-initial; -moz-background-inline-policy: -moz-initial;" class="yshortcuts" id="lw_1233410993_13">response rate and overall survival.

USE PEDIATRIC REGIMENS FOR PEDIATRIC CANCERS IN ADULTS

Adults With ALL Benefit From Pediatric-Type Intensive Chemotherapy

NEW YORK (Reuters Health) Jan 28 - Pediatric-inspired chemotherapy markedly improves the outcome of adult patients with Philadelphia chromosome-negative acute lymphoblastic leukemia (ALL), at least up to the age of 45 years. This finding comes from a multicenter phase II study by the Group for Research on Adult Acute Lymphoblastic Leukemia, a French/Swiss/Belgian consortium, and is published online by the Journal of Clinical Oncology.

The authors note that several earlier studies had found that patients age 15-20 years "markedly benefited from a pediatric approach." The purpose of this study was to examine whether a pediatric-inspired strategy could also help adults over 20.

Dr. Herve Dombret of the Hopital Saint-Louis, Paris, told Reuters Health that pediatric and adult approaches to treating ALL have progressively diverged over the last 30 years, with chemotherapy emphasized in children and stem cell transplantation (SCT) favored for adults.

Children better tolerate the higher cumulative chemotherapy doses, he explained, while the greater prevalence of chemotherapy-resistant ALL subtypes in adults led many hematologists to believe that SCT following a non-intensive course of chemotherapy was the only practical option in adults.

The study enrolled 225 adult patients (median age 31 years, range 15-60) between November 2003 and November 2005. One hundred forty-nine patients had B-cell precursor ALL, and the others had T-lineage ALL.

In the course of all phases of treatment (induction, salvage, consolidation, intensification and maintenance), patients in the trial received 16-fold more L-asparaginase, 3.7-fold more vincristine, and 8.6-fold more prednisone than had the patients in the France-Belgium Group for Lymphoblastic Acute Leukemia in Adults 94 (LALA-94) study. In addition to the pediatric-style chemotherapy protocol, the study retained treatment options generally used in adults, such as cranial irradiation, early intensive administration of growth factors, and allogeneic SCT in first complete remission.

The authors retrospectively compared their results to those from the LALA-94 trial, which had included 712 patients age 15-55. The complete remission rate, event-free survival, and overall survival in the current study were significantly better than the LALA-94 results.

Older age "remained an important bad prognostic factor," the team reports, with 45 years the best cutoff for benefit.

"Currently, we propose using unmodified pediatric protocols in teenagers and adapted pediatric-inspired protocols in younger adults," the researchers write. "To reduce treatment-related toxicity in patients older than 45 years, we are currently recommending systemic anti-infectious prophylaxis during induction and delayed intensification."

USE ONLY ZUCRAZOL WITH PLAVIX

Increased Risk of Reinfarction With Clopidogrel and Proton-Pump Inhibitors

(UPDATED January 30, 2009) January 29, 2009 (Toronto, Ontario) — The addition of a proton-pump inhibitor (PPI) to clopidogrel (Plavix, Bristol-Myers Squibb/Sanofi-Aventis) in acute-MI patients significantly increases the risk of recurrent infarction, a new study has shown [1]. The findings support suspicions that the drug combination diminishes the beneficial effect of the antiplatelet therapy and increases the risk of future events, say researchers.

"Effectively, we're taking a patient who should be getting a benefit from clopidogrel, they have the genetic makeup that allows them to get the benefit, but we're turning them into the equivalent of someone who cannot activate clopidogrel by prescribing selected PPIs," lead investigator Dr David Juurlink (Institute for Clinical Evaluative Science, Toronto, ON) told heartwire. "We're doing this unintentionally, and we're doing it on a massive scale, and we're doing it, quite frankly, without any appreciation of what we're doing."

The study, published online January 28, 2009 in the Canadian Medical Association Journal, showed that while selected PPIs seem to "turn off" the body's natural process of converting clopidogrel into its active form, pantoprazole (Protonix, Wyeth Pharmaceuticals), which does not interfere with clopidogrel's conversion, was not associated with an increased risk of reinfarction.

FDA Now Has Eye on Possible Interaction

Earlier this week, the Food and Administration (FDA) announced that it was working with Bristol-Myers Squibb and Sanofi-Aventis, the makers of clopidogrel, to further study the effectiveness of the drug in patients taking other medications, particularly PPIs, and in those with genetic variants linked with clopidogrel resistance.

Clopidogrel is a prodrug converted in the liver to its active form by cytochrome P450 isoenzymes, with P450 2C19 playing a particularly important role. Speaking with heartwire, Juurlink said there is evidence suggesting that various PPIs can inhibit P450 2C19, which would alter the effectiveness of clopidogrel and potentially lead to an increased risk of adverse cardiovascular outcomes.

To assess the potential effects of the drug interaction, researchers identified more than 13 000 patients prescribed clopidogrel following an acute MI. Of these, 734 patients were readmitted with MI and 2057 served as event-free controls matched based on age, PCI, and risk score.

Among patients currently prescribed a PPI along with clopidogrel, the risk of reinfarction within 90 days was 27% greater than among those taking clopidogrel only. The risk is limited to those currently taking a PPI and did not extend to pantoprazole, a drug that does not interfere with the conversion of clopidogrel to its active form.

Association Between Acid-Reducing Therapy and Recurrent MI

End point	Odds ratio (95% CI)
Recurrent MI within 90 d
Current exposure to PPI (within 30 d)	1.27 (1.03–1.57)
Previous exposure to PPI (31–90 d)	0.86 (0.63–1.19)
Remote exposure to PPI (91–180 d)	0.81 (0.57–1.18)
End point based on PPI type
Pantoprazole	1.02 (0.70–1.47)
Other	1.40 (1.10–1.77)

Juurlink noted that recent guidelines issued by the American Heart Association, American College of Cardiology, and American College of Gastroenterology call for PPI therapy for a majority of patients taking aspirin after MI, including all patients 60 years and older.

"This is important, because patients taking clopidogrel are almost always taking aspirin," he said. "As a result, we're going to end up with millions of people who are taking the combination of clopidogrel and a proton pump inhibitor, and our results suggest that if this is not done with some caution, thousands, perhaps tens of thousands, of recurrent heart attacks could result."

Still, the news is not all bad for patients who need to turn off gastric acid, as they can take an older drug, such as an H2 blocker like Zantac or Pepcid, or pantoprazole, he added.

Speaking with heartwire, Dr Dan Roden (Vanderbilt University School of Medicine, Nashville, TN), who was not part of the Canadian analysis, said that the interaction between clopidogrel and PPIs was addressed by several abstracts presented at the most recent AHA meeting.

"I think it's evident there are people out there in which this is a big deal," he said. "The basic science is there, and the fact that CYP 2C19 affects cardiovascular outcomes is also there, so it's not rocket science to think there are patients being treated with clopidogrel with the expectation they're going to be better, but they're not because they're also getting a drug that inhibits its bioactivation."

Despite the results from this and other studies, Roden said a randomized trial would still be the best way to prove a clinically significant interaction and to estimate its severity, although he doubts one will be ever done.

