PELVIC LYMPHADENECTOMY FOR EARLY STAGE ENDOMETRIAL CANCER?

Pelvic Lymphadenectomy Does Not Improve Outcomes in Early-Stage Endometrial Cancer

November 25, 2008 — Systematic pelvic lymphadenectomy does not improve disease-free or overall survival in patients with early-stage endometrial cancer, according to a report by Italian researchers published online November 25 in the Journal of the National Cancer Institute.

In this first direct and fully reported survival comparison of systematic pelvic lymphadenectomy and no lymphadenectomy after conventional surgery in patients with stage I endometrial carcinoma, no differences were seen in survival.

The 5-year disease-free survival rates were 81% among patients who underwent lymphadenectomy and 81.7% among patients who did not undergo lymphadenectomy. Similarly, overall survival rates were 85.9% in the lymphadenectomy group and 90.0% in the no-lymphadenectomy group. The median time to relapse was similar in both groups: 14 months in the lymphadenectomy group and 13 months in the no-lymphadenectomy group.

However, although there was no survival benefit, the authors note that lymphadenectomy is still important in determining prognosis and tailoring adjuvant therapies.

The findings from this study are consistent with those from an earlier randomized controlled trial that found no survival benefit associated with pelvic lymphadenectomy in early-stage endometrial cancer (Gynecol Oncol. 2006:101:S21–S22), according to an accompanying editorial.

"Lymphadenectomy does not appear to improve overall survival," lead author Pierluigi Benedetti Panici, MD, chair of the Department of Obstetrics and Gynecology at La Sapienza University, in Rome, Italy, told Medscape Oncology. "The study conclusion is that lymphadenectomy maintains its role for staging."

"This is particularly important because patients who are not completely 'staged' are addressed to adjuvant treatment," Dr. Panici added. "As a result of overtreatment — usually with radiotherapy — women suffer from long-term side effects."

Endometrial cancer care is rapidly evolving toward more personalized treatment recommendations, improving outcome and minimizing toxicity and cost, write Christine Walsh, MD, and Beth Karlan, MD, from the Cedars-Sinai Medical Center, in Los Angeles, California. But they also question whether these new findings "obviate the need for lymph-node assessment in early-stage endometrial cancer."

The answer to that question comes down, in part, to one's personal philosophy, the editorialists write. "We have level I evidence demonstrating that neither pelvic lymphadenectomy nor adjuvant radiation therapy confers any survival benefit in early-stage endometrial cancer. These results bust the myth that is based on previous retrospective studies, that lymphadenectomy, in and of itself, provides therapeutic benefit and survival advantage in endometrial cancer."

"Yet, this trial continues to support the notion that lymphadenectomy can provide important prognostic information and can help guide adjuvant treatment recommendations," they conclude.

No Differences Noted in Survival

Pelvic lymph nodes are the most common site of extrauterine tumor spread in early-stage endometrial cancer, but to date, definitive results from well-designed randomized trials comparing outcomes of pelvic lymphadenectomy with standard hysterectomy and bilateral adnexectomy alone have not been forthcoming. In this study, Dr. Panici and colleagues conducted a randomized controlled trial in which women with stage I endometrial cancer were assigned to have a standard hysterectomy and ovary removal with or without lymphadenectomy.

The authors randomized 514 patients with preoperative stage I endometrial carcinoma to undergo pelvic systematic lymphadenectomy (n = 264) or no lymphadenectomy (n = 250). Adjuvant therapy could be administered after surgery at the discretion of the treating physician.

The primary outcome was overall survival, defined as the time from randomization to death from any cause, and secondary end points were disease-free survival and surgical morbidity.

In the lymphadenectomy group, the overall median number of lymph nodes removed was 30 (interquartile range, 22 - 42), whereas none were removed in the no-lymphadenectomy group (P < .001). At a median follow-up of 49 months, 67 patients (13%) experienced a recurrence of endometrial cancer. Of these patients, 34 (12.9%) were in the lymphadenectomy group and 33 (13.2%) were in the no-lymphadenectomy group. During this time period, there were 53 deaths: 42 (8.2%) from endometrial cancer and 11 (2.1%) from other causes, without evidence of relapse.

The sites of first disease recurrences were similar between the 2 patient groups.

Sites of Disease Recurrence

Recurrence site	Lymphadenectomy group, n (%)	No-lymphadenectomy group, n (%)
No recurrence	231 (87.5)	217 (86.8)
Lung	8 (3)	8 (3.2)
Intraperitoneum	8 (3)	7 (2.8)
Vagina	7 (2.6)	6 (2.4)
Lymph node	4 (1.5)	4 (1.6)
Bone	4 (1.5)	3 (1.2)
Liver	2 (0.7)	3 (1.2)
Missing data	3 (1.1)	3 (1.2)

The researchers also observed a statistically significantly higher rate of early- and late-postoperative complications in patients who had undergone pelvic systematic lymphadenectomy (81 vs. 34 patients).

However, surgical staging of the disease was improved with the systematic use of lymphadenectomy, and statistically significantly more patients with lymph-node metastases were found in the lymphadenectomy group than in the no-lymphadenectomy group (13.3% vs 3.2%; difference, 10.1%)

"Pelvic systematic lymphadenectomy did not change the natural history of the disease, as can be inferred from the pattern of disease recurrence, which was similar between the 2 groups," write the authors. "However, pelvic lymphadenectomy did allow for an accurate prognosis on the basis of a pathological lymph-node assessment and, in our trial, provided for approximately 10% of the upstaging to surgical stage IIIC."

Therefore, they conclude, "lymphadenectomy maintained its importance in determining a patient's prognosis and in tailoring adjuvant therapies."

The study was partially funded by grants from Università di Roma La Sapienza and the Mario Negri Institute, in Milan, Italy.

NO USE OF ERLOTINIB IN GLIOMAS

Erlotinib Does Not Improve Survival in Glioblastoma Multiforme

NEW YORK (Reuters Health) Nov 24 - Erlotinib added to temozolomide and radiation therapy does not improve survival in patients with glioblastoma multiforme (GBM), according to a report in the Journal of Clinical Oncology, published October 27th ahead of print.

