FALLOPIAN TUBE CANCER STAGING

PRIMARY TUMOR (T)

TX: Primary tumor cannot be assessed
T0: No evidence of primary tumor
Tis:Carcinoma in situ (limited to tubal mucosa)
T1: Tumor limited to the fallopian tube(s)
T1A: Tumor limited to one tube, without penetrating the serosal surface; no ascites
T1B: Tumor limited to both tubes, without penetrating the serosal surface; no ascites
T1C: Tumor limited to one or both tubes with extension onto or through the tubal
         serosa, or with malignant cells in ascites or peritoneal washings
T2: Tumor involves one or both fallopian tubes with pelvic extension
T2A: Extension and/or metastasis to the uterus and/or ovaries
T2B: Extension to other pelvic structures
T2C: Pelvic extension with malignant cells in ascites or peritoneal washings
T3: Tumor involves one or both fallopian tubes, with peritoneal implants outside the
       pelvis
T3A: Microscopic peritoneal metastasis outside the pelvis
T3B: Macroscopic peritoneal metastasis outside the pelvis 2 cm or less in greatest
dimension
T3C: Peritoneal metastasis outside the pelvis and more than 2 cm in diameter
* FIGO no longer includes Stage 0 (Tis)
Note: Liver capsule metastasis is T3/Stage III; liver parenchymal metastasis
M1/Stage IV. Pleural effusion must have positive cytology for M1/Stage IV.

REGIONAL LYMPH NODES (N)
NX: Regional lymph nodes cannot be assessed
N0: No regional lymph node metastasis
N1: Regional lymph node metastasis

DISTANT METASTASIS (M)
M0:  No distant metastasis (no pathologic M0; use clinical M to complete stage group)
M1: Distant metastasis (excludes metastasis within the peritoneal cavity)

PATHOLOGIC STAGE GROUPING
GROUP                        T    N    M
0*                                 Tis N0 M0
I                                    T1 N0 M0
IA                                 T1a N0 M0
IB                                 T1b N0 M0
IC                                 T1c N0 M0
II                                  T2 N0 M0
IIA                               T2a N0 M0
IIB                               T2b N0 M0
IIC                               T2c N0 M0
III                                T3 N0 M0
IIIA                             T3a N0 M0
IIIB                             T3b N0 M0
IIIC                             T3c N0 M0-Any T N1 M0
IV                               Any T Any N M1
*FIGO no longer includes Stage 0 (Tis)

