Int J Radiat Oncol Biol Phys. 2010 Oct 30. [Epub ahead of print]
Addition of Bevacizumab to Standard Radiation Therapy and Daily Temozolomide Is Associated with Minimal Toxicity in Newly Diagnosed Glioblastoma Multiforme.
Vredenburgh JJ, Desjardins A, Kirkpatrick JP, Reardon DA, Peters KB, Herndon JE 2nd, Marcello J, Bailey L, Threatt S, Sampson J, Friedman A, Friedman HS.
Department of Medicine, Duke University Medical Center, Durham, NC.
Abstract
PURPOSE: To determine the safety of the addition of bevacizumab to standard radiation therapy and daily temozolomide for newly diagnosed glioblastoma multiforme (GBM).
METHODS AND MATERIALS: A total of 125 patients with newly diagnosed GBM were enrolled in the study, and received standard radiation therapy and daily temozolomide. All patients underwent a craniotomy and were at least 2 weeks postoperative. Radiation therapy was administered in 1.8-Gy fractions, with the clinical target volume for the primary course treated to a dose of 45 to 50.4 Gy, followed by a boost of 9 to 14.4 Gy, to a total dose of 59.4 Gy. Patients received temozolomide at 75 mg/m(2) daily throughout the course of radiation therapy. Bevacizumab was given at 10 mg/kg intravenously every 14 days, beginning a minimum of 4 weeks postoperatively.
RESULTS: Of the 125 patients, 120 (96%) completed the protocol-specified radiation therapy. Five patients had to stop the protocol therapy, 2 patients with pulmonary emboli, and 1 patient each with a Grade 2 central nervous system hemorrhage, Grade 4 pancytopenia, and wound dehiscence requiring surgical intervention. All 5 patients ultimately finished the radiation therapy. After radiation therapy, 3 patients had progressive disease, 2 had severe fatigue and decreased performance status, 1 patient had a colonic perforation, and 1 had a rectal fissure; these 7 patients therefore did not proceed with the protocol-specified adjuvant temozolomide, bevacizumab, and irinotecan. However, 113 patients (90%) were able to continue on study.
CONCLUSIONS: The addition of bevacizumab to standard radiation therapy and daily temozolomide was found to be associated with minimal toxicity in patients newly diagnosed with GBM.
Κυριακή, 7 Νοεμβρίου 2010
AN INTERESTING SECOND LINE TREATMENT FOR HORMONE REFRACTORY PROSTATE CANCER
Anticancer Res. 2010 Oct;30(10):4317-23.
Metronomic oral cyclophosphamide prednisolone chemotherapy is an effective treatment for metastatic hormone-refractory prostate cancer after docetaxel failure.
Ladoire S, Eymard JC, Zanetta S, Mignot G, Martin E, Kermarrec I, Mourey E, Michel F, Cormier L, Ghiringhelli F.
Department of Medical Oncology, Georges François Leclerc Center, Centre de Recherche INSERM 866, Faculté de Médecine, Dijon, France. sladoire@cgfl.fr
Abstract
BACKGROUND: There is currently no standard of treatment for patients with hormone refractory prostate cancer (HRPC) after failure of docetaxel-based chemotherapy. The purpose of this study was to assess the anticancer activity and tolerance of metronomic cyclophosphamide prednisolone combination in this setting.
PATIENTS AND METHODS: From 2005 to 2010, patients with HRPC who failed at least docetaxel-based chemotherapy were proposed metronomic cyclophosphamide-prednisolone regimen, and were prospectively registered. Twenty-three patients received 50 mg cyclophosphamide and 10 mg prednisolone per os daily until disease progression. Treatment tolerance and efficacy on PSA decrease and pain were studied.
RESULTS: Metronomic cyclophosphamide prednisolone was safe, well tolerated, and demonstrated interesting clinical activity, yielding a prostate specific antigen decrease by ≥50% in 26% of patients and decrease by ≥30% in 48% of patients, but also favorable palliative effects on pain in 43% of patients. The median progression-free survival was 6 months (95% CI: 4-8 months) and the median overall survival was 11 months (95% CI: 7-19 months).
CONCLUSION: For this patient population, low dose metronomic cyclophosphamide prednisolone might be a viable alternative. Its convenient oral administration, low cost, and lack of toxicity justify further studies alone, or in combination with other agents in HRPC patients.
Metronomic oral cyclophosphamide prednisolone chemotherapy is an effective treatment for metastatic hormone-refractory prostate cancer after docetaxel failure.
Ladoire S, Eymard JC, Zanetta S, Mignot G, Martin E, Kermarrec I, Mourey E, Michel F, Cormier L, Ghiringhelli F.
Department of Medical Oncology, Georges François Leclerc Center, Centre de Recherche INSERM 866, Faculté de Médecine, Dijon, France. sladoire@cgfl.fr
Abstract
BACKGROUND: There is currently no standard of treatment for patients with hormone refractory prostate cancer (HRPC) after failure of docetaxel-based chemotherapy. The purpose of this study was to assess the anticancer activity and tolerance of metronomic cyclophosphamide prednisolone combination in this setting.
PATIENTS AND METHODS: From 2005 to 2010, patients with HRPC who failed at least docetaxel-based chemotherapy were proposed metronomic cyclophosphamide-prednisolone regimen, and were prospectively registered. Twenty-three patients received 50 mg cyclophosphamide and 10 mg prednisolone per os daily until disease progression. Treatment tolerance and efficacy on PSA decrease and pain were studied.
RESULTS: Metronomic cyclophosphamide prednisolone was safe, well tolerated, and demonstrated interesting clinical activity, yielding a prostate specific antigen decrease by ≥50% in 26% of patients and decrease by ≥30% in 48% of patients, but also favorable palliative effects on pain in 43% of patients. The median progression-free survival was 6 months (95% CI: 4-8 months) and the median overall survival was 11 months (95% CI: 7-19 months).
CONCLUSION: For this patient population, low dose metronomic cyclophosphamide prednisolone might be a viable alternative. Its convenient oral administration, low cost, and lack of toxicity justify further studies alone, or in combination with other agents in HRPC patients.
ADJUVANT CHEMOTHERAPY USEFUL FOR COLORECTAL CANCER WITH METACHRONOUS RESECTED SOLITARY LIVER METASTASES
Ann Surg. 2010 Nov;252(5):774-787.
Is Perioperative Chemotherapy Useful for Solitary, Metachronous, Colorectal Liver Metastases?
Adam R, Bhangui P, Poston G, Mirza D, Nuzzo G, Barroso E, Ijzermans J, Hubert C, Ruers T, Capussotti L, Ouellet JF, Laurent C, Cugat E, Colombo PE, Milicevic M.
*Centre Hépato-Biliaire, Hôpital Paul Brousse, Assistance Publique-Hôpitaux de Paris, Univ Paris-Sud, UMR-S 776, Villejuif, France †Department of Surgery, University Hospital Aintree, Liverpool, UK ‡Queen Elizabeth Hospital Birmingham, Birmingham, UK; §Catholic University School of Medicine, Rome, Italy; ¶Centro Hepato-Bilio-Pancreatico e de Transplantacao do Hospital de Curry Cabral, Lisbon, Portugal; **Erasmus Medical Center, Rotterdam, the Netherlands; ††UCL St Luc, Brussels, Belgium; ‡‡St Radboud University Medical Centre, Nijmegen, the Netherlands; §§Ospedale Mauriziano Umberto I, Turin, Italy; ¶¶Chuq-Hotel Dieu de Quebec, Quebec, Canada; ***Hopital Saint-Andre, Saint-Andre, France; †††Hospital Mutua de Terrassa, Terrassa, Spain; ‡‡‡CRLC Val d'Aurelle, France; and §§§HPB and Liver Transplant Center, Clinic for Digestive Surgery, Clinical Center of Serbia, Belgrade, Serbia.
Abstract
BACKGROUND: Chemotherapy is increasingly used in colorectal liver metastases (CRLMs) even when they are initially resectable. The aim of our study was to address the still pending question of whether perioperative chemotherapy is really beneficial in patients developing solitary metastases at a distance from surgery of the primary.
METHODS: We analyzed a multicentric cohort of 1471 patients resected for solitary, metachronous, primarily resectable CRLMs without extrahepatic disease in the LiverMetSurvey International Registry over a 15-year period. Patients who received at least 3 cycles of oxaliplatin- or irinotecan-based chemotherapy before liver surgery (group CS, n = 169) were compared with those who were resected upfront (group S, n = 1302).
RESULTS: Patients of group CS were more frequently females (49% vs 36%, P = 0.001) and had larger metastases (≥5 cm, 33% vs 23%, P = 0.007); no difference was observed with regard to age, site of the primary tumour, time delay to occurrence of metastases, and carcinoembryonic antigen (CEA) levels at the time of diagnosis in the 2 groups. The rate of postoperative complications was significantly higher in group CS (37.2% vs 24% in group S, P = 0.006). At univariate analysis, preoperative chemotherapy did not impact the overall survival (OS) (60% at 5 years in both groups); however, postoperative chemotherapy was associated with better OS (65% vs 55% at 5 years, P < 0.01). At multivariate analysis, age 70 years or older (P = 0.05), lymph node positivity in the primary tumor (P = 0.02), a primary-to-metastases time delay of less than 12 months (P = 0.04), raised CEA levels of more than 5 ng/mL at diagnosis (P < 0.01), a tumor diameter of 5 cm or more (P < 0.01), noncurative liver resection (P < 0.01), and the absence of postoperative chemotherapy (P < 0.01) were independent prognostic factors of survival. The disease-free survival (DFS) was negatively influenced by CEA level of more than 5 ng/mL (P < 0.01), size of the metastases 5 cm or more (P = 0.05), and the absence of postoperative chemotherapy (P < 0.01). When patients with metastases of less than 5 cm in size were compared to those with metastases of size 5 cm or more, preoperative chemotherapy did not influence the OS or DFS in either group. Postoperative chemotherapy, on the other hand, improved OS and DFS in patients with metastases of size 5 cm or more but not in patients with metastases of less than 5 cm in size.
CONCLUSIONS: Although preoperative chemotherapy does not seem to benefit the outcome of patients with solitary, metachronous CRLM, postoperative chemotherapy is associated with better OS and DFS, mainly when the tumor diameter exceeds 5 cm.
Is Perioperative Chemotherapy Useful for Solitary, Metachronous, Colorectal Liver Metastases?
Adam R, Bhangui P, Poston G, Mirza D, Nuzzo G, Barroso E, Ijzermans J, Hubert C, Ruers T, Capussotti L, Ouellet JF, Laurent C, Cugat E, Colombo PE, Milicevic M.
*Centre Hépato-Biliaire, Hôpital Paul Brousse, Assistance Publique-Hôpitaux de Paris, Univ Paris-Sud, UMR-S 776, Villejuif, France †Department of Surgery, University Hospital Aintree, Liverpool, UK ‡Queen Elizabeth Hospital Birmingham, Birmingham, UK; §Catholic University School of Medicine, Rome, Italy; ¶Centro Hepato-Bilio-Pancreatico e de Transplantacao do Hospital de Curry Cabral, Lisbon, Portugal; **Erasmus Medical Center, Rotterdam, the Netherlands; ††UCL St Luc, Brussels, Belgium; ‡‡St Radboud University Medical Centre, Nijmegen, the Netherlands; §§Ospedale Mauriziano Umberto I, Turin, Italy; ¶¶Chuq-Hotel Dieu de Quebec, Quebec, Canada; ***Hopital Saint-Andre, Saint-Andre, France; †††Hospital Mutua de Terrassa, Terrassa, Spain; ‡‡‡CRLC Val d'Aurelle, France; and §§§HPB and Liver Transplant Center, Clinic for Digestive Surgery, Clinical Center of Serbia, Belgrade, Serbia.
Abstract
BACKGROUND: Chemotherapy is increasingly used in colorectal liver metastases (CRLMs) even when they are initially resectable. The aim of our study was to address the still pending question of whether perioperative chemotherapy is really beneficial in patients developing solitary metastases at a distance from surgery of the primary.
METHODS: We analyzed a multicentric cohort of 1471 patients resected for solitary, metachronous, primarily resectable CRLMs without extrahepatic disease in the LiverMetSurvey International Registry over a 15-year period. Patients who received at least 3 cycles of oxaliplatin- or irinotecan-based chemotherapy before liver surgery (group CS, n = 169) were compared with those who were resected upfront (group S, n = 1302).
RESULTS: Patients of group CS were more frequently females (49% vs 36%, P = 0.001) and had larger metastases (≥5 cm, 33% vs 23%, P = 0.007); no difference was observed with regard to age, site of the primary tumour, time delay to occurrence of metastases, and carcinoembryonic antigen (CEA) levels at the time of diagnosis in the 2 groups. The rate of postoperative complications was significantly higher in group CS (37.2% vs 24% in group S, P = 0.006). At univariate analysis, preoperative chemotherapy did not impact the overall survival (OS) (60% at 5 years in both groups); however, postoperative chemotherapy was associated with better OS (65% vs 55% at 5 years, P < 0.01). At multivariate analysis, age 70 years or older (P = 0.05), lymph node positivity in the primary tumor (P = 0.02), a primary-to-metastases time delay of less than 12 months (P = 0.04), raised CEA levels of more than 5 ng/mL at diagnosis (P < 0.01), a tumor diameter of 5 cm or more (P < 0.01), noncurative liver resection (P < 0.01), and the absence of postoperative chemotherapy (P < 0.01) were independent prognostic factors of survival. The disease-free survival (DFS) was negatively influenced by CEA level of more than 5 ng/mL (P < 0.01), size of the metastases 5 cm or more (P = 0.05), and the absence of postoperative chemotherapy (P < 0.01). When patients with metastases of less than 5 cm in size were compared to those with metastases of size 5 cm or more, preoperative chemotherapy did not influence the OS or DFS in either group. Postoperative chemotherapy, on the other hand, improved OS and DFS in patients with metastases of size 5 cm or more but not in patients with metastases of less than 5 cm in size.
CONCLUSIONS: Although preoperative chemotherapy does not seem to benefit the outcome of patients with solitary, metachronous CRLM, postoperative chemotherapy is associated with better OS and DFS, mainly when the tumor diameter exceeds 5 cm.
BREAST CANCER AND HORMONE THERAPY
JAMA. 2010 Oct 20;304(15):1684-92.
Estrogen plus progestin and breast cancer incidence and mortality in postmenopausal women.
Chlebowski RT, Anderson GL, Gass M, Lane DS, Aragaki AK, Kuller LH, Manson JE, Stefanick ML, Ockene J, Sarto GE, Johnson KC, Wactawski-Wende J, Ravdin PM, Schenken R, Hendrix SL, Rajkovic A, Rohan TE, Yasmeen S, Prentice RL; WHI Investigators.
