January 6, 2011 — For the past 10 years, Steven Vogl, MD, a medical oncologist in private practice in the Bronx, New York, has attended the Annual San Antonio Breast Cancer Symposium (SABCS).
And at all of these meetings, Dr. Vogl has repeatedly left his seat, walked to microphone stations, and asked questions of speakers after their presentations.
"Vogl, New York," he says into the microphone, to identify himself and introduce his question. "Why say more?" he told Medscape Medical News about his verbal signature.
Dr. Vogl's questions, spoken in a distinctive New York accent, are often blunt and probing. Dr. Vogl has a freedom of speech that comes with being a community-based physician who is outside of the hierarchies of academia and industry. As any meeting-goer will tell you, Dr. Vogl does not kowtow to fame and status — renowned researchers and department chairs are addressed in the same manner as fellows and assistant professors.
"Some people like my questions, some don't," Dr. Vogl said. "I get some dirty looks — 'Oh, him again'."
A "famous" breast cancer oncologist told Dr. Vogl that he instructs his junior faculty to ready themselves for questions from the floor in San Antonio. "You've got to be prepared to answer Vogl," the eminent academic tells his young investigators, citing the ultimate challenge.
Dr. Vogl acknowledged that presenters and moderators have mixed reactions to him. "Sometimes, people moderating a session look to other microphones when they see me standing up," he explained.
His friends also have mixed feelings about his inquisitiveness. "I have a friend — she is a radiation oncologist — and she won't sit next to me in San Antonio because of my questions."
But for all of the people who avoid him at meetings, Dr. Vogl has developed, over the years, plenty of fans, including people in high places.
Last year at the American Society of Clinical Oncology (ASCO) annual meeting, while Dr. Vogl was trekking through the hallways of the gargantuan McCormick Center in Chicago, he was approached by Douglas Blayney, MD, who was president of ASCO at the time. "A lot of people like your questions," said Dr. Blayney, who is from the University of Michigan in Ann Arbor. "Keep asking them."
In 2009 at the SABCS, Dr. Vogl sat near Kent Osborne, MD, who is from Baylor College of Medicine in Houston, Texas, and is codirector of the meeting.
"Are you coming to the meeting next year?" Dr. Osborne asked.
"I hope I live until next year," answered Dr. Vogl, who then acknowledged that he would be present again.
The 2010 SABCS had 7900 attendees, including Dr. Vogl, of course. Many of the attendees were in the main auditorium at the San Antonio Convention Center on December 9 for the meeting's first general session oral presentation.
At the end of the presentation — on a phase 3 trial comparing the aromatase inhibitors exemestane and anastrozole in postmenopausal women, Dr. Vogl, as is his custom, asked a question. But he was interrupted! — by none other than Dr. Osborne, who was also in the audience and temporarily took over the program.
Dr. Osborne thanked Dr. Vogl for his annual contributions to the breast cancer meeting, which is the largest of its kind in the world. He then presented Dr. Vogl with a Lucite plaque that reads:"We gave the award to Dr. Vogl because of his consistent attendance at the meeting over many years and, more importantly, his astute and thoughtful questions during the question and answer periods after each talk," Dr. Osborne told Medscape Medical News in an email.
"He is a practicing clinician but has a unique ability to understand basic science and clinical research and to recognize the importance and/or the problems with a presentation," added Dr. Osborne.
The director of the SABCS also touched upon one of Dr. Vogl's gifts: "He can boil everything down to the important take-home message related to a given talk."
Finally, Dr. Osborne praised the medical oncologist from the Bronx in a manner that Dr. Vogl would surely object to: "Everyone respects his judgment and interpretations."
For His Patients
Dr. Vogl said that he has attended the SABCS annually for the past decade because "I treat a lot of breast cancer patients." He has also gone to ASCO annually since 1975, and he attends, on a biannual basis, a conference on adjuvant therapies in New York City.
Dr. Vogl attends meetings both for himself and his patients, he said.
He sees himself as an advocate and champion of patients. "It's the only chance I get to defend patients against drug companies," Dr. Vogl said about his tendency to be highly critical of some presentations.
"I think a large number of studies are being done to answer narrow questions that are of interest to drug companies," he explained.
His current frustration with drug companies revolves around the timing of the use of drugs, such as zoledronic acid (Zometa), pamidronate (Aredia), and denosumab (Xgeva), that treat bone metastases in breast cancers.
"No one knows when to start or stop these drugs. It's not in the drug companies' interest to tell us, especially when to stop them," Dr. Vogl said.
Dr. Vogl is critical of the pharmaceutical and health insurance industries and the regulation of the healthcare system in the United States. "We have the best government money can buy — and the insurance and drug companies have bought it," he said.
But he saves his most potent vitriol for the insurance companies. "Insurance companies have no interest in giving good service. They treat sick people like dirt," he told Medscape Medical News during a 7 pm phone interview that took place after a long day of seeing patients.
Dr. Vogl works in a relatively small office with a nurse, medical assistant, receptionist, and an accountant/office manager who happens to be his wife, Amalia. Her job is "hell" because she has to deal with the insurance companies, he said.
"You have to have somebody who will figure out what insurance companies will pay for and to challenge them," he said of his wife's role.
"That's the reason academic departments all lose money — they don't have someone who will go after the insurance companies," he said.
Free of Bosses and Employment Worries
Dr. Vogl knows quite a bit about academic medical departments; he used to work at the Albert Einstein College of Medicine in the Bronx.
After graduating from the Cornell Weill Medical College in New York City, being a resident at Jacobi Hospital in the Bronx, and completing a fellowship in oncology at Mount Sinai in New York City, Dr. Vogl served as an instructor, assistant, and associate professor at Albert Einstein. He resigned in 1982 for reasons that he chooses not to discuss.
As an investigator, Dr. Vogl participated in a number of Eastern Cooperative Oncology Group (ECOG) trials, including studies of platinum chemotherapy for a variety of malignancies, such as head and neck and ovarian cancer. At one time, he was chair of the ECOG Gynecologic Genitourinary Committee. "I made some noise," he said about his time as an academic and investigator. In short, Dr. Vogl is not your typical community-based physician. He is very familiar with clinical trial designs, statistical methods, and so on.
Not being an academic is freeing, reported Dr. Vogl
"I am not dependent on anyone for funding and I don't have to worry about offending a boss or drug company," he said. "If I had to worry about my next job or grant, I would have to be more circumspect."
Even though Dr. Vogl is a free agent, beholden only to his patients, he maintains high standards for himself. "I try very hard to phrase any questions politely, succinctly, and in good English," he said.
He approaches his time at meeting microphones with the consciousness of a performer. "I try to have a minimum of bombast. Occasionally, I use a one-sentence preamble with a question," he said, describing his technique.
"For instance, this year in San Antonio at José Baselga's presentation on lapatinib and [trastuzumab] for the treatment of HER2-positive patients, I asked a question with the preamble: 'Sometimes you learn more from patients who don't do what you want them to do than you do from the ones who do what you want'."
Dr. Vogl explained that, in this trial, the toxicity of lapatinib caused many patients to go off drug because of diarrhea and to subsequently have a dose reduction. In the end, the investigators found that they had the same positive results with patients who received less drug and had less toxicity, said Dr. Vogl.
Inherited Traits?
Dr. Vogl is the son of Austrian immigrants who met in New York City at a night school class they had both enrolled in to learn English. Both parents arrived in the United States in 1941.
About his father, Dr. Vogl said: "There's a legend that my father beat up an SS man [and had to subsequently flee Austria]."
About his mother, Dr. Vogl said that, as she was fleeing Austria and Europe, she had to take a train across Germany. "The German inspector looked at her suitcase, which was so neatly packed that the inspector said, 'I'm not touching this," and the future Mrs. Vogl went on her way undetained.
So Dr. Vogl certainly has had models of combative courage and purposeful orderliness — helpful traits for a medical doctor questioning and battling the status quo.
In the end, like most human beings, Dr. Vogl enjoys friendliness and harmony. "After I received the award in San Antonio, there were lots of smiles. Everybody was smiling at me."
Παρασκευή, 7 Ιανουαρίου 2011
Πέμπτη, 6 Ιανουαρίου 2011
PARP INHIBITORS FOR TRIPLE NEGATIVE BREAST CANCER-POSITIVE RESULTS PUBLISHED
January 5, 2011 — The investigational agent iniparib (Sanofi-Aventis) improved a number of clinical measures, including overall survival, in women with metastatic triple-negative breast cancer, according to final phase 2 study results.
The results for iniparib, which inhibits PARP, or poly(adenosine-disposphate-ribose) polymerase, were presented earlier at the 2010 European Society for Medical Oncology Congress and have been published online January 5 in the New England Journal of Medicine.
Women who received iniparib plus gemcitabine (Gemzar; Eli Lilly) and carboplatin had better rates of clinical benefit (by 22%) and progression-free survival (by 2 months) than those treated with chemotherapy alone. Clinical benefit is a measure of disease stabilization or durable response. Notably, those treated with iniparib survived nearly 5 months longer on average.
However, overall survival was neither a primary nor secondary end point in the 123-patient randomized trial, note the authors, led by Joyce O'Shaughnessy, MD, from Baylor-Charles A. Sammons Cancer Center in Dallas, Texas.
The small sample size "limits our assessment of overall survival," write the study authors.
They also point out that there was an imbalance between the 2 treatment groups. Patients in the iniparib group had some favorable prognostic factors, compared with the chemotherapy-alone group, such as fewer patients with 3 or more metastatic sites (57% vs 69%).
These imbalances in prognostic factors are a reason for caution when interpreting the trial results, say Lisa Carey, MD, and Norman Sharpless, MD, in an editorial that accompanies the study. They are both from the University of North Carolina Lineberger Comprehensive Cancer Center in Chapel Hill.
Other reasons for caution, say the editorialists, include the small cohort and the facts that end points were assessed by investigators and that the chemotherapy combination is "unconventional."
Excitement Is Appropriate
Despite their notes of caution, Dr. Carey and Dr. Sharpless note that "excitement" about the study data is also "appropriate."
Currently, there is no standard of care for women with metastatic triple-negative disease; they are an "underserved" group of patients, say the editorialists.
A phase 3 trial of iniparib is now underway. If these phase 2 results are confirmed, then the agent would be the first to show a survival advantage over chemotherapy alone in metastatic triple-negative breast cancer, the editorialists explain.
Excitement has surrounded iniparib since early phase 2 data on the compound, then known as BSI-201, was first presented at the American Society of Clinical Oncology 2009 annual meeting. At the time, a leading breast cancer expert called the results "one of the most exciting findings in breast cancer in a long time." Overall, the development of PARP inhibitors has been a cause for enthusiasm among researchers. In another editorial, published in 2009, a pair of cancer experts called PARP inhibition a "new direction in the development of anticancer drugs."
Different Than Other PARP Inhibitors?
Although there are a number of PARP inhibitors under development, there is a suggestion that iniparib is different from the others.
In their editorial, Dr. Carey and Dr. Sharpless ask how exactly iniparib improves outcome in patients with triple-negative breast cancer. "Does the activity of iniparib in this trial result from PARP inhibition or an unknown mechanism?" they write.
The editorialists point out that in small studies, other PARP inhibitors have not shown "promising results" outside of hereditary BRCA-associated breast cancer.
As a consequence, Dr. Carey and Dr. Sharpless raise the possibility that iniparib might only benefit a subgroup of triple-negative patients — those who also carry BRCA mutations.
"We cannot tell whether the benefit from the PARP inhibitor accrued to all triple-negative tumors equally or whether the benefit preferentially accrued to a subgroup of BRCA-deficient tumors, with less effect in those without the deficiency," they write.
However, in an interview with Medscape Medical News, Dr. Carey said that it is "unlikely" that the efficacy of iniparib in triple-negative disease is limited to women with who also have BRCA1 or 2 mutations because such cancers are rare.
So why does iniparib seem to work in women with triple-negative breast cancer when other PARP inhibitors do not?
The editorialists point out that iniparib is different from other PARP inhibitors in a number of ways.
Iniparib is a "much less potent inhibitor of PARP1," which is the most common form of PARP, than "most other agents of this class." In a perhaps related matter, it has been "challenging" to combine other PARP inhibitors with chemotherapy because of toxicity. In contrast, in the current study, there was no significant difference between the 2 treatment groups in the rate of adverse events.
The editorialists also note that, in the phase 2 study, there was no pharmacodynamic assessment of PARP activity in the patients receiving iniparib. "It is unclear whether the therapeutic efficacy of this agent correlates with PARP inhibition in these patients," they write. They also say that "at least part of its antitumor efficacy may be independent of PARP inhibition."
Study Results
The phase 2 study was sponsored by BiPar Sciences, which is now a wholly owned subsidiary of Sanofi-Aventis, and was conducted at 20 centers belonging to US Oncology.
In the study, 123 women with metastatic triple-negative breast cancer underwent randomization (1:1) and received either gemcitabine and carboplatin alone or gemcitabine and carboplatin plus iniparib. Gemcitabine (1000 mg/m2 of body surface area) and carboplatin (at a dose equivalent to an area under the curve of 2) were given on days 1 and 8, and intravenous iniparib (5.6 mg/kg) was given on days 1, 4, 8, and 11 — every 21 days. Patients in the chemotherapy-alone group were allowed to cross over to the iniparib group if disease progression occurred; in the end, 51% of patients did so.
The primary end points were safety, tolerability, and the rate of clinical benefit, defined as objective response rate (complete or partial response) plus the rate of stable disease for 6 months or more. Secondary objectives included progression-free survival and objective response rate.
The addition of iniparib to gemcitabine and carboplatin improved the rate of clinical benefit from 34% to 56% (P = .01) and the rate of overall response from 32% to 52% (P = .02). The addition of iniparib also improved median progression-free survival from 3.6 to 5.9 months (hazard ratio for progression, 0.59; P = .01) and overall survival from 7.7 to 12.3 months (hazard ratio for death, 0.57; P = .01).
The most frequent grade 3 or 4 adverse events in both treatment groups included neutropenia, anemia, and thrombocytopenia. The rate of serious adverse events was similar between the chemotherapy-alone and the iniparib groups (29% vs 28%). As noted above, there was also no significant difference between the 2 groups in terms of the rate of any adverse events.
The study was funded by BiPar Sciences, now owned by Sanofi-Aventis. The article was written by 1 academic and 1 industry author, with editorial assistance from the sponsor. Dr. Carey and Dr. Sharpless have disclosed no relevant financial relationships.
New Engl J Med. Published online January 5, 2011.
The results for iniparib, which inhibits PARP, or poly(adenosine-disposphate-ribose) polymerase, were presented earlier at the 2010 European Society for Medical Oncology Congress and have been published online January 5 in the New England Journal of Medicine.
Women who received iniparib plus gemcitabine (Gemzar; Eli Lilly) and carboplatin had better rates of clinical benefit (by 22%) and progression-free survival (by 2 months) than those treated with chemotherapy alone. Clinical benefit is a measure of disease stabilization or durable response. Notably, those treated with iniparib survived nearly 5 months longer on average.
