ADJUVANT RADIATION FOR HIGH RISK SALIVARY GLAND TUMORS

NEW YORK (Reuters Health) Nov 01 - Adjuvant radiation appears to help patients with high-risk tumors in major salivary glands, according to a study in the October issue of Archives of Otolaryngology -- Head & Neck Surgery
The new findings, drawn from a national cancer database, show that radiotherapy against high grade and locally advanced malignant salivary gland tumors "was associated with improved survival," lead author Dr. Usama Mahmood told Reuters Health by email.
Dr. Mahmood and colleagues at the University of Maryland in Baltimore note that although a number of retrospective studies showed adjuvant radiation improved local control, few reported a significant survival benefit. Given the low incidence major salivary gland malignancies, there have been no randomized controlled trials.
Dr. Mahmood's team examined data on 2,170 adults who had surgery for high-grade disease, including 1,565 (72%) who received adjuvant radiotherapy. The median age was 68.
Although the radiotherapy patients were younger (with a median age of 67, vs 71 for patients who didn't receive radiotherapy), their tumors fell into higher T and N categories. Even so, multivariable analysis showed significantly improved survival in that group(hazard ratio, 0.76; p <0.001).
Patients who particularly benefited from radiotherapy were those with involvement of the parotid gland or squamous cell carcinoma. There was also a survival benefit for patients with adenocarcinoma, but not a statistically significant one.
Younger age at diagnosis, less radical surgery, and lower T and N categories were also among the factors associated with improved survival.
"Further prospective studies are warranted to examine the role of radiation therapy in the management of this disease," the research team concludes.
SOURCE: http://bit.ly/ts9y4D
Arch Otolaryngol Head Neck Surg 2011;137:1025-1030.

NCCN RECOMMENDS CT LUNG CANCER SCREENING

November 4, 2011 — The National Comprehensive Cancer Network (NCCN) has come out in favor of lung cancer screening in an updated set of guidelines. It recommends the use of helical low-dose computed tomography (CT) screening for select patients at high risk for the disease.
This is a category 2A recommendation, which is based on "lower-level evidence," but there is NCCN consensus that the intervention is appropriate.
The NCCN is "the first professional organization to perform this comprehensive review and update their recommendations in light of all the evidence," noted Claudia Henschke, MD, principal investigator of the International Early Lung Cancer Action Program, which first reported benefits from low-dose CT scans in 1999.
"We can no longer ignore the proven potential that CT scanning holds for lung cancer: saving lives," she said in a statement.
Last year, the landmark National Lung Screening Trial was halted early after it showed that screening heavy smokers with low-dose CT scans reduced deaths from lung cancer, compared with screening by chest x-rays.
Lung cancer experts heaped praise on the result, but at the same time expressed some concern about how to proceed with this finding in clinical practice. Among the questions that still need to be addressed are who should be screened, how often, what should be done about unclear findings, and how should intervention for patients who turn out not to have lung cancer be minimized. Indeed, at a recent meeting, experts declared that lung cancer screening is "not yet ready for prime time."
Despite these misgivings, some American practices have already gone ahead and are offering lung cancer screening.
Complex and Controversial Topic
According to the new NCCN guidelines, "lung cancer screening with low-dose CT scans is a complex and controversial topic, with inherent risk and benefits."
The document addresses many of the concerns that have been raised about lung cancer screening, and provide:

• an overview of the risk factors for lung cancer
• recommendations for selecting high-risk individuals for screening
• recommendations for the evaluation and follow-up of nodules found during screening
• discussions about the accuracy of low-dose CT screening protocols and imaging modalities
• discussions of the benefits and risks of screening.

The guidelines also touch on cost issues, noting that low-dose CT scans are more expensive than many other screening programs. Each low-dose CT scans for lung cancer costs around $300; the cost of a mammogram for breast cancer screening is around $80 to $150.
"As policies for implementing lung cancer screening are designed, a focus on multidisciplinary programs (incorporating primary care doctors, pulmonologists, radiologists, thoracic surgeons, medical oncologists, and pathologists) will be helpful to optimize decision making and to minimize interventions for patients with benign lung disease," according to the guidelines.