BEVACIZUMAB-BAD NEWS CONTINUE

February 1, 2011 — More bad news is on the horizon for bevacizumab (Avastin). Just over a month after the US Food and Drug Administration proposed withdrawing its breast cancer indication, a new study has shown that the drug might be associated with an increased risk for treatment-related death.
The meta-analysis, which appears in the February 2 issue of the Journal of the American Medical Association, found that the overall incidence of fatal adverse events with bevacizumab in combination with chemotherapy was 2.5%; the incidence was 1.7% in patients who received chemotherapy alone.
Overall, adding bevacizumab to chemotherapy or biologic therapy was associated with an increased relative risk for fatal adverse events of 1.46 (95% confidence interval [CI], 1.09 to 1.94; P = .01). However, this association varied significantly with the type of chemotherapeutic agents that were combined with bevacizumab (P = .045).
The relative risk for fatal adverse events was 3.5-fold higher among patients receiving taxanes or platinum agents; there was no increased risk when bevacizumab was used in combination with other agents.
The incidence of fatal adverse events also varied among the different types of cancers. This variation, note the authors, reflected the nature of underlying tumor biology or associated treatment. However, the relative risk for fatal adverse events specifically associated with bevacizumab did not vary significantly by tumor type.
On the basis of these results, senior author Shenhong Wu, MD, PhD, assistant professor of medicine at Stony Brook University in New York, noted that caution might be needed when prescribing bevacizumab. This includes closer patient monitoring, more careful patient selection, and a weighing of the risk/benefit ratio in all patients.
Even though the absolute risk for treatment-related mortality seems to be low, it is important for physicians and patients to recognize the risks and benefits associated with this agent, Dr. Wu and colleagues conclude.
"I think it is important for physicians to discuss this issue before the therapy," Dr. Wu told Medscape Medical News. "Further trials are needed to select patients for survival benefit and less serious side effects."
Failures and Success
Bevacizumab has had a somewhat checkered history of failures and successes. For example, as previously reported by Medscape Medical News, a phase 3 trial showed that the addition of bevacizumab to standard therapy in early breast cancer had no benefit. Another phase 3 trial did not demonstrate a benefit in early colon cancer.
On the positive side, bevacizumab appeared to extend progression-free survival in advanced colorectal cancer and recurrent glioblastoma multiforme. It has also been approved for the treatment of metastatic renal cell carcinoma, although an overall survival benefit has not yet been observed.
In an accompanying editorial, Daniel F. Hayes notes that bevacizumab studies have produced results that are inconsistent and decidedly mixed when it comes to a survival benefit.
"Why, despite the impressively solid preclinical data and the promising early clinical results, has bevacizumab not been more successful in improving overall survival?" asks Dr. Hayes, from the University of Michigan Comprehensive Cancer Center in Ann Arbor.
Boon or Bust?
The answer to that and other questions are not easily discernible, he notes, pointing out that some investigators have questioned whether progression-free or disease-free survival, as opposed to overall survival, is the best end point for large-scale cancer therapeutic trials. "The biology of anti-[vascular endothelial growth factor] therapy may make the choice of end points a critical issue," he writes.
"Careful review of response rates to bevacizumab suggest that bevacizumab works well, but only in selected patients," Dr. Hayes notes.
However, the meta-analysis shows that bevacizumab therapy is associated with a higher rate of fatal adverse events, even though it is not associated with the degree of adverse effects encountered with most chemotherapies, he points out. Considering that optimal treatment with bevacizumab might require years of frequent treatment, the higher rate of fatal adverse events could negate any survival benefits.
"Is bevacizumab a boon or a bust?" asks Dr. Hayes, andswering that "the jury is still out. Although bevacizumab has benefit, it is currently not possible to determine in whom or for how long."
Therefore, he adds, "oncologists are forced to dilute the potential effects of bevacizumab by exposing all treated patients, and society, to enormous costs and occasional life-threatening toxic effects. These unfortunate circumstances are sad for those who pay the bills — and sadder for patients with solid tumors."
Study Details
For the meta-analysis, Dr. Wu and colleagues identified 16 randomized controlled trials that comprised a total of 10,217 patients with a variety of advanced solid tumors. In all of the studies considered eligible for inclusion, bevacizumab was used in combination with chemotherapy or biologic therapy, and was compared with chemotherapy alone or biologic therapy alone.
Data on 5589 patients who received bevacizumab were available for analysis. Within this cohort, there were 148 fatal adverse events. The highest incidence was observed in a phase 2 lung cancer study (13.4%; 95% CI, 7.1% to 23.8%), and the lowest incidence was observed in a phase 3 breast cancer trial in which no events were reported.
The most common specific causes of fatal adverse events were hemorrhage (23.5%), neutropenia (12.2%), gastrointestinal tract perforation (7.1%), pulmonary embolism (5.1%), and cerebrovascular accident (5.1%).
Partial funding was provided by the Research Foundation of the State University of New York at Stony Brook. Dr. Wu reports being a speaker for Onyx, Novartis, and Pfizer; and receiving honoraria from Onyx, Pfizer, Novartis, Amgen, and Genentech. His coauthors have disclosed no relevant financial relationships.
The editorial was supported by Fashion Footwear Charitable Foundation of New York/QVC Presents Shoes on Sale and by Komen for the Cure. Dr. Hayes has disclosed stock ownership in Oncimmune LLC and Halcyon Diagnostics Inc. He has received occasional honoraria for consulting from Compendia Bioscience, Chugai Pharmaceuticals, and Biomarker Strategies. He receives research funding support from GlaxoSmithKline, Pfizer, Novartis, and Veridex (Johnson & Johnson). He has disclosed no relevant financial relationships with Genentech or Roche.
JAMA. 2011;305:487-494, 506-508. Abstract

DACTINOMYCIN BETTER THAN METHOTRAXATE IN LOW RISK TROPHOBLASTIC DISEASE?