"Our trial found no additional benefit for erlotinib when combined with radiation therapy and temozolomide," Dr. Paul D. Brown told Reuters Health. "This result is similar to other studies that have not found epidermal growth factor receptor (EGFR) inhibitors (such as erlotinib) to be beneficial in the treatment of patients with newly diagnosed glioblastoma."

Dr. Brown from the Mayo Clinic, Rochester, Minnesota, and colleagues in the North Central Cancer Treatment Group (NCCTG) study N0177 investigated the feasibility and efficacy of combining standard radiotherapy and temozolomide with erlotinib in the treatment of newly diagnosed GBM.

The median progression-free survival was 7.2 months, and the median overall survival was 15.3 months, the authors report.

These results did not differ significantly from prior trials that combined radiotherapy with temozolomide without erlotinib.

"Despite compelling laboratory evidence that the EGFR pathway is key to glioma cell growth in many tumors, rigorous clinical trials are necessary to define the true benefit for patients," Dr. Brown said. "To further improve on temozolomide and radiotherapy in the treatment of patients with newly diagnosed GBM, future trials are needed such as those the Mayo Clinic and NCCTG are developing, targeting other signaling pathways or multiple different pathways."

Trials ongoing or under development will explore the efficacy of adding temsirolimus, everolimus, vorinostat, dasatinib, bevacizumab, and other agents to the basic radiotherapy-temozolomide regimen, Dr. Brown said.

J Clin Oncol 2008.

SMALL INTESTINAL CANCER AND FAT

Saturated Fat Tied to Small Intestine Cancers

NEW YORK (Reuters Health) Nov 21 - Diets high in saturated fat appear to increase the risk of small intestine carcinoid tumors, according to a report in the November 15th issue of Cancer Research.

"Identifying modifiable risk factors for cancer of the small intestine is important not only because the incidence of this cancer is on the rise, but it may enable us to further understand other gastrointestinal malignancies," lead author Dr. Amanda J. Cross, from the National Cancer Institute, Rockville, Maryland, said in a statement.

Findings from several studies have linked consumption of red and processed meats with colon cancer, but the association with small intestine cancer has received relatively little attention and has not been examined in a prospective study.

Using data from the NIH-AARP Diet and Health Study, the research team examined dietary associations with small intestine cancer in half a million men and women. Food frequency questionnaires were used to gauge meat and fat intake and the subjects were followed for up to 8 years for cancer.

During follow-up, 60 patients developed adenocarcinomas and 80 developed carcinoid tumors.

No statistically significant association between red or processed meat intake and small intestine malignancies was seen, the authors report.

Saturated fat intake, on the other hand, was positively associated with the development of carcinoid tumors. Relative to the lowest tertile of intake, the highest tertile conferred a 3.18-fold increased risk of carcinoid tumors.

"The associations identified in this study should be considered exploratory and need to be further investigated in a study with a larger number of cases by pooling existing studies with relevant data," the authors conclude.

Cancer Res 2008;68:9274-9279.

LET ME BE A DEPRESSIVE CENTENARIAN

Depression in Centenarians Often Unrecognized

NEW YORK (Reuters Health) Nov 24 - Although people over 100 years of age appear to be as prone to depression as younger individuals, only about a third of those affected are diagnosed, investigators reported today at the annual scientific meeting of the Gerontological Society of America in National Harbor, Maryland.

The findings come from the Georgia Centenarian Study, "the first population-based study of centenarians in the United States," lead researcher Dr. Adam Davey, a developmental psychologist from Temple University in Philadelphia, told Reuters Health.

"The overarching aim of this study is to understand what it is really like to be 100," the researcher added. "To get a realistic sense, we set out to identify all individuals who had reached 100 years of age in 44 counties of Northeast Georgia."

Based on responses on the 15-item Geriatric Depression Scale Short form, 27% of the 244 participants had clinically significant depressive symptoms, but only 8.2% were currently diagnosed with depression. The majority of those affected (94%) had a history of depression.

These results are "hardly surprising," said Dr. Davey, given the high levels of cognitive and sensory impairment and disability, as well as loss of family and friends, that centenarians must deal with.

"On the other hand, these findings stand out from previous research," he added, noting that earlier estimates for older adults in the US have suggested "rates of clinically significant depressive symptoms from 8% to 16%, and rates of diagnosis of major depression ranging from 1% to 3%."

As yet, it is unclear whether or not centenarians with depression are less likely than younger people to be diagnosed.

"Depression is a highly treatable illness," Dr. Davey pointed out, "but it may not always make the top of the list of priorities for physicians working with exceptional survivors." Moreover, diagnosis may be more difficult because "older adults in general may be less likely to present with symptoms of depression."

More detailed understanding of the efficacy of various approaches to the diagnosis and treatment of depression among the oldest old is an important topic for future research.

Meanwhile, "physicians should be sensitive to the apparently high rates in this very special population," Dr. Davey concluded.

ACTOS BETTER THAN AVANDIA

Older Patients Face Higher Mortality, CHF Hospitalizations With Rosiglitazone Over Pioglitazone

November 25, 2008 (Boston, Massachusetts) — Older diabetic patients treated with rosiglitazone (Avandia, GlaxoSmithKline) are at higher risk of dying or developing heart failure than patients treated with pioglitazone (Actos, Takeda Pharmaceuticals), a new analysis of Medicare beneficiaries suggests [1]. The observational study--the largest of its kind to date--appears in the November 24, 2008 issue of the Archives of Internal Medicine and is likely to fan the ongoing controversy over the adverse-effect profile of rosiglitazone as compared with other drugs in the thiazolidinedione (TZD) class.

Dr Wolfgang C Winkelmayer (Brigham and Women's Hospital, Boston, MA), lead author on the study, told heartwire that while the analysis was observational and retrospective, patients and physicians should nonetheless consider the findings on top of previous research in making decisions about treatment. As previously reported by heartwire, a number of meta-analyses published in the past year and a half have pointed to an increased risk of MI and/or cardiovascular death with rosiglitazone.

