EGF AND ESOPHAGEAL ADENOCARCINOMA

EGF Genetic Variant Increases Risk for GERD-Associated Esophageal Adenocarcinoma

January 16, 2009 (San Francisco, California) — Specific mutations in the epidermal growth factor (EGF) gene appear to increase the risk for esophageal cancer in patients with gastroesophageal reflux disease (GERD), according to research presented here at the 2009 Gastrointestinal Cancers Symposium. Compared with the EGF wild-type A/A genotype, presence of the G/G variant was associated with an odds ratio (OR) of 1.90 for esophageal cancer, but the correlation between the G/G genotype and esophageal cancer risk was evident only among patients who also had GERD.

"This study shows how GERD symptoms and genes intertwine to increase the risk of esophageal cancer," said Jennifer R. Obel, MD, assistant professor of medicine at the Feinberg School of Medicine, Northwestern University, in Chicago, Illinois, who was not involved in the study. "We've known for many years that GERD patients are at an increased risk of esophageal cancer, but we've never been able to predict how genetic alterations affect this increased risk."

If these findings can be validated, appropriate screening modalities can be offered to high-risk patients, explained Dr. Obel, who moderated a briefing where the data were presented. "It could be used to identify esophageal cancer early, when it is most treatable."

One of the Most Rapidly Growing Cancers

Esophageal adenocarcinoma is one of the most rapidly growing cancers in North America. "Over the last 10 years alone, the annual rate of esophageal cancer has increased dramatically, by about 4-fold, in white males," said lead study author Winson Cheung, MD, clinical research fellow at the University of Toronto, in Ontario. "Similar trends have been seen for Asians and females."

GERD is a common risk factor for esophageal cancer, and affects up to 15% of the adult population in North America, or approximately 20 million people. But not all people with GERD will ultimately develop esophageal cancer, emphasized Dr. Cheung; in fact, only a very small proportion ultimately does.

Single-nucleotide polymorphisms (SNPs) of key genes, such as EGF A61G, have been linked to an elevated risk for esophageal adenocarcinoma. It is been hypothesized that additional genetic factors and/or environmental variables most likely modify the effects of these SNPs on esophageal carcinogenesis.

"Our research group very recently demonstrated that variations in EGF were associated with a 2-fold greater risk of esophageal cancer," said Dr. Cheung. "Environmental factors, such as obesity, alcohol, and dietary factors, have already been shown to be significantly associated with the development esophageal cancer. Chronic GERD is also a factor, and is associated with a 7-fold increase in risk."

In this study, Dr. Cheung and colleagues evaluated whether the association between EGF polymorphism and the development of esophageal adenocarcinoma is altered by the presence of GERD. In a case–control study of 309 patients with esophageal adenocarcinoma and 275 matched healthy controls, the researchers performed EGF genotyping of DNA samples and obtained a GERD history for all participants.

The data were adjusted for confounders, including age, sex, smoking status, pack-years, and adult body mass index. The relation between GERD and genotype was assessed using analyses stratified by GERD history and joint-effects models, which encompassed both the severity and duration of GERD symptoms.

Although baseline characteristics were comparable between patients with esophageal cancer and controls, EGF variants A/G or G/G were more common in cases, as was the prevalence of GERD. Compared with the EGF wild-type A/A genotype, the G/G variant was associated with a higher risk for esophageal cancer (OR, 1.90; P = .007).

Risk for Esophageal Adenocarcinoma by EGF Polymorphism

Population	Patients/Controls	G/G Variant vs A/A Wildtype: OR
Total	309/275	1.9
Without GERD	159/213	0.4
With GERD	150/62	9.7

"When we separated those with GERD and those without GERD, the impact of the variant G/G genotype differed," said Dr. Cheung. "For those without significant GERD, the G/G variant was associated with a lower risk, of 0.4, but for those with GERD, the G/G genotype correlated with a substantially higher risk. It was almost 10 times higher, and that was significant."

The correlation between G/G genotype and cancer risk was evident only for the subset of patients with GERD. In addition, the risk for esophageal adenocarcinoma was greatest among patients with the G/G variant who either experienced frequent GERD (more than 1 time per week) or who had experienced GERD symptoms for more than 15 years.

"When we looked at GERD frequency and duration, there was evidence and perhaps even stronger support for the EGF gene and GERD," explained Dr. Cheung. "The risk of esophageal cancer becomes stronger as time goes on and the genotype becomes more abnormal."

For patients with a GERD duration of 15 years or more, the risk for esophageal cancer is 22.4-fold, a very dramatic difference, he pointed out, from the OR of 0.7 in patients who had experienced GERD for less than 1 year.

A similar trend was observed for GERD frequency. Those with the highest frequency of GERD, measured as more than once a week in this study, had a 21.8-fold higher risk for esophageal cancer.

Overall, the researchers found a highly significant interaction between the G/G genotype and the presence of GERD. "It appears that the combination of a specific EFG genotype and GERD history can help to identify individuals with a higher risk of esophageal cancer, and therefore these individuals may benefit most from esophageal screening," said Dr. Cheung.

However, these findings will have to be validated, either prospectively or with larger samples, before changes can be implemented, he concluded.

2009 Gastrointestinal Cancers Symposium (GICS): Abstract 2. Presented January 15, 2009.

USE CISPLATIN IN THE MORNING

Circadian Clock May Influence Response to Some Chemotherapy

January 16, 2009 — The circadian time of delivery of chemotherapeutic drugs, such as cisplatin, might be a significant contributing factor to the efficacy of the drug and the severity of its side effects, according to a report published online January 13 in the Proceedings of the National Academy of Sciences.

The study suggests that chemotherapy is most effective at certain times of day, because that is when a particular enzyme system, which can reverse the actions of chemotherapeutic drugs, is at its lowest levels in the body.

The enzyme system, known as nucleotide excision repair, fixes many types of DNA alterations that come from chemotherapy and other influences, such as sunlight.

"Timing is everything, and here we have molecular data showing why this is especially true with regard to cancer," said senior study author Aziz Sancar, MD, PhD, the Sarah Graham Kenan professor of biochemistry and biophysics in the University of North Carolina School of Medicine, in Chapel Hill, in a statement.

"By hitting cancer cells with chemo at a time when their ability to repair themselves is minimal, you should be able to maximize effectiveness and minimize side effects of treatment," he said, summarizing the potential practical applications of the new research.

Other Studies Have Lacked Mechanism of Action

Circadian rhythm or time is the daily oscillation in the biochemical, behavioral, and physiological functions of organisms. Circadian-clock disruption by environmental factors and behavioral patterns has been implicated as a contributing factor in carcinogenesis, according to the study authors.

Previous studies have indicated that the efficacy and adverse effects of chemotherapy and radiotherapy of cancer are influenced by the circadian time of administration of these therapies. Efforts have been made to put these findings into practice in preventive and clinical medicine, but the lack of mechanistic explanations for the findings has been one of the "serious obstacles" to making practical use of these findings, especially in oncology, write the authors.