S, Lane D, Granek I, Lawson W, Messina C, San Roman G, Jackson R, Harris R, Paskett
Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, 1124 W Carson St, Torrance, CA 90502, USA. rchlebowski@gmail.com
Comment in:
* JAMA. 2010 Oct 20;304(15):1719-20.
Abstract
CONTEXT: In the Women's Health Initiative randomized, placebo-controlled trial of estrogen plus progestin, after a mean intervention time of 5.6 (SD, 1.3) years (range, 3.7-8.6 years) and a mean follow-up of 7.9 (SD, 1.4) years, breast cancer incidence was increased among women who received combined hormone therapy. Breast cancer mortality among participants in the trial has not been previously reported.
OBJECTIVE: To determine the effects of therapy with estrogen plus progestin on cumulative breast cancer incidence and mortality after a total mean follow-up of 11.0 (SD, 2.7) years, through August 14, 2009.
DESIGN, SETTING, AND PARTICIPANTS: A total of 16,608 postmenopausal women aged 50 to 79 years with no prior hysterectomy from 40 US clinical centers were randomly assigned to receive combined conjugated equine estrogens, 0.625 mg/d, plus medroxyprogesterone acetate, 2.5 mg/d, or placebo pill. After the original trial completion date (March 31, 2005), reconsent was required for continued follow-up for breast cancer incidence and was obtained from 12,788 (83%) of the surviving participants.
MAIN OUTCOME MEASURES: Invasive breast cancer incidence and breast cancer mortality.
RESULTS: In intention-to-treat analyses including all randomized participants and censoring those not consenting to additional follow-up on March 31, 2005, estrogen plus progestin was associated with more invasive breast cancers compared with placebo (385 cases [0.42% per year] vs 293 cases [0.34% per year]; hazard ratio [HR], 1.25; 95% confidence interval [CI], 1.07-1.46; P = .004). Breast cancers in the estrogen-plus-progestin group were similar in histology and grade to breast cancers in the placebo group but were more likely to be node-positive (81 [23.7%] vs 43 [16.2%], respectively; HR, 1.78; 95% CI, 1.23-2.58; P = .03). There were more deaths directly attributed to breast cancer (25 deaths [0.03% per year] vs 12 deaths [0.01% per year]; HR, 1.96; 95% CI, 1.00-4.04; P = .049) as well as more deaths from all causes occurring after a breast cancer diagnosis (51 deaths [0.05% per year] vs 31 deaths [0.03% per year]; HR, 1.57; 95% CI, 1.01-2.48; P = .045) among women who received estrogen plus progestin compared with women in the placebo group.
CONCLUSIONS: Estrogen plus progestin was associated with greater breast cancer incidence, and the cancers are more commonly node-positive. Breast cancer mortality also appears to be increased with combined use of estrogen plus progestin.
Estrogen plus progestin and breast cancer incidence and mortality in postmenopausal women.
Chlebowski RT, Anderson GL, Gass M, Lane DS, Aragaki AK, Kuller LH, Manson JE, Stefanick ML, Ockene J, Sarto GE, Johnson KC, Wactawski-Wende J, Ravdin PM, Schenken R, Hendrix SL, Rajkovic A, Rohan TE, Yasmeen S, Prentice RL; WHI Investigators.
S, Lane D, Granek I, Lawson W, Messina C, San Roman G, Jackson R, Harris R, Paskett
Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, 1124 W Carson St, Torrance, CA 90502, USA. rchlebowski@gmail.com
Comment in:
* JAMA. 2010 Oct 20;304(15):1719-20.
Abstract
CONTEXT: In the Women's Health Initiative randomized, placebo-controlled trial of estrogen plus progestin, after a mean intervention time of 5.6 (SD, 1.3) years (range, 3.7-8.6 years) and a mean follow-up of 7.9 (SD, 1.4) years, breast cancer incidence was increased among women who received combined hormone therapy. Breast cancer mortality among participants in the trial has not been previously reported.
OBJECTIVE: To determine the effects of therapy with estrogen plus progestin on cumulative breast cancer incidence and mortality after a total mean follow-up of 11.0 (SD, 2.7) years, through August 14, 2009.
DESIGN, SETTING, AND PARTICIPANTS: A total of 16,608 postmenopausal women aged 50 to 79 years with no prior hysterectomy from 40 US clinical centers were randomly assigned to receive combined conjugated equine estrogens, 0.625 mg/d, plus medroxyprogesterone acetate, 2.5 mg/d, or placebo pill. After the original trial completion date (March 31, 2005), reconsent was required for continued follow-up for breast cancer incidence and was obtained from 12,788 (83%) of the surviving participants.
MAIN OUTCOME MEASURES: Invasive breast cancer incidence and breast cancer mortality.
RESULTS: In intention-to-treat analyses including all randomized participants and censoring those not consenting to additional follow-up on March 31, 2005, estrogen plus progestin was associated with more invasive breast cancers compared with placebo (385 cases [0.42% per year] vs 293 cases [0.34% per year]; hazard ratio [HR], 1.25; 95% confidence interval [CI], 1.07-1.46; P = .004). Breast cancers in the estrogen-plus-progestin group were similar in histology and grade to breast cancers in the placebo group but were more likely to be node-positive (81 [23.7%] vs 43 [16.2%], respectively; HR, 1.78; 95% CI, 1.23-2.58; P = .03). There were more deaths directly attributed to breast cancer (25 deaths [0.03% per year] vs 12 deaths [0.01% per year]; HR, 1.96; 95% CI, 1.00-4.04; P = .049) as well as more deaths from all causes occurring after a breast cancer diagnosis (51 deaths [0.05% per year] vs 31 deaths [0.03% per year]; HR, 1.57; 95% CI, 1.01-2.48; P = .045) among women who received estrogen plus progestin compared with women in the placebo group.
CONCLUSIONS: Estrogen plus progestin was associated with greater breast cancer incidence, and the cancers are more commonly node-positive. Breast cancer mortality also appears to be increased with combined use of estrogen plus progestin.
METFORMIN REDUCES CANCER RISK IN DIABETICS
Diabetes Care. 2010 Oct 27. [Epub ahead of print]
METFORMIN AND CANCER OCCURRENCE IN INSULIN-TREATED TYPE 2 DIABETIC PATIENTS.
Monami M, Colombi C, Balzi D, Dicembrini I, Giannini S, Melani C, Vitale V, Romano D, Barchielli A, Marchionni N, Rotella CM, Mannucci E.
Section of Geriatric Cardiology and Medicine, Department of Cardiovascular Medicine, University of Florence and Careggi Teaching Hospital, Florence, Italy.
Abstract
AbstractObjective: Metformin is associated with reduced cancer-related morbidity and mortality. This study is aimed at assessing the effect of metformin on cancer incidence in a consecutive series of insulin-treated patients. Research Design and Methods: A nested case-control study was performed within a cohort of 1,340 patients, by sampling, for each case, age-, sex- and BMI-matched controls from the same cohort. Results: During a median follow-up of 75.9 months, 112 cases of incident cancer were observed and compared with 370 controls. A significantly lower proportion of subjects was exposed to metformin and sulfanylureas among cases. After adjusting for comorbidity, glargine and total insulin doses, exposure to metformin, but not sulfonylureas, was associated with reduced incidence of cancer (OR 0.46[0.25-0.85],p=0.014, and 0.75[0.39-1.45],p=0.40, respectively). Conclusions: The reduction of cancer risk could be a further, relevant reason for maintaining metformin in insulin-treated patients.
METFORMIN AND CANCER OCCURRENCE IN INSULIN-TREATED TYPE 2 DIABETIC PATIENTS.
Monami M, Colombi C, Balzi D, Dicembrini I, Giannini S, Melani C, Vitale V, Romano D, Barchielli A, Marchionni N, Rotella CM, Mannucci E.
Section of Geriatric Cardiology and Medicine, Department of Cardiovascular Medicine, University of Florence and Careggi Teaching Hospital, Florence, Italy.
Abstract
AbstractObjective: Metformin is associated with reduced cancer-related morbidity and mortality. This study is aimed at assessing the effect of metformin on cancer incidence in a consecutive series of insulin-treated patients. Research Design and Methods: A nested case-control study was performed within a cohort of 1,340 patients, by sampling, for each case, age-, sex- and BMI-matched controls from the same cohort. Results: During a median follow-up of 75.9 months, 112 cases of incident cancer were observed and compared with 370 controls. A significantly lower proportion of subjects was exposed to metformin and sulfanylureas among cases. After adjusting for comorbidity, glargine and total insulin doses, exposure to metformin, but not sulfonylureas, was associated with reduced incidence of cancer (OR 0.46[0.25-0.85],p=0.014, and 0.75[0.39-1.45],p=0.40, respectively). Conclusions: The reduction of cancer risk could be a further, relevant reason for maintaining metformin in insulin-treated patients.
Σάββατο, 6 Νοεμβρίου 2010
TIME TO SCREEN HEAVY SMOKERS FOR LUNG CANCER
November 4, 2010 — The huge randomized National Lung Screening Trial (NLST) in the United States has been stopped after 8-year results showed that screening heavy smokers with low-dose helical computed tomography (CT) significantly reduced deaths from lung cancer, compared with screening with chest x-rays.
"This is the first time that we have seen clear evidence of a significant reduction in lung cancer mortality with a screening test in a randomized controlled clinical trial," said Christine Berg, MD, NLST project officer for the Lung Screening Study at the National Cancer Institute (NCI), which funded the trial. Her comments appear in a press release from the NCI announcing the results.
This finding will "have implications for the screening and management of lung cancer for many years to come," Dr. Berg predicted.
Initial Reactions
"The fact that the NLST was stopped early so that the tremendous positive results could be made known speaks volumes to the ability of helical CT screening of high-risk individuals to saves lives," according to a statement from the American College of Radiology (ACR). It also reports that the ACR looks forward to discussions about instigating a potential lung cancer screening program.
This is "a seminal moment" for the lung cancer community, the Lung Cancer Alliance declared in a press release. It also quoted James Mulshine, MD, from the Rush University Medical Center in Chicago, Illinois, as saying: "With this positive trial result, we have the opportunity to realize the greatest single reduction of cancer mortality in the history of the war on cancer."
Results Eagerly Anticipated
The NLST results have been eagerly anticipated. Previous studies on CT screening for lung cancer have yielded conflicting results. The major trial to date (the I-ECLAP trial headed by Claudia Henschke, MD, from the New York–Presbyterian/Weill Cornell Medical Center in New York City) suggested a mortality benefit, but it lacked a control group, and then became shrouded in controversy when it was revealed that the researchers received some funding from the tobacco industry.
Despite the controversy and criticism of that trial, proponents of CT screening called for national screening programs for lung cancer to be set up, and one group of researchers even questioned whether it was ethical for the NLST to continue in light of the benefits that had been seen. But a number of lung cancer experts, and the NLST, insisted in 2007 that the field wait for results from randomized trials.
The NLST provides the first results to come out of a randomized trial. "This large and well-designed study used rigorous scientific methods to test ways to prevent death from lung cancer by screening patients at especially high risk," said NCI director Harold Varmus, MD, in a statement.
Significant Reduction in Mortality
The trial began in 2002 and has involved more than 53,000 current and former heavy smokers 55 to 74 years of age. Individuals were randomized to undergo screening annually for 3 years with either CT or chest x-rays, and were then followed for another 5 years.
The results, which were reviewed by the trial's Data and Safety Monitoring Board on October 20, show a statistically significant difference in lung cancer mortality in the 2 groups, which led to the trial being halted. There were 354 lung cancer deaths among those who underwent CT screening and 442 among those who underwent chest x-ray (a 20% reduction).
"Lung cancer is the leading cause of cancer mortality in the United States and throughout the world, so a validated approach that can reduce lung cancer mortality by even 20% has the potential to spare very significant numbers of people from the ravages of this disease," Dr. Varmus explained.
"The results of this trial provide objective evidence of the benefits of low-dose helical CT screening in an older high-risk population, and suggest that if low-dose helical screening is implemented responsibly and individuals with abnormalities are judiciously followed, we have the potential to save thousands of lives," said Denise Aberle, MD, NLST national principal investigator.
"However, given the [strong] association between lung cancer and cigarette smoking, the trial investigators re-emphasize that the single best way to prevent lung cancer deaths is to never start smoking and, if already smoking, to quit permanently," she added.
Another finding from the study, which was not the primary end point, was a 7% reduction in all-cause mortality among people who were screened by CT, compared with those screened by chest x-ray. About 25% of all the deaths were due to lung cancer; the other deaths were related to causes such as cardiovascular disease, the NCI notes in its press release.
A fuller analysis of the results is being prepared for publication in a peer-reviewed journal in the next few months, according to the NCI.
Many Questions Remain
Approached for comment on the new finding, Michael Unger, MD, FACP, FCCP, who is director of the Pulmonary Cancer Detection and Prevention Program at Fox Chase Cancer Center in Philadelphia, Pennsylvania, pointed out that the actual data from the study have not yet been published. The results released so far "in essence" confirm the findings from the study by Dr. Henschke and colleagues, but many questions remain, he told Medscape Medical News.
"The most important is: Who is really at high risk?" he said. "Other questions include when and how long we should study the subjects." Then there is the issue of false positives, where the CT screen picks up lesions that are not lung cancer, he noted. Previous studies have reported high rates of false positives with CT screening for lung cancer, ranging from 25% to 70%.
"Basically, screening is not a test, it is a process involving correct diagnosis and most appropriate management," Dr. Unger said.
There are still questions that need to be answered, agreed Ella Kazerooni, MD, who was a site principal investigator for the NLST at the University of Michigan in Ann Arbor, and is also chair of the ACR Thoracic Imaging Committee. The trial started screening heavy smokers who were 55 years of age, and screened once a year for 3 years, she explained, "but we don't know if we could start screening at an earlier or later age, and if we could screen only every 3 or 5 years."
However, the fact that a reduction in mortality was shown "marks a very big moment for the lung cancer field," Dr. Kazerooni told Medscape Medical News. This is the first time that any test or screen for lung cancer has shown this, she emphasized.
These results now "open up the dialogue" about potential screening programs for lung cancer, and she anticipates that the new data will be scrutinized by professional organizations that draw up such recommendations, such as the American Cancer Society, the US Preventive Services Task Force, and the National Comprehensive Cancer Network. In addition, before any screening program can be instigated, its cost-effectiveness will need to be considered; the NLST will provide some of these data, she said.
Thus far, there has been no recommendation for lung cancer screening from any authority, but these new data might be a turning point.
"The early termination of the trial (on effectiveness grounds) does represent an important and positive development. Hopefully, authoritative agencies, such as the US Preventive Services Task Force, the American Cancer Society, and the American College of Chest Physicians, will now reconsider their nihilistic recommendations regarding screening for lung cancer," said Igor Karp, MD, MPH, PhD, assistant professor, Department of Social and Preventive Medicine, Université de Montréal, Quebec.