February 1, 2011 — Cancers that arise from products of conception in the uterus, known collectively as gestational trophoblastic neoplasia (GTN), are rare but highly curable.
Low-risk GTN, which includes hydatidiform moles that have undergone malignant transformation and choriocarcinomas, has a high cure rate and there are many effective single-drug chemotherapy regimens. However, there is no consensus on which is the best drug and regimen to use.
The choice of drug and regimen is highly institution-specific, according to a group of gynecologic oncologists, led by Raymond Osborne, MD, FRCSC, MBA, from the Odette Cancer Center in Toronto, Ontario, Canada.
There is a historic preference for methotrexate, but they report a new phase 3 trial in which methotrexate was bested by dactinomycin.
The study is published online January 24 in the Journal of Clinical Oncology.
It involved 216 women with low-risk GTN who were enrolled over a period of 8 years, and compared 2 commonly used single-drug regimens.
Dr. Osborne and colleagues report that biweekly dactinomycin had a significantly higher complete response rate than a weekly intramuscular (IM) methotrexate regimen (70% vs 53%; P = .01); adverse effects were relatively modest with both regimens.
However, an accompanying editorial says this study "does not change standard practice at this time."
Most treating physicians will continue to use single-agent methotrexate, and will reserve dactinomycin for cases of methotrexate resistance or toxicity, writes editorialist Carol Aghajanian, MD, from the Memorial Sloan-Kettering Cancer Center in New York City.
But both the researchers and the editorialist agree that further trials exploring the dactinomycin regimen in this setting are warranted.
Definitions Were Changed
One of the issues with this particular study, according to Dr. Aghajanian, is that the definitions for GTN were changed while it was underway.
The study accrued patients between 1999 and 2007, but in 2002 the definitions of GTN were changed by the International Federation of Gynecology and Obstetrics (FIGO). The investigators chose not to change the definitions in their trial for logistical reasons, but because the criteria they were using are significantly different from current FIGO definitions, extrapolating from this study to clinical practice is "difficult," Dr. Aghajanian writes.
Another point is that dactinomycin is a vesicant — it can cause blisters — which makes administration more challenging and local tissue injury a possibility, she notes.
Furthermore, long-term safety data have not been compiled for dactinomycin, as they have for methotrexate, and the long-term safety and reproductive data from this study are not yet mature.
"Minimizing both long- and short-term toxicity is paramount in low-risk GTN," Dr. Aghajanian notes, because the cure rate is high (nearly 100%) and these women usually hope to have further pregnancies.
Further Testing Is Warranted
In the trial, IM methotrexate was used at a dose of 30 mg/m² once a week.
The regimen of dactinomycin that was shown to be superior was an intravenous (IV) dose of 1.25 mg/m² every 2 weeks. With this administration schedule, it is "relatively easy to administer and has a low toxicity profile," the researchers explain.
Dr. Osborne and colleagues say that further comparison of this biweekly dactinomycin regimen with other methotrexate regimens is warranted.
The editorialist agrees, and suggests that future trials should test it against IV or IM methotrexate 0.4 mg/kg given for 5 days and against the 8-day alternating methotrexate/leucovorin regimen (where IM methotrexate 1 mg/kg is given on days 1, 3, 5, and 7 and leucovorin 15 mg is given orally on days 2, 4, 6, and 8).
The authors have disclosed no relevant financial relationships.
J Clin Oncol. Published online January 24, 2011.

MAINTENANCE RITUXIMAB IN FOLLICULAR LYMPHOMA APPROVED

January 31, 2011 — The US Food and Drug Administration (FDA) has approved the CD20-directed monoclonal antibody rituximab (Rituxan, Roche) as a single-agent maintenance treatment for patients with previously untreated advanced follicular lymphoma who responded to initial treatment with rituximab plus chemotherapy.
The approval, given on January 28, was based on the Primary Rituxan and Maintenance (PRIMA) study, which found that rituximab administered every 2 months for 2 years in patients who responded to initial treatment with rituximab plus chemotherapy nearly doubled the likelihood of progression-free survival compared with in patients who received no maintenance therapy (hazard ratio, 0.54; 95% confidence interval, 0.42 - 0.70; P ≤ .0001).
The phase 3 study, conducted by the Groupe d'Etude des Lymphomes de l'Adulte, is an international, multicenter, randomized, phase 3 clinical study. A total of 1217 patients with previously untreated advanced follicular lymphoma were included in the analysis.
Patients received as initial therapy 8 cycles of rituximab plus chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone; cyclophosphamide, vincristine, and prednisone; or fludarabine, cyclophosphamide, and mitoxantrone. The 1018 patients who responded were randomly assigned to receive rituximab as single-agent maintenance, given once every 2 months for 2 years or to observation alone.
The safety profile was as expected and was consistent with previous studies. Infections of grade 2 or higher were reported more frequently in patients who received maintenance compared with the patients in the observation group (37% vs 22%). Grade 3 to 4 adverse reactions that occurred more frequently with maintenance therapy included infections (4% vs 1%) and low white blood cell count (4% vs <1%).
"This approval is important because it shows that maintenance treatment with Rituxan, after initial therapy with Rituxan and chemotherapy, further reduces the risk of relapse in people with follicular lymphoma," noted Hal Barron, MD, chief medical officer and head, Global Product Development, Roche, in a company written release.
Rituxan received FDA approval for rheumatoid arthritis in February 2006 and is currently indicated in combination with methotrexate in adult patients with moderately to severely active rheumatoid arthritis who have had inadequate response to one or more tumor necrosis factor antagonist therapies.

DOG SNIFFING OUT CANCER!!!