In the new study, Dr. Sancar and his colleagues investigated the effect of the circadian clock on nucleotide excision repair in mice. "Excision repair is a multicomponent system that removes virtually all DNA base lesions, and is the sole system in mice and humans for the repair of bulky lesions," such as those produced by cisplatin, write the authors.

Using an "excision assay," the researchers harvested organs from mice and tested them for nucleotide excision repair. They discovered that tissue from the cerebrum or brain was best for analysis of the molecular activity. They found that excision repair activity exhibits a "bona fide circadian rhythm," and that maximum activity was about 5- to 10-fold greater than minimum activity. Furthermore, they found that that the ability to repair damage was at a minimum in the early morning and reached a maximum in the evening hours.

They then looked at various proteins that can affect repair activity. One of them, enzyme XPA, exhibited a circadian-time-dependent change in expression. To determine if the reduced excision repair in the cerebrum was indeed caused by a circadian-influenced low level of XPA, the researchers used recombinant XPA and retested for activity. Their results were verified and the researchers concluded that "the main cause of circadian oscillation of excision repair activity in mouse cerebrum is the circadian oscillation of the XPA protein level."

The findings of the mouse-model study provide a "plausible molecular explanation" for the empirical observation that the time of delivery of chemotherapies, such as cisplatin, might be a "significant contributing factor to the efficacy of the drug and the severity of its side effects," note the authors.

What's Next?

Dr. Sancar wants to extend their research to determine whether the same cyclical changes in repair activity seen in mouse brains can also be observed in mouse testes. According to a statement from the University of North Carolina, this investigation is "particularly relevant" because cisplatin is a chemotherapeutic agent commonly used to treat testicular cancer and kills cancer cells by damaging DNA.

ADULT IMMUNIZATION SCHEDULE

Advisory Committee on Immunization Practices Issues 2009 Adult Immunization Schedule

January 13, 2009 — The Advisory Committee on Immunization Practices (ACIP) has issued the recommended Adult Immunization Schedule for 2009, published in the January 9 issue of the Morbidity and Mortality Weekly Report. The 2009 schedule has been approved by the American Academy of Family Physicians, the American College of Obstetricians and Gynecologists, and the American College of Physicians, in addition to the ACIP.

"The...ACIP annually reviews the recommended Adult Immunization Schedule to ensure that the schedule reflects current recommendations for the licensed vaccines," the ACIP statement authors write. "In October 2008, ACIP approved the Adult Immunization Schedule for 2009. No new vaccines were added to the schedule; however, several indications were added to the pneumococcal polysaccharide vaccine footnote, clarifications were made to the footnotes for human papillomavirus [HPV], varicella, and meningococcal vaccines, and schedule information was added to the hepatitis A and hepatitis B vaccine footnotes."

Changes for 2009 are as follows:

• For HPV, healthcare personnel are not at increased risk because of occupational exposure, but they should be vaccinated as recommended based on age. Vaccination for HPV may begin at 9 years of age.
• Adults who previously received only 1 dose of varicella vaccine should receive a second dose.
• Additional indications for pneumococcal polysaccharide (PPSV) vaccination are asthma and cigarette smoking. Vaccine use in Alaska Natives and American Indians has been clarified.
• Additional schedule information is included for the 4-dose combined hepatitis A/hepatitis B vaccine.
• For meningococcal vaccine, the revaccination interval is 5 years.

Some specific recommendations for each of the vaccinations follow:

• Tetanus, diphtheria, and acellular pertussis (Td/Tdap) vaccination: For adults aged 19 through 64 years who have not previously received a dose of Tdap, Tdap should replace a single dose of Td. A primary vaccination series should be given to adults with uncertain or incomplete history of primary vaccination; this consists of 3 doses of tetanus and diphtheria toxoid–containing vaccines, with the first 2 doses given at least 4 weeks apart and the third dose 6 to 12 months after the second. In the 3-dose primary series, Tdap can substitute for any 1 of the Td doses of Td. A booster dose of tetanus and diphtheria toxoid–containing vaccine should be given to adults who completed a primary series 10 or more years previously. Tdap or Td vaccine may be used, as indicated. Recommendations are also given for Td/Tdap vaccination during pregnancy and for Td as prophylaxis in wound management.
• HPV vaccination: Recommended for all females aged 11 through 26 years, regardless of sexual activity or clinical evidence of previous HPV infection, who have not completed the vaccine series. Ideally, vaccination should be given before potential exposure to HPV through sexual activity and may be given as early as age 9 years. The complete series consists of 3 doses, with the second dose given 2 months after the first dose and the third dose 6 months after the first dose.
• Varicella vaccination: Should be given to all adults who lack evidence of immunity unless they have a medical contraindication. Patients should receive 2 doses of single-antigen varicella vaccine if not previously vaccinated or the second dose if they have received only 1 dose. Special consideration is recommended for those with close contact with persons at high risk for severe disease or high risk for exposure or transmission. Pregnant women without evidence of varicella immunity should receive the first dose of varicella vaccine on completion or termination of pregnancy and before discharge from the healthcare facility, and they should receive the second dose 4 to 8 weeks after the first dose.
• Herpes zoster vaccination (single dose): Recommended for adults aged 60 years and older regardless of a history of herpes zoster, unless they have a specific contraindication.
• Measles, mumps, rubella (MMR) vaccination: 1 or more doses should be given to adults born during or after 1957 unless they have a medical contraindication, documentation of 1 or more doses, history of measles diagnosed by a healthcare provider, or laboratory evidence of immunity. A second dose of MMR is recommended for adults recently exposed to measles or in an outbreak setting, previously vaccinated with killed measles vaccine, or vaccinated with an unknown type of measles vaccine during 1963 to 1967, as well as for those who are students in postsecondary educational institutions, work in a healthcare facility, or plan international travel. Women of childbearing age, regardless of birth year, should be assessed for rubella immunity and counseled regarding congenital rubella syndrome. Women without evidence of immunity should receive MMR vaccine on completion or termination of pregnancy and before discharge from the healthcare facility.
• Influenza vaccination: Should be given to those with medical, occupational, or other indications. Medical indications are chronic disorders of the cardiovascular or pulmonary systems, chronic metabolic diseases, immunocompromising conditions, or any condition that compromises respiratory function or that increases risk for aspiration. All healthcare personnel and caregivers of children younger than 5 years should receive influenza vaccination, as should residents of nursing homes and other long-term care and assisted-living facilities, persons likely to transmit influenza to persons at high risk, and others who wish to decrease their risk of getting influenza. Healthy, nonpregnant adults younger than 50 years without high-risk medical conditions who are not contacts of severely immunocompromised persons in special care units can receive either intranasally administered live, attenuated influenza vaccine (FluMist, MedImmune) or inactivated vaccine, but others should receive the inactivated vaccine.
• PPSV vaccination: Should be given to those with chronic lung, cardiovascular, or liver disease; diabetes mellitus; chronic alcoholism; chronic renal failure or nephrotic syndrome; functional or anatomic asplenia; immunocompromising conditions; cochlear implants; or cerebrospinal fluid leaks. Vaccination should occur as close to HIV diagnosis as possible. Other indications for PPSV are being a resident of nursing homes or other long-term care facility and being a cigarette smoker. Public health authorities may consider recommending PPSV for Alaska Natives and American Indians aged 50 through 64 years living in areas with increased risk for invasive pneumococcal disease.
• One-time revaccination with PPSV: Recommended after 5 years for persons with chronic renal failure or nephrotic syndrome, functional or anatomic asplenia, or immunocompromising conditions, or for persons aged 65 years and older if they were vaccinated 5 or more years previously at younger than 65 years.
• Hepatitis A vaccination: Indicated for persons with chronic liver disease, those who receive clotting factor concentrates, men who have sex with men, illegal drug users, laboratory workers exposed to hepatitis A virus–infected primates, persons traveling to or working in countries with high or intermediate endemicity of hepatitis A, and those seeking protection from hepatitis A virus infection. Single-antigen vaccine formulations should be given in 2 doses either at 0 and 6 to 12 months (Havrix, GlaxoSmithKline) or at 0 and 6 to 18 months (Vaqta, Merck). Combined hepatitis A and hepatitis B vaccine (Twinrix, GlaxoSmithKline) should be given in 3 doses at 0, 1, and 6 months or in 4 doses on days 0, 7, and 21 to 30, followed by a booster dose at month 12.
• Hepatitis B vaccination: Indicated for persons with end-stage renal disease, HIV infection, or chronic liver disease; for healthcare personnel and public-safety workers exposed to blood or other potentially infectious body fluids; for sexually active persons not in a long-term, mutually monogamous relationship; for persons seeking evaluation or treatment of a sexually transmitted infection; for current or recent injection-drug users; and for men who have sex with men. Other indications and settings are also listed, as well as special formulation indications.
• Meningococcal vaccination: Should be given to adults with anatomic or functional asplenia or terminal complement component deficiencies, first-year college students living in dormitories, microbiologists routinely exposed to meningococcus, military recruits, and those in hyperendemic or epidemic countries.
• Haemophilus influenzae type b vaccine: Generally not recommended for persons 5 years and older but may be considered in those with sickle cell disease, leukemia, HIV infection, or asplenia.
• Immunocompromising conditions: Inactivated vaccines generally are acceptable, but live vaccines should be avoided.