However, overall survival was neither a primary nor secondary end point in the 123-patient randomized trial, note the authors, led by Joyce O'Shaughnessy, MD, from Baylor-Charles A. Sammons Cancer Center in Dallas, Texas.
The small sample size "limits our assessment of overall survival," write the study authors.
They also point out that there was an imbalance between the 2 treatment groups. Patients in the iniparib group had some favorable prognostic factors, compared with the chemotherapy-alone group, such as fewer patients with 3 or more metastatic sites (57% vs 69%).
These imbalances in prognostic factors are a reason for caution when interpreting the trial results, say Lisa Carey, MD, and Norman Sharpless, MD, in an editorial that accompanies the study. They are both from the University of North Carolina Lineberger Comprehensive Cancer Center in Chapel Hill.
Other reasons for caution, say the editorialists, include the small cohort and the facts that end points were assessed by investigators and that the chemotherapy combination is "unconventional."
Excitement Is Appropriate
Despite their notes of caution, Dr. Carey and Dr. Sharpless note that "excitement" about the study data is also "appropriate."
Currently, there is no standard of care for women with metastatic triple-negative disease; they are an "underserved" group of patients, say the editorialists.
A phase 3 trial of iniparib is now underway. If these phase 2 results are confirmed, then the agent would be the first to show a survival advantage over chemotherapy alone in metastatic triple-negative breast cancer, the editorialists explain.
Excitement has surrounded iniparib since early phase 2 data on the compound, then known as BSI-201, was first presented at the American Society of Clinical Oncology 2009 annual meeting. At the time, a leading breast cancer expert called the results "one of the most exciting findings in breast cancer in a long time." Overall, the development of PARP inhibitors has been a cause for enthusiasm among researchers. In another editorial, published in 2009, a pair of cancer experts called PARP inhibition a "new direction in the development of anticancer drugs."
Different Than Other PARP Inhibitors?
Although there are a number of PARP inhibitors under development, there is a suggestion that iniparib is different from the others.
In their editorial, Dr. Carey and Dr. Sharpless ask how exactly iniparib improves outcome in patients with triple-negative breast cancer. "Does the activity of iniparib in this trial result from PARP inhibition or an unknown mechanism?" they write.
The editorialists point out that in small studies, other PARP inhibitors have not shown "promising results" outside of hereditary BRCA-associated breast cancer.
As a consequence, Dr. Carey and Dr. Sharpless raise the possibility that iniparib might only benefit a subgroup of triple-negative patients — those who also carry BRCA mutations.
"We cannot tell whether the benefit from the PARP inhibitor accrued to all triple-negative tumors equally or whether the benefit preferentially accrued to a subgroup of BRCA-deficient tumors, with less effect in those without the deficiency," they write.
However, in an interview with Medscape Medical News, Dr. Carey said that it is "unlikely" that the efficacy of iniparib in triple-negative disease is limited to women with who also have BRCA1 or 2 mutations because such cancers are rare.
So why does iniparib seem to work in women with triple-negative breast cancer when other PARP inhibitors do not?
The editorialists point out that iniparib is different from other PARP inhibitors in a number of ways.
Iniparib is a "much less potent inhibitor of PARP1," which is the most common form of PARP, than "most other agents of this class." In a perhaps related matter, it has been "challenging" to combine other PARP inhibitors with chemotherapy because of toxicity. In contrast, in the current study, there was no significant difference between the 2 treatment groups in the rate of adverse events.
The editorialists also note that, in the phase 2 study, there was no pharmacodynamic assessment of PARP activity in the patients receiving iniparib. "It is unclear whether the therapeutic efficacy of this agent correlates with PARP inhibition in these patients," they write. They also say that "at least part of its antitumor efficacy may be independent of PARP inhibition."
Study Results
The phase 2 study was sponsored by BiPar Sciences, which is now a wholly owned subsidiary of Sanofi-Aventis, and was conducted at 20 centers belonging to US Oncology.
In the study, 123 women with metastatic triple-negative breast cancer underwent randomization (1:1) and received either gemcitabine and carboplatin alone or gemcitabine and carboplatin plus iniparib. Gemcitabine (1000 mg/m2 of body surface area) and carboplatin (at a dose equivalent to an area under the curve of 2) were given on days 1 and 8, and intravenous iniparib (5.6 mg/kg) was given on days 1, 4, 8, and 11 — every 21 days. Patients in the chemotherapy-alone group were allowed to cross over to the iniparib group if disease progression occurred; in the end, 51% of patients did so.
The primary end points were safety, tolerability, and the rate of clinical benefit, defined as objective response rate (complete or partial response) plus the rate of stable disease for 6 months or more. Secondary objectives included progression-free survival and objective response rate.
The addition of iniparib to gemcitabine and carboplatin improved the rate of clinical benefit from 34% to 56% (P = .01) and the rate of overall response from 32% to 52% (P = .02). The addition of iniparib also improved median progression-free survival from 3.6 to 5.9 months (hazard ratio for progression, 0.59; P = .01) and overall survival from 7.7 to 12.3 months (hazard ratio for death, 0.57; P = .01).
The most frequent grade 3 or 4 adverse events in both treatment groups included neutropenia, anemia, and thrombocytopenia. The rate of serious adverse events was similar between the chemotherapy-alone and the iniparib groups (29% vs 28%). As noted above, there was also no significant difference between the 2 groups in terms of the rate of any adverse events.
The study was funded by BiPar Sciences, now owned by Sanofi-Aventis. The article was written by 1 academic and 1 industry author, with editorial assistance from the sponsor. Dr. Carey and Dr. Sharpless have disclosed no relevant financial relationships.
New Engl J Med. Published online January 5, 2011.
Τετάρτη, 5 Ιανουαρίου 2011
VEGF GENE POLYMORPHISM AND RESPONSE TO AVASTIN
Int J Colorectal Dis. 2010 Dec 29. [Epub ahead of print]
Predictive value of VEGF gene polymorphisms for metastatic colorectal cancer patients receiving first-line treatment including fluorouracil, irinotecan, and bevacizumab.
Formica V, Palmirotta R, Del Monte G, Savonarola A, Ludovici G, De Marchis ML, Grenga I, Schirru M, Guadagni F, Roselli M.
Medical Oncology Unit, Internal Medicine Department, 'Tor Vergata' Clinical Center University of Rome, Viale Oxford, 0133, Rome, Italy, v.formica@fastwebnet.it.
Abstract
PURPOSE: The aim of this study is to evaluate the influence of germline vascular endothelial growth factor (VEGF) gene polymorphisms (VGPs) on the efficacy of the anti-VEGF antibody bevacizumab (Bev) in metastatic colorectal cancer (MCRC) patients.
METHODS: Forty MCRC patients eligible for a first-line therapy were enrolled in this prospective trial and treated with FOLinate/Fluorouracil/Irinotecan (FOLFIRI) + Bev (male/female = 22:18, age (median) = 61 years). Eight VGPs within the promoter/5'UTR region were evaluated in patient blood samples. Primary endpoint was association between VGPs and median progression-free survival (mPFS). Overall radiological response rate (ORR), overall survival (OS), and toxicity were assessed as secondary outcomes.
RESULTS: VGPs -2578, -1512, -1451, -1411, and -460 were in complete linkage disequilibrium and therefore analyzed as haplotype (two variants: Haplo1: A-18 bp insertion-T-4G-C and Haplo2: C-18 bp deletion-C-5G-T, respectively). Seventeen patients Haplo2/Haplo2 had significantly shorter mPFS compared to 23 patients Haplo1/Haplo1 or Haplo1/Haplo2 (mPFS, 9 vs. 15.4 months, respectively, p = 0.02; hazard ratio (HR), 2.64). Also, VGPs -152 (G/G vs. G/A + A/A) and -1154 (G/G vs. G/A + A/A) were significantly associated with PFS (mPFS, 8.9 vs. 15.4 months, p = 0.007; HR, 3.53 and 9.8 vs. 16 months, p = 0.03, HR, 2.32, respectively). In the multivariate analysis including also biochemical variables known to influence prognosis, VGP -1154 retained an independent predictive value for mPFS (G/G over G/A + A/A = HR, 4.43; p = 0.02). With regard to ORR, only VGP -634 was significantly associated with response (G/G vs. G/C + C/C = 64% vs. 14%, p = 0.03). No significant influence on OS and toxicity by the investigated VGPs was observed.
CONCLUSIONS: Although these data need to be confirmed in larger trials, investigation of germline VGPs may help identify patients who are more sensitive to anti-VEGF agents.
Predictive value of VEGF gene polymorphisms for metastatic colorectal cancer patients receiving first-line treatment including fluorouracil, irinotecan, and bevacizumab.
Formica V, Palmirotta R, Del Monte G, Savonarola A, Ludovici G, De Marchis ML, Grenga I, Schirru M, Guadagni F, Roselli M.
Medical Oncology Unit, Internal Medicine Department, 'Tor Vergata' Clinical Center University of Rome, Viale Oxford, 0133, Rome, Italy, v.formica@fastwebnet.it.
Abstract
PURPOSE: The aim of this study is to evaluate the influence of germline vascular endothelial growth factor (VEGF) gene polymorphisms (VGPs) on the efficacy of the anti-VEGF antibody bevacizumab (Bev) in metastatic colorectal cancer (MCRC) patients.
METHODS: Forty MCRC patients eligible for a first-line therapy were enrolled in this prospective trial and treated with FOLinate/Fluorouracil/Irinotecan (FOLFIRI) + Bev (male/female = 22:18, age (median) = 61 years). Eight VGPs within the promoter/5'UTR region were evaluated in patient blood samples. Primary endpoint was association between VGPs and median progression-free survival (mPFS). Overall radiological response rate (ORR), overall survival (OS), and toxicity were assessed as secondary outcomes.
RESULTS: VGPs -2578, -1512, -1451, -1411, and -460 were in complete linkage disequilibrium and therefore analyzed as haplotype (two variants: Haplo1: A-18 bp insertion-T-4G-C and Haplo2: C-18 bp deletion-C-5G-T, respectively). Seventeen patients Haplo2/Haplo2 had significantly shorter mPFS compared to 23 patients Haplo1/Haplo1 or Haplo1/Haplo2 (mPFS, 9 vs. 15.4 months, respectively, p = 0.02; hazard ratio (HR), 2.64). Also, VGPs -152 (G/G vs. G/A + A/A) and -1154 (G/G vs. G/A + A/A) were significantly associated with PFS (mPFS, 8.9 vs. 15.4 months, p = 0.007; HR, 3.53 and 9.8 vs. 16 months, p = 0.03, HR, 2.32, respectively). In the multivariate analysis including also biochemical variables known to influence prognosis, VGP -1154 retained an independent predictive value for mPFS (G/G over G/A + A/A = HR, 4.43; p = 0.02). With regard to ORR, only VGP -634 was significantly associated with response (G/G vs. G/C + C/C = 64% vs. 14%, p = 0.03). No significant influence on OS and toxicity by the investigated VGPs was observed.
CONCLUSIONS: Although these data need to be confirmed in larger trials, investigation of germline VGPs may help identify patients who are more sensitive to anti-VEGF agents.
vegf gene
Int J Colorectal Dis. 2010 Dec 29. [Epub ahead of print]
Predictive value of VEGF gene polymorphisms for metastatic colorectal cancer patients receiving first-line treatment including fluorouracil, irinotecan, and bevacizumab.
Formica V, Palmirotta R, Del Monte G, Savonarola A, Ludovici G, De Marchis ML, Grenga I, Schirru M, Guadagni F, Roselli M.
Medical Oncology Unit, Internal Medicine Department, 'Tor Vergata' Clinical Center University of Rome, Viale Oxford, 0133, Rome, Italy, v.formica@fastwebnet.it.
Abstract
PURPOSE: The aim of this study is to evaluate the influence of germline vascular endothelial growth factor (VEGF) gene polymorphisms (VGPs) on the efficacy of the anti-VEGF antibody bevacizumab (Bev) in metastatic colorectal cancer (MCRC) patients.
METHODS: Forty MCRC patients eligible for a first-line therapy were enrolled in this prospective trial and treated with FOLinate/Fluorouracil/Irinotecan (FOLFIRI) + Bev (male/female = 22:18, age (median) = 61 years). Eight VGPs within the promoter/5'UTR region were evaluated in patient blood samples. Primary endpoint was association between VGPs and median progression-free survival (mPFS). Overall radiological response rate (ORR), overall survival (OS), and toxicity were assessed as secondary outcomes.
RESULTS: VGPs -2578, -1512, -1451, -1411, and -460 were in complete linkage disequilibrium and therefore analyzed as haplotype (two variants: Haplo1: A-18 bp insertion-T-4G-C and Haplo2: C-18 bp deletion-C-5G-T, respectively). Seventeen patients Haplo2/Haplo2 had significantly shorter mPFS compared to 23 patients Haplo1/Haplo1 or Haplo1/Haplo2 (mPFS, 9 vs. 15.4 months, respectively, p = 0.02; hazard ratio (HR), 2.64). Also, VGPs -152 (G/G vs. G/A + A/A) and -1154 (G/G vs. G/A + A/A) were significantly associated with PFS (mPFS, 8.9 vs. 15.4 months, p = 0.007; HR, 3.53 and 9.8 vs. 16 months, p = 0.03, HR, 2.32, respectively). In the multivariate analysis including also biochemical variables known to influence prognosis, VGP -1154 retained an independent predictive value for mPFS (G/G over G/A + A/A = HR, 4.43; p = 0.02). With regard to ORR, only VGP -634 was significantly associated with response (G/G vs. G/C + C/C = 64% vs. 14%, p = 0.03). No significant influence on OS and toxicity by the investigated VGPs was observed.
CONCLUSIONS: Although these data need to be confirmed in larger trials, investigation of germline VGPs may help identify patients who are more sensitive to anti-VEGF agents.
Predictive value of VEGF gene polymorphisms for metastatic colorectal cancer patients receiving first-line treatment including fluorouracil, irinotecan, and bevacizumab.
Formica V, Palmirotta R, Del Monte G, Savonarola A, Ludovici G, De Marchis ML, Grenga I, Schirru M, Guadagni F, Roselli M.
Medical Oncology Unit, Internal Medicine Department, 'Tor Vergata' Clinical Center University of Rome, Viale Oxford, 0133, Rome, Italy, v.formica@fastwebnet.it.
Abstract
PURPOSE: The aim of this study is to evaluate the influence of germline vascular endothelial growth factor (VEGF) gene polymorphisms (VGPs) on the efficacy of the anti-VEGF antibody bevacizumab (Bev) in metastatic colorectal cancer (MCRC) patients.
METHODS: Forty MCRC patients eligible for a first-line therapy were enrolled in this prospective trial and treated with FOLinate/Fluorouracil/Irinotecan (FOLFIRI) + Bev (male/female = 22:18, age (median) = 61 years). Eight VGPs within the promoter/5'UTR region were evaluated in patient blood samples. Primary endpoint was association between VGPs and median progression-free survival (mPFS). Overall radiological response rate (ORR), overall survival (OS), and toxicity were assessed as secondary outcomes.