"I believe the results, but this isn't a very strong paper to prove it," he added. "The problem here is whether the increased MI rates observed are a result of the drug interaction or because sicker patients tend to end up on proton-pump inhibitors. The finding that the most potent CYP 2C19 inhibitor has the greatest effect makes one think this is a real result."

Last week it was announced that Cogentus Pharmaceuticals (Palo Alto, CA) halted its COGENT 1 trial, a 4000-patient study testing a single-pill combination of clopidogrel and omeprazole to reduce the incidence of GI side effects. The company has filed for bankruptcy.

STEM CELL TRANSPLANTATION FOR RELAPSING REMITTING MS

Hemopoietic Stem Cells Safe, May Reverse Neurologic Disability in RRMS

January 30, 2009 — Results of a phase 1/2 trial of autologous nonmyeloablative hemopoietic stem-cell transplantation show that the technique appears safe and is associated with stabilization and, in some cases, even reversal of neurologic disability in patients with relapsing-remitting multiple sclerosis (RRMS).

"This is the first study that has shown with an intervention or therapy that it's not just stabilization of disease but actual reversal of disability that has occurred," lead author Richard K. Burt, MD, from Northwestern University Feinberg School of Medicine, in Chicago, Illinois, told Medscape Neurology & Neurosurgery.

The caveat is that this was a phase 1/2 trial, he added, and the results of a phase 3 randomized trial will be required to confirm their findings. A phase 3 trial with participating centers in Canada, Brazil, and their own institution is already under way.

Their report is published online January 30 in Lancet Neurology.

"Resetting" the Immune System

Autologous hemopoietic stem-cell transplantation for MS was first done by Fassas and colleagues in 1997 and has now been used in many countries, the authors write. However, they note, it has previously been used mostly in secondary progressive MS, where it was not associated with improvements in disability, although stabilization of disease has been reported.

"The rationale behind autologous hemopoietic stem-cell transplantation in MS is to reset the immune system; that is, to produce new and self-tolerant lymphocytes from the hemopoietic stem-cell (immune stem-cell) transplant after chemotherapy-induced elimination of self-reactive or autoreactive lymphocytes," they write.

The process produces intense immune suppression, they note. Peripheral blood stem cells are first mobilized, using 2 g/m² of cyclophosphamide followed by 10 µg/kg subcutaneous filgrastim, and then collected using apheresis after neutrophil recovery.

After 3 weeks, a conditioning regimen of 200 mg/kg of cyclophosphamide and 20 mg of alemtuzumab was given to remove self-reactive lymphocytes in 17 of the 21 patients included in this study. However, after the Food and Drug Administration reported that alemtuzumab was associated with the occurrence of immune thrombocytopenic purpura in some patients with MS, they switched alemtuzumab for 6 mg/kg of rabbit antithymocyte globulin given over 5 days in the final 4 patients.

At 36 hours after completion of the cyclophosphamide, the hemopoietic stem cells that had been collected were reinfused. Engraftment occurred on a median of day 9 after the infusion (range, 8 – 11 days), and patients were released on a mean of day 11 (range, 8 – 13 days)

A total of 21 RRMS patients were included in this study, 11 women and 10 men who had not responded to at least 6 months of interferon-beta therapy; despite treatment, eligible patients had 2 corticosteroid-treated relapses within the previous 12 months. Unlike previous trials of this strategy, patients were young, with an average age of 33 years (range, 20 – 53 years) and did not have severe disability. Primary outcomes of this phase 1/2 study were progression-free survival and reversal of neurological disability at 3 years after transplantation.

The researchers report that at an average follow-up of 3 years, 17 of the 21 patients (81%) had improved by at least 1 point on the Kurtzke expanded disability status scale (EDSS).

After a mean of 37 months, progression-free survival was 100%, with all patients free from progression on the EDSS score, and 16 were free of relapses. Five patients (24%) relapsed but achieved remission with further immunosuppression.

In addition, statistically significant improvements were seen in neurological disability as measured by the EDSS score, neurological rating scale score, paced auditory serial addition test, and 25-foot walk, as well as in quality of life, measured using the SF-36 questionnaire.

Treatment was well tolerated, they note. One patient had diarrhea due to Clostridium difficile, and 2 patients had dermatomal zoster at 20 and 22 months after the procedure. Of the 17 patients who had received alemtuzumab, 2 developed late immune thrombocytopenic purpura that remitted to standard therapy.

"Autologous nonmyeloablative hemopoietic stem-cell transplantation for patients with relapsing-remitting MS with active inflammatory disease and frequent exacerbations is a feasible procedure that not only seems to prevent neurological progression but also appears to reverse neurological disability," they conclude.

"The current Multiple Sclerosis International Stem Cell Transplant (MIST) trial is investigating patients with relapsing-remitting MS who have not responded to interferon therapy and are randomly assigned to autologous nonmyeloablative hemopoietic stem-cell transplantation or continued standard therapy."

"The key, I think, is patient selection," Dr. Burt said. "This won't work if you do it in progressive MS. You have to do it while it's still an inflammatory disease, not a neurodegenerative disease, which progressive MS is."

Clear Results

In an accompanying commentary, Gianluigi Mancardi, MD, from the San Martino Hospital, University of Genova, in Italy, points out that "the possibility for improvement after autologous hemopoietic stem-cell transplantation has been reported in other studies, although not as clearly as in the results of Burt and colleagues."

The toxicity of the conditioning regimen was "modest, if not negligible," Dr. Mancardi notes; however, relapses among the 5 patients after 6 to 16 months suggests that nonmyeloablative conditioning regimens may not be sufficient to eradicate inflammatory activity in the long term, he writes.

"The study by Burt and colleagues is, however, the first report of a prospective single-center trial that has used such a regimen in patients with MS, and the results imply that this is a valuable alternative to the transplant conditioning therapies used so far," Dr. Mancardi writes. More research is needed, he adds, to identify which conditioning regimen — either the so-called BEAM regimen of carmustine, etoposide, cytarabine, and melphalan, or cyclophosphamide and antithymocyte globulin — has the best efficacy and safety equipoise.

"Only a large, prospective, randomized study with a clinical end point and of patients who are unresponsive to the approved treatment but are still in the early phase of the disease will definitely resolve the question of the clinical efficacy of autologous hemopoietic stem-cell transplantation in patients with severe forms of MS," he concludes.

SORAFENIB FOR PROSTATE CANCER

BJU Int. 2009 Jan 9. [Epub ahead of print]

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Final analysis of a phase II trial using sorafenib for metastatic castration-resistant prostate cancer.

Aragon-Ching JB, Jain L, Gulley JL, Arlen PM, Wright JJ, Steinberg SM, Draper D, Venitz J, Jones E, Chen CC, Figg WD, Dahut WL.

Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.