ASCO UPDATES ANTIEMETIC GUIDELINES

November 3, 2011 — For the first time in 5 years, the American Society of Clinical Oncology (ASCO) has updated its clinical practice guideline on the use of antiemetic medications to prevent vomiting and nausea resulting from treatment with chemotherapy and/or radiation.
The updated guideline includes recommendations on the use of antiemetics with chemotherapy drugs that are classified as high, moderate, minimal, and low risk for causing vomiting and nausea.
The updated guideline, published in the November 1 issue of the Journal of Clinical Oncology, is based on a systematic review of 37 relevant clinical trials in the medical literature.
More than half of all cancer patients experience nausea or vomiting during treatment, which can cause dehydration and other problems, according to the guideline.
"Over the past 2 decades, major strides have been made in recognizing the scope of this problem. There have been improvements in stratifying the risk of side effects according to the type of drug treatment used. This guideline update reflects progress in refining antiemetic approaches and minimizing these side effects," said panel cochair and lead author Ethan Basch, MD, from Memorial Sloan-Kettering Cancer Center in New York City, in a press statement.
The guideline details the risk for nausea and vomiting associated with specific chemotherapy and radiation therapy regimens, and recommends antiemetic regimens for each.
One of the highlights is the reclassification of combined anthracycline and cyclophosphamide regimens as highly emetic. Each drug alone is classified as having a moderate risk but, on the basis of new data, this combination, which is widely used in breast cancer and non-Hodgkin's lymphoma, is now considered high-risk. Patients who receive this combination or any highly emetic agents should receive a combination of a 5-HT₃-receptor antagonist, dexamethasone, and a neurokinin 1–receptor antagonist, according to the new guideline.
Other highlights from the include:

• the classification of fosaprepitant, a single-day intravenous formulation, as being equivalent to aprepitant
• the recommendation for the preferential use of palonosetron combined with dexamethasone for regimens of moderate emetic risk
• the recommendation that patients undergoing treatment with low-risk agents be offered dexamethasone before the first dose of chemotherapy
• the recommendation that patients undergoing high emetic risk radiation therapy receive a 5-HT₃-receptor antagonist before each fraction and for 24 hours after treatment, and can receive a 5-day course of dexamethasone during fractions 1 to 5.

The ASCO update committee notes the importance of continued symptom monitoring throughout therapy. "Clinicians underestimate the incidence of nausea, which is not as well controlled as emesis," they point out.
"In general, we have more effective and better tolerated antiemetic agents today, and we have also learned how to use the available agents in more effective ways," said panel cochair Gary Lyman, MD, MPH, professor of medicine at Duke University and the Duke Cancer Institute in Durham, North Carolina.
A number of the guideline authors have disclosed financial ties with industry.
J Clin Oncol. 2011;29:4189-4198. Full text