Dr. Karp was one of the researchers who, in 2007, questioned the ethics of continuing the NLST trial, arguing that the benefits of CT screening had already been shown.
"I, like many others, have been of the opinion that this trial was unnecessary, given the previously available evidence (notably from the I-ELCAP study) that low-dose [helical] CT-based screening serves to prevent death from lung cancer," he explained.
Dr. Karp said that he has "a somewhat mixed reaction" to the results that have been announced. "From the hypothesis-testing point of view, the NLST is not particularly interesting, [but] the question of the magnitude of the benefit is, indeed, very important," he told Medscape Medical News.
Benefit Might Be Underestimated
"However, it is unclear how informative this trial actually is in this regard, given its design and analysis (at least in its current form)," he noted, adding that he suspects that the magnitude of benefit might in fact be "much larger" than has been reported.
"One of the biggest issues here is that the reported 20% mortality reduction (which is, in fact, not really a mortality reduction, but just a proportional difference in empirical mortality rates) does not represent a meaningful parameter, so its interpretation presents a considerable challenge," he explained.
"What is clear, however, is that it certainly does not quantify the full potential benefit of the CT screening," he said, "because it is based on mixing relevant mortality experience during a relatively late subsegment of follow-up with irrelevant mortality experience during the early subsegment of follow-up (when no lung cancer deaths could have possibly been prevented by early intervention, so no survival advantage for the CT-screened arm could have been expected there a priori)."
Dr. Karp also pointed out that the results come from the "arbitrary regimen of 3 annual screenings, which by no means represents the optimal (or typical) regimen of screening."
In addition, there are no data yet on adherence to the protocol of screening; if this was low, the benefit of CT screening "would almost certainly be underestimated," he added.
"This is the first time that we have seen clear evidence of a significant reduction in lung cancer mortality with a screening test in a randomized controlled clinical trial," said Christine Berg, MD, NLST project officer for the Lung Screening Study at the National Cancer Institute (NCI), which funded the trial. Her comments appear in a press release from the NCI announcing the results.
This finding will "have implications for the screening and management of lung cancer for many years to come," Dr. Berg predicted.
Initial Reactions
"The fact that the NLST was stopped early so that the tremendous positive results could be made known speaks volumes to the ability of helical CT screening of high-risk individuals to saves lives," according to a statement from the American College of Radiology (ACR). It also reports that the ACR looks forward to discussions about instigating a potential lung cancer screening program.
This is "a seminal moment" for the lung cancer community, the Lung Cancer Alliance declared in a press release. It also quoted James Mulshine, MD, from the Rush University Medical Center in Chicago, Illinois, as saying: "With this positive trial result, we have the opportunity to realize the greatest single reduction of cancer mortality in the history of the war on cancer."
Results Eagerly Anticipated
The NLST results have been eagerly anticipated. Previous studies on CT screening for lung cancer have yielded conflicting results. The major trial to date (the I-ECLAP trial headed by Claudia Henschke, MD, from the New York–Presbyterian/Weill Cornell Medical Center in New York City) suggested a mortality benefit, but it lacked a control group, and then became shrouded in controversy when it was revealed that the researchers received some funding from the tobacco industry.
Despite the controversy and criticism of that trial, proponents of CT screening called for national screening programs for lung cancer to be set up, and one group of researchers even questioned whether it was ethical for the NLST to continue in light of the benefits that had been seen. But a number of lung cancer experts, and the NLST, insisted in 2007 that the field wait for results from randomized trials.
The NLST provides the first results to come out of a randomized trial. "This large and well-designed study used rigorous scientific methods to test ways to prevent death from lung cancer by screening patients at especially high risk," said NCI director Harold Varmus, MD, in a statement.
Significant Reduction in Mortality
The trial began in 2002 and has involved more than 53,000 current and former heavy smokers 55 to 74 years of age. Individuals were randomized to undergo screening annually for 3 years with either CT or chest x-rays, and were then followed for another 5 years.
The results, which were reviewed by the trial's Data and Safety Monitoring Board on October 20, show a statistically significant difference in lung cancer mortality in the 2 groups, which led to the trial being halted. There were 354 lung cancer deaths among those who underwent CT screening and 442 among those who underwent chest x-ray (a 20% reduction).
"Lung cancer is the leading cause of cancer mortality in the United States and throughout the world, so a validated approach that can reduce lung cancer mortality by even 20% has the potential to spare very significant numbers of people from the ravages of this disease," Dr. Varmus explained.
"The results of this trial provide objective evidence of the benefits of low-dose helical CT screening in an older high-risk population, and suggest that if low-dose helical screening is implemented responsibly and individuals with abnormalities are judiciously followed, we have the potential to save thousands of lives," said Denise Aberle, MD, NLST national principal investigator.
"However, given the [strong] association between lung cancer and cigarette smoking, the trial investigators re-emphasize that the single best way to prevent lung cancer deaths is to never start smoking and, if already smoking, to quit permanently," she added.
Another finding from the study, which was not the primary end point, was a 7% reduction in all-cause mortality among people who were screened by CT, compared with those screened by chest x-ray. About 25% of all the deaths were due to lung cancer; the other deaths were related to causes such as cardiovascular disease, the NCI notes in its press release.
A fuller analysis of the results is being prepared for publication in a peer-reviewed journal in the next few months, according to the NCI.
Many Questions Remain
Approached for comment on the new finding, Michael Unger, MD, FACP, FCCP, who is director of the Pulmonary Cancer Detection and Prevention Program at Fox Chase Cancer Center in Philadelphia, Pennsylvania, pointed out that the actual data from the study have not yet been published. The results released so far "in essence" confirm the findings from the study by Dr. Henschke and colleagues, but many questions remain, he told Medscape Medical News.
"The most important is: Who is really at high risk?" he said. "Other questions include when and how long we should study the subjects." Then there is the issue of false positives, where the CT screen picks up lesions that are not lung cancer, he noted. Previous studies have reported high rates of false positives with CT screening for lung cancer, ranging from 25% to 70%.
"Basically, screening is not a test, it is a process involving correct diagnosis and most appropriate management," Dr. Unger said.
There are still questions that need to be answered, agreed Ella Kazerooni, MD, who was a site principal investigator for the NLST at the University of Michigan in Ann Arbor, and is also chair of the ACR Thoracic Imaging Committee. The trial started screening heavy smokers who were 55 years of age, and screened once a year for 3 years, she explained, "but we don't know if we could start screening at an earlier or later age, and if we could screen only every 3 or 5 years."
However, the fact that a reduction in mortality was shown "marks a very big moment for the lung cancer field," Dr. Kazerooni told Medscape Medical News. This is the first time that any test or screen for lung cancer has shown this, she emphasized.
These results now "open up the dialogue" about potential screening programs for lung cancer, and she anticipates that the new data will be scrutinized by professional organizations that draw up such recommendations, such as the American Cancer Society, the US Preventive Services Task Force, and the National Comprehensive Cancer Network. In addition, before any screening program can be instigated, its cost-effectiveness will need to be considered; the NLST will provide some of these data, she said.
Thus far, there has been no recommendation for lung cancer screening from any authority, but these new data might be a turning point.
"The early termination of the trial (on effectiveness grounds) does represent an important and positive development. Hopefully, authoritative agencies, such as the US Preventive Services Task Force, the American Cancer Society, and the American College of Chest Physicians, will now reconsider their nihilistic recommendations regarding screening for lung cancer," said Igor Karp, MD, MPH, PhD, assistant professor, Department of Social and Preventive Medicine, Université de Montréal, Quebec.
Dr. Karp was one of the researchers who, in 2007, questioned the ethics of continuing the NLST trial, arguing that the benefits of CT screening had already been shown.
"I, like many others, have been of the opinion that this trial was unnecessary, given the previously available evidence (notably from the I-ELCAP study) that low-dose [helical] CT-based screening serves to prevent death from lung cancer," he explained.
Dr. Karp said that he has "a somewhat mixed reaction" to the results that have been announced. "From the hypothesis-testing point of view, the NLST is not particularly interesting, [but] the question of the magnitude of the benefit is, indeed, very important," he told Medscape Medical News.
Benefit Might Be Underestimated
"However, it is unclear how informative this trial actually is in this regard, given its design and analysis (at least in its current form)," he noted, adding that he suspects that the magnitude of benefit might in fact be "much larger" than has been reported.
"One of the biggest issues here is that the reported 20% mortality reduction (which is, in fact, not really a mortality reduction, but just a proportional difference in empirical mortality rates) does not represent a meaningful parameter, so its interpretation presents a considerable challenge," he explained.
"What is clear, however, is that it certainly does not quantify the full potential benefit of the CT screening," he said, "because it is based on mixing relevant mortality experience during a relatively late subsegment of follow-up with irrelevant mortality experience during the early subsegment of follow-up (when no lung cancer deaths could have possibly been prevented by early intervention, so no survival advantage for the CT-screened arm could have been expected there a priori)."
Dr. Karp also pointed out that the results come from the "arbitrary regimen of 3 annual screenings, which by no means represents the optimal (or typical) regimen of screening."
In addition, there are no data yet on adherence to the protocol of screening; if this was low, the benefit of CT screening "would almost certainly be underestimated," he added.
A BREAKTHROUG TREATMENT FOR RELAPSED HODGKIN LYMPHOMA
November 3, 2010 — A new drug for relapsed or refractory Hodgkin's lymphoma and anaplastic large-cell lymphoma — brentuximab vedotin (developed by Seattle Genetics and Millennium/Takeda) — is close to market.
"I never use the term breakthrough, but this is definitely a major step forward in the treatment of both of those types of lymphoma," Joseph Connors, MD, director of the Centre for Lymphoid Cancer in Vancouver, British Columbia, told Medscape Medical News. He was involved in 2 pivotal clinical trials that will be used for approval applications for brentuximab in both the United States and Europe, expected to be filed early next year.
Both studies are due to be presented next month at the American Society of Hematology annual meeting, but top-line results showing "very high response rates" were announced in press releases from the manufacturer.
Brentuximab used alone in patients with relapsed or refractory Hodgkin's lymphoma (n = 102) showed a 75% objective response rate; in patients with relapsed or refractory anaplastic large-cell lymphoma (n = 58), the drug produced an 86% objective response rate.
"These sorts of response rates are unheard of," said Anas Younes, MD, from the University of Texas M.D. Anderson Cancer Center in Houston.
"This is remarkable single-agent activity," Dr. Younes told Medscape Medical News, and it confirms results seen in an earlier phase 1 trial that he conducted, which has just been published in the November 4 issue of the New England Journal of Medicine.
These are patients who have no other therapeutic options, Dr. Younes said. They have failed on first-line chemotherapy, and then they have failed on second-line chemotherapy with an autologous stem-cell transplant, he explained.
"We can try other chemotherapies and even radiation, but these don't really work, and the average life-span for such a patient is about 2 and a half years," he said.
"Keep in mind that these are young patients," Dr. Younes added, pointing out that the average age of a patient diagnosed with Hodgkin's lymphoma is about 30 years.
Brentuximab will offer a new option for these patients, and "creates hope for these young men and women," he said. "They have been neglected in terms of drug development for more than 4 decades," Dr. Younes said, because "they represent a very small market."
Hodgkin's lymphoma affects about 8500 people annually in the United States, he noted, adding that "we expect to cure about 80% of all new comers. It's a highly curable disease." But the patients who fail on standard therapies have had, until now, no other hope, he said.
Antibody With Toxin Attached
The new product is an antibody–drug conjugate that targets CD30, which is expressed on the surface of cells in Hodgkin's lymphoma and anaplastic large-cell lymphoma, an aggressive type of T cell non-Hodgkin's lymphoma.
In both of these diseases, all of the cancer cells express CD30, so this protein represents an obvious target for therapy. However, previous attempts with antibodies directed against CD30 were unsuccessful. Even the antibody in this latest product, when used alone, showed little clinical activity, explained Dr. Younes — it was combining it with a toxin that did the trick.
The toxin in brentuximab is the antitubulin agent monomethyl auristatin E, and it is attached to anti-CD30-specific monoclonal antibody cAC10. The antibody acts as a delivery system to get the "cargo" into the cell, Dr. Younes explained.
The resultant product is "very well tolerated," he said, especially compared with chemotherapy. In the phase 1 trial that he headed, there were reports of fatigue, fever, diarrhea, some neutropenia, and cumulative neuropathy, he said.
That just-published phase 1 study involved 45 patients with relapsed or refractory Hodgkin's lymphoma or anaplastic large-cell lymphoma. Patients received brentuximab as a single agent, once every 3 weeks (as they did in the 2 pivotal phase 2 studies). The results showed objective responses in 17 patients, with complete remission in 11 patients; median duration of response was 9.7 months. In addition, 36 of 42 evaluable patients (86%) showed a tumor response.
"These sorts of responses are amazing with a single agent in such a refractory patient population," Dr. Younes noted. These initial results have since been confirmed by another phase 1 trial (presented recently at the 8th International Symposium on Hodgkin Lymphoma in Cologne, Germany [abstract 74]) and by the 2 larger pivotal phase 2 trials.
Having been involved in both of those pivotal trials, Dr. Connors predicts that brentuximab will "have a major role to play" in the management of both Hodgkin's lymphoma and anaplastic large-cell lymphoma.
"First, it will be useful all by itself for patients with no other good alternative," he said.
The 2 studies will be used as the basis for approval applications in both the United States and in Europe, which the manufacturer plans to file in early 2011. The product has been granted fast-track status by the US Food and Drug Administration for Hodgkin's lymphoma, which means review within 6 months, so brentuximab could be on the market before the end of next year.
The product has also been granted orphan drug status in both the United States and Europe, because relapsed and refractory Hodgkin's lymphoma represents a substantial unmet medical need, according to the company. Worldwide, almost one third of the 30,000 newly diagnosed patients relapse or become refractory to front-line therapy each year.
However, this use in relapsed/refractory patients might be just the beginning. Dr. Connors notes that "in future studies, it should be possible to include brentuximab in addition to standard treatments for both of those lymphomas in a way that boosts their cure rates without adding much to the toxicity of the treatments."
Further trials are already under way, the manufacturers note in a press release. A phase 3 clinical trial (known as AETHERA) is being conducted in patients at high risk for residual Hodgkin's lymphoma after autologous stem-cell transplant, a phase 2 trial is exploring retreatment in relapsed patients who have previously responded to brentuximab, and a phase 1 trial is investigating front-line combination treatment of Hodgkin's lymphoma.
All of the clinical trials with brentuximab have been/are being funded by the manufacturers, Seattle Genetics and Millennium/Takeda.