January 31, 2011 — The latest study demonstrating that dogs can sniff out cancer has confirmed the notion that a specific cancer smell does exist, and has added fuel to the idea of developing a test based on odor.
Previous studies have reported on dogs that can detect lung and breast cancer from breath samples, and there has been anecdotal evidence suggesting that dogs can detect melanoma, bladder, and ovarian cancers.
In this latest study, published online January 31 in Gut, a Labrador retriever was trained over several months to sniff out colorectal cancer in breath and watery stool samples.
Hideto Sonoda, MD, and colleagues from Kyushu University in Fukuoka, Japan, report that this dog was then tested with samples obtained from colorectal cancer patients and from volunteers, some of whom had gastrointestinal problems such as ulcers and inflammatory bowel disease.
The dog correctly identified cancer in 33 of 36 breath tests and in 37 of 38 stool tests. This equates to 95% accuracy overall for the breath test and 98% accuracy overall for the stool test, the researchers report.
The highest detection rates were among samples taken from patients with early-stage cancer, they add. Samples taken from smokers and from people with other gastrointestinal diseases, which might be expected to mask or interfere with cancer odors, did not appear to confuse the dog.
"This study shows that a specific cancer scent does indeed exist," the researchers conclude.
They are not suggesting using dogs in clinical practice, however. They point out that training the dog was expensive and time-consuming, and that ability and concentration vary between individual dogs and even the same dog on different days. The dog's concentration tends to decrease during the hot summer season; hence, they conducted their test between November and early June.
What they do propose is that this research could be used to develop cancer detection tests based on "odor materials."
This would involve identifying the cancer-specific volatile organic compounds (VOC) that are being detected by dogs using chemical analysis, and then developing an early cancer detection sensor that would substitute for the dog, they explain.
There has already been some work conducted on VOC in exhaled breath (using gas chromatography and mass spectroscopy) for the early detection of breast and lung cancer, they note, although they add that this work is still preliminary.
"We hope that the results of the present study will provide encouragement for the development of cancer detection and solving the biological character of cancer using odor material," Dr. Sonoda and colleagues conclude.
The researchers have disclosed no relevant financial relationships.
Gut. Published online January 31, 2011.

FIRST LINE ERLOTINIB IN EGEFR MUTATED LUNG CANCER

January 28, 2011 — In patients with newly diagnosed nonsmall-cell lung cancer (NSCLC), erlotinib (Tarceva) can significantly extend progression-free survival, according to the interim results of a phase 3 trial.
An independent data-monitoring committee has recommended that the European Randomized Trial of Tarceva vs Chemotherapy be stopped early because it has met its primary end point. The data showed that, compared with a platinum-based chemotherapy regimen, erlotinib significantly extended progression-free survival in patients with NSCLC tumors withepidermal growth-factor receptor (EGFR)-activating mutations.
EURTAC was sponsored by the Spanish Lung Cancer Group, which conducted it in conjunction with researchers in France and Italy. It is the first phase 3 study to show a progression-free survival benefit with first-line treatment in a Western population with advanced NSCLC with EGFR mutations.
Although the full results from EURTAC are not publicly available, the data will be submitted for presentation at a future medical meeting, according to the manufacturer.
Erlotinib is a tyrosine kinase inhibitor, which acts on the EGFR. It is currently indicated as maintenance therapy for patients with locally advanced or metastatic NSCLC who have failed other treatment regimens, and as first-line treatment for patients with locally advanced, unresectable, or metastatic pancreatic cancer.
Previous Results Promising
As previously reported by Medscape Medical News, the OPTIMAL study also found that erlotinib extended progression-free survival when used as first-line therapy in advanced NSCLC. That study was conducted in an Asian population, and progression-free survival tripled in patients with EGFR-activating mutations who were treated with erlotinib.
The results of the OPTIMAL study were presented at the 2010 European Society for Medical Oncology Congress. At that time, lead author Caicun Zhou, MD, from Shanghai Pulmonary Hospital, Tongji University, China, told Medscape Medical News that "the study shows us that erlotinib does much better than standard regimens in patients with EGFR-activating mutations."
"Progression-free survival tripled in patients on erlotinib," he said. "It should therefore be considered in preference to first-line chemotherapy in patients with this distinct disease."
Extending Indication
Erlotinib is being developed and marketed by OSI Pharmaceuticals, in partnership with Genentech in the United States, Chugai in Japan, and Roche in the rest of the world.
The new trial compared erlotinib with a regimen of platinum-based chemotherapy (cisplatin/gemcitabine, cisplatin/docetaxel, carboplatin/gemcitabine, or carboplatin/docetaxel). The primary end point was progression-free survival; secondary end points included overall survival, 1-year survival, objective response rate, and safety profile.
The manufacturer notes that a preliminary safety analysis showed that it was consistent with previous studies of this agent.
"We are pleased that the EURTAC study so quickly revealed [that erlotinib] may be a viable alternative to platinum-based chemotherapy in newly diagnosed NSCLC patients with EGFR-activating mutations," said Naoki Okamura, chief executive officer of OSI Pharmaceuticals, in a statement. "The interim analysis of the EURTAC study reinforces the role that [erlotinib] may have in treating patients beyond the Asian population, which has a historically higher instance of EGFR-activating mutations."
In June 2010, Roche applied to the European Medicines Agency to extend the indication and include first-line treatment for patients with advanced NSCLC whose tumors harbor EGFR-activating mutations. On the basis of the EURTAC data, OSI and Genentech have announced plans to discuss similar extended indications with the US Food and Drug Administration. Roche and OSI will collaborate regarding submissions to other health authorities.

TS AND ERCC1 PREDICTIVE VALUE IN MESOTHELIOMA

Clin Cancer Res. 2011 Jan 24. [Epub ahead of print]

THYMIDYLATE SYNTHASE AND EXCISION REPAIR-CROSS-COMPLEMENTING GROUP-1 AS PREDICTORS OF RESPONSIVENESS IN MESOTHELIOMA PATIENTS TREATED WITH PEMETREXED-CARBOPLATIN.