RESULTS: VGPs -2578, -1512, -1451, -1411, and -460 were in complete linkage disequilibrium and therefore analyzed as haplotype (two variants: Haplo1: A-18 bp insertion-T-4G-C and Haplo2: C-18 bp deletion-C-5G-T, respectively). Seventeen patients Haplo2/Haplo2 had significantly shorter mPFS compared to 23 patients Haplo1/Haplo1 or Haplo1/Haplo2 (mPFS, 9 vs. 15.4 months, respectively, p = 0.02; hazard ratio (HR), 2.64). Also, VGPs -152 (G/G vs. G/A + A/A) and -1154 (G/G vs. G/A + A/A) were significantly associated with PFS (mPFS, 8.9 vs. 15.4 months, p = 0.007; HR, 3.53 and 9.8 vs. 16 months, p = 0.03, HR, 2.32, respectively). In the multivariate analysis including also biochemical variables known to influence prognosis, VGP -1154 retained an independent predictive value for mPFS (G/G over G/A + A/A = HR, 4.43; p = 0.02). With regard to ORR, only VGP -634 was significantly associated with response (G/G vs. G/C + C/C = 64% vs. 14%, p = 0.03). No significant influence on OS and toxicity by the investigated VGPs was observed.
CONCLUSIONS: Although these data need to be confirmed in larger trials, investigation of germline VGPs may help identify patients who are more sensitive to anti-VEGF agents.
Τρίτη, 4 Ιανουαρίου 2011
TRABECTEDIN USE IN RELAPSED OVARIAN CANCER
December 30, 2010 — Trabectedin (Yondelis; Ortho Biotech) combined with pegylated liposomal doxorubicin (PLD) may be an effective option for patients with partially platinum-sensitive, relapsed ovarian cancer.
Trabectedin is already approved for use in platinum-sensitive relapsed ovarian cancer in many regions of the world, but not in the United States. These latest results suggest it may also work in patients who are partially platinum sensitive (with a 6 - 12-month platinum-free interval [PFI]).
The finding comes from a new analysis reported by Andres Poveda, MD, from the Instituto Valenciano de Oncologia, Valencia, Spain, and colleagues in the Annals of Oncology.
The combination of trabectedin and PLD resulted in a 35% reduced risk for disease progression or death among patients with partially platinum-sensitive relapsed disease (hazard ratio [HR], 0.65; 95% confidence interval [CI], 0.45 - 0.92; P = .0152), they report.
The median progression-free survival was 7.4 months among patients who received trabectedin/PLD compared with 5.5 months in the PLD-alone group.
A secondary, supportive analysis of progression-free survival conducted by an independent oncology review showed an HR of 0.54 (95% CI, 0.39 - 0.76), which translates to a statistically significant 46% risk reduction for disease progression or death (P = .0002).
The current study is a subset analysis of the OVA-301 study, a large, randomized trial that showed superiority of trabectedin plus PLD over PLD alone among patients with relapsed ovarian cancer who were platinum sensitive.
As previously reported by Medscape Medical News, the OVA-301 study was conducted in 672 women with recurrent ovarian cancer who had failed first-line platinum-based chemotherapy, who were randomly assigned to receive either trabectedin combined with PLD or PLD alone.
The results showed that in a subgroup of women with platinum-sensitive disease, there was a statistically significant improvement in progression-free survival — to 9.2 months for PLD plus trabectedin compared with 7.5 months for PLD alone (P = .017) — and in the overall response rate.
However, there was no improvement in progression-free survival or overall response rate in platinum-resistant patients.
On the basis of these results, trabectedin has been approved in Europe, Canada, and other regions of the world for use in platinum-sensitive recurrent ovarian cancer. However, a US Food and Drug Administration advisory committee rejected its approval in July 2009, and trabectedin remains unavailable in the United States.
Efficacy in Partially Platinum Sensitive
Although the OVA-301 study showed the superiority of trabectedin plus PLD over PLD alone in patients with platinum-sensitive disease, the optimal management of patients with partially platinum-sensitive relapse remains unclear, Dr. Poveda and colleagues comment.
Approximately one third of the patients who participated in the OVA-301 study (n = 214; 32%) had a PFI from 6 to 12 months. The effectiveness of platinum retreatment in relapsed ovarian cancer is highly correlated with the PFI, the authors explain, and point out that both preclinical and clinical data suggest that in relapses of ovarian cancer, "the artificial expansion of PFI with an intervening nonplatinum therapy may be beneficial possibly by reversing platinum resistance, which may be of particular interest to patients with partially platinum-sensitive disease."
In the current report, the authors focused on the outcomes of the subset of partially platinum-sensitive patients and on updated overall survival data (cut-off date, May 2009).
As of the updated cut-off date, 419 of the 672 patients had died (n = 215, PLD; n = 204, trabectedin/PLD). The updated survival data also show that for the entire study population, the trabectedin/PLD combination resulted in a 15% decrease in mortality risk compared with PLD alone (HR, 0.85; 95% CI, 0.70 - 1.03; P = .092).
The median overall survival was 22.4 months (95% CI, 19.4 - 25.1) in the trabectedin/PLD group compared with 19.5 months (95% CI, 17.4 - 22.1) in the PLD group.
Among the subset of partially platinum-sensitive subset of patients, combination trabectedin/PLD resulted in a significant 41% decrease in the risk for death vs PLD alone (HR, 0.59; 95% CI, 0.43 - 0.82; P = .0015). The median overall survival for this group was 23.0 months in the trabectedin/PLD group vs 17.1 months in the PLD group.
For the entire study population, a multivariate analysis showed a significantly longer survival with trabectedin/PLD after covariate adjustment for prognostic factors, with an 18% risk reduction for death (HR, 0.82; 95% CI, 0.67 - 0.99; P = .041).
The authors point out that one of the most relevant prognostic factors was PFI (P < .0001). However, because PFI was significantly unbalanced and favored the PLD group (mean PFI, 13.3 months in the PLD group vs 10.6 months in the trabectedin/PLD group; P = .009), they used a Cox proportional hazards model to compare overall survival in the 2 cohorts and adjusted it by PFI. This analysis subsequently showed a statistically significant 24% risk reduction for death (HR, 0.76; 95% CI, 0.62 - 0.92; P = .0046) for patients receiving combination therapy.
The final overall survival analysis will be conducted when the required 520 events are reached, write the authors. Until then, the current data "suggest that trabectedin in combination with PLD may prolong survival over PLD alone in the overall population of patients with relapsed ovarian cancer."
Time to Subsequent Therapy
The findings were associated with a significant delay in subsequent platinum-based therapy. In the overall OVA-301 study population, similar proportions of patients received subsequent therapy in each treatment group (77% vs 76%).
The authors also noted that the proportion of patients receiving further platinum-based regimens in the trabectedin/PLD group was slightly lower than in the PLD-alone group, at 49% vs 55% (56% vs 57%; P = .8900 in the PFI 6-12 subset).
However, for the partially platinum-sensitive subset of patients, time from randomization to subsequent platinum was significantly longer for patients receiving combination trabectedin/PLD (HR, 0.64; P = .0167; median, 9.8 vs 7.9 months).
In addition, they also experienced significantly longer survival period, counted from the initiation of subsequent platinum-based therapy (HR, 0.63; 95% CI, 0.41 - 0.97; P = .0357; median, 13.3 months for the trabectedin/PLD group vs 9.8 months in the PLD-alone group).
Can More Be Expected From Trabectedin?
In an accompanying editorial, Cristiana Sessa, MD, and Maurizio D'Incalci, MD, speculate whether "more" can be expected from trabectedin in ovarian cancer, aside from being part of an effective second-line therapy.
"A large body of data indicates that inflammation is relevant for ovarian cancer growth and progression and we can speculate that the trabectedin's ability to modulate inflammatory and angiogenic factors may play a therapeutic role," write Dr. Sessa, from San Giovanni Hospital, Bellinzona, Switzerland, and Dr. D'Incalci, from Istituto di Ricerche Farmacologiche "Mario Negri," Milano, Italy.
Thus, they explain, earlier use of the agent in ovarian cancer could provide the best effects. Data from preclinical models have shown that combination trabectedin and cisplatin "produced cures of ovarian cancer xenografts not curable with any other regimens."
Efforts should be made to assess whether combining trabectedin with platinum agents is clinically feasible, the authors write. "In addition, the observed inhibitory effect on proangiogenic factors [invites us] to speculate that T could be successfully combined with antiangiogenic therapies, a hypothesis that should be urgently tested at preclinical and clinical levels."
The study was supported by Johnson & Johnson Pharmaceutical Research & Development, LLC, and PharmaMar. Several of the authors have declared financial relationships with Johnson & Johnson or PharmaMar. The editorialists made no disclosures but note that some preclinical experiments were partially supported by PharmaMar.
Ann Oncol. 2011;22:39-48.
Trabectedin is already approved for use in platinum-sensitive relapsed ovarian cancer in many regions of the world, but not in the United States. These latest results suggest it may also work in patients who are partially platinum sensitive (with a 6 - 12-month platinum-free interval [PFI]).
The finding comes from a new analysis reported by Andres Poveda, MD, from the Instituto Valenciano de Oncologia, Valencia, Spain, and colleagues in the Annals of Oncology.
The combination of trabectedin and PLD resulted in a 35% reduced risk for disease progression or death among patients with partially platinum-sensitive relapsed disease (hazard ratio [HR], 0.65; 95% confidence interval [CI], 0.45 - 0.92; P = .0152), they report.
The median progression-free survival was 7.4 months among patients who received trabectedin/PLD compared with 5.5 months in the PLD-alone group.
A secondary, supportive analysis of progression-free survival conducted by an independent oncology review showed an HR of 0.54 (95% CI, 0.39 - 0.76), which translates to a statistically significant 46% risk reduction for disease progression or death (P = .0002).
The current study is a subset analysis of the OVA-301 study, a large, randomized trial that showed superiority of trabectedin plus PLD over PLD alone among patients with relapsed ovarian cancer who were platinum sensitive.
As previously reported by Medscape Medical News, the OVA-301 study was conducted in 672 women with recurrent ovarian cancer who had failed first-line platinum-based chemotherapy, who were randomly assigned to receive either trabectedin combined with PLD or PLD alone.
The results showed that in a subgroup of women with platinum-sensitive disease, there was a statistically significant improvement in progression-free survival — to 9.2 months for PLD plus trabectedin compared with 7.5 months for PLD alone (P = .017) — and in the overall response rate.
However, there was no improvement in progression-free survival or overall response rate in platinum-resistant patients.
On the basis of these results, trabectedin has been approved in Europe, Canada, and other regions of the world for use in platinum-sensitive recurrent ovarian cancer. However, a US Food and Drug Administration advisory committee rejected its approval in July 2009, and trabectedin remains unavailable in the United States.
Efficacy in Partially Platinum Sensitive
Although the OVA-301 study showed the superiority of trabectedin plus PLD over PLD alone in patients with platinum-sensitive disease, the optimal management of patients with partially platinum-sensitive relapse remains unclear, Dr. Poveda and colleagues comment.
Approximately one third of the patients who participated in the OVA-301 study (n = 214; 32%) had a PFI from 6 to 12 months. The effectiveness of platinum retreatment in relapsed ovarian cancer is highly correlated with the PFI, the authors explain, and point out that both preclinical and clinical data suggest that in relapses of ovarian cancer, "the artificial expansion of PFI with an intervening nonplatinum therapy may be beneficial possibly by reversing platinum resistance, which may be of particular interest to patients with partially platinum-sensitive disease."
In the current report, the authors focused on the outcomes of the subset of partially platinum-sensitive patients and on updated overall survival data (cut-off date, May 2009).
As of the updated cut-off date, 419 of the 672 patients had died (n = 215, PLD; n = 204, trabectedin/PLD). The updated survival data also show that for the entire study population, the trabectedin/PLD combination resulted in a 15% decrease in mortality risk compared with PLD alone (HR, 0.85; 95% CI, 0.70 - 1.03; P = .092).
The median overall survival was 22.4 months (95% CI, 19.4 - 25.1) in the trabectedin/PLD group compared with 19.5 months (95% CI, 17.4 - 22.1) in the PLD group.
Among the subset of partially platinum-sensitive subset of patients, combination trabectedin/PLD resulted in a significant 41% decrease in the risk for death vs PLD alone (HR, 0.59; 95% CI, 0.43 - 0.82; P = .0015). The median overall survival for this group was 23.0 months in the trabectedin/PLD group vs 17.1 months in the PLD group.
For the entire study population, a multivariate analysis showed a significantly longer survival with trabectedin/PLD after covariate adjustment for prognostic factors, with an 18% risk reduction for death (HR, 0.82; 95% CI, 0.67 - 0.99; P = .041).
The authors point out that one of the most relevant prognostic factors was PFI (P < .0001). However, because PFI was significantly unbalanced and favored the PLD group (mean PFI, 13.3 months in the PLD group vs 10.6 months in the trabectedin/PLD group; P = .009), they used a Cox proportional hazards model to compare overall survival in the 2 cohorts and adjusted it by PFI. This analysis subsequently showed a statistically significant 24% risk reduction for death (HR, 0.76; 95% CI, 0.62 - 0.92; P = .0046) for patients receiving combination therapy.
The final overall survival analysis will be conducted when the required 520 events are reached, write the authors. Until then, the current data "suggest that trabectedin in combination with PLD may prolong survival over PLD alone in the overall population of patients with relapsed ovarian cancer."
Time to Subsequent Therapy
The findings were associated with a significant delay in subsequent platinum-based therapy. In the overall OVA-301 study population, similar proportions of patients received subsequent therapy in each treatment group (77% vs 76%).
The authors also noted that the proportion of patients receiving further platinum-based regimens in the trabectedin/PLD group was slightly lower than in the PLD-alone group, at 49% vs 55% (56% vs 57%; P = .8900 in the PFI 6-12 subset).
However, for the partially platinum-sensitive subset of patients, time from randomization to subsequent platinum was significantly longer for patients receiving combination trabectedin/PLD (HR, 0.64; P = .0167; median, 9.8 vs 7.9 months).
In addition, they also experienced significantly longer survival period, counted from the initiation of subsequent platinum-based therapy (HR, 0.63; 95% CI, 0.41 - 0.97; P = .0357; median, 13.3 months for the trabectedin/PLD group vs 9.8 months in the PLD-alone group).
Can More Be Expected From Trabectedin?
In an accompanying editorial, Cristiana Sessa, MD, and Maurizio D'Incalci, MD, speculate whether "more" can be expected from trabectedin in ovarian cancer, aside from being part of an effective second-line therapy.
"A large body of data indicates that inflammation is relevant for ovarian cancer growth and progression and we can speculate that the trabectedin's ability to modulate inflammatory and angiogenic factors may play a therapeutic role," write Dr. Sessa, from San Giovanni Hospital, Bellinzona, Switzerland, and Dr. D'Incalci, from Istituto di Ricerche Farmacologiche "Mario Negri," Milano, Italy.