OBJECTIVE To determine if sorafenib is associated with an improved 4-month probability of progression-free survival, using radiographic and clinical criteria alone, in patients with metastatic castration-resistant prostate cancer. Secondary endpoints included pharmacokinetics, toxicity analysis and overall survival. PATIENTS AND METHODS The study was an open-label, phase II, two-stage design, focusing on the results from the second stage, as criteria for progression were modified after completing the first stage. Sorafenib was given at a dose of 400 mg orally twice daily in 28-day cycles. Clinical and laboratory assessments were done every 4 weeks, and radiographic scans were obtained every 8 weeks. RESULTS Twenty-four patients were accrued in the second stage; the median (range) age was 66 (49-85) years, the on-study prostate-specific antigen level was 68.45 (5.8-995) ng/mL, the Gleason score 8 (6-9) and Eastern Cooperative Oncology Group status 1 (in 17 patients). Of the 24 patients, 21 had previous chemotherapy with docetaxel. All patients had bony metastases, either alone (in 11) or with soft-tissue disease (in 13). One patient had a partial response; 10 patients had stable disease (median duration 18 weeks, range 15-48). At a median potential follow-up of 27.2 months, the median progression-free survival was 3.7 months and the median overall survival was 18.0 months. For the whole trial of 46 patients the median survival was 18.3 months. Most frequent toxicities included hand-foot skin reaction (grade 2 in nine patients, grade 3 in three), rash, abnormalities in liver function tests, and fatigue. CONCLUSIONS Sorafenib has moderate activity as a second-line treatment for metastatic castration-resistant prostate cancer.

CHILDHOOD CANCER CHEST RADIOTHERAPY AND BREAST CANCER

Childhood Cancer Survivors Not Being Appropriately Screened for Breast Cancer

January 29, 2009 — Despite guideline recommendations, the majority of young women at high risk for breast cancer because of chest-radiation treatment for childhood cancer are not being appropriately screened. A report published in the January 28 issue of JAMA found that 63.5% of women between the ages of 25 and 39 years and 23.5% of those between 40 and 50 years had not undergone mammography screening in the previous 2-year period.

"Women who have been treated for a pediatric cancer with moderate- to high-dose chest radiation have an increased risk of breast cancer at a young age," said lead author Kevin C. Oeffinger, MD, director of the Program for Adult Survivors of Pediatric Cancer at Memorial Sloan-Kettering Cancer Center, in New York CIty. "It is recommended that these women initiate breast cancer surveillance at a young age. The Children's Oncology Group and other international groups recommend an annual mammogram and breast magnetic resonance imaging (MRI) starting at age 25 years or 8 years after the radiation — whichever occurs last."

Most of the women in this risk group are not being followed-up at a cancer center, and both patients and clinicians might be unaware of this risk or of the current screening recommendations, Dr. Oeffinger told Medscape Oncology. "I think that the primary factor is that clinicians are not aware of this risk and so are not discussing breast cancer screening with these young women."

The median age of breast cancer diagnosis in this population ranges from 32 to 35 years, and the risk for disease begins to increase as soon as 8 years after radiation therapy. Breast cancer risk is greatest among women who received high-dose mantle radiation for Hodgkin's lymphoma, the authors note. It is estimated that from 12% to 20% of women treated with moderate- to high-dose chest radiation will be diagnosed with breast cancer by the age of 45 years. In addition, previous chest radiation and possible exposure to chemotherapy with anthracyclines often limits treatment options for the women who do subsequently develop breast cancer.

To date, published information about breast cancer surveillance practices in this population is limited. The goal of the current study was to determine the prevalence of screening mammography and to identify predictors of mammography and other methods of breast cancer surveillance in young female adult cancer survivors who were treated with radiation during childhood. The study cohort consisted of 551 women 25 to 50 years who had survived pediatric cancer, who had been treated with chest radiation, and who were participants in the Childhood Cancer Survivor Study (CCSS). Breast cancer surveillance was compared in the CCSS survivors, in similarly aged pediatric cancer survivors who had not been treated with radiation (n = 561), and in the siblings of CCSS survivors (n = 622).

Screening data were obtained with a 114-item cross-sectional survey that was administered by both mail and telephone interview between June 6, 2005 and August 24, 2006 to all study participants.

Lower Than Expected Screening Rates

Only 36.5% of women between 25 and 39 years with a history of chest radiation reported undergoing mammography screening in the previous 2 years. The rate was lower than the researchers had expected, but higher than in the other 2 groups. However, in the high-risk (chest radiation) group, nearly half (47.3%) had never had a mammogram, and only 23.3% had undergone screening or diagnostic mammography in the previous year.

Cancer survivors with chest radiation aged 40 to 50 years were more likely to report breast cancer screening than younger women. In the older group, 76.5% reported undergoing a screening mammogram in the previous 2 years; this rate was higher than in the 2 comparison groups (70.0% for cancer survivors without chest radiation and 67.0% for the CCSS sibling group). Of importance, the researchers noted, only about half (52.6%) of the women in the high-risk group had undergone regular screening, defined as at least 2 mammograms in 4 years.

Physician Recommendation the Strongest Predictor

For women 25 to 39 years old, the strongest predictor of mammography was having a physician recommendation, and the likelihood of undergoing a mammogram was 3 times higher among those who reported a physician recommendation than among those who did not.

Age was another important predictor of screening mammography, and for each 5-year incremental increase in age, the likelihood that women would report having undergone a screening mammography increased nearly 2-fold. The 2 barriers that were most commonly mentioned by women in this age group who had not undergone a mammogram in the previous 2 years were "doctor didn't order it" (31%) and "I'm too young" (30%).

In addition to older age, predictors of screening mammography among women 40 to 50 years included having a primary-care physician, having a physician recommendation, awareness of increased risk for breast cancer associated with chest radiation, increased general health concerns, and having weighed the pros and cons of mammography and deciding in favor of it. The most common barriers to screening mammography reported were "put it off" or "didn't get around to it" (27%) and "too expensive" or "no insurance/cost" (17%).

Dr. Oeffinger believes that cancer centers need to be more proactive in their follow-up. "We are working with cancer centers around the country to facilitate this process," he said. "However, not surprisingly, most adult survivors of childhood cancer are no longer followed at a cancer center, owing to reasons such as insurance, age limitations of children's hospitals, moving away from the area, and so on."

Is MRI a Better Screening Choice?

In an accompanying editorial, Aliki J. Taylor, MD, MPH, PhD, and Roger E. Taylor, MD, from the University of Birmingham, in the United Kingdom, point out that repeat mammograms carry their own risk. The estimated dose of radiation from a standard 2-view screening mammogram is approximately 3.85 mGy per mammogram.

"Although it is accepted that the additional dose is small compared with the higher therapeutic dose already received, it is not known to what extent repeated exposure to small doses of breast irradiation in women already at an increased risk of breast cancer may result in a significantly increased risk of second primary breast cancer," they write. "This is an important question that needs to be addressed in future studies."

Another concern is that the efficacy of standard mammography in detecting preinvasive and malignant lesions is relatively poor in young women because of the density of breast tissue. Guidelines from the Children's Oncology Group recommend breast MRI as an adjunct to mammography, and the editorialists write that future studies should explore the role of MRI as a replacement for mammography in this population.

PEMETREXED AND GEMCITABINE COMBINATION IN NSCLC

Lung Cancer. 2009 Jan 21. [Epub ahead of print]

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A phase II trial of pemetrexed and gemcitabine as first line therapy for poor performance status and/or elderly patients with stage IIIB/IV non-small cell lung cancer.

Blakely LJ, Schwartzberg L, Keaton M, Schnell F, Henry D, Epperson A, Walker MS.

Accelerated Community Oncology Research Network, 1770 Kirby Parkway, Suite 400, Memphis, TN 38138, United States.