For their study, Winkelmayer and colleagues looked at more than 28 000 diabetic patients over age 65 and followed them for a total of 29 060 person-years. The analysis was restricted to patients who stayed on the drug they'd initially been prescribed, without switching over to another agent. Over the study period--January 1, 2000 to December 31, 2005--1869 patients died.

In the study's primary analysis, which assumed that patients were exposed to the drug for just 60 days after the date of their most recently filled prescription (and adjusted for patient characteristics), diabetic patients initially treated with rosiglitazone had a 15% higher mortality rate than patients on pioglitazone. Rates of first hospitalization for congestive heart failure--a known side effect of TZDs--were 13% higher in the rosiglitazone group than in the pioglitazone group. In contrast to recent studies pointing to a risk of ischemic events with rosiglitazone, rates of MI and stroke were no different between the groups.

In a secondary analysis, which assumed patients to be exposed on a constant basis to either drug, the mortality findings for rosiglitazone were, in the authors' words, "less pronounced" for both all-cause mortality (8% higher), and time to first hospitalization for heart failure (11% higher).

Making Sense of Events

In an interview with heartwire, Winkelmayer explained that the secondary analysis (the constant-exposure analysis) most closely approximates an "intention-to-treat" analysis in a randomized controlled trial, but the primary analysis in this study (the as-treated analysis) is closer to that of drug-safety research. "In drug-safety research, you actually want to know whether a patient continues to take the drug and whether they cross over, because you want to be more certain that you can attribute an outcome to the correct exposure," he explained. "You're more likely to pick up any safety problems."

But more important, he notes, "The flavor of the finding is the same whether you use one approach or the other approach. In both cases, mortality was elevated, and, in both cases, hospitalization for heart failure was elevated. So there's no discussion of whether there is a risk or not, it was just the magnitude that was different."

Winkelmayer added that he was surprised not to see an increased risk of stroke or MI in the rosiglitazone group--an increased risk of ischemic events was seen in last year's meta-analyses of randomized clinical trials. But he pointed out that, in this study, average patient age was 76, much older than that of patients included in the randomized trials. As such, patients in this Medicare cohort may have actually died from MI or stroke, meaning that their events would not have been recorded in the Medicare records, and any difference between the two drug groups may not have been adequately captured.

Decision-Making in Diabetics

Winkelmayer would not comment on whether he thought the totality of data supports much stricter warnings on rosiglitazone's labeling or even its withdrawal from the market. Such decisions are up to policy makers, he emphasized.

"All I can say, very carefully, cautiously, is that our study provides yet another piece of evidence from another angle that is very much compatible with the increased risk that was found with rosiglitazone in the very high-quality meta-analyses of last year and which was absent in another high-quality meta-analysis for pioglitazone," he said. "This provides another piece of evidence: after this we can see things a little bit more clearly. But it is up to policy makers to decide when the picture is clear enough to draw any conclusions with regard to policy action."

But Winkelmayer believes the results, despite being nonrandomized, are powerful enough to be considered by doctors and their patients. Indeed, he points out, patient characteristics in the study were so closely matched at baseline that they actually resemble those of a randomized clinical trial--selection bias was likely limited, he suggested, since both drugs appeared on the market within months of each other and at the time were viewed as more or less equivalent. "The main driver of whether a patient was put on one drug or the other was probably practitioner preference, likely based on which drug rep came through the door last," he said.

As such, he concluded to heartwire, "Patients and their providers can make their own decisions. Some evidence was available before now that there might be a difference between these drugs; this study reinforces that impression. People who are considering glitazone therapy should have a good look both at the meta-analyses, as well as this current paper, and use it as the basis for the treatment decision."

Dr Steven Nissen (Cleveland Clinic, OH), a coauthor on the first meta-analysis to really galvanize the rosiglitazone safety debate, agreed to comment on the current study for heartwire.

"These findings are consistent with other observational studies and our two meta-analyses of cardiovascular outcomes, one with pioglitazone and the other with rosiglitazone," Nissen said. "There is no reason to expect that these differences are limited to older patients. . . . There is clearly a consensus that, if a TZD is prescribed, pioglitazone is strongly preferred over rosiglitazone."

Nissen also pointed to a "consensus algorithm" from the American Diabetes Association and the European Association for the Study of Diabetes on the initiation and adjustment of therapy for hyperglycemia [2]. In it, consensus group members "unanimously advised against using rosiglitazone," the document reads.

The consensus document was released last month.

Also contacted by heartwire, a spokesperson for GlaxoSmithKline emphasized that the latest study was nonrandomized and observational, and not the "gold-standard" randomized clinical trial. In a statement provided to heartwire, spokesperson Jeff McLaughlin said that the company "strongly supports the safety and efficacy of Avandia based on extensive clinical-trial experience and widespread postmarketing use. This new study is inconsistent with evidence from randomized clinical trials and has significant limitations."

Importantly, he noted, the primary outcome in this observational analysis is all-cause mortality, yet the ongoing long-term randomized clinical trial RECORD has shown no statistically significant differences between the rosiglitazone-treated patients and the control group regarding death from cardiovascular causes or any cause. "The results of this observational study for both all-cause mortality and cardiovascular outcomes may be biased due to imbalances in comorbid conditions--cardiovascular disease, chronic obstructive pulmonary disease, and malignancies--between the two treatment groups," the statement reads. "Final long-term data from ongoing cardiovascular outcome studies [including RECORD and BARI2D] should be available within a year and should be taken into consideration before final conclusions are reached about safety and effectiveness of Avandia."