Thus, they explain, earlier use of the agent in ovarian cancer could provide the best effects. Data from preclinical models have shown that combination trabectedin and cisplatin "produced cures of ovarian cancer xenografts not curable with any other regimens."
Efforts should be made to assess whether combining trabectedin with platinum agents is clinically feasible, the authors write. "In addition, the observed inhibitory effect on proangiogenic factors [invites us] to speculate that T could be successfully combined with antiangiogenic therapies, a hypothesis that should be urgently tested at preclinical and clinical levels."
The study was supported by Johnson & Johnson Pharmaceutical Research & Development, LLC, and PharmaMar. Several of the authors have declared financial relationships with Johnson & Johnson or PharmaMar. The editorialists made no disclosures but note that some preclinical experiments were partially supported by PharmaMar.
Ann Oncol. 2011;22:39-48.
VITAMIN SUPPLEMENTS IN BREAST CANCER
December 30, 2010 — The evidence continues to be unclear as to whether dietary supplements are helpful or harmful during cancer treatment. Many clinicians recommend that vitamin supplements — and in particular, high doses of antioxidants — not be used while therapy is ongoing because of concerns that they might reduce the efficacy of radiation and chemotherapy.
However, a new study finds no evidence that the use of vitamins during first 6 months after a diagnosis of breast cancer adversely affected outcomes. In fact, it found quite the opposite: vitamin use appeared to have a beneficial effect among patients with breast cancer who underwent chemotherapy.
Vitamin use — and the use of vitamins C and E in particular — appeared to be associated with reduced risk for mortality and recurrence.
The study was published online December 21 in Cancer Epidemiology, Biomarkers & Prevention.
Patients who used antioxidants (vitamin E, vitamin C, multivitamins) had an 18% reduction in their mortality risk (hazard ratio (HR), 0.82; 95% confidence interval [CI], 0.65 - 1.02), and the risk for recurrence was decreased by 22% (HR, 0.78; 95% CI, 0.63 - 0.95). This association was observed whether vitamin use was concurrent or nonconcurrent with chemotherapy. However, this benefit was only seen in patients who did not receive radiotherapy.
Although complete information was not available for dosages taken, approximately 85% of vitamin C users took 400 mg/day or less, and 99% of vitamin E users took 400 mg/day or less.
Helpful or Harmful?
"The recommendation to avoid supplements during cancer treatment is based on the concern that antioxidant supplements may protect tumor cells during radiotherapy and chemotherapy, thereby reducing the effectiveness of cancer treatments and potentially increasing risk of mortality and cancer recurrence," said Xiao Ou Shu, MD, MPH, PhD, lead author of the study and a professor of medicine at Vanderbilt University School of Medicine, Nashville, Tennessee.
Dr. Shu pointed out that the evidence to support this concern is largely based on laboratory studies and on 1 randomized controlled clinical trial of 540 patients with head and neck cancer. That randomized trial reported that risk for all-cause mortality was increased among participants who were given supplements and who smoked during radiotherapy.
"On the other hand, there is also evidence that antioxidant supplements may help protect normal cells from oxidative damage that occurs during cancer treatment, and thereby reduce the short- and long-term harmful effects of cancer treatment," Dr. Shu told Medscape Medical News.
A number of studies have evaluated the use of antioxidant supplements in the primary prevention of cancer. As previously reported by Medscape Medical News, 2 studies that examined the use of multivitamins and breast cancer risk came to very different conclusions: One study found that their use decreased the risk for breast cancer, and the other study showed that vitamin supplementation actually increased the risk for breast cancer.
The use of vitamin supplements is common among patients with breast cancer, but very few studies have investigated the role of vitamin supplement use during treatment and prognosis. "To our knowledge, our study is the first large prospective cohort study to investigate whether regular doses of vitamin supplement during cancer treatment influences breast cancer prognosis," Dr. Shu commented. "It should be noted that in our study, most breast cancer patients took a regular dose of vitamin supplement, while the above-mentioned head-neck cancer clinical trial investigated megadose vitamin supplements."
Opens Door for Discussion
This latest study is squarely at the heart of an ongoing controversy in integrative oncology, commented Mary Hardy, MD, medical director of the Simms/Mann University of California–Los Angeles Center for Integrative Oncology. "There are theoretical concerns with antioxidants that they can be harmful, while this paper says that there are beneficial. But even if you read this paper conservatively," she said, "it doesn't appear that antioxidants interfered with outcomes."
In an interview, Dr. Hardy noted that the study does have significant limitations — the primary one being that it is not a randomized trial. The study was also conducted in a population of women in Shanghai, China, so there may be issues such as diet, culture, genetics, and so forth that could affect outcome.
"But the most important aspect of this paper is that it begins to suggest...what a lot of us in integrative oncology have been saying,...that the monolithic absolute rejection of all antioxidants is probably not going to be supported by the literature," said Dr. Hardy.
The risks have always been theoretical, and many patients with cancer are using supplements, she explained. "And in many cases, when physicians would say not to use them, patients would just continue anyway and then not tell their physician."
The current study "allows physicians some degree of comfort, or to better tolerate some things that they may not have been comfortable with," Dr. Hardy told Medscape Medical News. "Patients really don't like absolutes, and this allows doctors to have a much more nuanced discussion about the subject."
However, it remains a complicated issue, and this study does not settle the question, she added.
Dr. Shu agrees. "Results from single observational study are not adequate to change the guidelines of vitamin use during cancer treatment," she said. "However, our study calls for more studies on this particular question, particularly in different settings and populations."
Lower Risk for Mortality and Recurrence
In this study, Dr. Shu and colleagues evaluated the associations of total mortality and breast cancer recurrence with vitamin supplement use in a population-based prospective cohort study of 4877 women diagnosed with invasive breast cancer. The study was conducted in Shanghai, China, between March 2002 and April 2006, and patients were interviewed approximately 6 months after their diagnosis.
At an average of 4.1 years of follow-up (range, 0.5 - 6.2 years), 444 women had died (389 from breast cancer, 55 from other causes). A total of 4325 patients remained disease free during the follow-up period, and 532 experienced a disease recurrence.
Of the breast cancer survivors, approximately 36.4% ever used any type of vitamin supplement after their diagnosis. Vitamin C was the most commonly used (17.5%), followed by B vitamins (16.3%), vitamin E (7.6%), vitamin A (1.7%), and vitamin D (0.4%). In addition, about 11% reported using multivitamins.
Vitamin users tended to have higher levels of education, income, daily intake of cruciferous vegetables, and soy protein and were more likely to have a lower body mass index. They were also more likely to be nonsmokers and to report consumption of tea and regular exercise.
The use of vitamins also did not significantly vary as far as age at diagnosis, joint estrogen receptor and progesterone receptor tumor status, TNM stage, type of cancer treatment (chemotherapy, radiotherapy, tamoxifen use), number of pregnancies, family history of breast cancer, alcohol intake, or meat intake.
Overall, use of vitamins within the first 6 months of cancer diagnosis (including any vitamins, multivitamins, vitamin E alone, vitamin C alone, and any antioxidants) was associated with a lower risk for total mortality and breast cancer recurrence, with the largest risk reduction observed in patients who used vitamins C or E for a longer duration after diagnosis.
More specifically, the authors note, women who used vitamin C for more than 3 months had a 44% decrease in risk for mortality (adjusted HR, 0.56; 95% CI, 0.37 - 0.87) and a 38% decrease in risk for disease recurrence (adjusted HR, 0.62; 95% CI, 0.43 - 0.90).
On a similar note, women who used vitamin E for more than 3 months had a reduced risk for both mortality (adjusted HR, 0.52; 95% CI, 0.27 - 1.01) and recurrence (adjusted HR, 0.57; 95% CI, 0.32 - 1.01), although point estimates were of marginal statistical significance.
Associations With Radiotherapy
The researchers also investigated the effect of radiotherapy (which was used in about one third of women) on the outcomes seen with vitamin use.
Among the women who did not receive radiotherapy (n = 3280), vitamin use was associated with a lower risk for both mortality and recurrence. This association was the strongest observed for use of any antioxidant (adjusted HR for mortality, 0.65; 95% CI, 0.47 - 0.92; adjusted HR for recurrence, 0.63; 95% CI, 0.46 - 0.86).
Patients who used vitamins and did not receive radiotherapy were at reduced risk for mortality (adjusted HR, 0.67; 95% CI, 0.48 - 0.94) and recurrence (adjusted HR, 0.66; 95% CI, 0.49 - 0.89) compared with those who did not receive radiotherapy or use vitamins.
Women who did undergo radiotherapy (n = 1597) showed slightly worse outcomes, but the results were not statistically significant. Women who underwent radiotherapy and who did not take antioxidant vitamins were at nonsignificant increased risk for mortality (adjusted HR, 1.26; 95% CI, 0.92 - 1.72) and recurrence (adjusted HR, 1.26; 95% CI, 1.00 - 1.57).
Similarly, patients treated with radiotherapy and who used antioxidant vitamins also had nonsignificant increased risk for mortality (adjusted HR, 1.27; 95% CI, 0.99 - 1.64) and recurrence (adjusted HR, 1.17; 95% CI, 0.88 - 1.54).
The study was funded by grants from the Department of Defense Breast Cancer Research Program and the National Cancer Institute. The authors have disclosed no relevant financial relationships.
Cancer Epidemiol Biomarkers Prev. Published online December 21, 2010.
However, a new study finds no evidence that the use of vitamins during first 6 months after a diagnosis of breast cancer adversely affected outcomes. In fact, it found quite the opposite: vitamin use appeared to have a beneficial effect among patients with breast cancer who underwent chemotherapy.
Vitamin use — and the use of vitamins C and E in particular — appeared to be associated with reduced risk for mortality and recurrence.
The study was published online December 21 in Cancer Epidemiology, Biomarkers & Prevention.
Patients who used antioxidants (vitamin E, vitamin C, multivitamins) had an 18% reduction in their mortality risk (hazard ratio (HR), 0.82; 95% confidence interval [CI], 0.65 - 1.02), and the risk for recurrence was decreased by 22% (HR, 0.78; 95% CI, 0.63 - 0.95). This association was observed whether vitamin use was concurrent or nonconcurrent with chemotherapy. However, this benefit was only seen in patients who did not receive radiotherapy.
Although complete information was not available for dosages taken, approximately 85% of vitamin C users took 400 mg/day or less, and 99% of vitamin E users took 400 mg/day or less.
Helpful or Harmful?
"The recommendation to avoid supplements during cancer treatment is based on the concern that antioxidant supplements may protect tumor cells during radiotherapy and chemotherapy, thereby reducing the effectiveness of cancer treatments and potentially increasing risk of mortality and cancer recurrence," said Xiao Ou Shu, MD, MPH, PhD, lead author of the study and a professor of medicine at Vanderbilt University School of Medicine, Nashville, Tennessee.
Dr. Shu pointed out that the evidence to support this concern is largely based on laboratory studies and on 1 randomized controlled clinical trial of 540 patients with head and neck cancer. That randomized trial reported that risk for all-cause mortality was increased among participants who were given supplements and who smoked during radiotherapy.
"On the other hand, there is also evidence that antioxidant supplements may help protect normal cells from oxidative damage that occurs during cancer treatment, and thereby reduce the short- and long-term harmful effects of cancer treatment," Dr. Shu told Medscape Medical News.
A number of studies have evaluated the use of antioxidant supplements in the primary prevention of cancer. As previously reported by Medscape Medical News, 2 studies that examined the use of multivitamins and breast cancer risk came to very different conclusions: One study found that their use decreased the risk for breast cancer, and the other study showed that vitamin supplementation actually increased the risk for breast cancer.
The use of vitamin supplements is common among patients with breast cancer, but very few studies have investigated the role of vitamin supplement use during treatment and prognosis. "To our knowledge, our study is the first large prospective cohort study to investigate whether regular doses of vitamin supplement during cancer treatment influences breast cancer prognosis," Dr. Shu commented. "It should be noted that in our study, most breast cancer patients took a regular dose of vitamin supplement, while the above-mentioned head-neck cancer clinical trial investigated megadose vitamin supplements."
Opens Door for Discussion
This latest study is squarely at the heart of an ongoing controversy in integrative oncology, commented Mary Hardy, MD, medical director of the Simms/Mann University of California–Los Angeles Center for Integrative Oncology. "There are theoretical concerns with antioxidants that they can be harmful, while this paper says that there are beneficial. But even if you read this paper conservatively," she said, "it doesn't appear that antioxidants interfered with outcomes."
In an interview, Dr. Hardy noted that the study does have significant limitations — the primary one being that it is not a randomized trial. The study was also conducted in a population of women in Shanghai, China, so there may be issues such as diet, culture, genetics, and so forth that could affect outcome.
"But the most important aspect of this paper is that it begins to suggest...what a lot of us in integrative oncology have been saying,...that the monolithic absolute rejection of all antioxidants is probably not going to be supported by the literature," said Dr. Hardy.
The risks have always been theoretical, and many patients with cancer are using supplements, she explained. "And in many cases, when physicians would say not to use them, patients would just continue anyway and then not tell their physician."
The current study "allows physicians some degree of comfort, or to better tolerate some things that they may not have been comfortable with," Dr. Hardy told Medscape Medical News. "Patients really don't like absolutes, and this allows doctors to have a much more nuanced discussion about the subject."
However, it remains a complicated issue, and this study does not settle the question, she added.
Dr. Shu agrees. "Results from single observational study are not adequate to change the guidelines of vitamin use during cancer treatment," she said. "However, our study calls for more studies on this particular question, particularly in different settings and populations."
Lower Risk for Mortality and Recurrence
In this study, Dr. Shu and colleagues evaluated the associations of total mortality and breast cancer recurrence with vitamin supplement use in a population-based prospective cohort study of 4877 women diagnosed with invasive breast cancer. The study was conducted in Shanghai, China, between March 2002 and April 2006, and patients were interviewed approximately 6 months after their diagnosis.
At an average of 4.1 years of follow-up (range, 0.5 - 6.2 years), 444 women had died (389 from breast cancer, 55 from other causes). A total of 4325 patients remained disease free during the follow-up period, and 532 experienced a disease recurrence.
Of the breast cancer survivors, approximately 36.4% ever used any type of vitamin supplement after their diagnosis. Vitamin C was the most commonly used (17.5%), followed by B vitamins (16.3%), vitamin E (7.6%), vitamin A (1.7%), and vitamin D (0.4%). In addition, about 11% reported using multivitamins.
Vitamin users tended to have higher levels of education, income, daily intake of cruciferous vegetables, and soy protein and were more likely to have a lower body mass index. They were also more likely to be nonsmokers and to report consumption of tea and regular exercise.
The use of vitamins also did not significantly vary as far as age at diagnosis, joint estrogen receptor and progesterone receptor tumor status, TNM stage, type of cancer treatment (chemotherapy, radiotherapy, tamoxifen use), number of pregnancies, family history of breast cancer, alcohol intake, or meat intake.