Pemetrexed and gemcitabine are both active agents for the treatment of locally advanced or metastatic NSCLC. We tested a novel biweekly combination of pemetrexed and gemcitabine for tolerability and efficacy in 45 elderly and/or poor performance status patients (44% female, mean age of 72.4 years) with measurable stage IIIB/IV NSCLC. Patients received biweekly cycles of pemetrexed 500mg/m(2) IV over 10min followed by gemcitabine 1500mg/m(2) IV with vitamin B12 1000mug IM, and folic acid 1mg po daily beginning 7 days before and continuing throughout treatment (median of 4 cycles). Ten patients experienced grade 3/4 neutropenia, two had grade 3 febrile neutropenia, and two had grade 3 anemia. Patients with ECOG PS 2 appeared poorly suited for the regimen, with 61.5% completing 24 weeks) was 26.7%, and the median progression free survival was 3.5 months. However, ECOG 0-1 patients had longer PFS and tended to have a better response rate than ECOG 2 patients.

GOSERELIN AND OVARIAN FUNCTION

Breast Cancer Res Treat. 2009 Jan 20. [Epub ahead of print]

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Adjuvant goserelin and ovarian preservation in chemotherapy treated patients with early breast cancer: results from a randomized trial.

Sverrisdottir A, Nystedt M, Johansson H, Fornander T.

Departments of Oncology, Karolinska Institute and University Hospital, Stockholm, Sweden, asgerds@landspitali.is.

The purpose of this randomized study was to examine if goserelin concomitant to CMF-chemotherapy as adjuvant treatment for premenopausal breast cancer, protects the ovaries from premature failure. A total of 285 premenopausal breast cancer patients, in a randomized adjuvant trial (Zoladex in premenopausal patients (ZIPP)), were assigned to a study on ovarian function. Node positive patients were assigned to CMF-(cyclophosphamide, methotrexate and 5-fluorouracil) chemotherapy in addition to endocrine therapy. All patients were randomly assigned to receive 2 years of goserelin, goserelin plus tamoxifen, tamoxifen alone or no endocrine treatment. We studied, if menses were affected in the treatment groups, up to 36 months after randomization. One year after completed CMF- and endocrine therapy, 36% of the women in the goserelin group reported menses, compared to 7% in the goserelin plus tamoxifen group, 13% in the tamoxifen group and 10% of the controls. Among women treated with goserelin, there was a statistically significant increase in the proportion of menstruating women, 1 year after completed treatment compared to at 24 months of treatment (P = 0.006), in contrast to all other treatment groups, who were unchanged or more often amenorrheic. In our study, there is some evidence of protective effect of goserelin on ovarian function in CMF treated women. This effect was not observed in the combined tamoxifen and goserelin treatment.

XP NOT INFERIOR TO FP FOR GASTRIC CANCER

: Ann Oncol. 2009 Jan 19. [Epub ahead of print]

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Capecitabine/cisplatin versus 5-fluorouracil/cisplatin as first-line therapy in patients with advanced gastric cancer: a randomised phase III noninferiority trial.

Kang YK, Kang WK, Shin DB, Chen J, Xiong J, Wang J, Lichinitser M, Guan Z, Khasanov R, Zheng L, Philco-Salas M, Suarez T, Santamaria J, Forster G, McCloud PI.

Division of Oncology, Department of Internal Medicine, Asan Medical Center.

BACKGROUND: To compare capecitabine/cisplatin with 5-fluorouracil/cisplatin as first-line treatment for advanced gastric cancer (AGC). PATIENTS AND METHODS: In this randomised, open-label, phase III study, patients received cisplatin (80 mg/m(2) i.v. day 1) plus oral capecitabine (1000 mg/m(2) b.i.d., days 1-14) (XP) or 5-FU (800 mg/m(2)/day by continuous infusion, days 1-5) (FP) every 3 weeks. The primary end point was to confirm noninferiority of XP versus FP for progression-free survival (PFS). RESULTS: A total of 316 patients were randomised to XP (n = 160) or FP (n = 156). In the per-protocol population, median PFS for XP (n = 139) versus FP (n = 137) was 5.6 versus 5.0 months. The primary end point was met with an unadjusted hazard ratio (HR) of 0.81 [95% confidence interval (CI) 0.63-1.04, P < hr =" 0.85," p =" 0.008" style="background: transparent none repeat scroll 0% 0%; cursor: pointer; -moz-background-clip: -moz-initial; -moz-background-origin: -moz-initial; -moz-background-inline-policy: -moz-initial;" class="yshortcuts" id="lw_1233409899_21">adverse events in XP versus FP patients were as follows: neutropenia (16% versus 19%), vomiting (7% versus 8%), and stomatitis (2% versus 6%). CONCLUSIONS: XP showed significant noninferiority for PFS versus FP in the first-line treatment of AGC. XP can be considered an effective alternative to FP.

CCBs ACEIs AND EDEMA

J Hum Hypertens. 2009 Jan 15. [Epub ahead of print]

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Mitigation of calcium channel blocker-related oedema in hypertension by antagonists of the renin-angiotensin system.

de la Sierra A.

1University of Barcelona, Barcelona, Spain.

This review is aimed at examining calcium channel blocker (CCB)-related oedema and how this can be attenuated through the use of agents that inhibit the renin-angiotensin system. CCBs are effective antihypertensive agents, but their propensity for causing oedema may reduce compliance. A review of the literature has indicated that the absolute incidence of this side effect is difficult to determine because reported rates vary widely, a factor that may stem from differences in the surveillance technique (active vs passive). In a recent trial incorporating active surveillance, 25% of patients who received amlodipine 10 mg per day experienced oedema. CCB-induced oedema is caused by increased capillary hydrostatic pressure that results from preferential dilation of pre-capillary vessels. Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) cause post-capillary dilation and normalize hydrostatic pressure, and are thus ideally suited for prevention/reversal of CCB-induced oedema. The efficacy of this strategy was proven using both subjective and objective techniques. ARB/CCB and ACEI/CCB combination therapy is also more effective than CCB monotherapy in controlling blood pressure. These combinations represent an important advance in the management of hypertension.Journal of Human Hypertension advance online publication, 15 January 2009; doi:10.1038/jhh.2008.157.

UNDERTREATMENT OF CANCER PATIENTS

Prevalence of Undertreatment in Cancer Pain. A Review of Published Literature

Posted 01/21/2009

S. Deandrea; M. Montanari; L. Moja; G. ApoloneAnn Oncol. 2008;19(12):1985-1991. ©2008 Oxford University Press
Copyright 2008 European Society for Medical Oncology. Published by Oxford University Press. All rights reserved.

Posted 01/21/2009

Abstract and Introduction

Abstract

Background: Pain is a major health care problem for patients with cancer: despite the existence of guidelines for cancer pain management, undertreatment is a widespread problem. Pain Management Indexes (PMIs) evaluate the congruence between the patient's reported level of pain and the intensity/strength of the analgesic therapy. Negative scores indicate inadequate prescriptions.
Materials and methods: We conducted a Medline search using terms for ‘pain management’, ‘index’ or ‘measure’ to select studies which measured undertreatment in cancer settings. Univariate and multivariate logistic regression identified associations between independent predictors and high prevalence of undertreatment.
Results: Among the 44 studies identified, 26 studies used the PMI as proposed by Cleeland. The range of negative PMI varied from 8% to 82% with a weighted mean value of 43%. In multivariate analyses, factors associated with negative PMI were date of publication before 2001, provenance from Europe or Asia and countries with a gross national income per capita <$40 000 per year and a care setting not specific for cancer. Age was not a significant predictor for undertreatment.
Conclusion: Nearly one of two patients with cancer pain is undertreated. The percentage is high, but consists of a large variability of undertreatment across studies and settings.