"These schedules indicate the recommended age groups and medical indications for which administration of currently licensed vaccines is commonly indicated for adults ages 19 years and older, as of January 1, 2009," the ACIP authors write. "Licensed combination vaccines may be used whenever any components of the combination are indicated and when the vaccine's other components are not contraindicated."

MMWR Morb Mortal Wkly Rep. 2009;57(53).

BILATERAL OOPHORECTOMY UPS CARDIOVASCULAR MORTALITY

Preventive Bilateral Oophorectomy Ups CV Mortality

January 14, 2009 — A new study has found that women who underwent preventive bilateral oophorectomy — removal of both ovaries — before the age of 45 were at increased risk of cardiovascular (CV) death some 20 to 30 years later [1]. But the results also show that this increased mortality can be attenuated by estrogen treatment, say Dr Cathleen M Rivera (Mayo Clinic, Rochester, MN) and colleagues in their paper in the January 2009 issue of Menopause.

Senior author Dr Walter A Rocca (Mayo Clinic) told heartwire that this paper provides new data to help guide the individualized assessment of the risks and benefits of prophylactic bilateral oophorectomy in young women. "People like myself and many others are contributing pieces of evidence that will be useful to a woman and the treating physician to make a decision. Each woman is different, and I don't want to say, 'do it, or don't do it,' because there is sometimes a reason that you still want to proceed and do the surgery. If we give this blank statement that something is good or bad, we damage women more than helping them."

However, he does believe that his and other research warrants a reconsideration of the guidelines regarding preventive bilateral oophorectomy. Thankfully, he notes that the American College of Obstetricians and Gynecologists (ACOG) has already issued a statement to this effect in January 2008.

Rocca stresses that he is a neurologist who got sidetracked into this research, but "I believe that any informed gynecologist in the UK, US, or Europe facing a case of very early preventive bilateral oophorectomy would definitely be aware of what has been in the literature in the past few years and would sit down with his or her patient and discuss the pros and cons of this surgery."

Bilateral Oophorectomy Patients Had 50% Higher CV Mortality

Rivera and colleagues explain that every year, around 300,000 women in the US decide to undergo bilateral oophorectomy for the prevention of ovarian cancer and, for women who don't carry genetic variants that increase the risk of ovarian cancer, the risk/benefit balance of this preventive surgery "remains uncertain and controversial." In addition, a further 300,000 women undergo bilateral oophorectomy for a benign condition every year. For all of these women, it also remains uncertain whether estrogen treatment should be started after surgery and for how many years it should continue, they note.

To address the long-term health consequences of unilateral or bilateral oophorectomy and subsequent estrogen treatment in young women, they studied all cardiovascular conditions reported anywhere on the death certificates for women included in the Mayo Clinic Cohort Study of Oophorectomy and Aging who had undergone oophorectomy before menopause between 1950 and 1987.

The mortality associated with cardiovascular disease was studied in a total of 1274 women who had undergone unilateral oophorectomy (removal of one ovary) and 1091 women who had bilateral oophorectomy; these were matched with the same outcomes for 2383 referent women from the same population who had not undergone oophorectomy.

Those who underwent unilateral oophorectomy experienced a reduced mortality associated with cardiovascular disease compared with referent women (hazard ratio [HR], 0.82; p=0.04). In contrast, those who had bilateral oophorectomy before age 45 years experienced an almost 50% increased mortality associated with cardiovascular disease, compared with the referent population (HR 1.44; p=0.04).

And in the women who underwent bilateral oophorectomy, the hazard ratio for mortality was increased further if they were not treated with estrogen through age 45 years (HR 1.84; p=0.001). However, in those who were treated with estrogen through age 45, the therapy appeared to offset the negative effects of bilateral oophorectomy (HR 0.65; p=0.28; test of interaction, p=0.01).

Estrogen Treatment Through Age 45 Alleviates CV Mortality Risk

"The most important finding is that women who undergo bilateral oophorectomy early in life (under age 45) do have an increased risk of cardiovascular mortality," Rocca told heartwire. "This has been suggested before by others and by us, but this is a full report in which the women were followed for a long time."