EVEN MODERATE ALCOHOL USE INCREASE BREAST CANCER RISK

November 1, 2011 — The regular consumption of a modest amount of alcohol — 3 to 6 glasses of wine per week — over a long period of time increases a woman's risk for invasive breast cancer by a small but statistically significant amount, according to researchers.
Their prospective observational study of 105,986 women comes from the large Nurses' Health Study and examines "cumulative average consumption" over the 28-year study period. Participants were followed from 1980 to 2008, and completed 8 updated alcohol-assessment questionnaires during that time.
The study appears in the November 2 issue of JAMA, The Journal of the American Medical Association.
It adds to the literature on the effects of alcohol consumption on breast cancer risk, particularly that of "low levels of drinking," which "has not been well quantified," say the authors, led by Wendy Y. Chen, MD, MPH, from Brigham and Women's Hospital and Harvard Medical School in Boston, Massachusetts.
Not surprisingly, larger amounts of alcohol consumption were associated with increased breast cancer risk over the study period, the authors report.
However, Dr. Chen and her coauthors found that the risk was statistically significant at levels as low as 5 to 9.9 g per day, which is the equivalent to 3 to 6 drinks per week (relative risk [RR], 1.15; 95% confidence interval [CI], 1.06 to 1.24). But the authors also described this 15% increase in risk as "quite small."
Drinking an average of 10.0 to 19.9 g of alcohol per day (6 to 12 drinks a week) resulted in a 22% increase in risk (RR, 1.22; 95% CI, 1.07 to 1.35). At the upper end of the drinking scale, drinking 30 g or more a day resulted in a 51% increased risk (RR, 1.51; 95% CI, 1.35 to 1.70), compared with drinking no alcohol at all.
Should all women be teetotalers?
The data do not suggest as much. Drinking an average of up to 4.9 g of alcohol a day over the study period was not associated with any significantly increased breast cancer risk, compared with never drinking (RR, 1.06; 95% CI, 0.99 to 1.12).
A little alcohol is okay, said Dr. Chen.
"I tell my patients to limit consumption to a few drinks per week or less, which is what I also practice," she told Medscape Medical News. "It is important to remember that we were looking at cumulative average alcohol intake over a long period of time."
Dr. Chen suggested that alcohol amounts should be consumed strategically.
For example, she explained, "if someone is on vacation or wants to 'unwind' by having a few extra drinks, they can offset that by drinking less at other time points."
The authors believe that, in making an individual decision about alcohol use, any breast cancer risk must be weighed against "the beneficial effects on cardiovascular disease."
Insight: Alcohol Effect Appears to Be Like HRT
This study indicates that "the cumulative amount of alcohol a woman consumes during adulthood is the best predictor of her breast cancer risk," writes Steven Narod, MD, from the Women's College Research Institute in Toronto, Ontario, Canada, in an editorial accompanying the study.
Dr. Narod also notes that alcohol seems akin to another known breast carcinogen — hormone replacement therapy (HRT). "Alcohol...appears similar to hormone therapy in that lifetime risk exposure also is associated with annual risk," he writes. He is referring to research that shows that lifetime hormonal exposure is the best predictor of breast cancer risk in women who are current users of HRT.
However, what is "not known" is whether the effect of alcohol on breast cancer risk will diminish once intake is stopped. This is the case with hormone therapy; the risk dissipates within 2 years of cessation. Dr. Narod, citing the likely effect of alcohol on sex hormones, believes that breast cancer risk "may be expected to decline after alcohol intake ceases."
The authors suspect that the link between alcohol consumption and breast cancer, although not understood, might be related to "alcohol's effects on circulating estrogen levels." Studies indicate that "moderate levels of alcohol consumption increased circulating sex hormone levels in both premenopausal and postmenopausal women.
Applies to American Women in General
The women in the study were 30 to 55 years old at baseline, were primarily white (93.7%), and had an alcohol intake that was "fairly similar" to that of American women in general, say the authors.
During the 28-year study period, which started in 1980, data on alcohol consumption were updated in 1984, 1986, 1990, 1994, 1998, 2002, and 2006. Cumulative average alcohol intake was calculated by averaging alcohol use over time, beginning in 1980.
Follow-up in the study was "extremely high," say the authors, with only 4.4% of "person-time" lost to follow-up.
There were 7690 cases of invasive breast cancer with 2.4 million person-years of follow-up.
Cox proportional hazards models were used to compute hazard ratios as estimates of age-adjusted and multivariate-adjusted relative risks and 95% confidence intervals. The variables included age and other commonly accepted breast cancer risk factors, such as menopausal status, age at menarche, parity, age at first birth, body mass index, family history, and cigarette smoking.
The authors also evaluated whether the association between alcohol consumption and breast cancer risk varied by type of alcohol, but found "little difference" between wine, beer, and liquor.
The study included some novel data, according to the authors. "To our knowledge, this is the first study to evaluate breast cancer risk in relation to both frequency of drinking and binge drinking," they write. Binge drinking, but not frequency of drinking, was associated with breast cancer risk after controlling for cumulative alcohol intake, they report.
The study was supported by the National Institutes of Health. The authors have disclosed no relevant financial relationships.
JAMA. 2011;306:1884-1890, 1920-1921. Abstract, Editorial