Overall, use of vitamins within the first 6 months of cancer diagnosis (including any vitamins, multivitamins, vitamin E alone, vitamin C alone, and any antioxidants) was associated with a lower risk for total mortality and breast cancer recurrence, with the largest risk reduction observed in patients who used vitamins C or E for a longer duration after diagnosis.
More specifically, the authors note, women who used vitamin C for more than 3 months had a 44% decrease in risk for mortality (adjusted HR, 0.56; 95% CI, 0.37 - 0.87) and a 38% decrease in risk for disease recurrence (adjusted HR, 0.62; 95% CI, 0.43 - 0.90).
On a similar note, women who used vitamin E for more than 3 months had a reduced risk for both mortality (adjusted HR, 0.52; 95% CI, 0.27 - 1.01) and recurrence (adjusted HR, 0.57; 95% CI, 0.32 - 1.01), although point estimates were of marginal statistical significance.
Associations With Radiotherapy
The researchers also investigated the effect of radiotherapy (which was used in about one third of women) on the outcomes seen with vitamin use.
Among the women who did not receive radiotherapy (n = 3280), vitamin use was associated with a lower risk for both mortality and recurrence. This association was the strongest observed for use of any antioxidant (adjusted HR for mortality, 0.65; 95% CI, 0.47 - 0.92; adjusted HR for recurrence, 0.63; 95% CI, 0.46 - 0.86).
Patients who used vitamins and did not receive radiotherapy were at reduced risk for mortality (adjusted HR, 0.67; 95% CI, 0.48 - 0.94) and recurrence (adjusted HR, 0.66; 95% CI, 0.49 - 0.89) compared with those who did not receive radiotherapy or use vitamins.
Women who did undergo radiotherapy (n = 1597) showed slightly worse outcomes, but the results were not statistically significant. Women who underwent radiotherapy and who did not take antioxidant vitamins were at nonsignificant increased risk for mortality (adjusted HR, 1.26; 95% CI, 0.92 - 1.72) and recurrence (adjusted HR, 1.26; 95% CI, 1.00 - 1.57).
Similarly, patients treated with radiotherapy and who used antioxidant vitamins also had nonsignificant increased risk for mortality (adjusted HR, 1.27; 95% CI, 0.99 - 1.64) and recurrence (adjusted HR, 1.17; 95% CI, 0.88 - 1.54).
The study was funded by grants from the Department of Defense Breast Cancer Research Program and the National Cancer Institute. The authors have disclosed no relevant financial relationships.
Cancer Epidemiol Biomarkers Prev. Published online December 21, 2010.
BONE TURNOVER MARKERS AS PROGNOSTIC FACTORS IN PROSTATE CANCER
Eur Urol. 2010 Dec 22. [Epub ahead of print]
Bone Turnover Markers as Predictors of Mortality Risk in Prostate Cancer Patients with Bone Metastases Following Treatment with Zoledronic Acid.
Jung K, Miller K, Wirth M, Albrecht M, Lein M.
Department of Urology, University Hospital Charité, Berlin, Germany; Berlin Institute for Urologic Research, Berlin, Germany.
Abstract
BACKGROUND: Clinical data have limited validity for predicting the survival of prostate cancer (PCa) patients with bone metastases. There is a need to improve the predictive evidence both for clinicians and patients.
OBJECTIVE: To evaluate the predictive ability of serum bone markers for mortality risk in PCa patients with bone metastases.
DESIGN, SETTING, AND PARTICIPANTS: We conducted a survival analysis in relation to bone markers in a subgroup of 52 patients treated with zoledronic acid (4mg every 4 wk for 15 mo) in a prospective, multicentre trial during 2002-2005, about 4 yr after the end of the trial.
MEASUREMENTS: Serum levels of total and bone-specific alkaline phosphatase, amino-terminal procollagen propeptides of type I collagen (PINP), cross-linked N-terminal (NTx) and cross-linked C-terminal telopeptides of type I collagen (ICTP), C-terminal telopeptides of type I collagen, prostate-specific antigen from the last visit of the treatment study, and clinical data were related to the overall survival (OS) status of patients in the follow-up. Univariate and multivariate Cox regression analyses with internal bootstrapping validation and concordance index calculations were performed.
RESULTS AND LIMITATIONS: Out of the 52 patients followed, 34 died within a median follow-up of 13.8 mo, and 18 patients were alive at a median follow-up of 43.8 mo. The patients who died within the follow-up period had significantly higher concentrations of ICTP, NTx, and PINP than the surviving patients. Cox regression models with clinical data and bone markers showed that ICTP and PINP were most predictive for mortality risk in addition to the occurrence of skeletal-related complications and the continuation of treatment with zoledronic acid. Internal validation confirmed the reliability of the results, although the sample size was small.
CONCLUSIONS: PINP and ICTP can be considered suitable predictors for the OS of PCa patients with bone metastases.
Bone Turnover Markers as Predictors of Mortality Risk in Prostate Cancer Patients with Bone Metastases Following Treatment with Zoledronic Acid.
Jung K, Miller K, Wirth M, Albrecht M, Lein M.
Department of Urology, University Hospital Charité, Berlin, Germany; Berlin Institute for Urologic Research, Berlin, Germany.
Abstract
BACKGROUND: Clinical data have limited validity for predicting the survival of prostate cancer (PCa) patients with bone metastases. There is a need to improve the predictive evidence both for clinicians and patients.
OBJECTIVE: To evaluate the predictive ability of serum bone markers for mortality risk in PCa patients with bone metastases.
DESIGN, SETTING, AND PARTICIPANTS: We conducted a survival analysis in relation to bone markers in a subgroup of 52 patients treated with zoledronic acid (4mg every 4 wk for 15 mo) in a prospective, multicentre trial during 2002-2005, about 4 yr after the end of the trial.
MEASUREMENTS: Serum levels of total and bone-specific alkaline phosphatase, amino-terminal procollagen propeptides of type I collagen (PINP), cross-linked N-terminal (NTx) and cross-linked C-terminal telopeptides of type I collagen (ICTP), C-terminal telopeptides of type I collagen, prostate-specific antigen from the last visit of the treatment study, and clinical data were related to the overall survival (OS) status of patients in the follow-up. Univariate and multivariate Cox regression analyses with internal bootstrapping validation and concordance index calculations were performed.
RESULTS AND LIMITATIONS: Out of the 52 patients followed, 34 died within a median follow-up of 13.8 mo, and 18 patients were alive at a median follow-up of 43.8 mo. The patients who died within the follow-up period had significantly higher concentrations of ICTP, NTx, and PINP than the surviving patients. Cox regression models with clinical data and bone markers showed that ICTP and PINP were most predictive for mortality risk in addition to the occurrence of skeletal-related complications and the continuation of treatment with zoledronic acid. Internal validation confirmed the reliability of the results, although the sample size was small.
CONCLUSIONS: PINP and ICTP can be considered suitable predictors for the OS of PCa patients with bone metastases.
A RARE SIDE EFFECT OF OXALIPLATIN
Anticancer Res. 2010 Dec;30(12):5113-5.
Oxaliplatin-induced Pancreatitis: A Case Series.
Butt W, Saadati H, Saif MW.
MBBS, Milstein Hospital, Division Hematology/Oncology 177 Fort Washington Avenue, Suite 6-435, New York, NY 10032, U.S.A. mws2138@columbia.edu.
Abstract
BACKGROUND: Drug-induced pancreatitis is less common compared to other causes of acute pancreatitis; the incidence ranges from between 0.1% to 2% of acute pancreatitis cases. Among alkylating agents, oxaliplatin has not been reported to be associated with acute pancreatitis.
PATIENTS AND METHODS: This case study presents a series of six cases of acute pancreatitis presumably related to exposure to oxaliplatin which had different gastrointestinal malignancies and were being treated with oxaliplatin in combination with other chemotherapeutic drugs. All other related causes of acute pancreatitis were excluded before implicating oxaliplatin as a possible cause.
RESULTS: In all cases, oxaliplatin was stopped and patients had resolution of their signs and symptoms, along with a decrease in serum amylase and lipase levels.
CONCLUSION: Knowledge regarding acute pancreatitis related to oxaliplatin is of paramount importance in order to diagnose cases early and institute effective treatment in patients who are undergoing chemotherapy with this drug.
Oxaliplatin-induced Pancreatitis: A Case Series.
Butt W, Saadati H, Saif MW.
MBBS, Milstein Hospital, Division Hematology/Oncology 177 Fort Washington Avenue, Suite 6-435, New York, NY 10032, U.S.A. mws2138@columbia.edu.
Abstract
BACKGROUND: Drug-induced pancreatitis is less common compared to other causes of acute pancreatitis; the incidence ranges from between 0.1% to 2% of acute pancreatitis cases. Among alkylating agents, oxaliplatin has not been reported to be associated with acute pancreatitis.
PATIENTS AND METHODS: This case study presents a series of six cases of acute pancreatitis presumably related to exposure to oxaliplatin which had different gastrointestinal malignancies and were being treated with oxaliplatin in combination with other chemotherapeutic drugs. All other related causes of acute pancreatitis were excluded before implicating oxaliplatin as a possible cause.
RESULTS: In all cases, oxaliplatin was stopped and patients had resolution of their signs and symptoms, along with a decrease in serum amylase and lipase levels.
CONCLUSION: Knowledge regarding acute pancreatitis related to oxaliplatin is of paramount importance in order to diagnose cases early and institute effective treatment in patients who are undergoing chemotherapy with this drug.
AN INTERESTING REGIMEN FOR PROSTATE CANCER
Ixabepilone, mitoxantrone, and prednisone for metastatic castration-resistant prostate cancer after docetaxel-based therapy: a phase 2 study of the department of defense prostate cancer clinical trials consortium.
Harzstark AL, Rosenberg JE, Weinberg VK, Sharib J, Ryan CJ, Smith DC, Pagliaro LC, Beer TM, Liu G, Small EJ.
Helen Diller Family Comprehensive Cancer Center, University of California at San Francisco, San Francisco, California.
Abstract
BACKGROUND: Mitoxantrone plus prednisone and ixabepilone each have modest activity as monotherapy for second-line chemotherapy in patients with docetaxel-refractory castration-resistant prostate cancer. Clinical noncross- resistance was previously observed. Phase 1 testing determined the maximum tolerated dose and dose-limiting toxicities with the combination regimen; a phase 2 study was conducted to evaluate the activity of the combination.
METHODS: Patients with metastatic progressive castration-resistant prostate cancer during or after 3 or more cycles of taxane-based chemotherapy enrolled in a phase 2 multicenter study of ixabepilone 35 mg/m(2) and mitoxantrone 12 mg/m(2) administered on Day 1 every 21 days with pegfilgrastim support, along with prednisone 5 mg twice daily. Patients were evaluated for disease response and toxicity.
RESULTS: Results are reported for the 56 evaluable patients. Twenty-five (45%; 95% confidence interval [CI], 31%-59%) experienced confirmed ≥50% prostate-specific antigen (PSA) declines, 33 (59%; 95% CI, 45%-72%) experienced confirmed ≥30% PSA declines, and 8 of 36 patients (22%; 95% CI, 10%-39%) with measurable disease experienced objective responses. Median time to PSA or objective progression was 4.4 months (95% CI, 3.5-5.6), and median progression-free survival was also 4.4 months (95% CI, 3.0-6.0). Median overall survival was 12.5 months (95% CI, 10.2-15.9). Thirty-two percent of patients experienced grade 3 of 4 neutropenia, and 11% experienced grade 3 or higher neutropenic infections, including 1 treatment-related death. Grade 2 and 3 neuropathy occurred in 11% and 12.5% of patients, respectively.
CONCLUSIONS: These results suggest that the combination of ixabepilone and mitoxantrone is both feasible and active in castration-resistant prostate cancer and requires dosing with pegfilgrastim. Cancer 2011;. © 2010 American Cancer Society.
Harzstark AL, Rosenberg JE, Weinberg VK, Sharib J, Ryan CJ, Smith DC, Pagliaro LC, Beer TM, Liu G, Small EJ.
Helen Diller Family Comprehensive Cancer Center, University of California at San Francisco, San Francisco, California.
Abstract
BACKGROUND: Mitoxantrone plus prednisone and ixabepilone each have modest activity as monotherapy for second-line chemotherapy in patients with docetaxel-refractory castration-resistant prostate cancer. Clinical noncross- resistance was previously observed. Phase 1 testing determined the maximum tolerated dose and dose-limiting toxicities with the combination regimen; a phase 2 study was conducted to evaluate the activity of the combination.
METHODS: Patients with metastatic progressive castration-resistant prostate cancer during or after 3 or more cycles of taxane-based chemotherapy enrolled in a phase 2 multicenter study of ixabepilone 35 mg/m(2) and mitoxantrone 12 mg/m(2) administered on Day 1 every 21 days with pegfilgrastim support, along with prednisone 5 mg twice daily. Patients were evaluated for disease response and toxicity.
RESULTS: Results are reported for the 56 evaluable patients. Twenty-five (45%; 95% confidence interval [CI], 31%-59%) experienced confirmed ≥50% prostate-specific antigen (PSA) declines, 33 (59%; 95% CI, 45%-72%) experienced confirmed ≥30% PSA declines, and 8 of 36 patients (22%; 95% CI, 10%-39%) with measurable disease experienced objective responses. Median time to PSA or objective progression was 4.4 months (95% CI, 3.5-5.6), and median progression-free survival was also 4.4 months (95% CI, 3.0-6.0). Median overall survival was 12.5 months (95% CI, 10.2-15.9). Thirty-two percent of patients experienced grade 3 of 4 neutropenia, and 11% experienced grade 3 or higher neutropenic infections, including 1 treatment-related death. Grade 2 and 3 neuropathy occurred in 11% and 12.5% of patients, respectively.
CONCLUSIONS: These results suggest that the combination of ixabepilone and mitoxantrone is both feasible and active in castration-resistant prostate cancer and requires dosing with pegfilgrastim. Cancer 2011;. © 2010 American Cancer Society.
Σάββατο, 1 Ιανουαρίου 2011
TIME FOR FLU VACCINATION
LONDON (Reuters) Dec 21 - More than 300 people are in intensive care in hospitals across Britain with flu, and European health officials say the region should act now to encourage more people to get vaccinated.
A spokeswoman for the British government's health department said a total of 302 people were in critical care beds with flu. She could not say how many had the H1N1 strain which spread around the world as a pandemic from 2009, but experts said it was likely that H1N1 would be dominant.
"From around the country, reports from frontline staff are showing unprecedented levels of hospitalization with severe flu in high-risk adults," said Peter Openshaw, director of the Center for Respiratory Infection at the National Heart and Lung Institute, Imperial College London.
According to the latest data from the UK Health Protection Agency, 14 people have died in Britain with confirmed H1N1 flu so far this flu season and another three have died with a strain known as flu type B. That number is expected to increase when new national figures are released later this week.