He concedes, however, that the methodology used in this study — in which CV mortality was defined as cardiovascular diseases mentioned anywhere on the death certificate — "is not as good as studying the incidence of cardiovascular disease, because, of course, many cardiovascular diseases are not causes of death. But at least it captures those instances of CVD [cardiovascular disease] that were severe enough to warrant mention on the death certificate. It's a broader net, but it's not a perfect net. However, it's a good approximation."

The second important finding of the study relates to the data on estrogen given after surgery, he says. "One big question has always been if a woman needs to have her ovaries removed — because in the balance of bad and good, the decision is still for removal — to what extent will estrogen treatment eliminate or offset the negative effects of these hormonal changes?

"In our study, we divided the women with [bilateral] oophorectomy into two groups: those who received treatment at least through the age of 45; and those who either got no treatment or got it for such a short period of time that it was not through age 45. We found that if women underwent the surgery and received estrogen at least through age 45, their risk [of cardiovascular death] went away or did not show, while if they did not receive that treatment — which we consider a kind of minimum — well, those are the ones, in a nutshell, who were driving the negative effect.

"If a [bilateral] oophorectomy has to be done before the age of 45, then the woman has to be made aware of this increased risk of cardiovascular problems and . . . considered for adequate estrogen-replacement therapy.

"So we conclude that if a [bilateral] oophorectomy has to be done before the age of 45, the woman has to be made aware of this increased risk of cardiovascular problems, and this would be one good reason to be considered for adequate estrogen-replacement therapy, at least to age 45 or maybe to age 50, which is the age of natural menopause."

NEW IMMUNOTHERAPEUTIC APPROACH FOR GLIOBLASTOMA

New Immunotherapy Approach to Be Tested in Glioblastoma

January 15, 2009 — A new immunotherapy approach to the treatment of glioblastoma has shown promise in animal studies and is due to be tested in patients later this year. The strategy involves injecting adenovirus vectors directly into the tumor-tissue cavity after resection, and the results from a mouse model suggest a potential for cure, says the lead researcher, Maria Castro, PhD, from the Cedars-Sinai Medical Center in Los Angeles, California.

The research was published online January 13 in PLoS Medicine.

Glioblastoma multiforme is a particularly aggressive cancer, and better treatments are badly needed, according to an editor's summary of the paper. One avenue that is being explored is immunotherapy, but past attempts to induce a clinically useful anti-tumor immune response in glioblastoma have been unsuccessful, it notes. In part, this is because the brain contains very few dendritic cells, which "kick start" effective immune responses by presenting foreign particles to other immune system cells. Another barrier is immune evasion, in which tumors find ways to avoid immune responses, such as by reducing the expression of proteins that would be recognized as foreign.

The new approach involves a 2-pronged strategy to overcome both of these problems. The researchers developed adenovirus vectors expressing 2 different proteins — Fms-like tyrosine kinase 3 ligand, which attracts dendritic cells into the tumor, and thymidine kinase, which kills tumor cells and causes them to release tumor-cell antigen. This antigen is the trigger for the immune response, Dr. Castro explained; it reacts with the dendritic cells and the complex drains into the lymphatic system, where it mounts a systemic anti-tumor immune response, leading to the release of cytotoxic T lymphocytes, which then kill the tumor.

"This is a very powerful approach," Dr. Castro said. These killer cells will destroy the tumor and, because they have memory, they will act on any new tumor cells that reappear.

Improved Survival

In a mouse model of glioma, this approach "shrank the tumors and greatly improved the survival of the mice," notes the editor's summary. Dr. Castro said that the untreated mice died within 1 month of tumor implantation, but 60% of the treated mice were still alive after 6 months. All the animals were sacrificed at the end of the study, but they would have continued to live indefinitely and they appeared to have been cured, Dr. Castro commented.

The editor's summary cautions that results from such mouse models do not always lead to effective treatments for human patients, but states: "Nevertheless, the findings from this study provide new insights into how an effective immune response against brain tumors may be brought about."

Dr. Castro told Medscape Oncology that, in addition to the mouse model of glioma described in the paper, her group has also shown that the technique is effective in 4 different rat models of glioma and in a mouse model of brain metastases from melanoma and lung cancers. Human trials are planned to start in mid-2009, with an early-phase study in patients with respectable recurrent glioma. The adenovirus vectors are stored in a frozen vial, and are injected directly into the tumor tissue after the resection. "This is very straightforward from a practical point of view, and it can be done anywhere in the world, providing you have neurosurgical skills," she added. The hope is that the immunotherapy will destroy any remaining tumor, and also prevent any further recurrences, Dr. Castro explained.

The discovery of the mechanisms involved in "overcoming immune ignorance to brain tumor antigens provides a new therapeutic approach in the fight against brain tumors," commented senior coauthor Pedro Lowenstein, MD, PhD, director of the Board of Governors Gene Therapeutics Research Institute at Cedars Sinai Medical Center. "Our conclusions relating to anti-glioma immune responses have also been extended to enhancing immune responses against a number of other metastatic brain cancers, such as melanoma," he said in a statement.

TANDEM TRANSPANTATIONS DO NOT IMPROVE SURVIVAL IN MM

Tandem Transplantation Does Not Improve Survival in Multiple Myeloma

January 13, 2009 — Tandem autologous hematopoietic cell transplantation (AHCT) does not appear to improve overall survival or event-free survival in patients with multiple myeloma, according to a meta-analysis published online January 13 in the Journal of National Cancer Institute. Researchers found that when compared with single AHCT, the tandem procedure improved response rates but led to a statistically significant increase in treatment-related mortality.

Pooled evidence from clinical trials did not show a benefit for either overall survival or event-free survival among patients who received tandem transplantation. Based on these results, the study authors conclude that "the routine use of tandem transplant in its current form is not justified."

Single and tandem transplant are recommended as standard treatment in patients who are transplant candidates, explained lead author Ambuj Kumar, MD, MPH, assistant professor in Oncologic Sciences at Moffitt Cancer Center & Research Institute, in Tampa, Florida.

"New treatments may eventually minimize the role of single or double transplant," Dr. Kumar told Medscape Oncology. "However, tandem transplant is widely used in current practice, including in all the US Comprehensive Cancer Centers. To this effect, double transplant is recommended in the [National Comprehensive Cancer Network] 2008 treatment guidelines."

According to unofficial estimates by the Center for International Blood and Marrow Transplant Research (CIBMTR) (numbers used are not published estimates and were provided by CIBMTR directly to Moffitt researchers), 496 tandem transplants were undertaken in 2006 and 244 were undertaken in 2007, said Dr. Kumar.

Conflicting Results From Trials

AHCT as a treatment strategy for multiple myeloma has been evaluated in several randomized controlled trials, and initial studies demonstrated a survival advantage over conventional treatments, the authors note. A recent systematic review and meta-analysis, however, only showed a benefit for event-free survival, relative to conventional treatment. The more intense tandem AHCT approach was proposed as a strategy that could lead to further improvements in therapeutic outcomes, but clinical trials have thus far revealed conflicting results.