COMBINING RADIATION AND LONG TERM ADT BETTER FOR HIGH RISK PROSTATE CANCER

November 2, 2012 — In a finding that challenges a reportedly common clinical practice, radiation therapy plus long-term androgen-deprivation therapy (ADT) improved overall survival in men with high-risk locally advanced prostate cancer, compared with ADT alone.
The benefits of this combined treatment "should be discussed with all patients with locally advanced prostate cancer," say the study authors, led by Padraig Warde, MBChB, from the University of Toronto's Princess Margaret Hospital in Ontario, Canada.
The findings from the randomized trial of 1205 men are published online November 3 in the Lancet. They were first presented at the 2010 annual meeting of the American Society of Clinical Oncology (ASCO), and were reported by Medscape Medical News at the time.
At that ASCO meeting, Dr. Warde said that "up to 45%" of patients with high-risk locally advanced prostate cancer are treated with ADT alone, citing information from the Cancer of the Prostate Research Endeavor (CaPSURE).
"In the past, many clinicians thought that these patients were incurable and should be treated with androgen-deprivation therapy alone," Dr. Warde explained at the time.
This study shows that adding radiation to ADT significantly improves survival. At 7 years, 74% of the 603 men who received ADT plus external-beam radiation were still alive, compared with 66% of the 602 men who received ADT alone (P = .033).
The combination therapy also reduced the risk of dying from prostate cancer. The 7-year cumulative disease-specific deaths were 9% for patients receiving ADT plus radiation therapy and 19% for patients receiving ADT alone (P = .001).
Furthermore, many fewer patients treated with combination therapy developed progressive disease. A total of 346 patients developed progressive disease — 251 treated with ADT alone and 95 treated with ADT plus radiation therapy.
All the men in the study had T3/T4 disease or T2 prostate adenocarcinoma with a prostate-specific antigen (PSA) level above 40 μg/L, or T2 prostate adenocarcinoma with a PSA level above 20 μg/L and a Gleason score of 8 or higher.
They were randomized, from 1995 to 2005, to lifelong ADT (bilateral orchiectomy or luteinizing hormone-releasing hormone agonist) with or without radiation therapy.
The radiation therapy was 65 to 69 Gy to the prostate, which was the standard dose when the trial started in the 1990s, with or without radiation to seminal vesicles. If needed, 45 Gy was delivered to the pelvic nodes.
"Today, we would use 74 to 78 Gy and 45 to 50 Gy to the nodes," Dr. Warde said at the ASCO meeting, explaining that the study probably "underestimates the value of radiation therapy," because radiation technology and doses were less potent than those currently used.
Strongest Evidence to Date
In an accompanying comment, an American prostate cancer expert not involved with the study praised the findings.
"This study has provided the strongest evidence to date that androgen-deprivation therapy alone for men with high-risk prostate cancer is not adequate. These patients require an aggressive multimodal approach, incorporating prostate-directed local therapy," said Matthew Cooperberg, MD, from the Department of Urology at the University of California, San Francisco.
The study improves on the major SPCG-7 trial, he reports. That study used antiandrogens rather than surgical or medical castration, and was thus dated in its approach, he says. In addition, the patients in the study by Dr. Warde and colleagues — a joint venture of European and North American cooperative groups — had less favorable prognoses.