Angus Nicoll, a flu specialist at the European Centre for Disease Prevention and Control (ECDC), which monitors disease in the region, said the situation in the UK was as he had expected for flu season, but should nevertheless serve as a warning to other countries in Europe to prepare themselves.
"Usually flu moves from west to east in Europe....so the fact that it's starting in a western country is not that surprising, but it's quite useful," he said in a telephone interview from Stockholm, where the ECDC is based.
"This is an indication of what we are likely to be seeing in other parts of Europe not too long from now."
Experts said the evidence from Britain suggested H1N1 flu, which is also known as swine flu, was behaving much as it did last year, affecting younger adults, those in high risk groups such as pregnant women and also some children.
"All the evidence we have so far is that the virus has not changed," Openshaw said in an e-mailed statement. "It is affecting the same type of person as last year and still behaves like swine flu rather than normal seasonal flu (which mostly affects the over 65s)."
The ECDC is asking European governments to encourage people, especially those in high risk groups, to get seasonal flu vaccinations, even if they had the H1N1 shot last year.
Seasonal flu vaccines being offered across the world include for the H1N1 strain this year after the WHO advised it was likely to be the most dominant strain of the northern hemisphere's 2010/2011 flu season.
A spokeswoman for the British government's health department said a total of 302 people were in critical care beds with flu. She could not say how many had the H1N1 strain which spread around the world as a pandemic from 2009, but experts said it was likely that H1N1 would be dominant.
"From around the country, reports from frontline staff are showing unprecedented levels of hospitalization with severe flu in high-risk adults," said Peter Openshaw, director of the Center for Respiratory Infection at the National Heart and Lung Institute, Imperial College London.
According to the latest data from the UK Health Protection Agency, 14 people have died in Britain with confirmed H1N1 flu so far this flu season and another three have died with a strain known as flu type B. That number is expected to increase when new national figures are released later this week.
Angus Nicoll, a flu specialist at the European Centre for Disease Prevention and Control (ECDC), which monitors disease in the region, said the situation in the UK was as he had expected for flu season, but should nevertheless serve as a warning to other countries in Europe to prepare themselves.
"Usually flu moves from west to east in Europe....so the fact that it's starting in a western country is not that surprising, but it's quite useful," he said in a telephone interview from Stockholm, where the ECDC is based.
"This is an indication of what we are likely to be seeing in other parts of Europe not too long from now."
Experts said the evidence from Britain suggested H1N1 flu, which is also known as swine flu, was behaving much as it did last year, affecting younger adults, those in high risk groups such as pregnant women and also some children.
"All the evidence we have so far is that the virus has not changed," Openshaw said in an e-mailed statement. "It is affecting the same type of person as last year and still behaves like swine flu rather than normal seasonal flu (which mostly affects the over 65s)."
The ECDC is asking European governments to encourage people, especially those in high risk groups, to get seasonal flu vaccinations, even if they had the H1N1 shot last year.
Seasonal flu vaccines being offered across the world include for the H1N1 strain this year after the WHO advised it was likely to be the most dominant strain of the northern hemisphere's 2010/2011 flu season.
A CLEVER IDEA
LONDON (Reuters) Dec 24 - Britain's state-run health service will get a partial rebate from GlaxoSmithKline if the company's new kidney cancer drug Votrient (pazopanib) does not match up to a rival medicine in a head-to-head clinical trial.
The unusual deal, the first of its kind, hints at the type of complex arrangements that could become commonplace as Britain moves to a system of value-based drug pricing from the end of 2013.
Draft guidance from cost-effectiveness watchdog the National Institute for Health and Clinical Excellence (NICE) on Friday recommends Votrient for use on the National Health Service (NHS), as long as GSK offers the special price scheme.
The deal provides for a straight 12.5% discount to bring the cost of Votrient to the NHS into line with that of Pfizer's Sutent (sunitinib), and also guarantees a financial rebate if Votrient proves inferior to Sutent in the clinical trial.
The results of the study will not be known until mid-2012.
"If we fail to confirm that they are comparable in efficacy -- which we do not expect -- then we provide a rebate back to the NHS as a result," GSK's head of British operations, Simon Jose, told Reuters.
"We are moving in the direction where price is driven by value and value is driven by evidence, and therefore we can start to construct different sorts of arrangements where we can balance this off."
The exact scale of the potential rebate has not been disclosed. The monthly cost of Votrient and Sutent -- both of which are tablets -- is just under 2,000 pounds ($3,085) per patient.
Carole Longson, NICE's health technology evaluation center director, said the rebate scheme made Votrient a cost-effective proposition. The drug offers patients an additional option and, for some, a more favorable side effect profile, she said.
NICE expects to issue final guidance on Votrient in February 2011.
Both Votrient and Sutent are protein kinase inhibitors, a relatively new class of targeted cancer treatment. Other new drugs for kidney cancer have been rejected by NICE, and GSK has previously failed to persuade NICE to endorse its Tyverb (lapatinib) for breast cancer.
Jose said it was often difficult to demonstrate the full value of new cancer medicines initially and the idea of linking prices to longer-term scientific evidence could be a model for future negotiations between government and industry.
The British government outlined plans last week for a radical shake-up of medicines policy from the end of 2013, after which it will introduce a system of "value-based" pricing.
The new scheme would allow companies to make drugs available at a "contingent" price that could be revised later in the light of further evidence about a drug's effectiveness.
The unusual deal, the first of its kind, hints at the type of complex arrangements that could become commonplace as Britain moves to a system of value-based drug pricing from the end of 2013.
Draft guidance from cost-effectiveness watchdog the National Institute for Health and Clinical Excellence (NICE) on Friday recommends Votrient for use on the National Health Service (NHS), as long as GSK offers the special price scheme.
The deal provides for a straight 12.5% discount to bring the cost of Votrient to the NHS into line with that of Pfizer's Sutent (sunitinib), and also guarantees a financial rebate if Votrient proves inferior to Sutent in the clinical trial.
The results of the study will not be known until mid-2012.
"If we fail to confirm that they are comparable in efficacy -- which we do not expect -- then we provide a rebate back to the NHS as a result," GSK's head of British operations, Simon Jose, told Reuters.
"We are moving in the direction where price is driven by value and value is driven by evidence, and therefore we can start to construct different sorts of arrangements where we can balance this off."
The exact scale of the potential rebate has not been disclosed. The monthly cost of Votrient and Sutent -- both of which are tablets -- is just under 2,000 pounds ($3,085) per patient.
Carole Longson, NICE's health technology evaluation center director, said the rebate scheme made Votrient a cost-effective proposition. The drug offers patients an additional option and, for some, a more favorable side effect profile, she said.
NICE expects to issue final guidance on Votrient in February 2011.
Both Votrient and Sutent are protein kinase inhibitors, a relatively new class of targeted cancer treatment. Other new drugs for kidney cancer have been rejected by NICE, and GSK has previously failed to persuade NICE to endorse its Tyverb (lapatinib) for breast cancer.
Jose said it was often difficult to demonstrate the full value of new cancer medicines initially and the idea of linking prices to longer-term scientific evidence could be a model for future negotiations between government and industry.
The British government outlined plans last week for a radical shake-up of medicines policy from the end of 2013, after which it will introduce a system of "value-based" pricing.
The new scheme would allow companies to make drugs available at a "contingent" price that could be revised later in the light of further evidence about a drug's effectiveness.
RASH IS A PROGNOSTIC FACTOR FOR NSCLC PATIENTS RECEIVING CETUXIMAB IN FLEX STUDY
December 23, 2010 — Patients with non–small cell lung cancer (NSCLC) who develop a rash after treatment with cetuximab (Erbitux; ImClone) appear to have better outcomes. According to a new study, patients who developed first-cycle rash during first-line treatment with chemotherapy plus cetuximab had improved overall survival compared with those patients who did not develop a rash.
Patients with a rash had a median overall survival of 15.0 months (95% confidence interval [CI], 12.8 - 16.4 months) compared with 8.8 months (95% CI, 7.6 - 11.1 months) for those in the same group who did not have a rash (hazard ratio [HR], 0.631; P < .0001).
The study was published online December 20 in the Lancet Oncology.
Possible Explanations
There are 2 possible explanations for the results seen in this study, commented Francesco Perrone, MD, from the Istituto Nazionale Tumori in Naples, Italy. The most appealing explanation is that patients who develop a rash have a survival advantage that could be attributed to cetuximab use.
However, the only way of verifying this hypothesis is to conduct a randomized trial that compares interruption vs continuation of cetuximab in patients with skin rash after 3 weeks of treatment with cetuximab and chemotherapy, Dr. Perrone writes in a commentary that accompanied the paper.
"This study could be extremely important: if skin rash does predict a large cetuximab effect, we should advise in favor of its use in clinical practice," writes Dr. Perrone. "We should also try to explain the mechanism of the detrimental effect for patients who did not develop the rash."
The second explanation, which may be more probable, is that the rash is simply a prognostic marker, he notes, and serves to identify a subset of patients who survive longer independent of treatment with cetuximab.
"The large survival difference between these two subgroups might be consistent with the prognostic hypothesis, because it is well known that the effect of strong prognostic factors is much larger than that of treatment," Dr. Perrone points out.
In any event, he emphasizes that these data must be validated prospectively before cetuximab can be introduced into clinical practice for the treatment of patients with advanced NSCLC.
Improved Overall and Progression-Free Survival
Ulrich Gatzemeier, MD, from Hospital Grosshansdorf in Heidelberg, Germany, and colleagues, conducted a subanalysis of patients who participated in the First-Line Erbitux in Lung Cancer (FLEX) study, which showed that the addition of cetuximab to platinum-based chemotherapy offered a small survival advantage in patients with advanced NSCLC.
The multicenter FLEX study, which included 1125 patients with epidermal growth factor receptor–expressing advanced NSCLC, demonstrated that cetuximab added to cisplatin and vinorelbine improved overall survival compared with chemotherapy alone (HR, 0.871; 95% CI, 0.762 - 0.996; P = .044).
In this analysis, the authors assessed the association of an acne-like rash — the main adverse effect associated with cetuximab — with clinical benefit in the intention-to-treat population who were alive on day 21.
The analysis included 518 patients who received cisplatin/vinorelbine chemotherapy plus cetuximab and 540 patients in the chemotherapy-alone group. Among those who received cetuximab, 290 developed first-cycle rash (rash that occurred on days 1 - 21 of the first cycle of treatment).
In addition to prolonged survival, patients who developed first-cycle rash also had a significantly prolonged progression-free survival (median, 5.4 months vs 4.3 months; HR, 0.741; P = .0031). Similarly, the response rate was also higher among patients with a first-cycle rash, at 44.8% vs 32.0% (odds ratio, 1.703; P = .0039).
The authors further evaluated the association between first-cycle rash and clinical outcome, according to NSCLC histology. The significant overall survival benefit was observed across all histology subgroups:
* adenocarcinoma: median, 16.9 months vs 9.3 months (HR, 0.614; P = .0015);
* squamous cell carcinoma: median, 13.2 months vs 8.1 months (HR, 0.659; P = .014); and
* carcinomas of other histology: median, 12.6 months vs 6.9 months (HR, 0.616; P = .033).
"Our findings represent the first sign of an association between the early development of acne-like rash and outcome in NSCLC patients treated with a chemotherapy plus cetuximab regimen," write the authors. "Further prospective clinical studies are needed before the usefulness of our findings can be fully assessed outside the investigational setting."
The FLEX study was supported by Merck KGaA. Several of the coauthors disclosed relationships with a number of pharmaceutical companies, as indicated in the paper. Dr. Perrone reports receiving a grant from Merck Italy.
Lancet Oncol. Published online December 20, 2010.
Patients with a rash had a median overall survival of 15.0 months (95% confidence interval [CI], 12.8 - 16.4 months) compared with 8.8 months (95% CI, 7.6 - 11.1 months) for those in the same group who did not have a rash (hazard ratio [HR], 0.631; P < .0001).
The study was published online December 20 in the Lancet Oncology.
Possible Explanations
There are 2 possible explanations for the results seen in this study, commented Francesco Perrone, MD, from the Istituto Nazionale Tumori in Naples, Italy. The most appealing explanation is that patients who develop a rash have a survival advantage that could be attributed to cetuximab use.
However, the only way of verifying this hypothesis is to conduct a randomized trial that compares interruption vs continuation of cetuximab in patients with skin rash after 3 weeks of treatment with cetuximab and chemotherapy, Dr. Perrone writes in a commentary that accompanied the paper.
"This study could be extremely important: if skin rash does predict a large cetuximab effect, we should advise in favor of its use in clinical practice," writes Dr. Perrone. "We should also try to explain the mechanism of the detrimental effect for patients who did not develop the rash."
The second explanation, which may be more probable, is that the rash is simply a prognostic marker, he notes, and serves to identify a subset of patients who survive longer independent of treatment with cetuximab.
"The large survival difference between these two subgroups might be consistent with the prognostic hypothesis, because it is well known that the effect of strong prognostic factors is much larger than that of treatment," Dr. Perrone points out.
In any event, he emphasizes that these data must be validated prospectively before cetuximab can be introduced into clinical practice for the treatment of patients with advanced NSCLC.
Improved Overall and Progression-Free Survival
Ulrich Gatzemeier, MD, from Hospital Grosshansdorf in Heidelberg, Germany, and colleagues, conducted a subanalysis of patients who participated in the First-Line Erbitux in Lung Cancer (FLEX) study, which showed that the addition of cetuximab to platinum-based chemotherapy offered a small survival advantage in patients with advanced NSCLC.
The multicenter FLEX study, which included 1125 patients with epidermal growth factor receptor–expressing advanced NSCLC, demonstrated that cetuximab added to cisplatin and vinorelbine improved overall survival compared with chemotherapy alone (HR, 0.871; 95% CI, 0.762 - 0.996; P = .044).
In this analysis, the authors assessed the association of an acne-like rash — the main adverse effect associated with cetuximab — with clinical benefit in the intention-to-treat population who were alive on day 21.
The analysis included 518 patients who received cisplatin/vinorelbine chemotherapy plus cetuximab and 540 patients in the chemotherapy-alone group. Among those who received cetuximab, 290 developed first-cycle rash (rash that occurred on days 1 - 21 of the first cycle of treatment).
In addition to prolonged survival, patients who developed first-cycle rash also had a significantly prolonged progression-free survival (median, 5.4 months vs 4.3 months; HR, 0.741; P = .0031). Similarly, the response rate was also higher among patients with a first-cycle rash, at 44.8% vs 32.0% (odds ratio, 1.703; P = .0039).
The authors further evaluated the association between first-cycle rash and clinical outcome, according to NSCLC histology. The significant overall survival benefit was observed across all histology subgroups:
* adenocarcinoma: median, 16.9 months vs 9.3 months (HR, 0.614; P = .0015);
* squamous cell carcinoma: median, 13.2 months vs 8.1 months (HR, 0.659; P = .014); and
* carcinomas of other histology: median, 12.6 months vs 6.9 months (HR, 0.616; P = .033).