Because "decision making should not depend on the results from selective trials," Dr. Kumar and colleagues conducted a systematic review and meta-analysis to comprehensively evaluate the effect of tandem AHCT on event-free and overall survival.

A total of 6 randomized controlled trials, which consisted of 1803 patients, met the inclusion criteria. Data were available for the primary end points of overall survival and event-free survival from all of the included studies. When the results were pooled, there was no statistically significant benefit for overall survival for tandem AHCT, and the hazard ratio (HR) for patients treated with tandem transplant vs single transplant was 0.94. Pooled results for event-free survival were similar and showed no statistically significant survival benefit for tandem vs single transplant (HR, 0.86). There was statistically significant heterogeneity among all trials for overall survival and event-free survival.

The researchers did observe a better response rate with tandem AHCT, and this reached statistical significance (risk ratio, 0.79; P = .004). However, tandem AHCT was associated with a statistically significant increase in treatment-related mortality (risk ratio, 1.71)

The authors note that it is not yet known whether tandem AHCT improves overall survival in a subgroup of patients, or if a survival benefit will emerge as strategies to reduce treatment-related mortality are improved.

"As shown in the results, based on the totality of the existing evidence, tandem transplant cannot be justified," said Dr. Kumar. "There might be some patients who can benefit from this procedure, but this question can be addressed in either an individual patient-data meta-analysis or in the context of a well-designed and adequately powered prospective randomized controlled trial."

MANAGMENT OF STAGE IIIA NSCLC REMAINS CONTROVERSIAL

Expert Rev Anticancer Ther. 2008;8(12):1913-1929. ©2008 Expert Reviews Ltd.

Posted 01/07/2009

Abstract and Introduction

Abstract

New developments in the management of non-small-cell lung cancer, as well as recent proposals for changing the current lung cancer staging system, are posing a challenge in the therapeutic decision making regarding this disease. For the last two decades, the management of stage IIIA (N2) disease has been controversial and the target for clinical trials has been to determine the best therapeutic approach that may result in better survival outcomes without increasing toxicity. For many years, combined modality treatment (systemic chemotherapy plus radiation therapy) became the standard of care in this setting. However, the poor outcomes seen with combined modality for N2 has obligated us to explore other possibilities. In this sense, recent clinical trials in the neoadjuvant setting using chemotherapy alone or combined modality are providing fruitful results and shifting the paradigm on this stage. A recent, large randomized multicenter trial argues against what has slowly become a current practice in some centers - the use of preoperative modality for N2 disease. Another controversy that we will discuss here is the acceptance of adjuvant therapy for resected stage IB-IIIA non-small-cell lung cancer. It was not long ago that adjuvant radiation therapy was still the standard of care for patients who have pathological nodal disease. We will present the current data on these debatable issues and how to implement this new knowledge into clinical practice.

Expert Commentary

The management of clinical N2 poses a challenge today due to novel therapeutic agents with a better toxicity profile, better RT-delivery methods and extensive data with provocative and controversial results from our clinical trials. The latter issue causes difficulty in interpreting trial results that do not subdivide patients appropriately. Thus, what is better: to offer neoadjuvant therapy (single or combined modality) followed by surgery or postoperative (adjuvant) CT? To date, we have not reached a final answer. We have meta-analyses, subanalyses and provocative observations that served as the platform for the new generation of clinical trials. A new lung cancer staging classification has been proposed (IASLC Lung Cancer Staging Project) and, if accepted, it means that we will be more aggressive in the management of this disease, and exhaust all possibilities to consider a patient a potential surgical candidate.

To answer the question of what is better, neoadjuvant or adjuvant CT in NSCLC, perhaps we will need to wait for the final results of the NATCH trial initially presented at the World Lung Cancer Congress in Seoul, Korea.^[84] This three-arm trial will address the question of whether DFS is improved with the use of neoadjuvant or adjuvant CT compared with surgery alone in early-stage NSCLC. Unfortunately, this trial does not include N2 disease, only clinical stages I (> 2 cm), II and T3N1. Patients are randomized to surgery alone or three cycles of neoadjuvant carboplatin/paclitaxel or surgery followed by three cycles of adjuvant carboplatin/paclitaxel (at the same schedule). This prospective, randomized trial planned to include 624 patients and mature survival data are expected in 2009.

Is single modality superior to combined modality for N2? To date, the ACCP does not recommend the use of combined modality (for downstaging) outside the context of clinical trials.^[19] Although this approach has shown clinical efficacy, there is concern in terms of toxicity and long-term results, and we still do not know what is the best CT combination and RT dosing and schedule. The vast majority of the data favored neoadjuvant CT (at least three cycles) rather than combined modality.^[30,32,85] When CT has been used as a single modality, the rate of progression was low for those who underwent neoadjuvant treatment and surgical results were also comparable to those randomized to surgery alone.^[32,85] A caveat on these studies^[30,32] is that they did not include N2 disease (stage IIIA was defined as T3N1). A systematic review that included seven clinical trials comparing preoperative CT followed by surgery versus surgery alone favored the neoadjuvant arm (HR: 0.82).^[86] When the EORTC 08012 was added to this population, the HR still favored neoadjuvant CT but to a lesser extent (HR: 0.88).^[85] In terms of preoperative concurrent CT/RT, a subanalysis from the INT 0139 suggested that, if pneumonectomy is planned ahead, perhaps this approach (trimodality) is not recommended due to the high mortality rate seen in this group; hence, the importance of a multidisciplinary approach among the treating physicians.

Presently, we consider there to be enough data to avoid the use of postoperative RT in patients with pathologic early-stage NSCLC. These patients are well served with cisplatin-based doublet adjuvant CT. As mentioned previously, we lack strong evidence for pN2 disease. However, a subset analysis from the ANITA trial showed that sequential adjuvant CT followed by RT results in a better outcome for these subjects.^[22] Thus, in this regard, we consider that the use of RT in this setting will be at the discretion of the treating physician.

The trimodality option studied in the INT 0139 trial needs longer follow-up to analyze the morbidity and mortality, especially when a pneumonectomy is performed. A concern for the trimodality approach is that those patients who are not candidate for surgical resection after induction will face a suboptimal treatment since RT is restarted after several weeks taken for restaging for possible surgery. This gap in the treatment delivery is associated with poor outcomes.^[87,88] Thus, this approach is better served in a multidisciplinary approach and a case-by-case basis.

Five-year View

Thus far, the management of clinical and pathologic N2 disease represents a challenge and debate in oncology. Several ongoing clinical trials will, in the near future, define the best combination of conventional and/or targeted agents either as a single modality or in combination with RT. We are waiting for the impact that targeted agents may have in early-stage NSCLC. The positive results found in ECOG 4599 in the metastatic setting created the background to move this agent into the adjuvant setting.^[89] Such a study (ECOG 1505) is already ongoing for stage IB-IIIA NSCLC. The results of the NATCH trial are eagerly anticipated and we hope that it will define the role of neoadjuvant versus adjuvant treatment for NSCLC.