Zucali PA, Giovannetti E, Destro A, Mencoboni M, Ceresoli GL, Gianoncelli L, Lorenzi E, De Vincenzo F, Simonelli M, Perrino M, Bruzzone A, Thunnissen E, Tunesi G, Giordano L, Roncalli M, Peters GJ, Santoro A.

Medical Oncology and Hematology, Istituto Clinico Humanitas IRCCS.

Abstract

PURPOSE: The pemetrexed/platinum-agent combination represents the standard of care in first-line treatment for malignant pleural mesothelioma (MPM). However, there are no established indicators of responsiveness that can be used to optimize treatment. This retrospective study aimed to assess the role of excision-repair-cross-complementing group-1 (ERCC1) and thymidylate-synthase (TS) in tumors, and correlate expression levels and polymorphisms of these key determinants of drug activity with the outcome of MPM patients treated with carboplatin/pemetrexed in first-line setting.Experimental design: Analysis of TS and ERCC1 polymorphisms, mRNA and protein-expression was performed by PCR and immunohistochemistry (using the H-score) in tumor specimens from 126 MPM patients, including 99 carboplatin/pemetrexed-treated patients.
RESULTS: A significant correlation between low TS protein-expression and disease-control (DC) to carboplatin/pemetrexed therapy (p=0.027), longer PFS (p=0.017), and longer OS (p=0.022) was found when patients were categorized according to median H-score. However, patients with the higher tertile of TS mRNA expression correlated with higher risk of progressive disease (p=0.022), shorter PFS (p<0.001) and shorter OS (p<0.001). At multivariate analysis, the higher tertile of TS mRNA level and TS-H-score confirmed their independent prognostic role for DC, PFS and OS. No significant associations were found among ERCC1 protein-expression, TS and ERCC1 polymorphisms and clinical outcome.
CONCLUSIONS: In our series of carboplatin/pemetrexed-treated MPM patients, low TS-protein and mRNA-levels were significantly associated to DC, improved PFS and OS. Prospective trials for the validation of the prognostic/predictive role of TS in MPM patients treated with pemetrexed-based regimens are warranted.

TREATMENT OF BREAST CANCER PATIENTS WITH BONE ONLY METASTASES

Oncologist. 2011 Jan 25. [Epub ahead of print]

Treatment Outcome and Prognostic Factors for Patients with Bone-Only Metastases of Breast Cancer: A Single-Institution Retrospective Analysis.

Niikura N, Liu J, Hayashi N, Palla SL, Tokuda Y, Hortobagyi GN, Ueno NT, Theriault RL.

Departments of Breast Medical Oncology and.

Abstract

Abstract Purpose. Limited information is available about the optimal management and clinical outcome of bone-only metastases in breast cancer patients. The objective of this study was to define prognostic factors for patients with bone-only metastases. Our second objective was to compare progression-free survival (PFS) and overall survival (OS) between patients with hormone receptor (HR)(+) tumors and bone-only metastases who received combinatory therapy (chemotherapy followed by endocrine therapy, or endocrine therapy combined with molecular targeted therapy) and those treated with endocrine or chemotherapy alone. Patients and Methods. We retrospectively identified 351 breast cancer patients diagnosed with bone-only metastasis in 1997-2008 at our institution. Results. Patients with metastasis detected at the time of their primary breast cancer diagnosis (rather than at recurrence), a single metastasis, or asymptomatic bone disease had a longer PFS interval, and patients with a performance status of 0-1, a single metastasis, or asymptomatic bone disease had a longer OS time. Among patients with HR(+) human epidermal growth factor receptor (HER)-2(-) disease, combinatory therapy was associated with longer PFS and OS times than with endocrine therapy. In multivariate analyses, combinatory therapy was not associated with longer PFS or OS times than with endocrine therapy. Among patients with HER-2(+) disease, trastuzumab led to a longer PFS interval but no difference in the OS time. Conclusion. Our results indicate that, for HR(+) disease, a prospective trial of chemotherapy followed by endocrine therapy is warranted to determine whether it prolongs survival more than endocrine therapy alone in patients with bone-only metastases.