"Our findings represent the first sign of an association between the early development of acne-like rash and outcome in NSCLC patients treated with a chemotherapy plus cetuximab regimen," write the authors. "Further prospective clinical studies are needed before the usefulness of our findings can be fully assessed outside the investigational setting."
The FLEX study was supported by Merck KGaA. Several of the coauthors disclosed relationships with a number of pharmaceutical companies, as indicated in the paper. Dr. Perrone reports receiving a grant from Merck Italy.
Lancet Oncol. Published online December 20, 2010.
RITUXIMAB EXTENDS PFS IN FOLLICULAR LYMPHOMA
December 29, 2010 — Rituximab (Rituxan; Genentech) maintenance therapy should be considered as first-line treatment in some patients with follicular lymphoma. According to new data published online December 21 in The Lancet, patients treated with rituximab have significantly better progression-free survival and higher response rates than those who did not receive this intervention.
At 2 years, 71.5% of patients in the rituximab group achieved complete or unconfirmed complete response compared with 52.2% in the observation group.
The authors also note that at a median follow-up of 36 months, progression-free survival was 74.9% (95% confidence interval [CI], 70.9 - 78.9) among patients receiving rituximab vs 57.6% (95% CI, 53.2 - 62.0) in the observation group (hazard ratio [HR], 0.55; 95% CI, 0.44 - 0.68; P < .0001).
These results suggest that "rituximab maintenance in patients with high tumor burden follicular lymphoma, who respond to rituximab plus chemotherapy induction, improves progression free survival and should now be considered as first-line treatment for these patients," note lead author Gilles Salles, MD, from the Hospices Civils de Lyon and Université Claude Bernard, Lyon, France, and colleagues.
These results were presented earlier this year at the American Society of Clinical Oncology annual meeting.
How to Interpret Findings
But how should these findings be interpreted? That is the question asked by Jonathan W. Friedberg, MD, in a commentary that accompanies the study.
"The scarcity of a benefit in overall survival after maintenance therapy should be emphasized," says Dr. Friedberg, from the James P. Wilmot Cancer Center, University of Rochester, New York. He also points out that "of considerable interest" is the fact that 2 quality-of-life questionnaires showed no differences between the rituximab group and the observation group.
Although the authors have interpreted this finding as "no decrement in quality of life with maintenance therapy," Dr. Friedberg notes that an alternative and equally plausible explanation is that "there is no benefit in quality of life to the patient in maintaining remission."
"The endpoint of progression-free survival in cancer is used as a surrogate of clinical benefit presuming improved quality of life maintaining remission," he writes. "These findings suggest that this improvement might not be the case in this indolent (and often asymptomatic) disease."
He also notes that longer follow-up of this study is needed to answer many important questions, such as whether rituximab resistance develops in the patients receiving maintenance therapy (which can preclude future therapies) and whether the findings extend to the large group of patients with asymptomatic follicular lymphoma that does not require therapy.
There is also the question of cost. What benefit is necessary to justify the cost? Dr. Friedberg notes that maintenance therapy would cost Medicare more than $60,000 per patient at his institution.
Progression-Free Survival Improved, Overall Survival Similar
In this study, Dr. Salles and colleagues evaluated the potential benefit of 2 years of rituximab maintenance therapy after first-line treatment in 1217 patients with follicular lymphoma.
Of this group, 1019 patients who achieved a complete or partial response were then randomly assigned to receive 2 years of rituximab maintenance therapy (375 mg/m² every 8 weeks; n = 505) or observation (n = 513). The primary endpoint was progression-free survival, and analysis was by intention to treat.
At a median follow-up of 36 months for both groups, 130 patients receiving rituximab and 218 patients in the observation group had documented disease progression. Five patients in the rituximab group and 3 in the observation group died before disease progression.
The authors also note that the risk for progression was significantly decreased among patients who received rituximab maintenance therapy. The median time to progression was not reached in the rituximab maintenance group and was an estimated 48.3 months (95% CI, 38.0 to not reached) in the observation group.
In a multivariate analysis adjusted by prognostic factors, a longer progression-free survival was significantly associated with receiving rituximab maintenance therapy (HR, 0.55; P < .0001), age 60 years or older (HR, 0.68; P = .0013), female sex (HR, 0.76; P = .013), lower Follicular Lymphoma International Prognostic Index score categories (overall P < .0001), and the use of R-CHOP (rituximab plus cyclophosphamide, hydroxydaunorubicin, vincristine [Oncovin], and prednisone) or R-FCM (rituximab plus fludarabine, cyclophosphamide, and mitoxantrone) as induction treatment (HR, 0.39; P = .0029).
However, overall survival did not significantly differ between the 2 groups (HR, 0.87; 95% CI, 0.51 - 1.47).
Rituximab maintenance therapy was generally well tolerated, but grade 3 or 4 adverse events were significantly more common in the rituximab group (24% vs 17%). Grade 2 to 4 infections were the most commonly reported adverse events, occurring in 187 patients (39%) in the rituximab group vs 84 patients (24%) in the observation group (risk ratio, 1.62; 95% CI, 1.35 - 1.96; P < .0001).
This study was funded by Groupe d’Etude des Lymphomes de l’Adulte (GELA; Paris, France) and F Hoffmann-La Roche. Several of the study coauthors have declared potential conflicts of interest, as indicated in the paper.
Lancet. Published online December 21, 2010.
At 2 years, 71.5% of patients in the rituximab group achieved complete or unconfirmed complete response compared with 52.2% in the observation group.
The authors also note that at a median follow-up of 36 months, progression-free survival was 74.9% (95% confidence interval [CI], 70.9 - 78.9) among patients receiving rituximab vs 57.6% (95% CI, 53.2 - 62.0) in the observation group (hazard ratio [HR], 0.55; 95% CI, 0.44 - 0.68; P < .0001).
These results suggest that "rituximab maintenance in patients with high tumor burden follicular lymphoma, who respond to rituximab plus chemotherapy induction, improves progression free survival and should now be considered as first-line treatment for these patients," note lead author Gilles Salles, MD, from the Hospices Civils de Lyon and Université Claude Bernard, Lyon, France, and colleagues.
These results were presented earlier this year at the American Society of Clinical Oncology annual meeting.
How to Interpret Findings
But how should these findings be interpreted? That is the question asked by Jonathan W. Friedberg, MD, in a commentary that accompanies the study.
"The scarcity of a benefit in overall survival after maintenance therapy should be emphasized," says Dr. Friedberg, from the James P. Wilmot Cancer Center, University of Rochester, New York. He also points out that "of considerable interest" is the fact that 2 quality-of-life questionnaires showed no differences between the rituximab group and the observation group.
Although the authors have interpreted this finding as "no decrement in quality of life with maintenance therapy," Dr. Friedberg notes that an alternative and equally plausible explanation is that "there is no benefit in quality of life to the patient in maintaining remission."
"The endpoint of progression-free survival in cancer is used as a surrogate of clinical benefit presuming improved quality of life maintaining remission," he writes. "These findings suggest that this improvement might not be the case in this indolent (and often asymptomatic) disease."
He also notes that longer follow-up of this study is needed to answer many important questions, such as whether rituximab resistance develops in the patients receiving maintenance therapy (which can preclude future therapies) and whether the findings extend to the large group of patients with asymptomatic follicular lymphoma that does not require therapy.
There is also the question of cost. What benefit is necessary to justify the cost? Dr. Friedberg notes that maintenance therapy would cost Medicare more than $60,000 per patient at his institution.
Progression-Free Survival Improved, Overall Survival Similar
In this study, Dr. Salles and colleagues evaluated the potential benefit of 2 years of rituximab maintenance therapy after first-line treatment in 1217 patients with follicular lymphoma.
Of this group, 1019 patients who achieved a complete or partial response were then randomly assigned to receive 2 years of rituximab maintenance therapy (375 mg/m² every 8 weeks; n = 505) or observation (n = 513). The primary endpoint was progression-free survival, and analysis was by intention to treat.
At a median follow-up of 36 months for both groups, 130 patients receiving rituximab and 218 patients in the observation group had documented disease progression. Five patients in the rituximab group and 3 in the observation group died before disease progression.
The authors also note that the risk for progression was significantly decreased among patients who received rituximab maintenance therapy. The median time to progression was not reached in the rituximab maintenance group and was an estimated 48.3 months (95% CI, 38.0 to not reached) in the observation group.
In a multivariate analysis adjusted by prognostic factors, a longer progression-free survival was significantly associated with receiving rituximab maintenance therapy (HR, 0.55; P < .0001), age 60 years or older (HR, 0.68; P = .0013), female sex (HR, 0.76; P = .013), lower Follicular Lymphoma International Prognostic Index score categories (overall P < .0001), and the use of R-CHOP (rituximab plus cyclophosphamide, hydroxydaunorubicin, vincristine [Oncovin], and prednisone) or R-FCM (rituximab plus fludarabine, cyclophosphamide, and mitoxantrone) as induction treatment (HR, 0.39; P = .0029).
However, overall survival did not significantly differ between the 2 groups (HR, 0.87; 95% CI, 0.51 - 1.47).
Rituximab maintenance therapy was generally well tolerated, but grade 3 or 4 adverse events were significantly more common in the rituximab group (24% vs 17%). Grade 2 to 4 infections were the most commonly reported adverse events, occurring in 187 patients (39%) in the rituximab group vs 84 patients (24%) in the observation group (risk ratio, 1.62; 95% CI, 1.35 - 1.96; P < .0001).
This study was funded by Groupe d’Etude des Lymphomes de l’Adulte (GELA; Paris, France) and F Hoffmann-La Roche. Several of the study coauthors have declared potential conflicts of interest, as indicated in the paper.
Lancet. Published online December 21, 2010.
GnRH DURING CHEMOTHERAPY DOES NOT IMPROVE PREGNANCY RATES
NEW YORK (Reuters Health) Dec 21 - Menses and ovulation are more likely to resume spontaneously after chemotherapy if ovarian function is suppressed during the treatment - but the odds of spontaneous pregnancy don't improve, a meta-analysis shows.
The authors of the study note that roughly one in 49 women will develop cancer in her reproductive years. Almost 70% now survive for at least 5 years, so preservation of fertility after gonadotoxic therapy is more important than ever.
Cryopreservation -- of embryos, unfertilized eggs or whole tissue - is expensive, may dangerously delay treatment, and isn't available everywhere. An alternative is ovarian suppression with a gonadotropin-releasing hormone (GnRH) analog, but studies of this technique have yielded mixed results.
Senior author Dr. Tommaso Falcone, from the Cleveland Clinic Foundation in Ohio, and his associates searched the literature for randomized controlled trials comparing GnRH cotreatment with chemotherapy alone in premenopausal women. Their findings appeared online December 10th in Fertility and Sterility.
The six trials included in their meta-analysis included 173 women randomly assigned to a GnRH analog plus chemotherapy and 167 randomized to chemotherapy alone. The indications for chemotherapy were Hodgkin's disease, ovarian cancer, and breast cancer. GnRH analogs included buserelin, diphereline, triptorelin, and goserelin.
None of the trials had information on premature ovarian failure, the primary outcome.
All six trials reported the incidence of spontaneous menstruation, which significantly favored GnRH: 99/173 (57%) in the GnRH group vs 59 of 167 (35%) in the control group, odds ratio 3.46.
The authors saw a similar pattern in the two trials that reported incidence of spontaneous ovulation: 29/48 (60%) vs 11/50 (22%), respectively; OR 5.70.
However, three trials showed low spontaneous pregnancy rates that did not differ significantly between groups: 1/52 (2%) with GnRH vs 4/55 (7%) with chemotherapy alone.
Still, Dr. Falcone's team maintains that GnRH agonist cotreatment with chemotherapy "may be beneficial in preserving future fertility." It has the additional advantage of suppressing menstruation, thereby helping to prevent menorrhagia-associated anemia.
"In the future," they conclude, "more well-designed, powered, and reported trials are needed to address all possible outcomes and strengthen the body of evidence."
Fertil Steril. Posted online Decembe 10, 2010. Abstract
The authors of the study note that roughly one in 49 women will develop cancer in her reproductive years. Almost 70% now survive for at least 5 years, so preservation of fertility after gonadotoxic therapy is more important than ever.
Cryopreservation -- of embryos, unfertilized eggs or whole tissue - is expensive, may dangerously delay treatment, and isn't available everywhere. An alternative is ovarian suppression with a gonadotropin-releasing hormone (GnRH) analog, but studies of this technique have yielded mixed results.
Senior author Dr. Tommaso Falcone, from the Cleveland Clinic Foundation in Ohio, and his associates searched the literature for randomized controlled trials comparing GnRH cotreatment with chemotherapy alone in premenopausal women. Their findings appeared online December 10th in Fertility and Sterility.
The six trials included in their meta-analysis included 173 women randomly assigned to a GnRH analog plus chemotherapy and 167 randomized to chemotherapy alone. The indications for chemotherapy were Hodgkin's disease, ovarian cancer, and breast cancer. GnRH analogs included buserelin, diphereline, triptorelin, and goserelin.
None of the trials had information on premature ovarian failure, the primary outcome.
All six trials reported the incidence of spontaneous menstruation, which significantly favored GnRH: 99/173 (57%) in the GnRH group vs 59 of 167 (35%) in the control group, odds ratio 3.46.
The authors saw a similar pattern in the two trials that reported incidence of spontaneous ovulation: 29/48 (60%) vs 11/50 (22%), respectively; OR 5.70.
However, three trials showed low spontaneous pregnancy rates that did not differ significantly between groups: 1/52 (2%) with GnRH vs 4/55 (7%) with chemotherapy alone.
Still, Dr. Falcone's team maintains that GnRH agonist cotreatment with chemotherapy "may be beneficial in preserving future fertility." It has the additional advantage of suppressing menstruation, thereby helping to prevent menorrhagia-associated anemia.
"In the future," they conclude, "more well-designed, powered, and reported trials are needed to address all possible outcomes and strengthen the body of evidence."
Fertil Steril. Posted online Decembe 10, 2010. Abstract
SPEAKING AND SWALLOWING AFTER CHEMORADIOTHERAPY FOR HEAD-NECK CANCER
December 27, 2010 — Most patients with locoregionally advanced head and neck cancer who were successfully treated with intensive chemoradiotherapy had no residual deficits in speaking or swallowing after their treatment, according to the results of a study done by University of Chicago researchers.
The study appears in the December issue of the Archives of Otolaryngology–Head & Neck Surgery.
Of 163 patients with head and neck cancer who were assigned a speaking score an average of 35 months after completing treatment, 84.7% were found to have no lasting difficulties and were given a score of 1 on a scale of 1 to 4, with 1 being the best and 4 being the worst function.
In addition, among 166 patients who were assigned a swallowing score an average of 35 months after treatment, 63.3% were found to have no lasting difficulties swallowing and were given a score of 1.
"We weren't surprised by our findings," senior author Joseph K. Salama, MD, told Medscape Medical News. "However, it was nice to quantify formally our clinical impressions—that most patients in the long run do well."