There are a lot of expectations of what changes may occur if the lung cancer staging system is modified in the near future. Several studies have shown that our current staging system does not discriminate sufficient among lung cancer patients within the same stage.^[90,91] N2 disease encompasses a large heterogeneity, and it will be very important for future trials to better define and measure this specific disease stage. Certainly, the use of PET, re-mediastinoscopy and endoscopic ultrasound will play a more important role in the restaging process of patients after induction treatments, and perhaps will replace the conventional computed tomography for this purpose.^[92]

Many questions remain unanswered. Unfortunately, the North American Intergroup trial (S0332/RTOG 0412) was closed prematurely, and hence, has left us without an answer for the controversial IIIA (N2) disease in terms of best induction treatment: CT alone versus combined modality. Thus, the results of a Phase II trial conducted by the Korean NCI: (looking at the same concept) are eagerly awaited for the significant importance that they have to better understand this disease.^[103]

CELL PHONES ARE SAFE

A Lahkola; T Salminen; J Raitanen; S Heinävaara; MJ Schoemaker; H Collatz Christensen; M Feychting; C Johansen; L Klæboe; S Lönn; AJ Swerdlow; T Tynes; A AuvinenInt J Epidemiol. 2008;37(6):1304-1313. ©2008 Oxford University Press

Posted 01/07/2009

Abstract and Introduction

Abstract

Background: Use of mobile telephones has been suggested as a possible risk factor for intracranial tumours. To evaluate the effect of mobile phones on risk of meningioma, we carried out an international, collaborative case-control study of 1209 meningioma cases and 3299 population-based controls.
Methods: Population-based cases were identified, mostly from hospitals, and controls from national population registers and general practitioners’ patient lists. Detailed history of mobile phone use was obtained by personal interview. Regular mobile phone use (at least once a week for at least 6 months), duration of use, cumulative number and hours of use, and several other indicators of mobile phone use were assessed in relation to meningioma risk using conditional logistic regression with strata defined by age, sex, country and region.
Results: Risk of meningioma among regular users of mobile phones was apparently lower than among never or non-regular users (odds ratio, OR = 0.76, 95% confidence interval, CI 0.65, 0.89). The risk was not increased in relation to years since first use, lifetime years of use, cumulative hours of use or cumulative number of calls. The findings were similar regardless of telephone network type (analogue/digital), age or sex.
Conclusions: Our results do not provide support for an association between mobile phone use and risk of meningioma.

No Link Between Eye Cancer and Cell-Phone Use

January 13, 2009 — There is no association between uveal melanoma, a rare form of eye cancer, and regular use of cell phones, says a group of German researchers who previously reported that there was an increased risk.

The current results come from a much larger study, which used very detailed exposure assessments, and so are likely to be more accurate than the previous findings, commented lead researcher Andreas Stang, MD, from the Clinical Epidemiology Unit at the Martin-Luther University of Halle-Wittenberg, in Germany. The latest results are "reassuring," he told Medscape Oncology, because there was no increase in risk up to 10 years' exposure, he added. "We did a very detailed analysis, and we did our very best to show an association, and we did not find one."

The latest results are published online January 13 in the Journal of the National Cancer Institute. They come from a case–control study that involved 459 cases, "which, for the rarity of this cancer, is a very big study," Dr. Stang said. The group matched the cases with 1194 control subjects, 827 of whom were from the general population, 180 of whom were from the ophthalmology clinics at which the cases were found, and 187 of whom were siblings of the patients who had uveal melanoma. There was no association between an increased risk for cancer and cell-phone use in any of these comparison, the researchers report.

The previous study by the same group, which found an increased risk, was reported several years ago in Epidemiology (2001;12:7-12). It involved only 118 cases and used a crude exposure assessment, focusing on use of cell phones while at work. "At that time, cell-phone technology was not very widespread in Germany, and so that was a very different scenario, compared to nowadays," Dr. Stang commented.

The current study did not corroborate the previous results, the group concludes.

Many other studies have looked at links between brain cancer and cell-phone use, but Dr. Stang explained that "the eye is exposed to a considerable dose of cell-phone radiation because of its topography, so if there is any danger from this radiation, then the eye is also a candidate." He would not comment more widely about the association between brain cancer and cell-phone use, saying that he could not generalize. There are questions remaining about the long-term use of cell phones, for example 20 to 30 years out. "We cannot say anything about this," he said. Most studies, including this one, have looked at only about 10 years of exposure.

J Natl Cancer Inst. 2006 Dec 6;98(23):1707-13.

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Comment in:

• J Natl Cancer Inst. 2007 Apr 18;99(8):655; author reply 655-6.

Cellular telephone use and cancer risk: update of a nationwide Danish cohort.

Schüz J, Jacobsen R, Olsen JH, Boice JD Jr, McLaughlin JK, Johansen C.

Institute of Cancer Epidemiology, Danish Cancer Society, Strandboulevarden 49, DK-2100 Copenhagen, Denmark. joachim@cancer.dk

BACKGROUND: The widespread use of cellular telephones has heightened concerns about possible adverse health effects. The objective of this study was to investigate cancer risk among Danish cellular telephone users who were followed for up to 21 years. METHODS: This study is an extended follow-up of a large nationwide cohort of 420,095 persons whose first cellular telephone subscription was between 1982 and 1995 and who were followed through 2002 for cancer incidence. Standardized incidence ratios (SIRs) were calculated by dividing the number of observed cancer cases in the cohort by the number expected in the Danish population. RESULTS: A total of 14,249 cancers were observed (SIR = 0.95; 95% confidence interval [CI] = 0.93 to 0.97) for men and women combined. Cellular telephone use was not associated with increased risk for brain tumors (SIR = 0.97), acoustic neuromas (SIR = 0.73), salivary gland tumors (SIR = 0.77), eye tumors (SIR = 0.96), or leukemias (SIR = 1.00). Among long-term subscribers of 10 years or more, cellular telephone use was not associated with increased risk for brain tumors (SIR = 0.66, 95% CI = 0.44 to 0.95), and there was no trend with time since first subscription. The risk for smoking-related cancers was decreased among men (SIR = 0.88, 95% CI = 0.86 to 0.91) but increased among women (SIR = 1.11, 95% CI = 1.02 to 1.21). Additional data on income and smoking prevalence, primarily among men, indicated that cellular telephone users who started subscriptions in the mid-1980s appeared to have a higher income and to smoke less than the general population. CONCLUSIONS: We found no evidence for an association between tumor risk and cellular telephone use among either short-term or long-term users. Moreover, the narrow confidence intervals provide evidence that any large association of risk of cancer and cellular telephone use can be excluded.