NO BENEFIT FOR LYMPHADENECTOMY IN STAGE I ENDOMETRIAL CANCER

Systematic Pelvic Lymphadenectomy vs No Lymphadenectomy in Early-Stage Endometrial Carcinoma: Randomized Clinical Trial

Pierluigi Benedetti Panici; Stefano Basile; Francesco Maneschi; Andrea Alberto Lissoni; Mauro Signorelli; Giovanni Scambia; Roberto Angioli; Saverio Tateo; Giorgia Mangili; Dionyssios Katsaros; Gaetano Garozzo; Elio Campagnutta; Nicoletta Donadello; Stefano Greggi; Mauro Melpignano; Francesco Raspagliesi; Nicola Ragni; Gennaro Cormio; Roberto Grassi; Massimo Franchi; Diana Giannarelli; Roldano Fossati; Valter Torri; Mariangela Amoroso; Clara Crocè; Costantino MangioniJ Natl Cancer Inst. 2008;100(23):1707-1716. ©2008 Oxford University Press

Posted 01/20/2009

Abstract and Introduction

Abstract

Background: Pelvic lymph nodes are the most common site of extrauterine tumor spread in early-stage endometrial cancer, but the clinical impact of lymphadenectomy has not been addressed in randomized studies. We conducted a randomized clinical trial to determine whether the addition of pelvic systematic lymphadenectomy to standard hysterectomy with bilateral salpingo-oophorectomy improves overall and disease-free survival.
Methods: From October 1, 1996, through March 31, 2006, 514 eligible patients with preoperative International Federation of Gynecology and Obstetrics stage I endometrial carcinoma were randomly assigned to undergo pelvic systematic lymphadenectomy (n = 264) or no lymphadenectomy (n = 250). Patients' clinical data, pathological tumor characteristics, and operative and early postoperative data were recorded at discharge from hospital. Late postoperative complications, adjuvant therapy, and follow-up data were collected 6 months after surgery. Survival was analyzed by use of the log-rank test and a Cox multivariable regression analysis. All statistical tests were two-sided.
Results: The median number of lymph nodes removed was 30 (interquartile range = 22-42) in the pelvic systematic lymphadenectomy arm and 0 (interquartile range = 0-0) in the no-lymphadenectomy arm (P < .001). Both early and late postoperative complications occurred statistically significantly more frequently in patients who had received pelvic systematic lymphadenectomy (81 patients in the lymphadenectomy arm and 34 patients in the no-lymphadenectomy arm, P = .001). Pelvic systematic lymphadenectomy improved surgical staging as statistically significantly more patients with lymph node metastases were found in the lymphadenectomy arm than in the no-lymphadenectomy arm (13.3% vs 3.2%, difference = 10.1%, 95% confidence interval [CI] = 5.3% to 14.9%, P < .001). At a median follow-up of 49 months, 78 events (ie, recurrence or death) had been observed and 53 patients had died. The unadjusted risks for first event and death were similar between the two arms (hazard ratio [HR] for first event = 1.10, 95% CI = 0.70 to 1.71, P = .68, and HR for death = 1.20, 95% CI = 0.70 to 2.07, P = .50). The 5-year disease-free and overall survival rates in an intention-to-treat analysis were similar between arms (81.0% and 85.9% in the lymphadenectomy arm and 81.7% and 90.0% in the no-lymphadenectomy arm, respectively).
Conclusion: Although systematic pelvic lymphadenectomy statistically significantly improved surgical staging, it did not improve disease-free or overall survival.

REVASCULARIZATION FOR STEMI

Revascularization Benefits Resuscitated Patients With STEMI Regardless of Neurologic Status

January 27, 2009 (Newark, Delware) — Patients with ST-segment-elevation MI (STEMI) who are resuscitated from cardiac arrest should undergo emergent angiography and revascularization regardless of neurologic status, a new study suggests [1].

In-hospital mortality was significantly lower in resuscitated patients with STEMI who are revascularized compared with patients who did not undergo revascularization, and this benefit extended to patients neurologically unresponsive after resuscitation, report investigators.

Although the study does not provide conclusive evidence for the benefits of revascularization in cardiac-arrest patients with MI, "these patients should be treated with the same urgency as patients with acute STEMI without cardiac arrest," write lead investigator Dr Vinay Hosmane (Christiana Care Health System, Newark, DE) and colleagues in the February 3, 2009 issue of the Journal of American College of Cardiology.

Revascularization for the Unresponsive

Although emergent PCI is the preferred treatment for patients who have an out-of-hospital cardiac arrest owing to MI, a number of patients show signs of neurologic impairment before revascularization. The prognosis of these patients and benefits of PCI compared with patients without neurologic damage are not well-known, and this has caused a dilemma about whether or not to proceed directly to angiography and possible revascularization, according to Hosmane and colleagues.

Over a five-year period, the researchers retrospectively identified consecutive patients resuscitated from cardiac arrest, regardless of the time to return of spontaneous circulation and neurologic status, and reviewed the outcomes of 98 patients who had STEMI.

Overall, 64% of these patients survived to hospital discharge, and 92% had full neurologic recovery. Survival to discharge was 96% among alert patients, 93% among patients minimally responsive to pain and stimuli, and 44% among those who were unresponsive. In multivariate analysis, unresponsive patients were 47 times more likely to die than alert patients. In addition, delays in the time to return of spontaneous circulation and older age increased the risk of dying. Women were also six times more likely to die than men.

Revascularization was performed in 77 of the 98 patients, with a majority of these undergoing PCI. In-hospital mortality was 25% among revascularized patients compared with 76% for those who were not revascularized. Among those classified as unresponsive following resuscitation, 40 of 59 patients underwent revascularization. In line with the entire cohort, in-hospital mortality was significantly higher in those who did not undergo emergent PCI or coronary artery bypass graft surgery compared with those who were revascularized (84% vs 42%, respectively).

Researchers point out that the study was not randomized, nor was it designed to assess the benefits of revascularization in this patient population. The difference in survival rates among unresponsive patients receiving and not receiving revascularization is likely attributable to selection bias, but the researchers add that the Should We Emergently Revascularize Occluded Coronaries for Cardiogenic Shock (SHOCK) study showed cardiogenic shock patients also derive benefit from revascularization.

THALIDOMIDE FOR PROSTATE CANCER?

Thalidomide for the Treatment of Biochemically Recurrent Prostate Cancer

January 28, 2009 — Thalidomide may have use in the treatment of men who have biochemical recurrence of prostate cancer or a rise in their prostate-specific antigen (PSA) count after definitive therapy, according to a new randomized study from the National Cancer Institute.

In this population, the use of thalidomide was associated with an increase in PSA progression-free survival after intermittent androgen-deprivation therapy (ADT).