Dr. Salama was with the University of Chicago, Illinois, at the time the study was conducted and is now at Duke University Medical Center in Durham, North Carolina.
Expert Disagrees
However, Robert L. Ferris, MD, PhD, professor and vice chair of the Department of Otolaryngology at the University of Pittsburgh Medical Center in Pennsylvania, disagreed with the view that so many patients with head and neck cancer retain good speech and swallowing function after such intensive treatment.
Pointing out that the study's results are from a single institution, Dr. Ferris told Medscape Medical News that "the problem is there are good data on the other side. Speech and swallowing outcomes are clearly negatively affected by chemoradiation."
He pointed out that a paper by Machtay et al (J Clin Oncol. 2008;26:3582-3589) showed the opposite results. "This has multicenter data from 3 prospective clinical trials that showed a 43% rate of long-term side effects and toxicities—data that conflict with this study," he said.
Those With Hypopharyngeal and Laryngeal Cancers Fared the Worst
The aim of the study was to identify factors that influenced long-term speech and swallowing outcomes after organ-preserving therapy. The cohort was drawn from a multi-institutional phase 2 study of 222 patients with locoregionally advanced head and neck cancer (stage IV nonmetastatic or stage III base of tongue or hypopharyngeal tumors) who received treatment between 1998 and 2002.
Patients enrolled in this trial received induction chemotherapy consisting of carboplatin and paclitaxel, followed by chemoradiotherapy with paclitaxel, fluorouracil, hydroxyurea, and 1 of 3 radiation dose levels. Of the original cohort, 184 were alive and free of locoregional recurrence at the outset of the current study.
In addition to the finding that most patients maintained normal or near-normal speaking and swallowing function after treatment, the authors found that female sex, smoking history, hypopharyngeal or laryngeal primary sites, and poor response to induction chemotherapy were factors associated with worse speaking outcomes. Factors that were associated with worse swallowing outcomes included advanced patient age, poor performance status, primary site, and neck dissection.
Patients who had hypopharyngeal or laryngeal tumors had significantly worse speaking outcomes than patients with primary sites in other locations (P < .001), and they also exhibited a trend toward worse swallowing outcomes (P = .17).
"These results were in line with prior work from our group which showed that pretherapy swallowing evaluation was worse for hypopharyngeal patients, and early posttherapy swallowing evaluation was worse for those sites as well," Dr. Salama told Medscape Medical News.
"This work is really the first step that defines what our outcomes at minimum should be," he added. "Further work needs to be done to identify ways to further improve swallowing and speech with modifications in radiation [and] surgical techniques, as well as methods to assist patients during and shortly after treatment with exercises."
Results Reflect the Work of a Group at the Top of Its Game
The stellar study results are most likely because the University of Chicago group comprises world-class experts in what they do, Dr. Ferris said. In their hands, the results would be excellent, but Dr. Ferris was skeptical that similar results would be the norm in community centers throughout the United States.
"I think a generic statement that people just do great with chemo and radiation would generate a lot of argument at our meetings," he said. "Their good outcome could be a reflection of a group who is at the top of their game.
"But do community oncology centers read this and say, 'OK, I can give that regimen and my patients will all do great'? That would be a concern," he added. "I think there is skepticism that aggressive, 3-drug chemo followed by combined chemo and radiation for 16 weeks can be managed by less experienced individuals who see a lower volume of these patients. There is skepticism that they could get the same good results in speaking and swallowing."
The University of Chicago team, "because of their long-term experience and expertise, their multidisciplinary, team-oriented approach, may be more capable of managing the speaking and swallowing and optimizing those outcomes," Dr. Ferris noted. "Whereas we see results not being the same when translated out into less experienced, community-based oncology practices."
The study was supported by the Robert and Valda Svendsen Foundation. Dr. Salama and Dr. Ferris have disclosed no relevant financial relationships.
Arch Otolaryngol Head Neck Surg. 2010;136:1226-1234. Abstract
The study appears in the December issue of the Archives of Otolaryngology–Head & Neck Surgery.
Of 163 patients with head and neck cancer who were assigned a speaking score an average of 35 months after completing treatment, 84.7% were found to have no lasting difficulties and were given a score of 1 on a scale of 1 to 4, with 1 being the best and 4 being the worst function.
In addition, among 166 patients who were assigned a swallowing score an average of 35 months after treatment, 63.3% were found to have no lasting difficulties swallowing and were given a score of 1.
"We weren't surprised by our findings," senior author Joseph K. Salama, MD, told Medscape Medical News. "However, it was nice to quantify formally our clinical impressions—that most patients in the long run do well."
Dr. Salama was with the University of Chicago, Illinois, at the time the study was conducted and is now at Duke University Medical Center in Durham, North Carolina.
Expert Disagrees
However, Robert L. Ferris, MD, PhD, professor and vice chair of the Department of Otolaryngology at the University of Pittsburgh Medical Center in Pennsylvania, disagreed with the view that so many patients with head and neck cancer retain good speech and swallowing function after such intensive treatment.
Pointing out that the study's results are from a single institution, Dr. Ferris told Medscape Medical News that "the problem is there are good data on the other side. Speech and swallowing outcomes are clearly negatively affected by chemoradiation."
He pointed out that a paper by Machtay et al (J Clin Oncol. 2008;26:3582-3589) showed the opposite results. "This has multicenter data from 3 prospective clinical trials that showed a 43% rate of long-term side effects and toxicities—data that conflict with this study," he said.
Those With Hypopharyngeal and Laryngeal Cancers Fared the Worst
The aim of the study was to identify factors that influenced long-term speech and swallowing outcomes after organ-preserving therapy. The cohort was drawn from a multi-institutional phase 2 study of 222 patients with locoregionally advanced head and neck cancer (stage IV nonmetastatic or stage III base of tongue or hypopharyngeal tumors) who received treatment between 1998 and 2002.
Patients enrolled in this trial received induction chemotherapy consisting of carboplatin and paclitaxel, followed by chemoradiotherapy with paclitaxel, fluorouracil, hydroxyurea, and 1 of 3 radiation dose levels. Of the original cohort, 184 were alive and free of locoregional recurrence at the outset of the current study.
In addition to the finding that most patients maintained normal or near-normal speaking and swallowing function after treatment, the authors found that female sex, smoking history, hypopharyngeal or laryngeal primary sites, and poor response to induction chemotherapy were factors associated with worse speaking outcomes. Factors that were associated with worse swallowing outcomes included advanced patient age, poor performance status, primary site, and neck dissection.
Patients who had hypopharyngeal or laryngeal tumors had significantly worse speaking outcomes than patients with primary sites in other locations (P < .001), and they also exhibited a trend toward worse swallowing outcomes (P = .17).
"These results were in line with prior work from our group which showed that pretherapy swallowing evaluation was worse for hypopharyngeal patients, and early posttherapy swallowing evaluation was worse for those sites as well," Dr. Salama told Medscape Medical News.
"This work is really the first step that defines what our outcomes at minimum should be," he added. "Further work needs to be done to identify ways to further improve swallowing and speech with modifications in radiation [and] surgical techniques, as well as methods to assist patients during and shortly after treatment with exercises."
Results Reflect the Work of a Group at the Top of Its Game
The stellar study results are most likely because the University of Chicago group comprises world-class experts in what they do, Dr. Ferris said. In their hands, the results would be excellent, but Dr. Ferris was skeptical that similar results would be the norm in community centers throughout the United States.
"I think a generic statement that people just do great with chemo and radiation would generate a lot of argument at our meetings," he said. "Their good outcome could be a reflection of a group who is at the top of their game.
"But do community oncology centers read this and say, 'OK, I can give that regimen and my patients will all do great'? That would be a concern," he added. "I think there is skepticism that aggressive, 3-drug chemo followed by combined chemo and radiation for 16 weeks can be managed by less experienced individuals who see a lower volume of these patients. There is skepticism that they could get the same good results in speaking and swallowing."
The University of Chicago team, "because of their long-term experience and expertise, their multidisciplinary, team-oriented approach, may be more capable of managing the speaking and swallowing and optimizing those outcomes," Dr. Ferris noted. "Whereas we see results not being the same when translated out into less experienced, community-based oncology practices."
The study was supported by the Robert and Valda Svendsen Foundation. Dr. Salama and Dr. Ferris have disclosed no relevant financial relationships.
Arch Otolaryngol Head Neck Surg. 2010;136:1226-1234. Abstract
PROGRESS IN CANCER GENOMIC RESEARCH
It would not be an overstatement to declare that 2010 was the year when personalized cancer care, based on defined molecular characteristics within an individual patient’s tumor, began to have genuine clinical relevance across multiple tumor types.
Three studies focused on the management of non-small cell lung cancer (NSCLC). In the first, investigators demonstrated considerable biological and clinical activity of a novel antineoplastic agent directed against a specific rearrangement in anaplastic lymphoma kinase, or ALK, which is found in approximately 2% to 7% of all patients with NSCLC.[1] Of the 82 patients with metastatic disease studied, the majority of whom had received prior treatment, an objective response rate of 57% was observed. Of perhaps even greater importance, the 6-month progression-free survival in this difficult setting was 72%. In addition, the side effect profile for the agent in this study was very acceptable.
Next, an important role for a targeted therapeutic approach in the primary treatment of metastatic disease was revealed in a phase 3 trial that documented the superiority of gefitinib (a tyrosine kinase inhibitor of the epidermal growth factor receptor [EGFR]) over cytotoxic chemotherapy (carboplatin plus paclitaxel) in individuals with a documented mutation in EGFR.[2] The study demonstrated an improved objective response rate (74% vs 31%) and median progression-free survival rate (10.8 months vs 5.4 months) in this patient population. In addition, gefitinib was reasonably well tolerated, with a different toxicity profile (rash and abnormal liver function tests) from that of standard chemotherapy.
Finally, in an analysis of 52 patients with adenocarcinoma of the lung who had never smoked and were of East Asian descent, investigators were able to identify 1 of 4 specific molecular abnormalities in 90% of the population.[3] These data suggest that it might someday be possible to identify very specific molecular defects in the majority of patients with NSCLC that can point the way to personalized targeted therapeutic regimens in these individuals.
In breast and ovarian cancers, investigators confirmed the utility of bilateral salphingo-oophorectomy as a strategy to reduce the risk for both breast and ovarian cancer in women with known BRCA1 and BRCA2 mutations.[4] Overall, in patients who underwent surgery, the risk for breast cancer was reduced by 50%, and the risk for ovarian and fallopian tube cancers was reduced by approximately 80%. The presence of BRCA1 and BRCA2 mutations was also shown to be associated with a substantially increased risk for breast cancer in the contralateral breast in women with a history of breast cancer, emphasizing the benefits associated with prophylactic mastectomy in this clinical setting.[5]
In malignant melanoma, a landmark study revealed the impressive activity of an inhibitor of activated BRAF in patients with metastatic melanoma, an abnormality present in approximately 50% of patients with this cancer.[6] In an initial exploration of clinical utility, 11 of 16 patients known to have a V600E BRAF mutation showed an objective response, and an additional 26 of 32 patients who were given the agent in an extension phase of the initial trial experienced substantial activity. Of considerable additional interest, the median time to disease progression for patients who participated in this trial was more than 7 months.
Finally, a highly provocative study explored the potential clinical utility of obtaining genetic analysis of individual tumors and to develop specific treatments based on that analysis.[7] Results showed that it was possible to define abnormalities that could be approached with particular antineoplastic agents. In addition, for a large percentage of the study population, there was evidence that the time to subsequent disease progression was substantially prolonged with this method compared with the prior treatment regimen used in the individual patient.
In light of the progress made in 2010, it is reasonable to anticipate that in coming years, we will see additional novel cancer treatment strategies based on unique molecular characteristics within individual tumors that significantly change clinical practice and -- most important -- that improve outcomes for patients with malignant disease.
Three studies focused on the management of non-small cell lung cancer (NSCLC). In the first, investigators demonstrated considerable biological and clinical activity of a novel antineoplastic agent directed against a specific rearrangement in anaplastic lymphoma kinase, or ALK, which is found in approximately 2% to 7% of all patients with NSCLC.[1] Of the 82 patients with metastatic disease studied, the majority of whom had received prior treatment, an objective response rate of 57% was observed. Of perhaps even greater importance, the 6-month progression-free survival in this difficult setting was 72%. In addition, the side effect profile for the agent in this study was very acceptable.
Next, an important role for a targeted therapeutic approach in the primary treatment of metastatic disease was revealed in a phase 3 trial that documented the superiority of gefitinib (a tyrosine kinase inhibitor of the epidermal growth factor receptor [EGFR]) over cytotoxic chemotherapy (carboplatin plus paclitaxel) in individuals with a documented mutation in EGFR.[2] The study demonstrated an improved objective response rate (74% vs 31%) and median progression-free survival rate (10.8 months vs 5.4 months) in this patient population. In addition, gefitinib was reasonably well tolerated, with a different toxicity profile (rash and abnormal liver function tests) from that of standard chemotherapy.
Finally, in an analysis of 52 patients with adenocarcinoma of the lung who had never smoked and were of East Asian descent, investigators were able to identify 1 of 4 specific molecular abnormalities in 90% of the population.[3] These data suggest that it might someday be possible to identify very specific molecular defects in the majority of patients with NSCLC that can point the way to personalized targeted therapeutic regimens in these individuals.
In breast and ovarian cancers, investigators confirmed the utility of bilateral salphingo-oophorectomy as a strategy to reduce the risk for both breast and ovarian cancer in women with known BRCA1 and BRCA2 mutations.[4] Overall, in patients who underwent surgery, the risk for breast cancer was reduced by 50%, and the risk for ovarian and fallopian tube cancers was reduced by approximately 80%. The presence of BRCA1 and BRCA2 mutations was also shown to be associated with a substantially increased risk for breast cancer in the contralateral breast in women with a history of breast cancer, emphasizing the benefits associated with prophylactic mastectomy in this clinical setting.[5]
In malignant melanoma, a landmark study revealed the impressive activity of an inhibitor of activated BRAF in patients with metastatic melanoma, an abnormality present in approximately 50% of patients with this cancer.[6] In an initial exploration of clinical utility, 11 of 16 patients known to have a V600E BRAF mutation showed an objective response, and an additional 26 of 32 patients who were given the agent in an extension phase of the initial trial experienced substantial activity. Of considerable additional interest, the median time to disease progression for patients who participated in this trial was more than 7 months.
Finally, a highly provocative study explored the potential clinical utility of obtaining genetic analysis of individual tumors and to develop specific treatments based on that analysis.[7] Results showed that it was possible to define abnormalities that could be approached with particular antineoplastic agents. In addition, for a large percentage of the study population, there was evidence that the time to subsequent disease progression was substantially prolonged with this method compared with the prior treatment regimen used in the individual patient.
In light of the progress made in 2010, it is reasonable to anticipate that in coming years, we will see additional novel cancer treatment strategies based on unique molecular characteristics within individual tumors that significantly change clinical practice and -- most important -- that improve outcomes for patients with malignant disease.
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