PROGRESS

U.S. Advisers Back 1st Drug From DNA-Altered Animals

ROCKVILLE, Maryland (Reuters) Jan 12 - The first drug made using genetically engineered animals to near U.S. approval won key support on Friday from an advisory panel that judged it safe and effective despite concerns from groups worried about the genetic tinkering.

GTC Biotherapeutics Inc's experimental anticlotting therapy, called Atryn, is made using a human protein gathered from female goats bred to produce it in their milk.

GTC is seeking approval to sell the intravenous therapy to prevent excessive blood clots in patients with an inherited disorder.

Company data showed the drug was safe and effective, a majority of the Food and Drug Administration's 19-member panel voted. The FDA will consider the advice in making its decision, expected by Feb. 7.

"This will... set a precedent for what will happen in the future," said Dr. Richard Colvin, the panel's consumer representative and a clinical assistant in medicine at Massachusetts General Hospital.

But some genetic-safety and animal advocates at the meeting expressed concern about the use of so-called transgenic animals despite the drug's benefits, saying more information is needed from the agency about genetically engineered animals.

The FDA issued preliminary guidelines in September about how it would regulate animals whose DNA has been altered and called for public comment, but it has not yet issued final details.

Approving Atryn "would be a back door way to approve transgenic animals," said Jaydee Hanson, a policy analyst for the nonprofit group Center for Food Safety.

Still, FDA officials said they were seeking advice on the specific product, not the larger issue of generically-altered animals. They added that the final regulations on such animals would be released soon.

Several patients and family members at the advisory meeting urged the FDA's approval of Atryn regardless of the transgenic issue.

Karen Janes, whose daughter died after a 7-inch-long clot, said it could help her remaining daughter live longer and have children. "I don't care how it's made," the New Mexico resident told the panel.

Between 60,000 and 600,000 people in the United States have the excessive clotting disorder, known as hereditary antithrombin deficiency, according to GTC.

GTC has estimated Atryn could generate up to $40 million to $50 million in U.S. annual sales in its first five years on the market. Shares of the company were halted Friday for news pending.

The goats used to make Atryn are bred using cells injected with human DNA. The company has a herd of about 200 at its Massachusetts facility, which are otherwise normal and screened for viruses, GTC said.

In a statement, company officials said the panel's vote helps get their key product closer to market. The drug is the biotech company's first therapy to reach the FDA for review.

Plasma derived products are also an option, but those are often in short supply and difficult for doctors to obtain for a variety of reasons, including the need for human plasma, the company and the FDA said.

"To me this is actually quite an exciting possibility that we actually can make much higher quantities... that are easily accessible," panelist Colvin said.

The drug is licensed to Ovation Pharmaceuticals Inc in the United States.

SLEEP WELL IF YOU DO NOT WANT TO CATCH A COLD

Poor Sleep Before Rhinovirus Exposure Linked to Lower Resistance to Illness

January 13, 2009 — Poorer sleep efficiency and shorter sleep duration in the weeks before exposure to a rhinovirus are linked to greater susceptibility to the common cold, according to the results of a study reported in the January 12 issue of the Archives of Internal Medicine.

"Sleep quality is thought to be an important predictor of immunity and, in turn, susceptibility to the common cold," write Sheldon Cohen, PhD, from the Department of Psychology, Carnegie Mellon University in Pittsburgh, Pennsylvania, and colleagues. "This article examines whether sleep duration and efficiency in the weeks preceding viral exposure are associated with cold susceptibility."

The study sample consisted of 153 healthy men and women volunteers aged 21 to 55 years. For 14 consecutive days, participants reported their sleep duration and sleep efficiency, defined as percentage of time in bed actually asleep for the previous night and whether they felt rested. The investigators calculated average scores for each sleep variable during the 14-day baseline. Participants were then quarantined, inoculated with nasal drops containing a rhinovirus, and monitored for the development of a clinical cold on the day before and for 5 days after rhinovirus exposure. Clinical cold was defined as infection in the presence of objective signs of illness.

Participants who reported less than 7 hours of sleep were 2.94 times (95% confidence interval [CI], 1.18 - 7.30) more likely to get a cold than those with 8 hours or more of sleep, suggesting a graded association with average sleep duration. Similarly, participants with less than 92% sleep efficiency were 5.50 times (95% CI, 2.08 - 14.48) more likely to get a cold than those with 98% or more efficiency, also suggesting a graded association with sleep efficiency.

Differences in prechallenge virus–specific antibody titers, demographics, season of the year, body mass, socioeconomic status, psychological variables, or health practices did not explain the observed associations. The percentage of days feeling rested was not associated with clinical colds.

Limitations of the study include inability to draw causal inference and reliance on self-report.

"Poorer sleep efficiency and shorter sleep duration in the weeks preceding exposure to a rhinovirus were associated with lower resistance to illness," the study authors write. "Because of the prospective design and the controls for multiple confounding factors, these results strongly suggest the possibility of sleep playing a causal role in cold susceptibility. Moreover, the use of a maximally reliable multiple day assessment of sleep habits increases our confidence in the findings of this study."

SLEEP WELL IF YOU DO NOT WANT TO CATCH A COLD

Poor Sleep Before Rhinovirus Exposure Linked to Lower Resistance to Illness

January 13, 2009 — Poorer sleep efficiency and shorter sleep duration in the weeks before exposure to a rhinovirus are linked to greater susceptibility to the common cold, according to the results of a study reported in the January 12 issue of the Archives of Internal Medicine.

"Sleep quality is thought to be an important predictor of immunity and, in turn, susceptibility to the common cold," write Sheldon Cohen, PhD, from the Department of Psychology, Carnegie Mellon University in Pittsburgh, Pennsylvania, and colleagues. "This article examines whether sleep duration and efficiency in the weeks preceding viral exposure are associated with cold susceptibility."

The study sample consisted of 153 healthy men and women volunteers aged 21 to 55 years. For 14 consecutive days, participants reported their sleep duration and sleep efficiency, defined as percentage of time in bed actually asleep for the previous night and whether they felt rested. The investigators calculated average scores for each sleep variable during the 14-day baseline. Participants were then quarantined, inoculated with nasal drops containing a rhinovirus, and monitored for the development of a clinical cold on the day before and for 5 days after rhinovirus exposure. Clinical cold was defined as infection in the presence of objective signs of illness.

Participants who reported less than 7 hours of sleep were 2.94 times (95% confidence interval [CI], 1.18 - 7.30) more likely to get a cold than those with 8 hours or more of sleep, suggesting a graded association with average sleep duration. Similarly, participants with less than 92% sleep efficiency were 5.50 times (95% CI, 2.08 - 14.48) more likely to get a cold than those with 98% or more efficiency, also suggesting a graded association with sleep efficiency.

Differences in prechallenge virus–specific antibody titers, demographics, season of the year, body mass, socioeconomic status, psychological variables, or health practices did not explain the observed associations. The percentage of days feeling rested was not associated with clinical colds.

Limitations of the study include inability to draw causal inference and reliance on self-report.