The median time to a new PSA increase was 17.1 months for thalidomide (vs 6.6 months for placebo) in the second phase of the study's crossover design. The effect occurred despite the fact that thalidomide, which has been shown to have antiangiogenic activity, had no effect on testosterone, note the study authors, led by William D. Figg, PharmD, head of the Molecular Pharmacology Section of the Center for Cancer Research at the National Cancer Institute, in Bethesda, Maryland, in a study published online January 23 in the Journal of Urology.

However, the study's use of ADT in men with "biochemical recurrence" was critically questioned in an accompanying editorial comment.

"PSA relapse after definitive therapy is common and is often associated with an excellent prognosis," writes Tomasz M. Beer, MD, associate professor of medicine in the Division of Hematology and Medical Oncology at the Oregon Health and Science University Cancer Institute, in Portland. "Hormonal therapy has not been shown to improve overall survival or delay clinically meaningful events in this setting."

But the researchers point out that intermittent ADT is "increasingly being used in patients with biochemical recurrence," and there might be "a role for instituting early treatment," they suggest.

In outlining their rationale for the study, the authors further explain that there is some research that suggests that ADT is better sooner rather than later. "The increasing use of ADT is based on studies suggesting clinical benefit in patients with early-stage prostate cancer treated earlier with ADT compared to those receiving it later in the disease course."

Dr. Figg and colleagues also note that the efficacy of antiangiogenic agents, such as thalidomide, is likely to be the greatest early on, when the disease burden is minimal.

Thalidomide was previously shown to be effective in combination with chemotherapy in patients with metastatic prostate cancer (Clin Cancer Res. 2001;7:1888; J Clin Oncol. 2004;22:2532) and, thus, was a candidate for treatment in earlier-stage disease, they suggest.

Study Details

All patients in the study had androgen-dependent adenocarcinoma of the prostate and 2 consecutively increasing PSA counts after local definitive therapy with radical prostatectomy, radiation therapy, or cryosurgery.

In phase A of the analysis, 147 patients were initially administered gonadotropin-releasing hormone agonists (GnRH-A) for 6 months, and subsequently received thalidomide or placebo. GnRH-A generally consisted of leuprolide (22.5 mg for 3 months) or goserelin (10.8 mg for 3 months).

For patients in phase A, the median time to PSA progression for those taking thalidomide was 15 months, compared with 9.6 months for those taking placebo (P = .21).

Once patients had PSA progression, defined by an increasing PSA greater than 5 ng/mL or reaching a minimum of 1 ng/mL, they were retreated with a GnRH-A for another 6 months, and then crossed over to the opposite treatment. This was phase B, which was completed by 88 patients.

The median time to PSA progression during phase B for the thalidomide group was 17.1 months, and for the placebo group was 6.6 months (P = .0002).

Thalidomide had no grade 3 or 4 toxicities that occurred in more than 5% of patients. Grade 2 hot flashes occurred in nearly half of the men in both the thalidomide and placebo groups, likely because of the ADT. The second most common side effect was grade 2 constipation, occurring in 41% of thalidomide-treated men and in 16% of placebo-treated men. Fatigue was also a common problem, occurring in 18.5% of thalidomide-treated men and in 10.6% of placebo-treated men.

Larger studies with longer follow-ups are needed to determine the usefulness of thalidomide in this setting, note the study authors.

Hormonal Therapy's Potential

Despite his criticisms, Dr. Beer praised the researchers for the novel approach to treatment in the study. "The authors should be congratulated for testing a novel antiangiogenic strategy in combination with androgen-deprivation therapy, rather than the more conventional approach of testing innovative approaches with chemotherapy," he writes in the editorial comment.

Dr. Beer also endorsed the idea of attempting to improve ADT. "Enhancement of hormonal therapy has great potential to improve outcomes in early- and late-stage prostate cancer," he writes. The potential is greater than that of chemotherapy, he notes, which has a much lower median time to progression (about 6 months) than hormonal therapy, with its median time to progression ranging from 16 to 48 months.

IS THERE AN OPTIMAL THERAPY FOR LARYNX CANCER?

Larynx Cancer: Optimal Approach Still Not Identified

January 28, 2008 — In the management of patients with head and neck cancer, "it is clear that the optimal approach for larynx preservation has not been identified," say a group of European researchers reporting a trial that compared 2 approaches and found no difference in outcomes.

The group, headed by Jean Lefebvre, MD, from the Centre Oscar Lambret, in Lille, France, compared sequential administration of chemotherapy and radiation with an approach that administered the 2 modalities in alternating cycles. The results, showing very similar outcomes for both approaches, were published online January 27 in the Journal of the National Cancer Institute.

In an accompanying editorial, experts from the United States agree with the group's conclusions that the optimal approach to larynx preservation has yet to be identified. Editorialists Arlene Forastiere, MD, from the Sidney Kimmel Cancer Center at John Hopkins University, in Baltimore, Maryland, and Andy Trotti, MD, from the H. Lee Moffitt Cancer Center at the University of South Florida, in Tampa, call for more studies, and say that "more effective and less toxic approaches are needed."

Success of Larynx Preservation

"Larynx preservation has been one of the most important achievements in head and neck oncology" over the past 2 decades, the researchers write. Before then, patients would undergo surgery, usually total laryngectomy, followed by radiation. But in the 1980s, several first-generation trials showed that chemotherapy with radiation — at the time considered to be an experimental approach — produced similar outcomes but preserved the larynx in 40% to 60% of patients.

Consequently, concurrent chemotherapy with radiation became a standard of care for advanced head and neck cancers, the researchers comment. But in an attempt to improve outcomes further, 2 second-generation trials comparing variations on this approach were carried out, and the current paper reports on 1 of these (the European Organization for Research and Treatment of Cancer EORTC 2495 trial).

The EORTC 2495 trial comprised 450 patients and had a median follow-up of 6.5 years. It compared sequential treatment with chemotherapy (up to 4 cycles of cisplatin and 5-fluorouracil) followed by radiotherapy (70 Gy total) with an approach that alternated the 2 modalities, in which each of the 4 cycles of chemotherapy was followed by radiotherapy (20 Gy) during the 2-week interval between cycles.

Dr. Lefebvre and colleagues report that overall survival, progression-free intervals, and larynx preservation were very similar in the 2 treatment groups, as were acute and late toxic effects.

There was no advantage for the regimen of alternating cycles of treatment over the traditional sequential approach, comment the editorialists. They also point out that 4 cycles of chemotherapy are not commonly used in practice because of toxicity, and that 3 cycles are more usual.

The other second-generation trial was conducted in the United States, and has already been published (N Engl J Med 2003;349:2091-2098). The Radiation Therapy Oncology Group 91-11 study was an intergroup trial comparing 3 therapies: induction chemotherapy followed by radiation; concurrent chemotherapy and radiation; and radiotherapy alone. This also showed similar outcomes (overall survival, disease-free survival, and laryngectomy-free interval) in the 3 different treatment groups, say Dr. Lefebvre and colleagues. The concurrent group did show better local control, they add, but it was associated with significantly more severe toxic effects than the other 2 groups.