N Engl J Med. 2010;363:1812-1821.
"I never use the term breakthrough, but this is definitely a major step forward in the treatment of both of those types of lymphoma," Joseph Connors, MD, director of the Centre for Lymphoid Cancer in Vancouver, British Columbia, told Medscape Medical News. He was involved in 2 pivotal clinical trials that will be used for approval applications for brentuximab in both the United States and Europe, expected to be filed early next year.
Both studies are due to be presented next month at the American Society of Hematology annual meeting, but top-line results showing "very high response rates" were announced in press releases from the manufacturer.
Brentuximab used alone in patients with relapsed or refractory Hodgkin's lymphoma (n = 102) showed a 75% objective response rate; in patients with relapsed or refractory anaplastic large-cell lymphoma (n = 58), the drug produced an 86% objective response rate.
"These sorts of response rates are unheard of," said Anas Younes, MD, from the University of Texas M.D. Anderson Cancer Center in Houston.
"This is remarkable single-agent activity," Dr. Younes told Medscape Medical News, and it confirms results seen in an earlier phase 1 trial that he conducted, which has just been published in the November 4 issue of the New England Journal of Medicine.
These are patients who have no other therapeutic options, Dr. Younes said. They have failed on first-line chemotherapy, and then they have failed on second-line chemotherapy with an autologous stem-cell transplant, he explained.
"We can try other chemotherapies and even radiation, but these don't really work, and the average life-span for such a patient is about 2 and a half years," he said.
"Keep in mind that these are young patients," Dr. Younes added, pointing out that the average age of a patient diagnosed with Hodgkin's lymphoma is about 30 years.
Brentuximab will offer a new option for these patients, and "creates hope for these young men and women," he said. "They have been neglected in terms of drug development for more than 4 decades," Dr. Younes said, because "they represent a very small market."
Hodgkin's lymphoma affects about 8500 people annually in the United States, he noted, adding that "we expect to cure about 80% of all new comers. It's a highly curable disease." But the patients who fail on standard therapies have had, until now, no other hope, he said.
Antibody With Toxin Attached
The new product is an antibody–drug conjugate that targets CD30, which is expressed on the surface of cells in Hodgkin's lymphoma and anaplastic large-cell lymphoma, an aggressive type of T cell non-Hodgkin's lymphoma.
In both of these diseases, all of the cancer cells express CD30, so this protein represents an obvious target for therapy. However, previous attempts with antibodies directed against CD30 were unsuccessful. Even the antibody in this latest product, when used alone, showed little clinical activity, explained Dr. Younes — it was combining it with a toxin that did the trick.
The toxin in brentuximab is the antitubulin agent monomethyl auristatin E, and it is attached to anti-CD30-specific monoclonal antibody cAC10. The antibody acts as a delivery system to get the "cargo" into the cell, Dr. Younes explained.
The resultant product is "very well tolerated," he said, especially compared with chemotherapy. In the phase 1 trial that he headed, there were reports of fatigue, fever, diarrhea, some neutropenia, and cumulative neuropathy, he said.
That just-published phase 1 study involved 45 patients with relapsed or refractory Hodgkin's lymphoma or anaplastic large-cell lymphoma. Patients received brentuximab as a single agent, once every 3 weeks (as they did in the 2 pivotal phase 2 studies). The results showed objective responses in 17 patients, with complete remission in 11 patients; median duration of response was 9.7 months. In addition, 36 of 42 evaluable patients (86%) showed a tumor response.
"These sorts of responses are amazing with a single agent in such a refractory patient population," Dr. Younes noted. These initial results have since been confirmed by another phase 1 trial (presented recently at the 8th International Symposium on Hodgkin Lymphoma in Cologne, Germany [abstract 74]) and by the 2 larger pivotal phase 2 trials.
Having been involved in both of those pivotal trials, Dr. Connors predicts that brentuximab will "have a major role to play" in the management of both Hodgkin's lymphoma and anaplastic large-cell lymphoma.
"First, it will be useful all by itself for patients with no other good alternative," he said.
The 2 studies will be used as the basis for approval applications in both the United States and in Europe, which the manufacturer plans to file in early 2011. The product has been granted fast-track status by the US Food and Drug Administration for Hodgkin's lymphoma, which means review within 6 months, so brentuximab could be on the market before the end of next year.
The product has also been granted orphan drug status in both the United States and Europe, because relapsed and refractory Hodgkin's lymphoma represents a substantial unmet medical need, according to the company. Worldwide, almost one third of the 30,000 newly diagnosed patients relapse or become refractory to front-line therapy each year.
However, this use in relapsed/refractory patients might be just the beginning. Dr. Connors notes that "in future studies, it should be possible to include brentuximab in addition to standard treatments for both of those lymphomas in a way that boosts their cure rates without adding much to the toxicity of the treatments."
Further trials are already under way, the manufacturers note in a press release. A phase 3 clinical trial (known as AETHERA) is being conducted in patients at high risk for residual Hodgkin's lymphoma after autologous stem-cell transplant, a phase 2 trial is exploring retreatment in relapsed patients who have previously responded to brentuximab, and a phase 1 trial is investigating front-line combination treatment of Hodgkin's lymphoma.
All of the clinical trials with brentuximab have been/are being funded by the manufacturers, Seattle Genetics and Millennium/Takeda.
N Engl J Med. 2010;363:1812-1821.
A NEW SERM WITH BETTER TOXICITY PROFILE
November 5, 2010 – Lasofoxifene (Oporia, Pfizer) is the third drug that has been shown to be effective in preventing breast cancer, and it might tip the balance toward wider use of these agents, says an expert.
Two other agents, tamoxifen and raloxifene, which, like lasofoxifene, is a selective estrogen-receptor (ER) modulator (SERM), have been proven to reduce the risk for breast cancer, but so far there has been little use of these drugs for chemoprevention in healthy women.
The latest results show that lasofoxifene, which is not yet marketed, at 0.5 mg a day reduced the risk for ER-positive invasive breast cancer by 79% and the overall risk for breast cancer by 83% in postmenopausal women with osteoporosis. The data come from a 5-year placebo-controlled randomized clinical trial with the acronym PEARL (Postmenopausal Evaluation and Risk-Reduction With Lasofoxifene).
The risk reduction for breast cancer with lasofoxifene is similar to that reported for tamoxifen and raloxifene, say the authors.
The findings by the PEARL investigators, led by Andrea Z. LaCroix, PhD, MPH, from the Fred Hutchinson Cancer Research Center in Seattle, Washington, were published online November 4 in the Journal of the National Cancer Institute.
Compared with placebo, lasofoxifene 0.5 mg daily also reduced the risk for coronary events by 32% and for strokes by 36% — effects not seen in trials with tamoxifen or raloxifene. Lasofoxifene also reduced vertebral fractures by 42% and nonvertebral fractures by 24%; raloxifene has not been shown to reduce the latter.
Notably, use of lasofoxifene was not associated, at 5 years, with a risk for other cancers, including endometrial cancer, which is a risk associated with tamoxifen.
Advance in This Drug Class
"Lasofoxifene appears to represent an advance in the progression of pharmacological agents at our disposal," writes Victor G. Vogel, MD, in an editorial that accompanies the study.
Dr. Vogel, who is from Geisinger Medical Center in Danville Pennsylvania, says that lasofoxifene has a favorable risk/benefit profile, compared with the tamoxifen and raloxifene. Neither of these "has been able to tip the clinical utility scale to broad usage within the high-risk population for breast cancer risk reduction," he says.
The scales might be ready to be tipped with the anticipated approval of lasofoxifene, which might be more potent than the other agents, "possibly because it binds with high affinity to both ER-alpha and ER-beta," writes Dr. Vogel.
"We have been waiting for a tipping point in breast cancer chemoprevention for more than a decade. Perhaps with lasofoxifene, the time has arrived," he speculates, borrowing a phrase from journalist Malcolm Gladwell's book The Tipping Point to describe how social change occurs incrementally until a critical point catapults it full-speed ahead.
At the same time, Dr. Vogel acknowledges the considerable array of stars that need to be aligned for breast cancer chemoprevention to be widely embraced.
"For a preventive strategy to be both effective and efficient, we need an easily identified target population, criteria for identifying those who would benefit from a risk-reduction strategy, a safe and effective agent, an informed group of practitioners who can provide care to the high-risk group, and an educated population of patients who understand the advantages and the risks of taking a drug to modify their risk," he writes.
In short, implementing breast cancer chemoprevention widely is a tall order. Nevertheless, the absence of its general acceptance vexes experts.
This past summer, at the annual ASCO meeting, when long-term data from the landmark Study of Raloxifene and Tamoxifen (STAR) trial were presented, a number of experts uttered comments such as: "We need to reassess why we don't use these drugs more broadly," and "It's a mystery [why raloxifene is not more widely used]."
As PEARL, which was funded by Pfizer, indicates, lasofoxifene does not escape another problem with breast cancer chemoprevention — the increased risk for venous thromboembolism.
PEARL Has Handicaps
In the international PEARL trial, 8556 postmenopausal women (aged 59 to 80 years) with low bone density and normal mammograms were randomly assigned to 1 of 2 doses of lasofoxifene — 0.25 or 0.50 mg daily — or placebo. The participating women were not at high-risk for breast cancer.
The primary end points of the PEARL trial were incidence of ER-positive breast cancer and nonvertebral fractures at 5 years.
Of the women in the trial, 77% completed the final visit; of these women, at 5 years, 62% in the lasofoxifene groups were taking the study medication, as were 64% in the placebo group.
Compared with placebo, lasofoxifene 0.50 mg statistically significantly reduced the risk for total breast cancer by 79% (hazard ratio [HR], 0.21; 95% confidence interval [CI], 0.08 - 0.55) and for ER-positive invasive breast cancer by 83% (HR, 0.17; 95% CI, 0.05 - 0.57), write the authors.
The effects of lasofoxifene 0.50 mg on total breast cancer were similar, regardless of a patient's Gail score; the effects were markedly stronger for women with baseline estradiol levels above the median (odds ratio [OR], 0.11; 95% CI, 0.02 - 0.51) than for those with levels below the median (OR, 0.78; 95% CI, 0.16 - 3.79; P interaction = .04).
These findings about estradiol levels are in agreement with a meta-analysis that showed a 2-fold increased risk for breast cancer among postmenopausal women in the highest quintile of estradiol, compared with the lowest quintile, say the authors.
With regard to gynecological problems at 5 years, there was an increase in benign endometrial thickening among women receiving lasofoxifene 0.50 mg, but no increase in endometrial hyperplasia, atypia, or cancer.
The study authors point out that PEARL has some important limitations, including the small number of incident breast cancer cases (n = 49) and a lack of follow-up data after 5 years.
Dr. Vogel agrees about the limitations. The "PEARL trial was handicapped by a small number of both subjects and adverse events," he writes. For instance, only 5 breast cancer events occurred in the 0.50 mg dose group, compared with 24 in the placebo group.
Dr. Vogel also suggests that comparing the PEARL and STAR trials is not straightforward. Women in PEARL were, on average, about 9 years older than STAR trial participants at entry (mean age, 67 vs 58.5 years). Also, average Gail score risk for breast cancer in 5 years in the PEARL trial was lower than in the STAR trial (1.7% vs 4.03%). Rates of venous thromboembolism were also lower with raloxifene in STAR than with lasofoxifene 0.5 mg in PEARL (1.38 vs 2.9 events per 1000 woman-years), "possibly reflecting the older age of the PEARL participants," says Dr. Vogel.
More information is needed about this new SERM in the long term, says Dr. Vogel. "We need more complete information about the long-term effects of lasofoxifene on both beneficial and unfavorable outcomes, but the early data regarding its risks and benefits are encouraging," he writes.
This study was funded by Pfizer, and editorial assistance was provided by Annie Neild, PhD, from PAREXEL.
J Natl Cancer Inst. Published online November 4, 2010.
Two other agents, tamoxifen and raloxifene, which, like lasofoxifene, is a selective estrogen-receptor (ER) modulator (SERM), have been proven to reduce the risk for breast cancer, but so far there has been little use of these drugs for chemoprevention in healthy women.
The latest results show that lasofoxifene, which is not yet marketed, at 0.5 mg a day reduced the risk for ER-positive invasive breast cancer by 79% and the overall risk for breast cancer by 83% in postmenopausal women with osteoporosis. The data come from a 5-year placebo-controlled randomized clinical trial with the acronym PEARL (Postmenopausal Evaluation and Risk-Reduction With Lasofoxifene).
The risk reduction for breast cancer with lasofoxifene is similar to that reported for tamoxifen and raloxifene, say the authors.
The findings by the PEARL investigators, led by Andrea Z. LaCroix, PhD, MPH, from the Fred Hutchinson Cancer Research Center in Seattle, Washington, were published online November 4 in the Journal of the National Cancer Institute.
Compared with placebo, lasofoxifene 0.5 mg daily also reduced the risk for coronary events by 32% and for strokes by 36% — effects not seen in trials with tamoxifen or raloxifene. Lasofoxifene also reduced vertebral fractures by 42% and nonvertebral fractures by 24%; raloxifene has not been shown to reduce the latter.
Notably, use of lasofoxifene was not associated, at 5 years, with a risk for other cancers, including endometrial cancer, which is a risk associated with tamoxifen.
Advance in This Drug Class
"Lasofoxifene appears to represent an advance in the progression of pharmacological agents at our disposal," writes Victor G. Vogel, MD, in an editorial that accompanies the study.
Dr. Vogel, who is from Geisinger Medical Center in Danville Pennsylvania, says that lasofoxifene has a favorable risk/benefit profile, compared with the tamoxifen and raloxifene. Neither of these "has been able to tip the clinical utility scale to broad usage within the high-risk population for breast cancer risk reduction," he says.
The scales might be ready to be tipped with the anticipated approval of lasofoxifene, which might be more potent than the other agents, "possibly because it binds with high affinity to both ER-alpha and ER-beta," writes Dr. Vogel.
"We have been waiting for a tipping point in breast cancer chemoprevention for more than a decade. Perhaps with lasofoxifene, the time has arrived," he speculates, borrowing a phrase from journalist Malcolm Gladwell's book The Tipping Point to describe how social change occurs incrementally until a critical point catapults it full-speed ahead.
At the same time, Dr. Vogel acknowledges the considerable array of stars that need to be aligned for breast cancer chemoprevention to be widely embraced.
"For a preventive strategy to be both effective and efficient, we need an easily identified target population, criteria for identifying those who would benefit from a risk-reduction strategy, a safe and effective agent, an informed group of practitioners who can provide care to the high-risk group, and an educated population of patients who understand the advantages and the risks of taking a drug to modify their risk," he writes.
In short, implementing breast cancer chemoprevention widely is a tall order. Nevertheless, the absence of its general acceptance vexes experts.