KRAS MUTATION IN FAMILIAL OVARIAN CANCER

MacConaill LE, Garraway LA
J Clin Oncol. 2010;28:5219-5228

Summary

Previous research identified an uncommon variant of the KRAS oncogene (rs61764370) that increases levels of KRAS in in vitro assays, suggesting that it may be associated with a biologically relevant increased risk for cancer development.^[1] Indeed, 2 case-control studies revealed a greater risk for the development of non-small cell lung cancer in individuals with this mutation vs those without the mutation. Although the variant is seen in fewer than 20% of patients with all solid tumors, it is present in more than 25% of patients with epithelial ovarian cancer.^[1]
In the analysis by Ratner and colleagues, investigators exploring an association between the presence of rs61764370 and the risk of developing ovarian cancer found the mutation in 25% of patients examined vs only 15% of individuals in a non-cancer "control" population. Of greatest interest, however, the KRAS mutation was found in 19 (61%) of 31 patients who appeared to have a familial history of ovarian cancer but no evidence of a BRCA1 or BRCA2 mutation. When compared with families with a BRCA association, patients in this group were less likely to have Jewish Ashkenazi ethnicity, and were more likely to be older and to have a history of lung cancer within the family.
In their review article, MacConaill and Garraway identify KRAS and BRCA as classic examples of synthetic lethality, in which cancer cell growth driven by expression of an oncogene is, in turn, dependent on expression of a second gene for survival. Whether a druggable target will be found for KRAS-mutated ovarian cancer similar to poly ADP ribose polymerase (PARP) inhibitors in BRCA-mutated breast cancer^[2] remains to be seen, but the identification of the KRAS mutation in this patient population certainly points to new possible avenues for therapeutic intervention.

NECITUMUMAB TRIAL STOPPED FOR SAFETY REASONS

February 2, 2011 — A phase 3 trial of necitumumab, an investigational agent for the first-line treatment of advanced nonsmall cell lung cancer (NSCLC), has stopped enrolling patients because of safety concerns related to thromboembolism in the experimental group of the study.
Eli Lilly and Bristol-Myers Squibb — the sponsors of the trial and codevelopers of the agent — made the announcement today in a press statement.
The INSPIRE trial compares necitumumab, a fully human IgG1 monoclonal antibody, in combination with pemetrexed (Alimta; Eli Lilly) and cisplatin with a control regimen of the latter 2 drugs for patients with advanced nonsquamous NSCLC.
No new safety issues were seen in the control group.
According to the press statement, the decision to stop enrollment followed a recommendation by the independent Data Monitoring Committee that no new or recently enrolled patients continue treatment in the trial because of safety concerns.
Notably, the Data Monitoring Committee said that patients who have received 2 or more cycles of necitumumab appear to have a lower ongoing risk for thromboembolism. These patients might choose to remain in the trial after being informed of the potential risks. Investigators will continue to assess patients after 2 cycles to determine if there is a benefit from treatment, says the statement.
Meanwhile, another phase 3 trial of necitumumab — SQUIRE — continues on with no concerns about thromboembolism at this time. In that trial, necitumumab is being studied as a potential treatment for squamous NSCLC in combination with gemcitabine (Gemzar; Lilly) and cisplatin. "The same independent Data Monitoring Committee recommended that this trial continue because no safety concerns have been observed," according to the press statement.
"Patient safety is paramount. While stopping enrollment in 1 of the 2 phase 3 trials is disappointing, the SQUIRE phase 3 study of necitumumab in lung cancer continues," said Richard Gaynor, MD, vice president of oncology product development and medical affairs at Eli Lilly.

TREATMENT OF STAGE I SEMINOMA

J Clin Oncol. 2011 Jan 31. [Epub ahead of print]

Randomized Trial of Carboplatin Versus Radiotherapy for Stage I Seminoma: Mature Results on Relapse and Contralateral Testis Cancer Rates in MRC TE19/EORTC 30982 Study (ISRCTN27163214).

Oliver RT, Mead GM, Rustin GJ, Joffe JK, Aass N, Coleman R, Gabe R, Pollock P, Stenning SP.

St Bartholomews and the London Hospital; Medical Research Council Clinical Trials Unit, Cancer Group, London; Department of Medical Oncology, Southampton General Hospital, Southampton; Medical Oncology, Mount Vernon Cancer Centre, Northwood; Department of Medical Oncology, Huddersfield Royal Infirmary, Huddersfield; and Weston Park Hospital, Sheffield, United Kingdom; and Norwegian Radium Hospital, Oslo, Norway.

Abstract

PURPOSE Initial results of a randomized trial comparing carboplatin with radiotherapy (RT) as adjuvant treatment for stage I seminoma found carboplatin had a noninferior relapse-free rate (RFR) and had reduced contralateral germ cell tumors (GCTs) in the short-term. Updated results with a median follow-up of 6.5 years are now reported. PATIENTS AND METHODS Random assignment was between RT and one infusion of carboplatin dosed at 7 × (glomerular filtration rate + 25) on the basis of EDTA (n = 357) and 90% of this dose if determined on the basis of creatinine clearance (n = 202). The trial was powered to exclude a doubling in RFRs assuming a 96-97% 2-year RFR after radiotherapy (hazard ratio [HR], approximately 2.0). Results Overall, 1,447 patients were randomly assigned in a 3-to-5 ratio (carboplatin, n = 573; RT, n = 904). RFRs at 5 years were 94.7% for carboplatin and 96.0% for RT (RT-C 90% CI, 0.7% to 3.5%; HR, 1.25; 90% CI, 0.83 to 1.89). One death as a result of seminoma (in RT arm) occurred. Patients receiving at least 99% of the 7 × AUC dose had a 5-year RFR of 96.1% (95% CI, 93.4% to 97.7%) compared with 92.6% (95% CI, 88.0% to 95.5%) in those who received lower doses (HR, 0.51; 95% CI, 0.24 to 1.07; P = .08). There was a clear reduction in the rate of contralateral GCTs (carboplatin, n = 2; RT, n = 15; HR, 0.22; 95% CI, 0.05 to 0.95; P = .03), and elevated pretreatment follicle-stimulating hormone (FSH) levels (> 12 IU/L) was a strong predictor (HR, 8.57; 95% CI, 1.82 to 40.38). CONCLUSION These updated results confirm the noninferiority of single dose carboplatin (at 7 × AUC dose) versus RT in terms of RFR and establish a statistically significant reduction in the medium term of risk of second GCT produced by this treatment.