Reporting of Adverse Events Questioned
Dr. Cooperberg also voiced some important disclaimers about the study.
First, he noted that it is not clear whether radiation therapy plus ADT is the best initial treatment for these men.
"The crucial question — whether the optimum initial strategy should include radiation combined with androgen-deprivation therapy, or surgery followed by selective radiation on the basis of pathological findings and early biochemical outcomes — is still open," he writes.
More important, Dr. Cooperberg questions the toxicity findings.
The study authors reported that toxicity and health-related quality-of-life results showed a "small effect" of radiation on late gastrointestinal toxicity: 3 patients (0.5%) in the ADT group and 2 patients (0.3%) in the combination group developed rectal bleeding of grade 3 or higher; 4 patients (0.7%) in the ADT group and 8 patients (1.3%) in the combination group developed diarrhea of grade 3 or higher; and 14 patients (2.3%) in each treatment group developed urinary toxicity of grade 3 or higher.
"Warde and colleagues' assertion...that the benefit of radiation comes at no expense to long-term urinary or bowel effects challenges clinical experience and many other studies," says Dr. Cooperberg.
The questionnaires used to assess patient-reported toxicities are relatively insensitive, compared with newer measures, he says. Plus, the Functional Assessment of Cancer Therapy–Prostate instrument, completed by the large majority of patients in the trial, does not capture bowel symptoms; the instrument used for those symptoms was completed by only 10% of the patients, he points out.
Debate About Standard of Care
At the ASCO meeting, there was some disagreement among prostate cancer experts about what the current standard of care in the field is.
"It's what we are already doing," said Oliver Sartor, MD, from the Tulane Cancer Center in New Orleans, Louisiana, about radiation combined with ADT.
"I trained from 1999 to 2001, and this [combination therapy] is what we were doing then," said Timothy Gilligan, MD, from the Cleveland Clinic in Ohio.
Dr. Gilligan explained that previous studies established the value of combining hormone therapy and radiation therapy.
"Multiple randomized controlled trials have shown that men with high-risk locally advanced prostate cancer live longer if they receive hormone therapy at the same time as radiation therapy," he said.
However, Dr. Gilligan said the study design raises a question: Is it the hormone therapy that is responsible for the improved survival?
"This study shows that radiation therapy makes a difference — it provides very important data," he said, adding that there is still no clinical trial that proves that radiation therapy alone improves survival. Hormone therapy, however, provides "an unquestioned survival benefit in locally advanced disease," he said.
Not all men with locally advanced disease should receive radiation, Dr. Warde noted at the ASCO meeting. The general rule is that in men with a life expectancy of 5 to 10 years should receive both hormone therapy and radiation. However, in older men with few years of life remaining and in men with considerable comorbidities, especially those of a cardiovascular nature, radiation should be avoided.
The study authors, Dr. Cooperberg, and Dr. Gilligan have disclosed no relevant financial relationships. Dr. Sartor reports being a consultant or advisor to and receiving honoraria and research funding from sanofi-aventis.
Lancet. Published online November 3, 2011. Abstract, Comment