This past summer, at the annual ASCO meeting, when long-term data from the landmark Study of Raloxifene and Tamoxifen (STAR) trial were presented, a number of experts uttered comments such as: "We need to reassess why we don't use these drugs more broadly," and "It's a mystery [why raloxifene is not more widely used]."
As PEARL, which was funded by Pfizer, indicates, lasofoxifene does not escape another problem with breast cancer chemoprevention — the increased risk for venous thromboembolism.
PEARL Has Handicaps
In the international PEARL trial, 8556 postmenopausal women (aged 59 to 80 years) with low bone density and normal mammograms were randomly assigned to 1 of 2 doses of lasofoxifene — 0.25 or 0.50 mg daily — or placebo. The participating women were not at high-risk for breast cancer.
The primary end points of the PEARL trial were incidence of ER-positive breast cancer and nonvertebral fractures at 5 years.
Of the women in the trial, 77% completed the final visit; of these women, at 5 years, 62% in the lasofoxifene groups were taking the study medication, as were 64% in the placebo group.
Compared with placebo, lasofoxifene 0.50 mg statistically significantly reduced the risk for total breast cancer by 79% (hazard ratio [HR], 0.21; 95% confidence interval [CI], 0.08 - 0.55) and for ER-positive invasive breast cancer by 83% (HR, 0.17; 95% CI, 0.05 - 0.57), write the authors.
The effects of lasofoxifene 0.50 mg on total breast cancer were similar, regardless of a patient's Gail score; the effects were markedly stronger for women with baseline estradiol levels above the median (odds ratio [OR], 0.11; 95% CI, 0.02 - 0.51) than for those with levels below the median (OR, 0.78; 95% CI, 0.16 - 3.79; P interaction = .04).
These findings about estradiol levels are in agreement with a meta-analysis that showed a 2-fold increased risk for breast cancer among postmenopausal women in the highest quintile of estradiol, compared with the lowest quintile, say the authors.
With regard to gynecological problems at 5 years, there was an increase in benign endometrial thickening among women receiving lasofoxifene 0.50 mg, but no increase in endometrial hyperplasia, atypia, or cancer.
The study authors point out that PEARL has some important limitations, including the small number of incident breast cancer cases (n = 49) and a lack of follow-up data after 5 years.
Dr. Vogel agrees about the limitations. The "PEARL trial was handicapped by a small number of both subjects and adverse events," he writes. For instance, only 5 breast cancer events occurred in the 0.50 mg dose group, compared with 24 in the placebo group.
Dr. Vogel also suggests that comparing the PEARL and STAR trials is not straightforward. Women in PEARL were, on average, about 9 years older than STAR trial participants at entry (mean age, 67 vs 58.5 years). Also, average Gail score risk for breast cancer in 5 years in the PEARL trial was lower than in the STAR trial (1.7% vs 4.03%). Rates of venous thromboembolism were also lower with raloxifene in STAR than with lasofoxifene 0.5 mg in PEARL (1.38 vs 2.9 events per 1000 woman-years), "possibly reflecting the older age of the PEARL participants," says Dr. Vogel.
More information is needed about this new SERM in the long term, says Dr. Vogel. "We need more complete information about the long-term effects of lasofoxifene on both beneficial and unfavorable outcomes, but the early data regarding its risks and benefits are encouraging," he writes.
This study was funded by Pfizer, and editorial assistance was provided by Annie Neild, PhD, from PAREXEL.
J Natl Cancer Inst. Published online November 4, 2010.
HPV TESTING HELPFUL FOR ASC-US
November 2, 2010 (San Francisco, California) — A new study from an inner-city hospital in Atlanta, Georgia, of 348 patients with a diagnosis of atypical squamous cells of undetermined significance (ASC-US) confirms that high-risk human papillomavirus (HPV) assay testing is essential for pinpointing patients with high-grade dysplasia who need follow-up treatment, according to research presented here at the American Society for Clinical Pathology (ASCP) 2010 Annual Meeting.
In the retrospective study, high-risk HPV testing was able to identify all patients with cervical intraepithelial neoplasia (CIN) 3 lesions and almost all patients (96%) with CIN 2 lesions, using the Hybrid Capture 2 (HC2) HPV assay for detecting cervical cancer precursor lesions on SurePath specimens.
"These are patients who don't come in for regular testing and tend to present with pretty advanced disease. We wanted to evaluate patients with a diagnosis of ASC-US in this population to see the rate of high-risk HPV positivity," said presenting researcher Beth Chastain, MD, from Emory University School of Medicine and Grady Memorial Hospital in Atlanta.
"If we can give these patients an HPV test during their initial visit, we can assess where they are at and get them treated more easily," Dr. Chastain said. "It's important not to let these patients fall through the cracks."
From 2006 to 2008, data collected from SurePath Pap tests interpreted as ASC-US on high-risk HPV testing and histologic follow-up — such as cervical/cone biopsy, endocervical curettage, and hysterectomy — were analyzed.
At Grady Hospital, Dr. Chastain reported that the rate of ASC-US is 11.5%, which is twice the national average. Among patients with ASC-US, 63% were high-risk HPV-positive. In this subgroup, 54% had high-grade dysplasia, and the rate of severe dysplasia/carcinoma in situ was 10.4%. In contrast, no patients who tested high-risk HPV-negative had severe dysplasia/carcinoma on follow-up.
Of 220 high-risk HPV-positive samples, 60 patients (27.3%) had negative histology on follow-up, a finding that might be explained by regression or limited sampling, the researchers say. These conflicting results suggest a need for further follow-up of these patients, Dr. Chastain and colleagues conclude.
"The ALTS [ASC-US/LSIL Triage Study] showed unequivocally that you should do a clinically valid test for high-risk HPV types to distinguish patients in the ASC-US population who are at risk for CIN 3 and those who aren't," said Mark Stoler, MD, professor of pathology and gynecology and associate director of surgical pathology and cytopathology at the University of Virginia Health System in Richmond. Dr. Stoler is president of the ASCP.
"This is another confirmatory study that shows us that with a diagnosis of ASC-US, the standard of care is to do an HPV test," he added. Dr. Stoler noted that although the ALTS trial was performed using ThinPrep Pap tests, the Grady Hospital study adds to the developing literature concerning the clinical validity of SurePath liquid-based Pap tests, he said.
Dr. Chastain has disclosed no relevant financial relationships. Dr. Stoler reports being a consultant for both BD, the manufacturer of SurePath, and Qiagen, the manufacturer of HC2.
American Society for Clinical Pathology (ASCP) 2010 Annual Meeting: Abstract 13. Presented October 28, 2010.
In the retrospective study, high-risk HPV testing was able to identify all patients with cervical intraepithelial neoplasia (CIN) 3 lesions and almost all patients (96%) with CIN 2 lesions, using the Hybrid Capture 2 (HC2) HPV assay for detecting cervical cancer precursor lesions on SurePath specimens.
"These are patients who don't come in for regular testing and tend to present with pretty advanced disease. We wanted to evaluate patients with a diagnosis of ASC-US in this population to see the rate of high-risk HPV positivity," said presenting researcher Beth Chastain, MD, from Emory University School of Medicine and Grady Memorial Hospital in Atlanta.
"If we can give these patients an HPV test during their initial visit, we can assess where they are at and get them treated more easily," Dr. Chastain said. "It's important not to let these patients fall through the cracks."
From 2006 to 2008, data collected from SurePath Pap tests interpreted as ASC-US on high-risk HPV testing and histologic follow-up — such as cervical/cone biopsy, endocervical curettage, and hysterectomy — were analyzed.
At Grady Hospital, Dr. Chastain reported that the rate of ASC-US is 11.5%, which is twice the national average. Among patients with ASC-US, 63% were high-risk HPV-positive. In this subgroup, 54% had high-grade dysplasia, and the rate of severe dysplasia/carcinoma in situ was 10.4%. In contrast, no patients who tested high-risk HPV-negative had severe dysplasia/carcinoma on follow-up.
Of 220 high-risk HPV-positive samples, 60 patients (27.3%) had negative histology on follow-up, a finding that might be explained by regression or limited sampling, the researchers say. These conflicting results suggest a need for further follow-up of these patients, Dr. Chastain and colleagues conclude.
"The ALTS [ASC-US/LSIL Triage Study] showed unequivocally that you should do a clinically valid test for high-risk HPV types to distinguish patients in the ASC-US population who are at risk for CIN 3 and those who aren't," said Mark Stoler, MD, professor of pathology and gynecology and associate director of surgical pathology and cytopathology at the University of Virginia Health System in Richmond. Dr. Stoler is president of the ASCP.
"This is another confirmatory study that shows us that with a diagnosis of ASC-US, the standard of care is to do an HPV test," he added. Dr. Stoler noted that although the ALTS trial was performed using ThinPrep Pap tests, the Grady Hospital study adds to the developing literature concerning the clinical validity of SurePath liquid-based Pap tests, he said.
Dr. Chastain has disclosed no relevant financial relationships. Dr. Stoler reports being a consultant for both BD, the manufacturer of SurePath, and Qiagen, the manufacturer of HC2.
American Society for Clinical Pathology (ASCP) 2010 Annual Meeting: Abstract 13. Presented October 28, 2010.
SECOND LINE CHEMOTHERAPY FOR SCLC
NEW YORK (Reuters Health) Oct 27 - Second-line chemotherapy, especially platinum-based chemotherapy, may prolong survival in patients with small-cell lung cancer (SCLC), according to a multicenter retrospective study published online October 15th in Lung Cancer.
"There is not enough evidence to recommend a second-line treatment over another, but when a platinum-based regimen is feasible and the patient had a prolonged response after first-line, this could be the best option," the investigators say.
Their advice is based on an audit of 161 SCLC patients who failed first-line platinum-etoposide chemotherapy and received second-line chemotherapy in 15 institutions across Europe between May 1999 and July 2008.
Overall, re-treatment with platinum-based chemotherapy was associated with a 54% reduction of mortality compared with other regimens.
Until now, said lead author Dr. Marina Chiara Garassino from Ospedale Fatebenefratelli e Oftalmico, Milano, Italy and colleagues, second-line therapy has been linked with tumor regression but there's been only limited evidence of a clinical benefit.
Second-line chemotherapy regimens in the study included platinum-based rechallenge (18.6%), anthracycline-based chemotherapy (44.8%), topotecan (21.7%), and a variety of others (14.9%).
Most patients (70%) had responded to first-line platinum-based chemotherapy. After second-line chemotherapy, 1.2% achieved complete remission, 21.7% had partial remission, 20.5% had stable disease, and 56.6% had progressive disease.
Response rates were higher in patients who responded to first-line therapy, and rates were numerically (but not statistically) higher in patients who were rechallenged with a platinum-based therapy (34.5%) than in those who did not receive platinum-based therapy (17.5%; p=0.06).
For all patients treated with second-line chemotherapy, median progression-free survival was 4.3 months, and median overall survival was 5.8 months.
Progression-free survival and overall survival were significantly higher among patients who received platinum-based rechallenge than among patients who received other regimens.
In multivariate analysis, there was a non-significant trend for superior progression-free and overall survival with the platinum-based regimen among patients who relapsed at least 3 months after completion of first-line treatment.
Additional analysis identified a time-to-progression of 12 months after completion of first-line chemotherapy as the best cut-off to achieve the highest benefit from platinum-based rechallenge.
The researchers believe their results "are provocative for further evaluation of platinum rechallenge compared to topotecan in SCLC patients independently of their platinum sensitivity."
Lung Cancer. Posted online October 15, 2010. Abstract
"There is not enough evidence to recommend a second-line treatment over another, but when a platinum-based regimen is feasible and the patient had a prolonged response after first-line, this could be the best option," the investigators say.
Their advice is based on an audit of 161 SCLC patients who failed first-line platinum-etoposide chemotherapy and received second-line chemotherapy in 15 institutions across Europe between May 1999 and July 2008.
Overall, re-treatment with platinum-based chemotherapy was associated with a 54% reduction of mortality compared with other regimens.
Until now, said lead author Dr. Marina Chiara Garassino from Ospedale Fatebenefratelli e Oftalmico, Milano, Italy and colleagues, second-line therapy has been linked with tumor regression but there's been only limited evidence of a clinical benefit.
Second-line chemotherapy regimens in the study included platinum-based rechallenge (18.6%), anthracycline-based chemotherapy (44.8%), topotecan (21.7%), and a variety of others (14.9%).
Most patients (70%) had responded to first-line platinum-based chemotherapy. After second-line chemotherapy, 1.2% achieved complete remission, 21.7% had partial remission, 20.5% had stable disease, and 56.6% had progressive disease.
Response rates were higher in patients who responded to first-line therapy, and rates were numerically (but not statistically) higher in patients who were rechallenged with a platinum-based therapy (34.5%) than in those who did not receive platinum-based therapy (17.5%; p=0.06).
For all patients treated with second-line chemotherapy, median progression-free survival was 4.3 months, and median overall survival was 5.8 months.
Progression-free survival and overall survival were significantly higher among patients who received platinum-based rechallenge than among patients who received other regimens.
In multivariate analysis, there was a non-significant trend for superior progression-free and overall survival with the platinum-based regimen among patients who relapsed at least 3 months after completion of first-line treatment.
Additional analysis identified a time-to-progression of 12 months after completion of first-line chemotherapy as the best cut-off to achieve the highest benefit from platinum-based rechallenge.
The researchers believe their results "are provocative for further evaluation of platinum rechallenge compared to topotecan in SCLC patients independently of their platinum sensitivity."
Lung Cancer. Posted online October 15, 2010. Abstract
SEGMENTECTOMY MAY BE ENOUGH FOR STAGE I NSCLC
NEW YORK (Reuters Health) Nov 02 - In treatment of stage I non-small cell lung cancer (NSCLC), anatomic segmentectomy prevents locoregional recurrence as well as lobectomy, according to data presented yesterday afternoon at CHEST 2010, the annual international scientific assembly of the American College of Chest Physicians in Vancouver.
Wedge resection, on the other hand, provides inferior locoregional control, reported Dr. Matthew J. Schuchert, from the University of Pittsburgh Medical Center.
A parenchyma-sparing procedure, segmentectomy removes one of the 19 lung segments, each of which is supplied by a direct branch of a lobar bronchus and its accompanying pulmonary artery branch and separated from adjacent segments by connective tissue septa.
"For a segmentectomy, the surgeon ligates the bronchus and arterial branch that go to that segment, goes through the anatomic planes between segments, and takes out the whole segment" and its associated lymph nodes, Dr. Loren Harris explained to Reuters Health. "For a wedge resection, you basically grab a piece of the lung that includes the tumor and take a stapler across it."
Dr. Harris is spokesman for the American College of Chest Physicians and a cardiothoracic surgeon at Richmond University Medical Center in Staten Island, New York; he did not participate in the study.