ALVEOLAR SOFT PART SARCOMA

Alveolar soft part sarcoma

Alveolar soft part sarcoma was first described in 1952 by Christopherson, Foote, and Stewart as a soft tissue sarcoma with unique clinical and pathological features.^[1] The name was derived from its microscopic appearance. Alveolar soft part sarcoma is a high-grade malignant tumor comprising 0.5% to 1% of all soft tissue sarcomas in adults and 0.8% to 1.8% of those in children.^[2,3]

Alveolar soft part sarcoma most commonly presents between the ages of 10 and 35 years, with women being diagnosed on the average at 20 to 22 years and men at 27 to 30 years. It has been documented in children as young as 2 years of age.^[4] Alveolar soft part sarcoma is overall more common in females; however, after the age of 30, men are more frequently diagnosed. The most common site of origin is within the lower extremity, particularly the fascial planes or skeletal muscle of the anterior thigh. In children, the head and neck region is a more common site of origin, with the orbit and tongue as predominant locations.1 The usual presentation is that of a slow-growing, painless mass within the lower extremity without other symptoms. Possibly because of this insidious onset, the tumor size is usually quite large and metastasis is detected in approximately 20% to 33% of patients at the time of initial diagnosis.2,4 The most common locations of metastasis are lungs, bone, and brain, in that order. Therefore, whole-body bone scintigraphy and chest CT are required for staging. Bones may be affected by direct or metastatic spread; however, distant bony metastasis is much more common, and local bony extension is reported as relatively rare.^[5] Many cases of metastasis may be detected as late as 10 years after the initial diagnosis.

Macroscopically, the tumor is well circumscribed and usually measures 3 to 6 cm. Tumors up to 20 cm have been reported.^[6] The larger tumors often exhibit hemorrhage and necrosis. Alveolar soft part sarcoma has a characteristic microscopic appearance. Nests of large granular cells surrounded by capillaries are seen in a pattern resembling alveoli. These cells contain periodic acid-Schiff (PAS)-positive and diastase-resistant crystals, which helps make the diagnosis a certainty.^[2] The histogenesis of ASPS is still unclear. Muscle-associated proteins are often found in immunohistochemical studies, suggesting a myogenic origin; however, there is conflicting data regarding these studies. This remains an area of continued research.

Radiographic findings, though not specific, can, when combined with an adequate history, usually lead to the correct diagnosis. Ultrasound will typically show a hypoechoic, hypervascular mass. CT may reveal a well-circumscribed mass with marked contrast enhancement. MRI is the most sensitive and specific imaging modality. Typical findings include isointensity to a slight increase in intensity on T1W images, increased signal with T2W sequences, and strong enhancement. Multiple large flow voids consistent with peritumoral vessels may also be appreciated.^[2] Angiography shows a highly vascular lesion with enlarged feeding arteries, arteriovenous shunts, and delayed washout. As mentioned previously, a CT chest and whole-body bone scan are performed for staging. These studies will show a typical appearance for metastatic disease if present.

Despite its slow growth, ASPS has a grave prognosis. Several studies report a 5-year survival rate of approximately 60% with a range of 45% to 88% depending on the selection of the patients. Two of these studies reported a median survival time of only 6 to 7 years.^[2,6] The size of the tumor and the presence of metastasis have been implicated as the main prognostic factors. There is some evidence to suggest that age is also a significant prognostic factor, with children exhibiting a much longer survival time than those diagnosed at an older age.^[7] The initial treatment of ASPS is radical excision with negative surgical margins. Local recurrence is uncommon if complete excision is performed. The metastatic disease is the most difficult aspect of treatment. If it is possible, the resection of pulmonary metastatic lesions can significantly increase survival time. Chemotherapy and radiation have shown inconsistent results and may be used successfully with individual patients.

GEFITINIB AS EFFECTIVE AS DOCETAXEL

Gefitinib as Effective as Docetaxel in Non-Small-Cell Lung Cancer

November 25, 2008 — A large phase 3 trial has shown that the oral drug gefitinib (Iressa, AstraZeneca) is just as effective as but has fewer adverse effects than intravenous docetaxel (Taxotere, Sanofi Aventis) when used in the second-line treatment of patients with non-small-cell lung cancer (NSCLC).

The oral drug presents an "alternative treatment option" and represents an "important shift in the treatment paradigm for this disease," say the authors of a study published in the November 22 issue of the Lancet.

"Based on our findings, I'm hopeful that gefitinib can return as a treatment for lung cancer is the United States," said lead author Edward Kim, MD, assistant professor of thoracic head and neck medical oncology at the University of Texas MD Anderson Cancer Center, in Houston, in a statement.

Gefitinib fell out of use in the United States in 2005 after a large study showed no significant improvement in survival, compared with placebo, in patients with NSCLC. The drug continues to be available for patients who were already taking it and were judged to be doing well on it, but the US Food and Drug Association (FDA) ruled that no new patients were to be given the drug.

However, gefitinib continued to be used elsewhere in the world, and the current study enrolled patients from 24 countries (Europe, Asia, and the Americas, but not the United States). Known as INTEREST (Iressa in NSCLC Trial Evaluating REsponse and Survival vs Taxotere), the study was mandated by the FDA and sponsored by AstraZeneca.

A total of 1466 patients were enrolled, and 1433 were evaluable. All had locally advanced or metastatic disease and had previously been treated with at least 1 platinum-containing regimen. Patients were randomized to receive either gefitinib 250 mg/day every day, or docetaxel 75 mg/m² in a 1-hour infusion every 3 weeks.

The results were similar for the 2 groups, the researchers report. Median overall survival was 7.6 months in the gefitinib group and 8.0 months in the docetaxel group, and 1-year survival was 32% and 34%, respectively. Median progression-free survival was 2.2 months with gefitinib and 2.7 months with docetaxel, and progression-free survival at 6 months was 19% vs 18%, respectively. Objective response rates were also similar: 9.1% with gefitinib and 7.6% with docetaxel.

However, gefitinib was associated with lower rates of treatment-related adverse events than docetaxel, and the 2 drugs showed a different pattern of adverse effects. The most common adverse effects were rash or acne and diarrhea with gefitinib, and hematological toxicity, asthenic disorders, and alopecia with docetaxel.

Treatment-Related Adverse Events

Adverse Events	Gefitinib	Docetaxel
Overall	72%	82%
Serious	4%	18%
Leading to discontinuation of therapy	4%	11%
Grade 3 or 4	9%	41%
Leading to death	1%	2%

In addition, significantly more patients on gefitinib had a sustained and clinically relevant improvement in quality of life, as assessed by Functional Assessment of Cancer Therapy-Lung questionnaires.