TIME FOR COMBINING MDV3100 AND ABIRATERONE

November 3, 2011 — The experimental oral agent for metastatic castration-resistant prostate cancer, MDV3100 (Medivation), improved survival by 4.8 months, compared with placebo, in a phase 3 trial, the company announced.
A planned interim analysis of the AFFIRM trial revealed that estimated median survival was 18.4 months for men treated with MDV3100, compared with 13.6 months for men treated with placebo (P < .0001). This translates into a 37% reduction in the risk for death with MDV3100 (hazard ratio, 0.631).
As a result, the trial's Independent Data Monitoring Committee recommended that AFFIRM be stopped early and that men who were receiving placebo be offered MDV3100.
The recommendation was based on the fact that the study's prespecified interim efficacy stopping criteria were successfully met. The committee also examined the safety profile to date and determined that MDV3100 demonstrated a risk/benefit ratio that was favorable enough to stop the study, according to a company press statement.
"MDV3100 was rationally designed to target androgen-receptor signaling, a key driver of prostate cancer growth," said Howard I. Scher, MD, coprincipal investigator of the AFFIRM study, in a press statement. He is chief of the genitourinary oncology service at the Memorial-Sloan Kettering Cancer Center in New York City. "If approved, MDV3100 will be a welcome option for men with prostate cancers who have progressed on hormones and after initial chemotherapy."
The full results from AFFIRM, including safety data, will be presented at an upcoming scientific congress, according to the company.
The study is a randomized, double-blind, multinational trial comparing MDV3100 (160 mg/day) with placebo in 1199 men with advanced prostate cancer who were previously treated with docetaxel-based chemotherapy. Enrollment was completed in November 2010, and the interim analysis was triggered at 520 events.
If approved by the US Food and Drug Administration, MDV3100 will move into an increasingly crowded marketplace of products for the treatment of castration-resistant prostate cancer.
In phase 3 clinical trials in this setting, the immunotherapy sipuleucel-T (Provenge, Dendreon) has demonstrated a 4.1-month median survival benefit, and abiraterone (Zytiga, Johnson & Johnson) has shown a 3.9-month benefit. In addition, the chemotherapy cabazitaxel (Jevtana, sanofi-aventis) demonstrated a 2.4-month overall survival advantage over standard therapy.
MDV3100 and Abiraterone
MDV3100 was codeveloped by Charles Sawyers, MD, chair of human oncology and pathogenesis at Memorial Sloan-Kettering, and Michael Jung, PhD, professor of chemistry at the University of California, Los Angeles.
They theorized that androgen-receptor signaling is a driver in prostate cancer and that blocking the signaling would stop its growth. MDV3100 was designed to do just that.
In an earlier report on MDV3100, Dr. Scher told Medscape Medical News that it is a very potent antagonist of androgen receptors, and binds to the receptor very tightly.
MDV3100 is more potent and more specific than the older antiandrogens, such as flutamide (Drogenil) and bicalutamide (Casodex), which have been and are still being used in prostate cancer, usually with gonadotropin-releasing hormone agonists/antagonists, such as leuprolide (Lupron) and goserelin (Zoladex), said Dr. Scher. These older antiandrogen compounds also have some agonist activity, and have been found to stimulate prostate cancer growth in some men, Dr. Scher explained. This has not been seen with MDV3100, he noted at the time.
The mechanism of action of MDV3100 is very different from that of abiraterone, which is an inhibitor of androgen synthesis but does not block androgen binding, Dr. Scher said.
Because they act in different ways, there might be benefits from using the drugs together, he added.
Dr. Scher reports receiving research funding from Medivation. Coauthor Dr. Sawyers is a codeveloper of MDV3100, and is entitled to royalties that could result from its commercial success.