Dr. Schuchert and colleagues reviewed outcomes for 1093 patients who underwent resection for clinical stage I NSCLC at their center between 2002 and 2009. Average age was 68 (range 22-99). While mean tumor size was 2.9 cm, the largest one removed was 23 cm.
A total of 235 patients had anatomic segmentectomy, 130 had wedge resection, and 728 had lobectomy.
During mean follow-up of 30.5 months, overall survival was similar in the three groups, although there was a trend toward reduced peri-operative mortality with segmentectomy compared with lobectomy (0.4% vs 1.8%, p = 0.12).
Locoregional recurrence was significantly higher in the wedge resection group (14.6%) than in the segmentectomy group (8.9%, p = 0.006). However, locoregional recurrence and recurrence-free survival were equivalent for segmentectomy and lobectomy.
The investigators note in their meeting abstract that pathological examination resulted in upstaging in 22.3% of patients. Nevertheless, the extent of resection didn't affect survival in this group.
"Sublobar resection, even for stage I lung cancer, has been viewed as a 'compromise procedure,' where results are not expected to be that good," Dr. Schuchert told Reuters Health. "That's why this (study) is exciting news because we have a lesser resection technique showing very good efficacy."
He noted that the surgeons decided which type of resection to perform, based primarily on tumor size and location.
"Small tumors and ones positioned in a discreet segment are the ones we strongly consider for segmentectomy," he said. "But if the tumor overlaps segments or is very central, segmentectomy may not be possible."
Other factors influencing surgery were pulmonary function, age, and a previous lobectomy.
Dr. Schuchert theorized that with a wedge resection, "we may be missing tumor cells within the lymphatic system or N1 lymph nodes that we would get with segmentectomy or lobectomy, which then pop up as locoregional recurrence later on."
"This study confirms mounting evidence showing that anatomic sublobectomy, including lymph node sampling or resections, provides similar results in early lung cancer," Dr. Harris said.
Still, he said, the equivalence of outcomes between the two procedures remains to be proven. "We don't want to jump the gun and offer a surgery that doesn't have same long term outcome," he added.
A national trial to compare segmentectomy and lobectomy is now enrolling patients. According to Dr. Schuchert, "Our findings underscore the need for centers around the country to participate in that trial so we can really answer this question with a well designed prospective study."
Wedge resection, on the other hand, provides inferior locoregional control, reported Dr. Matthew J. Schuchert, from the University of Pittsburgh Medical Center.
A parenchyma-sparing procedure, segmentectomy removes one of the 19 lung segments, each of which is supplied by a direct branch of a lobar bronchus and its accompanying pulmonary artery branch and separated from adjacent segments by connective tissue septa.
"For a segmentectomy, the surgeon ligates the bronchus and arterial branch that go to that segment, goes through the anatomic planes between segments, and takes out the whole segment" and its associated lymph nodes, Dr. Loren Harris explained to Reuters Health. "For a wedge resection, you basically grab a piece of the lung that includes the tumor and take a stapler across it."
Dr. Harris is spokesman for the American College of Chest Physicians and a cardiothoracic surgeon at Richmond University Medical Center in Staten Island, New York; he did not participate in the study.
Dr. Schuchert and colleagues reviewed outcomes for 1093 patients who underwent resection for clinical stage I NSCLC at their center between 2002 and 2009. Average age was 68 (range 22-99). While mean tumor size was 2.9 cm, the largest one removed was 23 cm.
A total of 235 patients had anatomic segmentectomy, 130 had wedge resection, and 728 had lobectomy.
During mean follow-up of 30.5 months, overall survival was similar in the three groups, although there was a trend toward reduced peri-operative mortality with segmentectomy compared with lobectomy (0.4% vs 1.8%, p = 0.12).
Locoregional recurrence was significantly higher in the wedge resection group (14.6%) than in the segmentectomy group (8.9%, p = 0.006). However, locoregional recurrence and recurrence-free survival were equivalent for segmentectomy and lobectomy.
The investigators note in their meeting abstract that pathological examination resulted in upstaging in 22.3% of patients. Nevertheless, the extent of resection didn't affect survival in this group.
"Sublobar resection, even for stage I lung cancer, has been viewed as a 'compromise procedure,' where results are not expected to be that good," Dr. Schuchert told Reuters Health. "That's why this (study) is exciting news because we have a lesser resection technique showing very good efficacy."
He noted that the surgeons decided which type of resection to perform, based primarily on tumor size and location.
"Small tumors and ones positioned in a discreet segment are the ones we strongly consider for segmentectomy," he said. "But if the tumor overlaps segments or is very central, segmentectomy may not be possible."
Other factors influencing surgery were pulmonary function, age, and a previous lobectomy.
Dr. Schuchert theorized that with a wedge resection, "we may be missing tumor cells within the lymphatic system or N1 lymph nodes that we would get with segmentectomy or lobectomy, which then pop up as locoregional recurrence later on."
"This study confirms mounting evidence showing that anatomic sublobectomy, including lymph node sampling or resections, provides similar results in early lung cancer," Dr. Harris said.
Still, he said, the equivalence of outcomes between the two procedures remains to be proven. "We don't want to jump the gun and offer a surgery that doesn't have same long term outcome," he added.
A national trial to compare segmentectomy and lobectomy is now enrolling patients. According to Dr. Schuchert, "Our findings underscore the need for centers around the country to participate in that trial so we can really answer this question with a well designed prospective study."
FIRST THERAPY FOR TUBEROUS SCLEROSIS APPROVED BY FDA
November 2, 2010 ( UPDATED November 3, 2010 ) — The US Food and Drug Administration (FDA) has granted accelerated approval for everolimus (Afinitor tablets; Novartis Pharmaceuticals, Inc) as the first medication for children and adults with subependymal giant cell astrocytoma (SEGA) who require therapeutic intervention but are not candidates for curative surgical resection.
SEGAs are slow-growing, benign brain tumors that occur in up to 20% of patients with tuberous sclerosis, a genetic disorder that affects about 25,000 to 40,000 people in the United States.
"Patients with this disease currently have limited treatment options beyond surgical intervention," explained Richard Pazdur, MD, director of the Office of Oncology Drug Products in the FDA's Center for Drug Evaluation and Research, in an agency news release. "It is important for research to continue in rare diseases where patients have few or no existing drug treatment options."
The accelerated approval program allows FDA approval of treatments for serious diseases with an unmet medical need, based on an endpoint reasonably expected to predict clinical benefit. As a result, patients have earlier access to the drug while additional long-term safety and efficacy data are still being collected.
In this instance, FDA approval was based on a priority review of data from an open-label, single-arm clinical study of everolimus (n = 28) showing that almost one third (9; 32%) of patients achieved more than 50% shrinkage of their largest SEGA tumor at 6 months. Of 4 patients whose tumors returned after surgery, 3 met the endpoint of a 50% or greater reduction in tumor volume.
Overall duration of response ranged from about 3 months to 2.5 years (median, 266 days). Although SEGAs did not resolve completely, new tumors did not occur during treatment.
Adverse events reported in 30% or more of SEGA study patients included mouth sores, upper respiratory tract infections, sinusitis, middle ear infections, and fever. Common laboratory test abnormalities included elevated liver enzymes, creatinine and glucose, as well as hyperlipidemia, leukopenia, anemia, and thrombocytopenia.
The data from this 28-patient study, which led to approval of the new indication, have just been published in the New England Journal of Medicine (2010;363:1801-1811). Lead author Darcy Krueger, MD, PhD, and colleagues from the Cincinnati Children's Hospital conclude that everolimus therapy was associated with a "marked reduction" in the volume of SEGAs and seizure frequency and that "it may offer a potential alternative to neurosurgical resection in some cases." However, they add that long-term studies are needed.
According to the company news release, an international phase 3 randomized, placebo-controlled study (EXamining everolimus In a Study of Tuberous sclerosis complex; EXIST-1) is currently underway to further explore the benefits of everolimus therapy for SEGAs associated with tuberous sclerosis; endpoints include SEGA response, seizure rate, and skin lesion response rate.
As reported by Medscape Medical News, everolimus previously was approved by the FDA for the treatment of advanced renal cell carcinoma refractory to sunitinib or sorafenib therapy. Marketed as Zortress (Novartis), it is also indicated for use with low-dose cyclosporine, basiliximab, and corticosteroids to prevent organ rejection in adult kidney transplant patients at low to moderate immunologic risk.
The SEGA indication for everolimus is currently being evaluated for approval in the European Union and Switzerland.
SEGAs are slow-growing, benign brain tumors that occur in up to 20% of patients with tuberous sclerosis, a genetic disorder that affects about 25,000 to 40,000 people in the United States.
"Patients with this disease currently have limited treatment options beyond surgical intervention," explained Richard Pazdur, MD, director of the Office of Oncology Drug Products in the FDA's Center for Drug Evaluation and Research, in an agency news release. "It is important for research to continue in rare diseases where patients have few or no existing drug treatment options."
The accelerated approval program allows FDA approval of treatments for serious diseases with an unmet medical need, based on an endpoint reasonably expected to predict clinical benefit. As a result, patients have earlier access to the drug while additional long-term safety and efficacy data are still being collected.
In this instance, FDA approval was based on a priority review of data from an open-label, single-arm clinical study of everolimus (n = 28) showing that almost one third (9; 32%) of patients achieved more than 50% shrinkage of their largest SEGA tumor at 6 months. Of 4 patients whose tumors returned after surgery, 3 met the endpoint of a 50% or greater reduction in tumor volume.
Overall duration of response ranged from about 3 months to 2.5 years (median, 266 days). Although SEGAs did not resolve completely, new tumors did not occur during treatment.
Adverse events reported in 30% or more of SEGA study patients included mouth sores, upper respiratory tract infections, sinusitis, middle ear infections, and fever. Common laboratory test abnormalities included elevated liver enzymes, creatinine and glucose, as well as hyperlipidemia, leukopenia, anemia, and thrombocytopenia.
The data from this 28-patient study, which led to approval of the new indication, have just been published in the New England Journal of Medicine (2010;363:1801-1811). Lead author Darcy Krueger, MD, PhD, and colleagues from the Cincinnati Children's Hospital conclude that everolimus therapy was associated with a "marked reduction" in the volume of SEGAs and seizure frequency and that "it may offer a potential alternative to neurosurgical resection in some cases." However, they add that long-term studies are needed.
According to the company news release, an international phase 3 randomized, placebo-controlled study (EXamining everolimus In a Study of Tuberous sclerosis complex; EXIST-1) is currently underway to further explore the benefits of everolimus therapy for SEGAs associated with tuberous sclerosis; endpoints include SEGA response, seizure rate, and skin lesion response rate.
As reported by Medscape Medical News, everolimus previously was approved by the FDA for the treatment of advanced renal cell carcinoma refractory to sunitinib or sorafenib therapy. Marketed as Zortress (Novartis), it is also indicated for use with low-dose cyclosporine, basiliximab, and corticosteroids to prevent organ rejection in adult kidney transplant patients at low to moderate immunologic risk.
The SEGA indication for everolimus is currently being evaluated for approval in the European Union and Switzerland.
A NICE CHEAP TREATMENT FOR CROHN DISEASE
November 3, 2010 — An antibiotic currently indicated for hepatic encephalopathy and traveler's diarrhea has shown promise in the treatment of Crohn's disease (CD).
RETIC-03, a large phase 2 trial presented at the 18th Annual United European Gastroenterology Week in Barcelona, Spain, showed that rifaximin-EIR (extended intestinal release) was able to achieve clinical remission of Crohn's sequelae in up to 62% of patients out to 12 weeks, according to study investigator, Herbert Lochs, MD, from the Medical University in Innsbruck, Austria.
RETIC-03, a multicenter, multinational, randomized, double-blind, placebo-controlled study, was a comparison of 3 twice-daily doses of rifaximin-EIR (400 mg, 800 mg, and 1200 mg) and placebo in a cohort of 402 patients with active CD. The study's primary end point was remission of CD at 12-week follow-up.
Results showed that at 12 weeks, all active treatment groups achieved remission more often than placebo (P < .04), with the highest rate (62.2%) observed for the 800 mg regimen.
Response to treatment was initially dose-dependent, rising from the 400 mg to the 800 mg threshold. However, the highest dose (1200 mg) produced the least efficacy (47.5%) among the active treatment group, and the highest rate of discontinuations. Reasons for this are unclear, said Dr. Lochs. "The main adverse events tended to be mild, and the majority were gut-related, as in pain, vomiting, and diarrhea — which, frankly, are very difficult to separate out from the symptoms of Crohn's itself."
Commenting on his motivation for conducting RETIC-03, Dr. Lochs said that he was trying to move away from CD treatment methods that rely on suppression of the patient's immune system. "It's not something you ideally want to do — not in the long term."
In the current hypothesis for the pathogenesis of CD, he explained, there is a change in the intestinal microbiota, whereby pathogenic bacteria disrupt the gut's mucosa, which activates the immune system. Rather than inhibit the immune response, Dr. Lochs wants to attenuate the reasons for its activation.
The choice of rifaximin was based on case reports of its potential utility in CD, and the fact that it is specific to the gut. "The formulation stays in the lumen; there's no systemic effect that might lead to overall antibiotic resistance," said Dr. Lochs. In theory, this should lead to fewer adverse events than other antibiotics, he added.
"We need to do a confirmatory study, of course, but this study has shown 2 things that are different and important. First, it was possible to initiate remission with an antibiotic in active Crohn's disease, and second, this remission could be maintained." Dr. Lochs said that future studies (as yet unplanned) would address long-term maintenance of remission.
If it's so simple, why haven't we tried it before?
"The data for antibiotics [in CD] are out there, and the science makes sense," said Sunanda Kane, MD, from the Mayo Clinic in Rochester, Minnesota, and chair of the Patient Education Committee of the Crohn's and Colitis Foundation. "The problem up to now has been that no company has wanted to fund a large enough trial with the appropriate antibiotic."
Dr. Kane said that there is perhaps a different sort of motivation for such a study in the European Union, pointing out that the biologics commonly used in CD are very expensive and often not covered; in some countries, they are not even approved.
"What they are trying to do is to find an alternative to biologics that may be safer and work just as well," she observed.
Dr. Kane finds the choice of rifaximin in this study to be both prudent and just a bit ironic. "There are case studies that show efficacy, and the fact that it's so [gastrointestinal]-specific, so targeted, is great, but rifaximin is not a cheap antibiotic." Still, she admitted, the price is nowhere near that of a biologic, nor does it carry the same potential for serious adverse effects.
Drs. Lochs reports a financial relationship with Alfa Wassermann SpA. Dr. Kane has disclosed no relevant financial relationships.
18th Annual United European Gastroenterology Week: Abstract 3075. Presented October 26, 2010.