"The clinical management of advanced NSCLC remains challenging, but an oral agent that has similar efficacy, has a more favorable tolerability profile, and results in a better quality of life than intravenous chemotherapy is an important shift in the treatment paradigm of this disease and presents an alternative option for patients," Dr. Kim and colleagues conclude.

Previous Trial Involved Predominantly Refractory Patients

In their paper, Dr. Kim and colleagues refer back to the study that prompted the FDA to restrict the use of gefitinib. That study, known as ISEL (Iressa Survival Evaluation in Lung Cancer), involved 1692 patients randomized to gefitinib or placebo (Lancet 2005;366:1527-1537). It showed no significant improvement in survival from the drug (median overall survival, 5.6 months with gefitinib vs 5.1 months with placebo).

However, Dr. Kim and colleagues point out that most of the participants (90%) in that study were refractory patients unsuitable for further chemotherapy, and these patients are known to have a poor prognosis. This may partly explain the lack of a significant effect on survival, they suggest. In contrast, the current study had only 58% of participants in this category.

Previous Findings Overturns

The current study overturns several previous findings related to biomarkers and patient characteristics influencing outcomes.

Gefitinib acts as an inhibitor of epidermal growth-factor receptor (EGFR), and previous studies with other agents in this class have suggested that a better response to these drugs is seen in patients whose tumors have high EGFR gene-copy numbers. However, the current study did not find this to be the case.

An unexpected finding from the INTEREST study is that patients with high EBFR gene-copy numbers showed no difference in survival between gefitinib and docetaxel, Dr. Kim and colleagues report.

In addition, clinical factors, such as never having smoked, being female, being of Asian origin, and having adenocarcinoma histology, have also been reported to predict a better response to EGFR inhibitors, and also to predict a better overall patient outcome. Another unexpected finding from the INTEREST trial is that patients with these characteristics had longer survival in both the gefitinib and the docetaxel groups, the researchers note. This contrasts with previous findings suggesting that docetaxel produces similar survival in all patients.

"The implication is that these groupings are prognostic factors unrelated to treatment or nonspecific factors that predict increased sensitivity to quite different interventions," comment the authors of an accompanying editorial, Michael Cullen, MD, and Nicholas Thatcher, FRCP, from the Birmingham University Hospital Cancer Centre in the United Kingdom. But the finding that patients with high EGFR gene-copy numbers do not have a better response to gefitinib is "even more disconcerting," say the editorialists.

One of the important lessons to learn from this experience, they write, is "not to jump to conclusions about specific predictive factors only because they fit the scientific foundations that underpin the design and development of new targeted agents with the fashionable goal of tailoring treatment to the individual patient and the tumor's biology."

Dr. Kim and several coauthors report having served on the advisory board and receiving consultancy fees from AstraZeneca as well as several other companies; 4 of the coauthors are employees of AstraZeneca. Both of the editorialists report having received honoraria from AstraZeneca.

FAMILY HISTORY INCREASES BREAST CANCER RISK

AACR FCPR 2008: Family History Increases Breast Cancer Risk

November 26. 2008 — Women with a significant family history of breast cancer, even if they are negative for the BRCA1 and BRAC2 mutations, remain at increased risk of developing the disease. Having 2 or more cases of breast cancer among close relatives younger than 50 years or 3 cases among close relatives of any age is associated with a risk for breast cancer that is 4 times greater than that seen in the general population.

The data, which were presented at the Seventh Annual American Association for Cancer Research International Conference on Frontiers in Cancer Prevention Research, held in Washington, DC, show that women with a strong family history who lack BRCA1 and BRCA2 mutations are still much more at risk than average women.

"All women are at risk for breast cancer and about 10% will eventually develop the disease," said lead author Steven Narod, MD, who holds the Canada Research Chair in breast cancer at the University of Toronto and Women's College Research Institute, in Ontario. "We need to look at screening those who are at the highest risk. When the BRCA mutation was identified, it led to a genetic test."

Relatively few women carry mutations for BRCA1/2, but it increases the risk for breast cancer to 80%, Dr. Narod pointed out. "These women tend to have a family history or young onset, so they go and get tested . . . . About 1 in 5 of these women will be told that they carry a mutation. but what about the thousands who have a negative test and yet have a strong family history of breast cancer?"

To answer that question, Dr. Narod and colleagues conducted a prospective study in which they estimated risk for women with a family history of breast cancer who had tested negative for a BRCA1 or BRCA2 mutation. They identified 1492 women from 365 families who met the criteria of either having 2 or more breast cancers in members younger than 50 years or having 3 breast cancer in members of any age.

The researchers collected follow-up information on cancer status in all first-degree relatives of breast cancer cases. They calculated the standardized incidence ratios (SIRs) for breast cancer by dividing the observed number of breast cancers by the expected number, based on available rates in provincial cancer registries.

Risk of Disease is 4-Fold

The 1492 first-degree relatives of breast cancer cases contributed 9109 person-years of follow-up. Compared with control rates, the number of cancer cases was much higher among women with a strong family history. A total of 65 women developed breast cancer, although the expected number was 15.2 (SIR, 4.3). The highest relative risk was for women younger than 40 years, where the increased risk was nearly 15 times higher than the average risk (SIR, 14.9). The SIR decreased with advancing age, but the absolute risk was higher for women between 50 and 70 years (1% per year) than for those between the ages of 30 and 50 years (0.4% per year).

No elevated risk for ovarian or any other type of cancer was observed in this cohort.

The women with strong family histories had a 40% risk for breast cancer, and the findings suggest that other genetic mutations could play a role in the disease. Although these findings do not call for prophylactic surgery, Dr. Narod suggests that this population consider undergoing magnetic resonance imaging (MRI) screening. "The American Cancer Society recommends MRI for women with a 20% to 25% risk," he said. "It is much more sensitive than mammography."

Dr. Narod also points out that women with strong family histories might be candidates for tamoxifen chemoprevention. "We do need to confirm this in other studies, and we need to pinpoint what is putting these women at high risk."