A SIMPLE MATHEMATICAL PROBLEM

1.

Am J Clin Oncol. 2011 Jan 26. [Epub ahead of print] Phase II Trial of Pegylated Liposomal Doxorubicin in Combination With Gemcitabine in Metastatic Breast Cancer Patients. Jacquin JP, Chargari C, Thorin J, Mille D, Mélis A, Orfeuvre H, Clavreul G, Chaigneau L, Nourissat A, Dumanoir C, Savary J, Merrouche Y, Magné N. Departments of*Medical Oncology ‡Public Health, Statistical Unit **Radiotherapy, Institut de Cancérologie de la Loire, St Priest en Jarez †Service of Oncology Radiotherapy, Hôpital d'Instruction des Armées du Val-de-Grâce ¶Department of Oncology Development, Laboratoire Schering Plough ♯Department of Oncology Development, Laboratoire Elli Lilly, Paris §Department of Medical Oncology, Centre Hospitalier de Bourg en Bresse, Bourg en Bresse ∥Department of Medical Oncology, Centre Hospitalier Universitaire Jean Minjoz, Besançon, France. Abstract OBJECTIVE: To assess the efficacy and toxicity of pegylated liposomal doxorubicin combined with gemcitabine as first-line chemotherapy in metastatic breast cancer patients in a phase II trial. PATIENTS AND METHODS: All breast cancer patients with HER2-negative status, hormone refractory tumor, assessable targets, with preserved performance status, and who had not received chemotherapy earlier as treatment for their metastatic disease were eligible. The patients received pegylated liposomal doxorubicin (30 mg/m, venous injection, day 1) concurrently with gemcitabine (1000 mg/m, venous injection, days 1 and 8), 1 cycle every 3 weeks. RESULTS: Although 38 patients should have been included, this study was prematurely discontinued after recruiting 20 patients because of excessive toxicity: 75% of the patients experienced grade 3 or 4 treatment-related toxicity, including neutropenia, thrombopenia, hand-foot syndrome, and stomatitis, which significantly affected the quality of life. Cardiac toxicity was mild. With regard to efficacy, 50% of the patients (95% confidence interval, 26%-74%) experienced tumor response. The response rate was 40% in patients who had earlier received anthracyclines as adjuvant therapy. Median progression-free survival and median overall survival were 8.8 months and 19 months, respectively. CONCLUSIONS: This combination was efficient, but not well tolerated. From these results, we could not recommend these doses for further assessment and lower doses should be preferred.

FOUR GENE SIGNATURE TO DETECT LETHAL PROSTATE CANCER

CHICAGO (Reuters) Feb 02 - Prostate tumors with a distinctive four-gene "signature" are far more lethal than others, laying the groundwork for a test to predict which tumors need aggressive treatment, U.S. researchers said on Wednesday.

Tests of this four-gene signature method alone accurately identified 83% of deadly prostate tumors from tissue samples taken in a national health study.

When they combined this method with a standard test of a prostate tumor's aggressiveness, the team accurately identified more than 90% of tumors that later killed patients.

"This would have 92% accuracy relative to what we currently have, which is at best 75% accuracy," said Dr. Ronald DePinho of Dana-Farber's Belfer Institute for Applied Cancer Science in Massachusetts.

"There is no question this will influence the practical management of these cases," Dr. DePinho, whose study appeared online today in Nature, said in telephone interview.

He said such a test would spare many men from unnecessary treatment for cancers that might never have killed them.

"The vast majority of prostate cancers would not become life-threatening, even if left untreated. But because we can't accurately forecast which are likely to spread and which aren't, there is a tendency to unnecessarily subject many men to draconian interventions," he said in a statement.

Currently, he said, about 48 men must be treated for prostate cancer to save one life, and the main forms of prostate cancer treatment - surgery and radiation therapy - can cause impotence and incontinence.

"This will clearly shift the numbers of individuals that are treated," Dr. DePinho said.

To find genes that drive the aggressiveness of prostate tumors, Dr. DePinho said, his team "ping-ponged" between mouse and human studies.

They started out with mice that lack a working copy of the Pten gene, which is involved with cell growth. These mice develop tumors, but the tumors do not spread.