More Recent Studies

Since those 2 second-generation trials, several more have been reported, note the editorialists. Three published trials (N Engl J Med. 2007;357:1695–1704; N Engl J Med. 2007;357:1705–1715; J Clin Oncol. 2005 23:8636–8645) have now shown that adding a third drug — a taxane — to the regimen of cisplatin plus 5-fluorouracil improves outcomes. Although the results from these 3 trials are not uniform, the editorialists comment that together the results "clearly support use of the 3-drug regimen when induction therapy is indicated," adding that hypopharynx cancer is such an indication.

The editorialists also emphasize the "strong need to standardize end point definitions" in future trials, because the studies conducted to date have differed in their definitions of larynx preservation and other outcomes. Towards this end, they note, the National Cancer Institute Head and Neck Steering Committee has appointed a Working Group on Endpoints, looking at definitions, the use of composite organ-preservation end points, and local–regional progression. This group intends to issue formal recommendations in 2009.

8 CYCLES OF PREOPERATIVE CHEMOTHERAPY ARE ENOUGH

GICS 2009: Extended Chemotherapy Increases Risk for Hepatic Injury

January 26, 2009 (San Francisco, California) — The type of chemotherapy regimen has a greater impact on response than the duration of treatment after hepatic resection for colorectal liver metastases. In fact, extended preoperative chemotherapy increases the risk for hepatotoxicity in this population and does not improve pathologic response, according to new data presented here at the 2009 Gastrointestinal Cancers Symposium.

Researchers from the University of Texas MD Anderson Cancer Center, in Houston, reported that preoperative chemotherapy with 5-fluorouracil and oxaliplatin (FOLFOX) plus bevacizumab (Avastin, Genentech) was associated with a significantly higher frequency of complete or major pathologic responses, compared with FOLFOX alone. This was the case for both long- and short-course chemotherapy.

However, among patients who received 9 or more cycles of chemotherapy, the incidence of sinusoidal injury was higher than in those who received fewer cycles (26% vs 42%), as was as was the incidence of liver insufficiency (4% vs 11%). Extended chemotherapy was the only independent predictor of postoperative liver insufficiency upon multivariate analysis.

In colorectal cancer with liver metastasis, chemotherapy should only be given if it can cure the patient or help them live longer, said David P. Ryan, MD, from the Massachusetts General Hospital Cancer Center, in Boston. "The potentially curative situation is what we are looking at today, and there is some confusion in the oncologic community as to how to best manage these patients."

"We know that resecting liver metastases can cure patients in approximately 30% of cases, and that unresectable patients can occasionally become resectable after chemotherapy," explained Dr. Ryan, who served as a discussant during the presentation of this paper.

"Perioperative FOLFAX may be associated with improved progression-free survival," he said, "but chemotherapy is associated with various types of liver injury, including steatohepatitis, and preoperative therapy increases surgical morbidity."

The study shows that longer-term chemotherapy does not improve pathologic response, only liver injury, and the addition of bevacizumab increases the pathologic response, he pointed out.

"This MD Anderson experience, along with other experiences that have been reported, provides enough rationale to move forward with larger multi-institutional phase 3 trials in patients with resectable disease," Dr. Ryan said.

No Benefit Seen With Longer-Term Therapy

The optimal benefit, duration, and safety of preoperative chemotherapy in patients with colorectal liver metastases remain undefined. The goal of this study was to evaluate the association between the duration of preoperative chemotherapy with FOLFOX with or without bevacizumab, along with the pathologic response and the incidence of hepatotoxicity after hepatic resection, in patients with colorectal liver metastases.

Specific liver injury resulting from chemotherapy has been previously described, said lead author Daria Zorzi, MD. Steatohepatitis is associated with an increased 90 day mortality (15% vs 2% for no steatohepatitis) and an increased risk for death from liver failure (6%).

Dr. Zorzi and colleagues used a prospective hepatobiliary database and selected a cohort of 219 consecutive patients who underwent hepatic resection for colorectal liver metastases after receiving a preoperative chemotherapy regimen of FOLFOX. The patients were divided into 2 study groups, based on the duration of chemotherapy: the short course consisted of 157 patients who received from 1 to 8 cycles of treatment, and the extended course consisted of 62 patients who received 9 or more cycles.

They found that the clinical, surgical, and pathologic variables were similar in the short- and extended-course groups.

Pathologic Response to Preoperative Chemotherapy

Response	Short course, n = 157 (%)	Extended course, n = 62 (%)
Complete response	11 (7)	7 (11)
Major response	79 (50)	27 (44)
<50%>	90 (57)	34 (55)

Increased Response With Bevacizumab

However, patients in both study goups who received combination FOLFOX and bevacizumab had a significantly higher frequency of complete or major pathologic response than those who received FOLFOX alone. Among patients who received FOLFOX alone (n = 117), 53 (45%) experienced less than 50% residual tumor, as did 71 (70%) of those who received FOLFOX plus bevacizumab (n = 102).

"An improvement in response was seen with bevacizumab in both short- and [extended-course] chemotherapy," said Dr. Zorzi. "Extended chemotherapy resulted in increased sinusoidal injury, but when bevacizumab was added to the regimen, the incidence of sinusoidal injury was decreased in both regimens."

However, even though bevacizumab significantly reduces the incidence of sinusoidal injury, the researchers found that the rate of hepatic insufficiency was similar after correcting for duration of chemotherapy.

"Extended preoperative chemotherapy increases the risk of hepatotoxicity after hepatic resection for colorectal liver metastases, and does not improve pathologic response," Dr. Zorzi concluded, adding that the type of chemotherapy has more impact on pathologic response than duration, and the pathophysiology of liver insufficiency after FOLFOX appears to be independent of sinusoidal injury.

Ki67 IN BLADDER CANCER

Ki67 Biomarker in Bladder Cancer May Lead to Improved Outcomes

January 26, 2009 — Measuring the biomarker Ki67 in patients with bladder cancer may help improve outcomes in these patients, say researchers.

A multicenter trial of 713 patients has validated the predictive role of the marker, and now a prospective trial of 300 patients is underway to investigate if therapy based on the biomarker can improve outcomes, said one of the principal investigators, Shahrokh Shariat, MD, PhD, now at the Memorial Sloan–Kettering Cancer Center, in New York City (but until very recently at the University of Texas Southwestern, in Dallas).

Currently, about half of the patients with bladder cancer who undergo a radical cystectomy succumb to the disease, Dr. Shariat explained in an interview with Medscape Oncology. Although survival is improved with the use of perioperative chemotherapy, very few patients currently receive it (about 12%).

Dr. Shariat and colleagues have already shown that Ki67 can identify bladder cancer patients who have a worse prognosis after radical cystectomy, and now they are hoping to show that these patients are the most likely to benefit from chemotherapy.

Ki67 is an established marker of cell proliferation, and has been investigated as a biomarker in several different cancers. However, Ki67 was found not to be useful for predicting chemotherapy benefit in breast cancer, and the American Society of Clinical Oncology Tumor Markers Expert Panel maintains that measurements of the cell cycle should not be used for chemotherapy decision-making, as previously reported by Medscape Oncology.