These studies help us to identify patients at risk for cancer, commented Steven M. Dubinett, MD, director of the Lung Cancer Research Program at the UCLA Jonsson Comprehensive Cancer Center, in Los Angeles, California, and moderator of a press briefing in which these data were presented. "The utilization of genetic studies helps us move forward with defining risk in these populations."

American Association for Cancer Research's Seventh Annual International Conference on Frontiers in Cancer Prevention Research: Abstract B7. Presented November 17, 2008.

MOTESANIB IN LUNG CANCER

Phase 3 Trial of Motesanib in Non-Small-Cell Lung Cancer Suspended

November 21, 2008 — A phase 3 clinical trial of non-small-cell lung cancer (NSCLC) patients has been temporarily suspended after a planned safety review showed more deaths with the investigational drug than with placebo.

The drug is motesanib (also known as AMG 706), an oral angiogenesis inhibitor that acts by targeting vascular endothelial growth-factor receptor (VEGFR)1, VEGFR2, and VEGFR3. It is being developed by Amgen, Takeda, and Millennium, and the companies announced the finding in a joint press release.

This is the second such compound that has run into safety problems while being investigated in NSCLC patients.

Immediate Discontinuation in Squamous NSCLC

The company-sponsored trial, known as MONET1, was evaluating motesanib in combination with paclitaxel and carboplatin for the first-line treatment of advanced NSCLC. It included patients with both squamous and nonsquamous type NSCLC, and the trial was almost fully enrolled (1100 of a planned total of 1240 patients).

The safety-data review involved 600 patients and was carried out by an independent Data Monitoring Committee. The review found higher early mortality rates in the motesanib group than in the placebo group, the companies announced. In addition, there was a higher incidence of hemoptysis with motesanib than with placebo among patients with squamous NSCLC. Because of this, the Data Monitoring Committee recommended immediate discontinuation of the drug among this patient population. However, the committee did not recommend discontinuation of the drug in patients with nonsquamous NSCLC (about two thirds of the patients enrolled in the trial).

"While we are disappointed in this outcome, it is consistent with data seen with some other anti-VEGF therapies and appears to constitute a class effect of these types of agents," commented Roger Perlmutter, MD, PhD, executive vice president of research and development at Amgen.

Earlier this year, safety concerns stopped a similar trial with a very similar investigational product, cediranib (Recentin, formerly AZD2171), a highly potent oral inhibitor of VEGFR1, 2, and 3, under development by AstraZeneca. This drug is also being investigated in colorectal cancer. The trial that was halted was a phase 2/3 study investigating the addition of cediranib to a combination of carboplatin and paclitaxel in the first-line treatment of NSCLC. An interim analysis suggested an imbalance of toxicity in the cediranib group, as previously reported by Medscape Oncology.

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CAN BREAST CANCER SPONTANEOUSLY REGRESS?

Mammography Study Suggests Some Breast Cancer May Spontaneously Regress

November 25, 2008 – A mammography study from Norway has come up with the controversial proposal that one fifth of breast cancer detected on screening may spontaneously regress. But there is no easy way to verify whether this is the case, say experts.

The study was published in the November 24 issue of the Archives of Internal Medicine. It found that the cumulative incidence of invasive breast cancer in a cohort of women, aged 50 to 64 years, who received 3 mammograms over 6 years was 22% higher than in a control group of age-matched women who received only 1 mammogram at the end of a 6-year period.

In their review of possible explanations for the difference in the breast cancer rates between the 2 groups — which had similar risk factors for breast cancer — the researchers write that the "natural course for some screen-detected breast cancers may be to spontaneously regress."

"I anticipate that many clinicians will react negatively to the possibility of spontaneous regression, said coauthor Jan Maehlen, MD, PhD, professor of pathology at the Ulleval University Hospital, in Oslo, Norway, in an interview with Medscape Oncology.

"We believe that there are 'pseudo' cancers in this population [of mammography-screened women], and we suggest that most of these pseudo cancers regress," he added.

What clinicians should do with such pseudo breast cancers is not known, admitted Dr. Maehlen. "We have presented [on the topic] before and had clinicians say angrily: 'Why are you presenting these data? We cannot tell which invasive cancers are a result of overdiagnosis and which ones will progress'."

However, Dr. Maehlen believes the "first thing we have to accept" is that some detected cancer will not cause symptoms and some will regress. He cites pediatric neuroblastomas as an example of tumors that spontaneously regress.

The authors of an accompanying editorial say that the study's spontaneous regression hypothesis is "difficult to rule out" but impossible to verify without a randomized controlled trial that would leave some participants untreated. The editorialists, Robert M. Kaplan, PhD, from the University of California, Los Angeles, and Franz Porzsolt, MD, PhD, from Clinical Economics, University of Ulm, in Germany, credit the study authors with using "a clever study design in an attempt to estimate the value of [mammography] screening."

"Despite the appeal of early detection of breast cancer, uncertainty about the value of mammography continues," observe the editorialists.

Study Details

In addition to Dr. Maehlen, Per-Henrik Zahl, MD, PhD, from the Norwegian Institute of Public Health, in Oslo, and Gilbert Welch, MD, MPH, from the Dartmouth Institute of Health Policy and Clinical Practice, in Hanover, New Hampshire, examined breast cancer rates among 119,472 women, aged 50 to 64 years, who were all invited to receive 3 biennial screening mammograms between 1996 and 2001 as part of the Norwegian Breast Cancer Screening Program. The researchers compared the rate of breast cancer among this "screened" group with rates among a control group of 109,784 women, aged 50 to 64 years in 1992, who would have been invited for screening if the program had existed at that time. Cancers were tracked for 6 years using a national registry.

As anticipated, breast cancer rates were higher among screened women than among the control group. "If you screen for cancer, you will find more cancer [than is detected clinically]," commented Dr. Maehlen.

However, at the end of 6 years, all participants — those in both the screened and control groups — were invited to undergo a 1-time screening to assess breast cancer prevalence.

This is where the researchers found "something much less expected" — the fact that the rates continued to be higher in the screened group than in the control group. "Even after prevalence screening in controls, however, the cumulative incidence of invasive breast cancer remained 22% higher in the screened group," the authors write. Of every 100,000 screened women, 1909 had breast cancer during the 6-year period, compared with 1564 of every 100,000 in the control group. Screened women were more likely to have breast cancer at every age.