RETIC-03, a large phase 2 trial presented at the 18th Annual United European Gastroenterology Week in Barcelona, Spain, showed that rifaximin-EIR (extended intestinal release) was able to achieve clinical remission of Crohn's sequelae in up to 62% of patients out to 12 weeks, according to study investigator, Herbert Lochs, MD, from the Medical University in Innsbruck, Austria.
RETIC-03, a multicenter, multinational, randomized, double-blind, placebo-controlled study, was a comparison of 3 twice-daily doses of rifaximin-EIR (400 mg, 800 mg, and 1200 mg) and placebo in a cohort of 402 patients with active CD. The study's primary end point was remission of CD at 12-week follow-up.
Results showed that at 12 weeks, all active treatment groups achieved remission more often than placebo (P < .04), with the highest rate (62.2%) observed for the 800 mg regimen.
Response to treatment was initially dose-dependent, rising from the 400 mg to the 800 mg threshold. However, the highest dose (1200 mg) produced the least efficacy (47.5%) among the active treatment group, and the highest rate of discontinuations. Reasons for this are unclear, said Dr. Lochs. "The main adverse events tended to be mild, and the majority were gut-related, as in pain, vomiting, and diarrhea — which, frankly, are very difficult to separate out from the symptoms of Crohn's itself."
Commenting on his motivation for conducting RETIC-03, Dr. Lochs said that he was trying to move away from CD treatment methods that rely on suppression of the patient's immune system. "It's not something you ideally want to do — not in the long term."
In the current hypothesis for the pathogenesis of CD, he explained, there is a change in the intestinal microbiota, whereby pathogenic bacteria disrupt the gut's mucosa, which activates the immune system. Rather than inhibit the immune response, Dr. Lochs wants to attenuate the reasons for its activation.
The choice of rifaximin was based on case reports of its potential utility in CD, and the fact that it is specific to the gut. "The formulation stays in the lumen; there's no systemic effect that might lead to overall antibiotic resistance," said Dr. Lochs. In theory, this should lead to fewer adverse events than other antibiotics, he added.
"We need to do a confirmatory study, of course, but this study has shown 2 things that are different and important. First, it was possible to initiate remission with an antibiotic in active Crohn's disease, and second, this remission could be maintained." Dr. Lochs said that future studies (as yet unplanned) would address long-term maintenance of remission.
If it's so simple, why haven't we tried it before?
"The data for antibiotics [in CD] are out there, and the science makes sense," said Sunanda Kane, MD, from the Mayo Clinic in Rochester, Minnesota, and chair of the Patient Education Committee of the Crohn's and Colitis Foundation. "The problem up to now has been that no company has wanted to fund a large enough trial with the appropriate antibiotic."
Dr. Kane said that there is perhaps a different sort of motivation for such a study in the European Union, pointing out that the biologics commonly used in CD are very expensive and often not covered; in some countries, they are not even approved.
"What they are trying to do is to find an alternative to biologics that may be safer and work just as well," she observed.
Dr. Kane finds the choice of rifaximin in this study to be both prudent and just a bit ironic. "There are case studies that show efficacy, and the fact that it's so [gastrointestinal]-specific, so targeted, is great, but rifaximin is not a cheap antibiotic." Still, she admitted, the price is nowhere near that of a biologic, nor does it carry the same potential for serious adverse effects.
Drs. Lochs reports a financial relationship with Alfa Wassermann SpA. Dr. Kane has disclosed no relevant financial relationships.
18th Annual United European Gastroenterology Week: Abstract 3075. Presented October 26, 2010.
BENEFITS OF RADIATION THERAPY IN EARLY BREAST CANCER
November 3, 2010 (San Diego, California) — Further evidence that radiation therapy after breast-conserving surgery reduces the risk for recurrence or death from breast cancer comes from a new meta-analysis, presented here at the American Society for Radiation Oncology 52nd Annual Meeting. The new data also show a reduction in all-cause mortality.
The results of the analysis of a combined cohort of almost 11,000 women show that adding radiation to breast-conserving therapy lowers the risk for recurrence within 10 years by nearly 15%.
"The effect of radiotherapy on breast cancer mortality is very little in the first 5 years after randomization, but by 15 years, there is a very clear effect on breast cancer mortality, with a 3.8% reduction," said study author Sarah Darby, PhD, professor of medical statistics at the Clinical Trial Service Unit and Epidemiological Studies Unit at Oxford University, United Kingdom.
"Most important," she added, "radiotherapy not only reduces breast cancer mortality, but also all-cause mortality — by 3% at 15 years after randomization."
Although this confirms what we already know about radiation therapy in early breast cancer, this study provides further evidence of a larger magnitude, she told Medscape Medical News.
"This study also shows that there is a real survival benefit, not just a benefit for local recurrence," said Dr. Wilson, professor of therapeutic radiology and dermatology at Yale University School of Medicine, New Haven, Connecticut, who was not involved with the study. "It definitely adds to the evidence."
Impact Greater in Certain Subgroups
Although there is much evidence to support the use of radiation therapy after breast-conserving therapy, it might be more effective for certain types of breast cancer than for other types. To examine the evidence of any such differences, and to quantify them when appropriate, collaborative meta-analyses were undertaken.
Dr. Darby and colleagues reviewed data from studies that had begun by 2000 (and were initiated between 1976 and 1999). A total of 10,906 women from 17 randomized trials were included in the analysis, which had a median follow-up period of 9.5 years.
In addition to reducing overall risk for recurrence, the authors found that the impact of radiation varied among the different subtypes of breast cancer. Most notably, radiation therapy conferred a substantial benefit on women with node-positive disease and on women with higher-risk node-negative disease in terms of the 10-year risk for any recurrence of breast cancer and the 15-year risk for breast-cancer-related mortality.
For the 7334 patients with pathologically node-negative breast cancer, radiation therapy decreased the 10-year risk for isolated loco-regional recurrence by 15.4% (7.1% vs 22.5%) and the 10-year risk for any recurrence by 14.5% (18.9% vs 33.4%).
Among this subgroup, the reduction in risk varied according to confounders, such as age, grade, estrogen-receptor (ER) status in combination with tamoxifen use, and extent of surgery.
As an example, note the authors, women with ER-positive tumors participating in trials where breast-conserving surgery was performed and tamoxifen was planned, the 10-year reduction in the risk for recurrence in women younger than 40 years with high-grade tumors was 35%. In contrast, for women 70 years and older with low-grade tumors, it was only 5%.
Among the 1108 women with pathologically node-positive disease, radiation therapy reduced the 10-year risk for isolated loco-regional recurrence by 30.8% (42.7% vs 11.9%), but the impact was lower for the risk for any recurrence (17.7%; 46.8% vs 64.5%; P < .00001). This difference is due to the higher percentage of women in this group with distant recurrence or a contralateral breast cancer as their first event by the 10th year, the authors explain.
Also, within this subgroup, radiotherapy reduced the 15-year risk for breast-cancer-related mortality by 7.8% (43.4% vs 51.2%; P = .04).
American Society for Radiation Oncology (ASTRO) 52nd Annual Meeting: Abstract LB2. Presented November 1, 2010.
The results of the analysis of a combined cohort of almost 11,000 women show that adding radiation to breast-conserving therapy lowers the risk for recurrence within 10 years by nearly 15%.
"The effect of radiotherapy on breast cancer mortality is very little in the first 5 years after randomization, but by 15 years, there is a very clear effect on breast cancer mortality, with a 3.8% reduction," said study author Sarah Darby, PhD, professor of medical statistics at the Clinical Trial Service Unit and Epidemiological Studies Unit at Oxford University, United Kingdom.
"Most important," she added, "radiotherapy not only reduces breast cancer mortality, but also all-cause mortality — by 3% at 15 years after randomization."
Although this confirms what we already know about radiation therapy in early breast cancer, this study provides further evidence of a larger magnitude, she told Medscape Medical News.
"This study also shows that there is a real survival benefit, not just a benefit for local recurrence," said Dr. Wilson, professor of therapeutic radiology and dermatology at Yale University School of Medicine, New Haven, Connecticut, who was not involved with the study. "It definitely adds to the evidence."
Impact Greater in Certain Subgroups
Although there is much evidence to support the use of radiation therapy after breast-conserving therapy, it might be more effective for certain types of breast cancer than for other types. To examine the evidence of any such differences, and to quantify them when appropriate, collaborative meta-analyses were undertaken.
Dr. Darby and colleagues reviewed data from studies that had begun by 2000 (and were initiated between 1976 and 1999). A total of 10,906 women from 17 randomized trials were included in the analysis, which had a median follow-up period of 9.5 years.
In addition to reducing overall risk for recurrence, the authors found that the impact of radiation varied among the different subtypes of breast cancer. Most notably, radiation therapy conferred a substantial benefit on women with node-positive disease and on women with higher-risk node-negative disease in terms of the 10-year risk for any recurrence of breast cancer and the 15-year risk for breast-cancer-related mortality.
For the 7334 patients with pathologically node-negative breast cancer, radiation therapy decreased the 10-year risk for isolated loco-regional recurrence by 15.4% (7.1% vs 22.5%) and the 10-year risk for any recurrence by 14.5% (18.9% vs 33.4%).
Among this subgroup, the reduction in risk varied according to confounders, such as age, grade, estrogen-receptor (ER) status in combination with tamoxifen use, and extent of surgery.
As an example, note the authors, women with ER-positive tumors participating in trials where breast-conserving surgery was performed and tamoxifen was planned, the 10-year reduction in the risk for recurrence in women younger than 40 years with high-grade tumors was 35%. In contrast, for women 70 years and older with low-grade tumors, it was only 5%.
Among the 1108 women with pathologically node-positive disease, radiation therapy reduced the 10-year risk for isolated loco-regional recurrence by 30.8% (42.7% vs 11.9%), but the impact was lower for the risk for any recurrence (17.7%; 46.8% vs 64.5%; P < .00001). This difference is due to the higher percentage of women in this group with distant recurrence or a contralateral breast cancer as their first event by the 10th year, the authors explain.
Also, within this subgroup, radiotherapy reduced the 15-year risk for breast-cancer-related mortality by 7.8% (43.4% vs 51.2%; P = .04).
American Society for Radiation Oncology (ASTRO) 52nd Annual Meeting: Abstract LB2. Presented November 1, 2010.
AN ALTERNATIVE TREATMENT FOR STAGE NSCLC
November 5, 2010 (San Diego, California) — Stereotactic radiation might be an option for patients with operable early-stage nonsmall-cell lung cancer (NSCLC). According to the results of a Japanese study, presented here at the American Society for Radiation Oncology 52nd Annual Meeting, stereotactic radiation is both effective and safe in this population.
"Stereotactic radiation is a standard treatment for patients with inoperable disease," said lead author Yasushi Nagata, MD, professor and radiation oncologist at Hiroshima University in Japan. "But it can be an alternative for operable patients."
The 3-year overall survival, the primary end point of the study, was 76.0% (95% confidence interval [CI], 63.3 - 84.8). According to Dr. Nagata, this survival rate is comparable to historic data of patients with similar stage I NSCLC who underwent surgery.
However, Lynn D. Wilson, MD, MPH, from Yale University School of Medicine, in New Haven, Connecticut, who moderated a press briefing at which highlights of the study by Dr. Nagata and colleagues were presented, explained that surgery is the primary treatment in the United States for patients with early lung cancer.
"Stereotactic radiation is used in the United States," he said, "but generally not as an alternative for a patient who has an operable tumor."
More data are needed in larger populations, he added.
Effective and Safe
Stereotactic body radiation therapy (SBRT) has become an increasingly popular treatment and has shown efficacy in medically inoperable stage I NSCLC. Even though it has been used in patients with operable disease, prospective data are lacking.
When using stereotactic radiation therapy, a much higher dose can be delivered — as much as 6 times the normal radiation dose — when it is localized directly to the tumor, Dr. Nagata pointed out.
Therefore, he explained, the purpose of this study was to evaluate the safety and efficacy of SBRT in patients with operable and with medically inoperable NSCLC. These results are the first ones reported for an operable population.
From 2004 to 2007, Dr. Nagata and colleagues enrolled 65 patients from 15 institutions with operable early-stage NSCLC. The patients were primarily male (45 male, 20 female), with a median age of 79 years (range, 50 to 91 years). The median tumor size was 21 mm (range, 10 to 30 mm); 40 patients had adenocarcinomas, 21 had squamous cell carcinomas, and 4 had other types.
Per protocol, patients received 48 Gy at the isocenter in 4 fractions over a period of 4 to 8 days. All patients in the cohort completed the treatment.
The last follow-up was in November 2009, and the median follow-up of censored cases was 45.4 months. Secondary end points included progression-free survival (54.5%; 95% CI, 41.5 - 65.7), local progression-free survival (68.5%; 95% CI, 55.5 - 78.4), and event-free survival (51.4%; 95% CI, 38.6 - 62.9). A total of 25 progressions have been observed to date.
Overall, SBRT was well tolerated. Grade 3 toxicity included chest pain (n = 1; 1.5%), dyspnea (n = 2; 3.1%), hypoxia (n = 1; 1.5%), and pneumonitis (n = 2; 3.1%). No grade 4 or 5 toxicity was observed.
"Patients in the United States with early lung cancer should consider SBRT as a treatment option," concluded Dr. Nagata.
The authors have disclosed no relevant financial relationships.
American Society for Radiation Oncology (ASTRO) 52nd Annual Meeting: Abstract 59. Presented November 2, 2010.
"Stereotactic radiation is a standard treatment for patients with inoperable disease," said lead author Yasushi Nagata, MD, professor and radiation oncologist at Hiroshima University in Japan. "But it can be an alternative for operable patients."
The 3-year overall survival, the primary end point of the study, was 76.0% (95% confidence interval [CI], 63.3 - 84.8). According to Dr. Nagata, this survival rate is comparable to historic data of patients with similar stage I NSCLC who underwent surgery.
However, Lynn D. Wilson, MD, MPH, from Yale University School of Medicine, in New Haven, Connecticut, who moderated a press briefing at which highlights of the study by Dr. Nagata and colleagues were presented, explained that surgery is the primary treatment in the United States for patients with early lung cancer.
"Stereotactic radiation is used in the United States," he said, "but generally not as an alternative for a patient who has an operable tumor."
More data are needed in larger populations, he added.
Effective and Safe
Stereotactic body radiation therapy (SBRT) has become an increasingly popular treatment and has shown efficacy in medically inoperable stage I NSCLC. Even though it has been used in patients with operable disease, prospective data are lacking.
When using stereotactic radiation therapy, a much higher dose can be delivered — as much as 6 times the normal radiation dose — when it is localized directly to the tumor, Dr. Nagata pointed out.