Ki67 may prove to be useful in bladder cancer because it is very responsive to chemotherapy, Dr. Shariat commented. He explained that a biomarker needs to go through 3 stages of investigation — hypothesis-generating small studies, validation in a multicenter trial, and then a prospective trial investigating whether therapy based on the biomarker can improve outcomes. Ki67 is now at the third stage, and the results of second stage, the multicenter validation, were published January 21 in the Journal of the National Cancer Institute.

Validation of Predictive Role

A predictor role for the biomarker had been suggested by several smaller studies, including 1 carried out by Dr. Shariat and colleagues. That single-center trial of 226 patients treated with radical cystectomy showed that high Ki67 labelling was independently associated with disease recurrence and bladder-cancer-specific mortality after adjustment for tumor stage, grade, and presence of lymphovascular invasion (Clin Cancer Res. 2006;12:7369-7373).

To validate these findings, Dr. Shariat and colleagues conducted this multicenter trial, spanning the United States, Canada, and Europe, involving 713 patients treated with radical cystectomy and bilateral pelvic lymph node removal. They found that Ki67 was a strong predictor of outcome, even after adjustment for age, sex, tumor status, grade, number of positive lymph nodes, and surgical margin status.

Patients with tumors that expressed a high level of Ki67 were 2.4 times more likely to have disease recurrence than those with tumors that expressed low levels of ki67, and were 1.8 times more likely to die from bladder cancer.

The researchers then incorporated Ki67 into a model that includes all known risk factors for predicting disease recurrence, including tumor stage, grade, nodal status, and the presence of lymphovascular invasion.

This model improved the accuracy of predicting which patients would experience disease recurrence (by 2.9% for all patients, and by 4.4% for a subgroup of patients with node-negative disease) and which patients would succumb to disease-specific mortality (by 2.4% for all patients, and by 4.6% for the subgroup).

"In conclusion, routine assessment of Ki67 expression status, along with the assessment of other established predictors of urothelial carcinoma outcome, has the potential to improve identification of patients who are at increased risk for disease progression after radical cystectomy and thus may benefit from perioperative systemic chemotherapy," the researchers write.

May Increase Use of Perioperative Chemotherapy

Bladder cancer is very sensitive to chemotherapy, and the use of perioperative systemic chemotherapy can reduce the development of systemic disease and improve survival after radical cystectomy, the researchers note. The results are modest but are comparable to those achieved in lung, breast, and colon cancers, they add.

However, only about 12% of patients receive perioperative chemotherapy after radical cystectomy, according to data from the National Cancer Database. Although there are likely to be many reasons for this, one that is "of major importance" is the lack of a way to predict outcomes and, hence, identify the patients most likely to benefit, the authors comment.

This is where they hope that Ki67, along with other factors, will play a useful role.

In the trial that Dr. Shariat and colleagues are currently conducting, they are using Ki67 and 4 other biomarkers to decide what treatment the 300 enrolled patients should receive. The biomarkers will be tested in a biopsy sample taken before cystectomy, and will determine whether the patient will undergo an early cystectomy or receive neoadjuvant chemotherapy and a delayed cystectomy. In addition, the biomarkers will be used to determine whether or not the patient will receive adjuvant chemotherapy after the surgery.

It will take several years to answer these questions, Dr. Shariat said, but he hopes that some results will be available in 2 or 3 years' time.

5-FU AND OXALIPLATIN FOR MUCINOUS OVARIAN ADENOCARCINOMA

Cancer Sci. 2008 Dec 19. [Epub ahead of print]

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Combination chemotherapy of oxaliplatin and 5-fluorouracil may be an effective regimen for mucinous adenocarcinoma of the ovary: A potential treatment strategy.

Sato S, Itamochi H, Kigawa J, Oishi T, Shimada M, Sato S, Naniwa J, Uegaki K, Nonaka M, Terakawa N.

Department of Obstetrics and Gynecology, Tottori University School of Medicine, 36-1 Nishicho, Yonago 683-8504, Japan.

Resistance of ovarian mucinous adenocarcinoma to standard chemotherapy with paclitaxel and carboplatin is associated with poor prognosis, and an effective treatment is needed. The present study aimed to identify an effective chemotherapy for ovarian mucinous adenocarcinoma. Five human ovarian mucinous adenocarcinoma cell lines (MN-1, OMC-1, RMUG-L, RMUG-S, TU-OM-1) were used in this study. Sensitivity of the cells to the anticancer agents was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, and we assessed drug sensitivity by calculating the assay area under the curve for each agent. Protein expression was confirmed by Western blot analysis. We also examined the efficacy of combination chemotherapy on survival in a xenograft model of nude mice. The IC(50) to anticancer agents ranged widely. The assay area under the curve indicated that two of five cell lines (MN-1, TU-OM-1) were sensitive to oxaliplatin, 5-fluorouracil and etoposide, and only one (TU-OM-1) was sensitive to 7-ethyl-10-hydroxycamptothecin, which is an active metabolite of camptothecin. All cell lines were resistant to cisplatin and paclitaxel. The combination of oxaliplatin and 5-fluorouracil resulted in additive or synergistic effects on all cell lines. The combination of oxaliplatin and 5-fluorouracil significantly prolonged survival in a ovarian mucinous adenocarcinoma xenograft model of nude mice. Protein expression levels of the excision repair cross-complementation group 1 were lower in oxaliplatin sensitive cell lines. Exposure to 5-fluorouracil down-regulated cross-complementation group 1 expression in ovarian mucinous adenocarcinoma cells. We conclude that combination chemotherapy consisting of oxaliplatin and 5-fluorouracil was an effective treatment for ovarian mucinous adenocarcinoma and may be a pivotal candidate for a novel treatment strategy. (Cancer Sci 2009).

PET HAS LOW SENSITIVITY IN mCRC

Ann Oncol. 2009 Jan 22. [Epub ahead of print]

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Early prediction of response to first-line chemotherapy by sequential [18F]-2-fluoro-2-deoxy-D-glucose positron emission tomography in patients with advanced colorectal cancer.

Byström P, Berglund A, Garske U, Jacobsson H, Sundin A, Nygren P, Frödin JE, Glimelius B.

Department of Oncology and Pathology, Karolinska Institute, Stockholm.

BACKGROUND: To evaluate [(18)F]-2-fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET), for early evaluation of response to palliative chemotherapy and for prediction of long-term outcome, in patients with metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: In a randomized trial, patients with mCRC received irinotecan-based combination chemotherapy. FDG-PET was carried out before treatment and after two cycles in 51 patients at two centers. Visual changes in tumor FDG uptake and changes measured semi-automatically, as standard uptake values (SUVs), were compared with radiological response after four and eight cycles. RESULTS: The mean baseline SUV for all tumor lesions per patient was higher in nonresponders than in responders (mean 7.4 versus 5.6, P = 0.02). There was a strong correlation between metabolic response (changes in SUV) and objective response (r = 0.57, P = 0.00001), with a sensitivity of 77% and a specificity of 76%. There was no significant correlation between metabolic response and time to progression (P = 0.5) or overall survival (P = 0.1). CONCLUSIONS: Although metabolic response assessed by FDG-PET reflects radiological tumor volume changes, the sensitivity and specificity are too low to support the routine use of PET in mCRC. Furthermore, PET failed to reflect long-term outcome and can, thus, not be used as surrogate end point for hard endpoint benefit.