Why the Difference in Rates?

In search of the answer for the difference in cumulative breast cancer rates between the 2 groups — in which 1 group received 3 mammography screenings over 6 years and 1 group received only 1 screening at the end of 6 years — the researchers evaluated a range of possible explanations.

"One possibility is that the case ascertainment in the Norwegian Cancer Registry became more complete over the period. However, during the period, the registry was documented to have almost perfect (98%–99%) solid tumor ascertainment rates, and its reported breast cancer incidence among women not of screening age (ie, age 30-49 years and 70 years) was remarkably constant," write the authors.

The increased incidence in the screened group probably does not reflect any increasing sensitivity of mammography, add the study authors. "A number of factors leading to increased sensitivity over time could be hypothesized, such as the following: the interpretation skills of mammographers may be increasing with practice, prior mammograms may be increasingly available for comparison, and the technology itself may be improving. The available data, however, suggest that the sensitivity is stable," they note.

The authors also consider and dismiss explanations about possible temporal differences between the 2 groups and possible differences in uses of hormone replacement therapy.

The authors settle on the explanation of spontaneous regression. "Because the cumulative incidence among controls never reached that of the screened group, it appears that some breast cancers detected by repeated mammographic screening would not persist to be detectable by a single mammogram at the end of 6 years. This raises the possibility that the natural course of some screen-detected invasive breast cancers is to spontaneously regress," the study authors write. They also note that other studies have suggested the same, including a Canadian trial in which the excess incidence of detected breast cancer was also 22% in a screened vs unscreened cohort study model (Ann Intern Med. 2002;137:305-312).

Very few case reports support the concept of spontaneous regression. "[The lack of case reports] may reflect the fact that these cancers are rarely allowed to follow their natural course," explain the study authors.

A randomized placebo controlled trial is unlikely to answer the questions raised by this new study, note the editorialists. "At present, most would consider a trial unethical," they write.

The United States is not likely to be a source of new comparative studies on this subject because mammography is now common. However, other countries are just phasing in national programs and could be provide further nonexperimental comparisons, say the editorialists.

This study was supported in part by a Research Enhancement Award from the Department of Veterans Affairs.

Arch Intern Med. 2008;168:2311-2316, 2302-2303.

GESTATIONAL HYPERTENSION AND TESTICULAR CANCER

Gestational Hypertension May Reduce Testicular Cancer Risk

NEW YORK (Reuters Health) Nov 21 - Males born to mothers with severe gestational hypertension appear to be at reduced risk of germ cell testicular cancer, Swedish and Italian investigators report in the November 1st issue of Cancer Research.

"Our findings suggest that the altered levels of pregnancy hormones that seem to occur in gestational hypertensive disorders are a factor in the causation of testicular cancer," Dr. Andreas Pettersson told Reuters Health.

Because altered levels of pregnancy hormones are theorized to initiate testicular cancer in the male fetus, Dr. Pettersson of the Karolinska Institute, Stockholm, and colleagues analyzed exposure to gestational hypertension in 293 patients diagnosed with testicular cancer at age 15 or younger and in 861 controls.

Subjects exposed to severe gestational hypertension were at markedly lower risk of testicular cancer (odds ratio 0.29) compared to those in whom there was no hypertension exposure. However, subjects who were exposed to mild gestational hypertension were at increased risk (odds ratio, 1.62).

"The mechanism behind the association between pregnancy hypertension and testicular cancer is unclear," the investigators observe, "but our findings may reflect a potentially protective effect of the altered pregnancy hormones such as human chorionic gonadotropin that occur in severe gestational hypertension and preeclampsia."

"Hopefully," added Dr. Pettersson, "a better understanding of the mechanisms that cause testicular cancer can help us identify and eradicate important risk factors, and thereby stop and reverse the increase in testicular cancer occurrence."

IMATINIB RESISTANT GIST

J Clin Oncol. 2008 Nov 20;26(33):5352-5359. Epub 2008 Oct 27.

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Primary and Secondary Kinase Genotypes Correlate With the Biological and Clinical Activity of Sunitinib in Imatinib-Resistant Gastrointestinal Stromal Tumor.

Heinrich MC, Maki RG, Corless CL, Antonescu CR, Harlow A, Griffith D, Town A, McKinley A, Ou WB, Fletcher JA, Fletcher CD, Huang X, Cohen DP, Baum CM, Demetri GD.

Division of Hematology/Oncology, Departments of Medicine and Cell and Developmental Biology, Portland Veterans Affairs Medical Center and Oregon Health and Science University Cancer Institute, R&D-19, 3710 SW US Veterans Hospital Rd, Portland, OR 97239; Heinrich@ohsu.edu.

PURPOSE Most gastrointestinal stromal tumors (GISTs) harbor mutant KIT or platelet-derived growth factor receptor alpha (PDGFRA) kinases, which are imatinib targets. Sunitinib, which targets KIT, PDGFRs, and several other kinases, has demonstrated efficacy in patients with GIST after they experience imatinib failure. We evaluated the impact of primary and secondary kinase genotype on sunitinib activity. PATIENTS AND METHODS Tumor responses were assessed radiologically in a phase I/II trial of sunitinib in 97 patients with metastatic, imatinib-resistant/intolerant GIST. KIT/PDGFRA mutational status was determined for 78 patients by using tumor specimens obtained before and after prior imatinib therapy. Kinase mutants were biochemically profiled for sunitinib and imatinib sensitivity. Results Clinical benefit (partial response or stable disease for >/= 6 months) with sunitinib was observed for the three most common primary GIST genotypes: KIT exon 9 (58%), KIT exon 11 (34%), and wild-type KIT/PDGFRA (56%). Progression-free survival (PFS) was significantly longer for patients with primary KIT exon 9 mutations (P = .0005) or with a wild-type genotype (P = .0356) than for those with KIT exon 11 mutations. The same pattern was observed for overall survival (OS). PFS and OS were longer for patients with secondary KIT exon 13 or 14 mutations (which involve the KIT-adenosine triphosphate binding pocket) than for those with exon 17 or 18 mutations (which involve the KIT activation loop). Biochemical profiling studies confirmed the clinical results. CONCLUSION The clinical activity of sunitinib after imatinib failure is significantly influenced by both primary and secondary mutations in the predominant pathogenic kinases, which has implications for optimization of the treatment of patients with GIST.