INCREASING RATE OF AGGRESIVE RECTAL CANCER IN YOUNG PATIENTS

October 28, 2011 (San Francisco, California) — The incidence of rectal adenocarcinoma has more than doubled among persons younger than 40 years of age, and such tumors are 5 times more likely to have a signet cell histology suggestive of an aggressive phenotype, according to a study presented here at the American College of Surgeons (ACS) 97th Clinical Congress.
"Given the worse outcomes associated with signet cell histology, these data highlight the need to identify and address the cause of this emerging problem," said Patrick S. Tawadros, MD, PhD, from the University of Minnesota in Minneapolis.
The increasing incidence of rectal cancer among young adults has been reported in the literature in recent years. Dr. Tawadros said his own interest in this topic stemmed from a 26-year-old patient of his.
"In my first week of fellowship I had a young patient with very advanced rectal cancer anteriorally invading to his right seminal vesicle. He required a multivisceral resection at 26 years old. And I went on to see other patients under the age of 40. Although there is probably a selection bias for patients seen at the University of Minnesota, this made me question what we know about the possible rise in rectal cancer among young adults," he said.
Recent studies have, indeed, suggested that rectal cancer rates are rising among younger adults and their disease tends to be more advanced at presentation, which led Dr. Tawadros and colleagues to question whether signet cell histology might be playing a role, he said.
Signet cell histology is rare, occurring in only about 1% of rectal cancers. It is associated with advanced stage at presentation, young age, and worse prognosis.
"We hypothesized that an increased incidence of rectal cancer in young persons may be associated with an increased signet ring cell phenotype," he said.
He and his colleagues performed a retrospective cohort study of all patients diagnosed with rectal adenocarcinoma from 1980 to 2007 using the Surveillance, Epidemiology, and End Results (SEER) cancer registry (n = 117,813). They found that although the incidence of rectal cancer for all ages remained stable from 1980 to 2007, there was essentially a doubling since the year 2000 in malignancies in persons younger than 40 years of age.
Among this younger age group, the incidence has increased linearly from 0.4 to 1.2 per 100,000 population, he said.
Importantly, and as they hypothesized, they found a significantly higher prevalence of signet cell histology in young adults than in patients older than age 40 (4.63% vs 0.78%; P = .001).
"Signet cell histology comprised about 5% of rectal adenocarcinomas in patients under the age of 40, compared with 1% in patients over 40," he reported.
Multivariate regression analysis revealed an adjusted odds ratio of 5.12 (95% confidence interval, 4.22 - 6.20) for signet cell histology in rectal adenocarcinoma in persons younger than age 40 years.
Signet cell histology was also significantly associated with more advanced stage at presentation, poorly differentiated tumor grade, and worse prognosis compared with mucinous and nonmucinous rectal adenocarcinoma.
"Given the worse outcomes associated with signet cell histology, these data highlight the need to identify and address the cause of this emerging problem. Young adults with lower gastrointestinal symptoms should undergo prompt evaluation and not just assumed to have bleeding hemorrhoids," he said.
Martin R. Weiser, MD, from Memorial Sloan-Kettering Cancer Center in New York, New York, said the findings should bring much-needed awareness to clinicians. "Anecdotally, we have often seen young patients present with signet histology, and these are the patients that often do quite poorly with chemoradiation and surgery. They have very aggressive tumors. We should be aware of this when we see young patients with this histology."
Dr. Tawadros and Dr. Weiser have disclosed no relevant financial relationships.
American College of Surgeons 97th Annual Clinical Congress. Presented October 26, 2011.