Therefore, he explained, the purpose of this study was to evaluate the safety and efficacy of SBRT in patients with operable and with medically inoperable NSCLC. These results are the first ones reported for an operable population.
From 2004 to 2007, Dr. Nagata and colleagues enrolled 65 patients from 15 institutions with operable early-stage NSCLC. The patients were primarily male (45 male, 20 female), with a median age of 79 years (range, 50 to 91 years). The median tumor size was 21 mm (range, 10 to 30 mm); 40 patients had adenocarcinomas, 21 had squamous cell carcinomas, and 4 had other types.
Per protocol, patients received 48 Gy at the isocenter in 4 fractions over a period of 4 to 8 days. All patients in the cohort completed the treatment.
The last follow-up was in November 2009, and the median follow-up of censored cases was 45.4 months. Secondary end points included progression-free survival (54.5%; 95% CI, 41.5 - 65.7), local progression-free survival (68.5%; 95% CI, 55.5 - 78.4), and event-free survival (51.4%; 95% CI, 38.6 - 62.9). A total of 25 progressions have been observed to date.
Overall, SBRT was well tolerated. Grade 3 toxicity included chest pain (n = 1; 1.5%), dyspnea (n = 2; 3.1%), hypoxia (n = 1; 1.5%), and pneumonitis (n = 2; 3.1%). No grade 4 or 5 toxicity was observed.
"Patients in the United States with early lung cancer should consider SBRT as a treatment option," concluded Dr. Nagata.
The authors have disclosed no relevant financial relationships.
American Society for Radiation Oncology (ASTRO) 52nd Annual Meeting: Abstract 59. Presented November 2, 2010.
Τρίτη, 2 Νοεμβρίου 2010
A RARE RENAL TUMOR
Pediatr Blood Cancer. 2010 Dec 1;55(6):1217-20.
Complete response to carboplatin, gemcitabine, and paclitaxel in a patient with advanced metastatic renal medullary carcinoma.
Walsh A, Kelly DR, Vaid YN, Hilliard LM, Friedman GK.
Division of Pediatric Hematology Oncology, University of Alabama at Birmingham, Birmingham, Alabama.
Abstract
Renal medullary carcinoma (RMC) is a rare and aggressive malignancy seen primarily in patients with sickle-cell trait. We report a complete response to carboplatin, paclitaxel, and gemcitabine in a patient with advanced metastatic RMC. Pediatr Blood Cancer. 2010;55:1217-1220.
Complete response to carboplatin, gemcitabine, and paclitaxel in a patient with advanced metastatic renal medullary carcinoma.
Walsh A, Kelly DR, Vaid YN, Hilliard LM, Friedman GK.
Division of Pediatric Hematology Oncology, University of Alabama at Birmingham, Birmingham, Alabama.
Abstract
Renal medullary carcinoma (RMC) is a rare and aggressive malignancy seen primarily in patients with sickle-cell trait. We report a complete response to carboplatin, paclitaxel, and gemcitabine in a patient with advanced metastatic RMC. Pediatr Blood Cancer. 2010;55:1217-1220.
AN INTERESTING OBSERVATION
Br J Cancer. 2010 Oct 26. [Epub ahead of print]
Inhibition of renin-angiotensin system affects prognosis of advanced pancreatic cancer receiving gemcitabine.
Nakai Y, Isayama H, Ijichi H, Sasaki T, Sasahira N, Hirano K, Kogure H, Kawakubo K, Yagioka H, Yashima Y, Mizuno S, Yamamoto K, Arizumi T, Togawa O, Matsubara S, Tsujino T, Tateishi K, Tada M, Omata M, Koike K.
Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo Bunkyo-ku, Tokyo 113-8655, Japan.
Abstract
Background:The renin-angiotensin system (RAS) is thought to have a role in carcinogenesis, and RAS inhibition may prevent tumour growth.Methods:We retrospectively investigated the impact of angiotensin I-converting enzyme inhibitors (ACEIs) and angiotensin II type-1 receptor blockers (ARBs) in 155 patients with pancreatic cancer receiving gemcitabine monotherapy. Patients were divided into three groups: the ACEI/ARB group (27 patients receiving an ACEI or ARB for hypertension (HT)), the non-ACEI/ARB with HT group (25 patients receiving antihypertensive drugs other than ACEIs or ARBs), and the non-HT group (103 patients receiving no antihypertensive drugs).Results:Patient characteristics were not different, except for age and HT medications. Progression-free survival (PFS) was 8.7 months in the ACEI/ARB group, 4.5 months in the non-ACEI/ARB with HT group, and 3.6 months in the non-HT group. Overall survival (OS) was 15.1 months in the ACEI/ARB group, 8.9 months in the non-ACEI/ARB with HT group, and 9.5 months in the non-HT group. The use of ACEIs/ARBs was a significant prognostic factor for both PFS (P=0.032) and OS (P=0.014) in the multivariate analysis.Conclusions:The ACEIs/ARBs in combination with gemcitabine might improve clinical outcomes in patients with advanced pancreatic cancer. Prospective trials are needed to test this hypothesis.British Journal of Cancer advance online publication, 26 October 2010;
Inhibition of renin-angiotensin system affects prognosis of advanced pancreatic cancer receiving gemcitabine.
Nakai Y, Isayama H, Ijichi H, Sasaki T, Sasahira N, Hirano K, Kogure H, Kawakubo K, Yagioka H, Yashima Y, Mizuno S, Yamamoto K, Arizumi T, Togawa O, Matsubara S, Tsujino T, Tateishi K, Tada M, Omata M, Koike K.
Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo Bunkyo-ku, Tokyo 113-8655, Japan.
Abstract
Background:The renin-angiotensin system (RAS) is thought to have a role in carcinogenesis, and RAS inhibition may prevent tumour growth.Methods:We retrospectively investigated the impact of angiotensin I-converting enzyme inhibitors (ACEIs) and angiotensin II type-1 receptor blockers (ARBs) in 155 patients with pancreatic cancer receiving gemcitabine monotherapy. Patients were divided into three groups: the ACEI/ARB group (27 patients receiving an ACEI or ARB for hypertension (HT)), the non-ACEI/ARB with HT group (25 patients receiving antihypertensive drugs other than ACEIs or ARBs), and the non-HT group (103 patients receiving no antihypertensive drugs).Results:Patient characteristics were not different, except for age and HT medications. Progression-free survival (PFS) was 8.7 months in the ACEI/ARB group, 4.5 months in the non-ACEI/ARB with HT group, and 3.6 months in the non-HT group. Overall survival (OS) was 15.1 months in the ACEI/ARB group, 8.9 months in the non-ACEI/ARB with HT group, and 9.5 months in the non-HT group. The use of ACEIs/ARBs was a significant prognostic factor for both PFS (P=0.032) and OS (P=0.014) in the multivariate analysis.Conclusions:The ACEIs/ARBs in combination with gemcitabine might improve clinical outcomes in patients with advanced pancreatic cancer. Prospective trials are needed to test this hypothesis.British Journal of Cancer advance online publication, 26 October 2010;
LEVEL OF HER-2 AMPLIFICATION AND RESPONSE TO TREATMENT
Br J Cancer. 2010 Oct 26;103(9):1335-42.
Pathological complete response and survival according to the level of HER-2 amplification after trastuzumab-based neoadjuvant therapy for breast cancer.
Guiu S, Gauthier M, Coudert B, Bonnetain F, Favier L, Ladoire S, Tixier H, Guiu B, Penault-Llorca F, Ettore F, Fumoleau P, Arnould L.
Department of Oncology, Georges-François Leclerc Cancer Center, F-21000 Dijon, France.
Abstract
Background:We analysed whether the level of human epidermal growth factor receptor-2 (HER-2) amplification significantly influenced either pathological complete response (pCR) or recurrence-free survival (RFS) and overall survival (OS) after trastuzumab-based neoadjuvant therapy.Methods:In all, 99 patients with an HER-2-amplified breast tumour treated with trastuzumab-based neoadjuvant therapy were included. Tumours were classified as low amplified (LA; 6-10 signals per nuclei) or highly amplified (HA; >10 signals). Pathological response was assessed according to Chevallier's classification (pCR was defined as grade 1 or 2). Median follow-up lasted 46 months (6-83). Cox uni- and multivariate analyses were performed.Results:In all, 33 tumour samples were LA and 66 were HA. The pCR in HA tumours was significantly higher than in LA tumours (55% vs 24%, P=0.005), whereas no association was found between the pCR rate and tumour stage, grade or hormone receptor status. In multivariate analysis, the pathological nodal status (P=0.005) and adjuvant trastuzumab (P=0.037) were independently associated with RFS, whereas the level of HER-2 amplification nearly reached statistical significance (P=0.057). There was no significant difference between LA and HA tumours for OS (P=0.22, log-rank).Conclusion:The level of HER-2 gene amplification significantly influenced pCR but not RFS or OS in non-metastatic breast cancer treated with trastuzumab-based neoadjuvant therapy. However, RFS in patients with HA tumours tended to be shorter.
Pathological complete response and survival according to the level of HER-2 amplification after trastuzumab-based neoadjuvant therapy for breast cancer.
Guiu S, Gauthier M, Coudert B, Bonnetain F, Favier L, Ladoire S, Tixier H, Guiu B, Penault-Llorca F, Ettore F, Fumoleau P, Arnould L.
Department of Oncology, Georges-François Leclerc Cancer Center, F-21000 Dijon, France.
Abstract
Background:We analysed whether the level of human epidermal growth factor receptor-2 (HER-2) amplification significantly influenced either pathological complete response (pCR) or recurrence-free survival (RFS) and overall survival (OS) after trastuzumab-based neoadjuvant therapy.Methods:In all, 99 patients with an HER-2-amplified breast tumour treated with trastuzumab-based neoadjuvant therapy were included. Tumours were classified as low amplified (LA; 6-10 signals per nuclei) or highly amplified (HA; >10 signals). Pathological response was assessed according to Chevallier's classification (pCR was defined as grade 1 or 2). Median follow-up lasted 46 months (6-83). Cox uni- and multivariate analyses were performed.Results:In all, 33 tumour samples were LA and 66 were HA. The pCR in HA tumours was significantly higher than in LA tumours (55% vs 24%, P=0.005), whereas no association was found between the pCR rate and tumour stage, grade or hormone receptor status. In multivariate analysis, the pathological nodal status (P=0.005) and adjuvant trastuzumab (P=0.037) were independently associated with RFS, whereas the level of HER-2 amplification nearly reached statistical significance (P=0.057). There was no significant difference between LA and HA tumours for OS (P=0.22, log-rank).Conclusion:The level of HER-2 gene amplification significantly influenced pCR but not RFS or OS in non-metastatic breast cancer treated with trastuzumab-based neoadjuvant therapy. However, RFS in patients with HA tumours tended to be shorter.
ANTHRACYCLINE RECHALLENGE WITH CAELYX
Br J Cancer. 2010 Oct 26. [Epub ahead of print]
Anthracycline rechallenge using pegylated liposomal doxorubicin in patients with metastatic breast cancer: a pooled analysis using individual data from four prospective trials.
Al-Batran SE, Güntner M, Pauligk C, Scholz M, Chen R, Beiss B, Stopatschinskaja S, Lerbs W, Harbeck N, Jäger E.
Klinik für Onkologie und Hämatologie am Krankenhaus Nordwest, Krankenhaus Nordwest, Steinbacher Hohl 2-26, 60488 Frankfurt am Main, Germany.
Abstract
Background:The aim of this study was to determine the activity of anthracycline rechallenge using pegylated liposomal doxorubicin (PLD) in patients with metastatic breast cancer (MBC) previously treated with conventional anthracyclines.Methods:Pooled individual data from four prospective trials were used, and the primary end point of the pooled analysis was clinical benefit rate (CBR). The studies comprised 935 patients, of whom 274 had received PLD in the metastatic setting after prior exposure to conventional anthracyclines (rechallenge population).Results:The majority of patients were heavily pretreated. Previous anthracycline therapy was administered in the adjuvant (14%) or metastatic setting (46%), or both (40%). The overall CBR from rechallenge with PLD was 37.2% (95% CI, 32.4-42.0). In univariate analyses, the CBR was significantly higher in patients with less exposure to prior chemotherapy, in taxane-naive patients, and in patients with a favourable Eastern Cooperative Group performance status of 0 vs 1 vs 2 (53.3 vs 35.5 vs 18.2%; P<0.001). In multivariate analyses, performance status proved to be the only independent predictor of the CBR achieved with PLD rechallenge (P=0.038). There was no statistically significant difference in CBR regarding the setting, cumulative dose of and/or resistance to prior anthracyclines, or time since prior anthracycline administration.Conclusion:Anthracycline rechallenge using PLD is effective in patients with MBC who have a favourable performance status, regardless of setting, resistance, cumulative dose or time since prior conventional anthracycline therapy.British Journal of Cancer advance online publication, 26 October 2010
Anthracycline rechallenge using pegylated liposomal doxorubicin in patients with metastatic breast cancer: a pooled analysis using individual data from four prospective trials.
Al-Batran SE, Güntner M, Pauligk C, Scholz M, Chen R, Beiss B, Stopatschinskaja S, Lerbs W, Harbeck N, Jäger E.
Klinik für Onkologie und Hämatologie am Krankenhaus Nordwest, Krankenhaus Nordwest, Steinbacher Hohl 2-26, 60488 Frankfurt am Main, Germany.
Abstract
Background:The aim of this study was to determine the activity of anthracycline rechallenge using pegylated liposomal doxorubicin (PLD) in patients with metastatic breast cancer (MBC) previously treated with conventional anthracyclines.Methods:Pooled individual data from four prospective trials were used, and the primary end point of the pooled analysis was clinical benefit rate (CBR). The studies comprised 935 patients, of whom 274 had received PLD in the metastatic setting after prior exposure to conventional anthracyclines (rechallenge population).Results:The majority of patients were heavily pretreated. Previous anthracycline therapy was administered in the adjuvant (14%) or metastatic setting (46%), or both (40%). The overall CBR from rechallenge with PLD was 37.2% (95% CI, 32.4-42.0). In univariate analyses, the CBR was significantly higher in patients with less exposure to prior chemotherapy, in taxane-naive patients, and in patients with a favourable Eastern Cooperative Group performance status of 0 vs 1 vs 2 (53.3 vs 35.5 vs 18.2%; P<0.001). In multivariate analyses, performance status proved to be the only independent predictor of the CBR achieved with PLD rechallenge (P=0.038). There was no statistically significant difference in CBR regarding the setting, cumulative dose of and/or resistance to prior anthracyclines, or time since prior anthracycline administration.Conclusion:Anthracycline rechallenge using PLD is effective in patients with MBC who have a favourable performance status, regardless of setting, resistance, cumulative dose or time since prior conventional anthracycline therapy.British Journal of Cancer advance online publication, 26 October 2010
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