GIST AND KINASE GENOTYPE

1: J Clin Oncol. 2008 Nov 20;26(33):5360-5367. Epub 2008 Oct 27.

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Correlation of Kinase Genotype and Clinical Outcome in the North American Intergroup Phase III Trial of Imatinib Mesylate for Treatment of Advanced Gastrointestinal Stromal Tumor: CALGB 150105 Study by Cancer and Leukemia Group B and Southwest Oncology Group.

Heinrich MC, Owzar K, Corless CL, Hollis D, Borden EC, Fletcher CD, Ryan CW, von Mehren M, Blanke CD, Rankin C, Benjamin RS, Bramwell VH, Demetri GD, Bertagnolli MM, Fletcher JA.

Portland VA Medical Center and Oregon Health and Science University, Division of Hematology/Oncology, 3710 SW US Veterans Hospital Road, R&D-19, Portland, OR 97239; heinrich@ohsu.edu.

PURPOSE Imatinib mesylate is standard treatment for patients who have advanced gastrointestinal stromal tumor (GIST), but not all patients benefit equally. In previous studies, GIST genotype correlated with treatment outcome and optimal imatinib dosing. PATIENTS AND METHODS We examined the relationship between kinase genotype and treatment outcome for 428 patients enrolled on the North American phase III study SWOG S0033/CALGB 150105 and treated with either 400 mg or 800 mg daily doses of imatinib. Results The presence of KIT exon 11-mutant genotype (n = 283) correlated with improved treatment outcome when compared with KIT exon 9-mutant (n = 32) and wild-type (WT; n = 67) genotypes for objective response (complete response [CR]/partial response [PR], 71.7% v 44.4% [P = .007]; and 44.6% [P = .0002], respectively); time to tumor progression (TTP; median 24.7 months v 16.7 and 12.8 months, respectively); and overall survival (OS; median 60.0 months v 38.4 and 49.0 months, respectively). The survival outcomes for patients with exon 9-mutant, exon 11-mutant or WT GIST were not affected by imatinib dose. However, there was evidence of improved response rates for patients with exon 9-mutant tumors treated with imatinib 800 mg versus 400 mg (CR/PR, 67% v 17%; P = .02). Patients who had CD117-negative GIST had similar TTP but inferior OS compared with patients who had CD117-positive disease, which suggests that patients who have CD117-negative GIST may benefit from imatinib treatment. In addition, we identified novel but rare mutations of the KIT extracellular domain (exons 8 and 9). CONCLUSION We confirmed the favorable impact of KIT exon 11 genotype when compared with KIT exon 9 and wild-type genotype for patients with advanced GIST who are treated with imatinib.

INFUSIONAL 5-FU vs CAPECITABINE

J Clin Oncol. 2008 Nov 17. [Epub ahead of print]

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Efficacy of Oxaliplatin Plus Capecitabine or Infusional Fluorouracil/Leucovorin in Patients With Metastatic Colorectal Cancer: A Pooled Analysis of Randomized Trials.

Arkenau HT, Arnold D, Cassidy J, Diaz-Rubio E, Douillard JY, Hochster H, Martoni A, Grothey A, Hinke A, Schmiegel W, Schmoll HJ, Porschen R.

Royal Marsden Hospital, London and Surrey; Beatson Oncology Centre, Glasgow, United Kingdom; Martin-Luther-University, Halle; WiSP Research Institute, Langenfeld; Ruhr University Bochum; Hospital Bremen East, Bremen, Germany; Hospital Clínico San Carlos Madrid, Spain; Centre R. Gauducheau Saint Herblain, France; New York University School of Medicine, New York, NY; S. Orsola-Malphigi Hospital Bologna, Italy; Mayo Clinic, Rochester, MN.

PURPOSE: Six randomized phase II and III trials have investigated the role of oxaliplatin (OX) in combination with capecitabine (CAP) or infusional fluorouracil (FU) in metastatic colorectal cancer. This meta-analysis compared the efficacy of CAP/OX compared with infusional FU/OX. PATIENTS AND METHODS: This analysis compared all published CAP/OX versus infusional FU/OX regimens. A total of 3,494 patients (FU, n = 1,737; CAP, n = 1,757) were analyzed for response rate (RR), progression-free (PFS), overall survival (OS), and toxicity. RESULTS: The fixed-effect pooled estimate for RR showed higher RR for FU-based regimens (Odds ratio [OR] = 0.85; 95% CI, 0.74 to 0.97; P = .02) whereas the analysis of chemotherapy-only trials, excluding the bevacizumab containing NO16966 and TREE 2 trials, led to an OR of 0.74 (95% CI, 0.60 to 0.92; P = .007). However, for PFS (hazard ratio [HR] = 1.04; 95% CI, 0.96 to 1.12; P = .17) and OS (HR = 1.04; 95% CI, 0.95 to 1.12; P = .41) all models suggested similar outcome within the range of noninferiority. Grade 3/4 toxicities (thrombocytopenia-HR = 2.07, 95% CI, 1.42 to 3.03; P < .0002; diarrhea-HR = 1.34; 95% CI, 1.08 to 1.66; P < .0009; and grade 2/3 hand-foot-syndrome [HFS]-HR = 3.54; 95% CI, 2.07 to 6.05; P < .00001) were less prominent with FU-based regimens whereas neutropenia (HR = 0.15; 95% CI, 0.11 to 0.19; P < .00001) was lower in the CAP regimens. CONCLUSION: The combination of CAP and OX resulted in lower RR, but this did not affect PFS and OS, which were similar in both treatment arms. The toxicity analysis showed the characteristic toxicity of each of the different FU schedules, with thrombocytopenia and HFS consistently more prominent in the CAP regimens.