NSCLC WITH HIGH EGFR EXPRESSION BENIFIT FROM CETUXIMAB

November 3, 2011 — Adding the targeted agent cetuximab (Erbitux) to chemotherapy significantly improves overall survival in some patients with nonsmall-cell lung cancer (NSCLC), and an approach to identifying the patients who will benefit has now been found.
The finding comes from an analysis of the FLEX study, published online November 4 in the Lancet Oncology. It was presented earlier this year at the World Conference on Lung Cancer, and reported at the time by Medscape Medical News.
The analysis shows that NSCLC patients who have a high expression of epidermal growth-factor receptor (EGFR) in their tumors have the best response when cetuximab (a monoclonal antibody directed against EGFR) is added to chemotherapy. This high EGFR expression was found in 31% of patients who were tested.
"This is the first predictive biomarker for overall survival in advanced NSCLC," lead author Robert Pinker, MD, from the Vienna Medical University in Austria, reported at the meeting.
Patients with this high EGFR expression who were treated with the combination had a median overall survival of 12 months, compared with 9.6 months for those treated with chemotherapy alone (hazard ratio [HR], 0.73; P = .011), "with no meaningful increase in side effects," the researchers report.
One-year survival with the combination was 50%, compared with 37% with chemotherapy alone; 2-year survival was 24% and 15%, respectively.
"I believe that this is such an improvement in survival — one that we have never seen before — that this [treatment] should be available to our patients," Dr. Pinker said at the meeting.
However, other lung cancer experts at the meeting were cautious in their reactions to the finding, emphasizing that it needs to be validated prospectively before being incorporated into clinical practice.
These sentiments are echoed in a comment accompanying the publication of the findings.
This seems to be "an encouraging step toward personalized medicine for patient subgroups with advanced lung cancer who will potentially receive cetuximab," write editorialists Fred Hirsch, MD, from the University of Colorado Cancer Center, Aurora, and Roy Herbst, MD, from the Yale Cancer Center, Smilow Cancer Hospital, New Haven, Connecticut.
However, they emphasize that "further prospective validation is essential."
This is already planned in a large ongoing prospective phase 3 study (SWOG 0819), which is comparing cetuximab plus chemotherapy with chemotherapy alone.
Reanalysis of Results
The results of the FLEX study were first presented at the 2008 annual meeting of the American Society of Clinical Oncology, and subsequently published in the Lancet (2009;373:1525-1531). The trial involved 1125 chemotherapy-naive adult patients with advanced EGFR-expressing stage 3B or stage 4 NSCLC, who were randomly assigned to chemotherapy plus cetuximab or chemotherapy alone. The results showed a small but significant improvement in median overall survival with the combination (11.3 vs 10.1 months; HR, 0.87; P = .04).
However, progression-free survival was similar in both groups (median, 4.8 months).
When these results were first presented, discussant Thomas J. Lynch, MD, professor of medicine at Harvard University in Boston, Massachusetts, wondered about the "marginal" improvement in overall survival. He pointed out that it would cost about $62,000 to add cetuximab to the chemotherapy regimen. He questioned whether a "median of 1.4 months is worth it, especially if we don't know if the quality of life has been improved."
"If we can bring survival up to 2.5 months, then it would be in line with other therapies," Dr. Lynch said at the time.
Since the original presentation of the data, the FLEX investigators have been looking for a biomarker to predict which patients will respond best to the combination of cetuximab plus chemotherapy, Dr. Pinker explained.
Now they report having found one — high EGFR expression. In the subgroup of patients with high EGFR expression, the difference in overall survival between those treated with cetuximab plus chemotherapy and those treated with chemotherapy alone is nearly exactly what Dr. Lynch asked for at that meeting (12.0 vs 9.6 months; a difference of 2.4 months).
Maybe Other Biomarkers?
The biomarker was found during the immunochemistry assessment of tumor EGFR expression in 1121 of the 1125 patients participating in the FLEX study. The researchers assigned an immunohistochemistry score (H score) and determined a cutoff point (200 or more on a scale of 0 to 300) for high EGFR rates. The immunohistochemistry assessment was carried out prospectively, but the determination of the cutoff point was retrospective, based on response rates.
It is this retrospective part of the analysis that is causing concern for the experts who say that prospective validation of the findings is needed. "Even if the H score system was prespecified in the FLEX study, the cutoff value of 200 for high expression versus low expression was not," the editorialists note.
"The H score assessment seems to help select a group of patients that may particularly benefit," the editorialists note. However, they also wonder whether other approaches — such as automated assessment of EGFR protein expression (i.e., AQUA assessment) or other digital scoring systems (i.e., ACIS < APERIO or LECIA) — can improve the selection of patients for treatment with cetuximab and similar drugs.
The FLEX study was supported by Merck KGaA, the manufacturers of cetuximab. Dr. Pinker reports receiving consulting fees, honoraria, and travel to meetings from Merck Serono and Merck KGaA. Three of his coauthors are employees of Merck KGaA. Dr. Hirsch reports serving as a consultant to Merck Serono, Bristol-Myers Squibb, Lilly-ImClone, Pfizer, OSI/Roche/Genentech, Celgene, and Boehringer Ingelheim; and is coinventor on a patent for predicting clinical outcome in response to EGFR inhibitors in cancer licensed to Abbott. Dr. Herbst reports serving as a consultant to Bristol-Myers Squibb and OSI/Roche/Genentech.
Lancet Oncol. Published online November 4, 2011. Abstract, Comment