"Poorer sleep efficiency and shorter sleep duration in the weeks preceding exposure to a rhinovirus were associated with lower resistance to illness," the study authors write. "Because of the prospective design and the controls for multiple confounding factors, these results strongly suggest the possibility of sleep playing a causal role in cold susceptibility. Moreover, the use of a maximally reliable multiple day assessment of sleep habits increases our confidence in the findings of this study."

MVAC IS PROBABLY BETTER FOR NEOADJUVANT TREATMENT

Cancer. 2009 Jan 6. [Epub ahead of print]

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Lack of pathologic down-staging with neoadjuvant chemotherapy for muscle-invasive urothelial carcinoma of the bladder: a contemporary series.

Weight CJ, Garcia JA, Hansel DE, Fergany AF, Campbell SC, Gong MC, Jones JS, Klein EA, Dreicer R, Stephenson AJ.

Glickman Urologic and Kidney Institute, Cleveland Clinic, Cleveland, Ohio.

BACKGROUND:: The postcystectomy survival benefit associated with the combination of methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) neoadjuvant chemotherapy (NC) for muscle-invasive bladder cancer has been most evident in patients who achieve a pathologic complete response. The outcome of NC and open radical cystectomy (RC) was evaluated in a contemporary cohort of patients in a tertiary referral setting. METHODS:: From January 2006 to November 2007, 117 patients underwent open RC at Cleveland Clinic for muscle-invasive bladder cancer, 29 (25%) of whom received NC. Patient information was obtained from a prospective database. RESULTS:: Clinical stage at the time of diagnosis in the NC cohort was T2 in 23 (79%) and T3-4a in 6 (21%) patients. A total of 20 (69%) patients received the combination of gemcitabine and cisplatin (GC), 4 (14%) received MVAC, and 5 (17%) received other regimens. The median interval from the time of diagnosis of muscle-invasive bladder cancer to RC was 208 days (interquartile range, 149 days -327 days) in the NC cohort. Overall, only 2 patients (7%; 95% confidence interval [95% CI], 0 patients-17 patients) achieved a pathologic complete response, 18 (62%; 95% CI, 43 patients-81 patients) had nonorgan-confined residual cancer, and the overall median progression-free survival was 10.5 months (95% CI, 7 months -14 months). CONCLUSIONS:: Few RC patients in these investigators' recent experience achieved a pathologic complete response with NC, and most experienced rapid disease progression. These poor outcomes may be related to the use of non-MVAC-based regimens or excessive delay in performing RC. In the absence of supportive data for GC in the neoadjuvant setting, MVAC remained the preferred regimen. Excessive delays in performing RC may negate the benefit of NC. Cancer 2009. (c) 2009 American Cancer Society.

INTENSIFIED REGIMENS FOR ADVANCED HODGKIN LYMPHOMA

J Clin Oncol. 2009 Jan 5. [Epub ahead of print]

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ABVD Compared With BEACOPP Compared With CEC for the Initial Treatment of Patients With Advanced Hodgkin's Lymphoma: Results From the HD2000 Gruppo Italiano per lo Studio dei Linfomi Trial.

Federico M, Luminari S, Iannitto E, Polimeno G, Marcheselli L, Montanini A, La Sala A, Merli F, Stelitano C, Pozzi S, Scalone R, Di Renzo N, Musto P, Baldini L, Cervetti G, Angrilli F, Mazza P, Brugiatelli M, Gobbi PG.

Dipartimento di Oncologia ed Ematologia, Università di Modena e Reggio Emilia; Divisione di Ematologia e Trapianto di Midollo Osseo, Policlinico di Palermo; Unita Operativa (UO) Semplice di Oncoematologia, Divisione di Medicina, Ospedale "F. Miulli", Acquaviva delle Fonti; Divisione di Ematologia, Centro trapianti di Midollo Osseo, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Casa Sollievo della Sofferenza, S.G. Rotondo; UO di Ematologia, Azienda Ospedaliera Arcispedale S. Maria Nuova, Reggio Emilia; Divisione di Ematologia, Azienda Ospedaliera "Bianchi-Melacrino-Morelli", Reggio Calabria; Divisione di Ematologia, Casa di Cura La Maddalena, Palermo; UO Complessa di Ematologia, Presidio Ospedaliero V. Fazzi, Lecce; Ematologia e Trapianto di Cellule Staminali, IRCCS, Centro di Referimento Oncologico Della Basilicata, Rionero in Vulture; UO Ematologia 1/CMTO, Fondazione Ospedale Maggiore Policlinico Mare, IRCCS, Universita "Degli Studi, Milano"; UO Ematologia, Azienda Ospedaliera Universitaria Pisana, Pisa; Dipartimento di Ematologia, USL di Pescara, Ospedale S. Spirito, Pescara; Struttura Complessa di Ematologia, Azienda Ospedaliera "SS. Annunziata", Presidio Ospedaliero S.G. Moscati, Taranto; Divisione di Ematologia, Azienda Ospedaliera Papardo, Messina; and the Medicina Interna e Oncologia Medica, Università di Pavia, IRCCS Policlinico San Matteo, Pavia, Italy.

PURPOSE: To compare doxorubicin, bleomycin, vinblastine, dacarbazine (ABVD) versus bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) versus cyclophosphamide, lomustine, vindesine, melphalan, prednisone, epidoxirubicin, vincristine, procarbazine, vinblastine, and bleomycin (COPPEBVCAD; CEC) for advanced Hodgkin's lymphoma (HL). PATIENTS AND METHODS: Three hundred seven patients with advanced HL (stage IIB, III, and IV) were randomly assigned to receive six courses of ABVD, four escalated plus two standard courses of BEACOPP, or six courses of CEC, plus a limited radiation therapy program. RESULTS: After a median follow-up of 41 months, BEACOPP resulted in a superior progression-free survival (PFS), with a significant reduction in risk of progression (hazard ratio [HR] = 0.50) compared with ABVD. No differences between BEACOPP and CEC, or CEC and ABVD were observed. The 5-year PFS was 68% (95% CI, 56% to 78%), 81% (95% CI, 70% to 89%), and 78% (95% CI, 68% to 86%), for ABVD, BEACOPP, and CEC, respectively (BEACOPP v ABVD, P = .038; CEC v ABVD and BEACOPP v CEC, P = not significant [NS]). The 5-year overall survival was 84% (95% CI, 69% to 92%), 92% (95% CI, 84% to 96%), and 91% (95% CI, 81% to 96%) for ABVD, BEACOPP, and CEC, respectively (P = NS). BEACOPP and CEC resulted in higher rates of grade 3-4 neutropenia than ABVD (P = .016); BEACOPP was associated with higher rates of severe infections than ABVD and CEC (P = .003). CONCLUSION: As adopted in this study BEACOPP is associated with a significantly improved PFS compared with ABVD, with a predictable higher acute toxicity.