They looked to see what genes kept those tumors from spreading and found a gene known as Smad4 that acts as a brake to cancer growth.

Blocking this gene in mice that also lacked a working copy of Pten appeared to flip a growth switch. Mice without working copies of both genes developed fast-growing tumors that spread to their lymph nodes and beyond.

Once they had narrowed down what kept the cancers from growing, Dr. DePinho's team conducted a series of experiments to find genes that were key to driving this growth. They found two: SPP1 and CyclinD1. Both genes play a role in cell division and both work closely with Smad4.

They tested this four-gene signature in human prostate tumor samples taken from the Physicians' Health Study, a 30-year study of U.S. physicians.

They found this four-gene signature was more accurate in predicting the ultimate course of the illness than the Gleason score.

Dr. DePinho said the results will make a big impact on how men are tested and treated for prostate cancer, the second most common cancer in men worldwide after lung cancer, killing 254,000 a year.

Dana-Farber has licensed the technology to Metamark Genetics Inc, a Massachusetts-based company that will commercialize the test.

"The goal is to do this within about a year or maybe a bit longer than that," said Dr. DePinho, who has a stake in the company.

On Tuesday, a team at the U.S. national Institutes of Health identified a compound that tumors make when they are most likely to spread and they hope to make a similar test.

SOURCE: http://bit.ly/fvvRcT

MAMMOGRAMS BETTER TO BEGIN AT AGE 40

February 3, 2011 — A new analysis is poised to reignite the debate that has been raging over the value of mammography in women younger than 50 years of age.

There was a furor when the revised US Preventative Service Task Force (USPSTF) recommendations for breast cancer screening were released in November 2009. The most notable changes were to advise against routine screening mammograms for women 40 to 49 years of age, to change the screening interval from 1 to 2 years in women 50 years and older, and to end screening at 74 years.

The updated guidelines became mired in controversy as soon as they were published, as previously reported by Medscape Medical News. A number of organizations, including the American Cancer Society (ACS), the American College of Radiology, and the American College of Obstetricians and Gynecologists, recommended that physicians and patients continue to follow earlier guidelines.

Now, a study published in the February issue of the American Journal of Radiology that analyzed the same data as the USPSTF has come up with very different results.

R. Edward Hendrick, PhD, clinical professor of radiology at the University of Colorado School of Medicine in Denver, and Mark Helvie, MD, director of breast imaging at the University of Michigan Comprehensive Cancer Center in Ann Arbor, found that beginning screening at a younger age and at more frequent intervals can save more lives.

What is most important is to save the most lives," Dr. Hendrick told Medscape Medical News, "not to do the fewest mammograms. If you want to save the most lives, then doing annual mammograms from age 40 to 84 years clearly is superior."

According to the analysis, women who receive annual mammograms starting at age 40 can significantly reduce the risk of dying from breast cancer by 71%. This is in contrast to women who follow the USPSTF recommendations, who had a 23.2% reduction in mortality.

Lower Mortality With Earlier Screening

Dr. Hendrick and Dr. Helvie used 6 model scenarios of screening mammography that were created by the Cancer Intervention and Surveillance Modeling Network, which is the same modeling data used by the USPSTF. They compared mortality reduction for women who followed the 2009 USPSTF recommendations with that for women who followed the ACS recommendations (annual screening beginning at age 40).

"In their summary paper, the USPSTF did not do any averaging over the 6 models," explained Dr. Hendrick. In our analyses, we selected a model that was "somewhere in the middle, but it wasn't an average over the 6."

When the USPSTF looked at any of these modeling data, they chose the point on the graph when it first begins to turn over in terms of mortality reduction per mammogram done. "That was biennial screening beginning at age 50," he said.

In contrast, the authors of new analysis averaged the 6 models and found that for women 40 to 84 years, annual screening conveyed an estimated 39.6% reduction in mortality (range over the 6 models, 29.4% to 54%). This was compared with biennial screening at 50 to 74 years, which showed an estimated mortality reduction of 23.2% (range, 20% to 28%).

They found that approximately 12 lives per 1000 women screened would be saved with annual screening beginning at age 40, whereas with the USPSTF-recommended screening regimen, an estimated 7 lives per 1000 women screened would be saved. Overall, the ACS screening guidelines would result in 5 more lives per 1000 women saved than the USPSTF screening guidelines.

Overemphasis of Harms

The USPSTF also overemphasized the potential harms of screening mammography, explained Dr. Hendrick.

You can't really compare having a call back for additional testing to dying of breast cancer," he said. "They were comparing something with mild implications to something with huge implications. They looked at the potential harms of screening without looking at lives saved from a proper perspective."

The actual number of false-positive tests is also actually quite low, Dr. Hendrick noted. For a woman 40 to 49 years who receives annual screening, a false-positive test will occur once every 10 years on average. She will be recalled for additional imaging once every 12 years and undergo a false-positive biopsy once every 149 years. A missed malignancy will happen once every 1000 years.

In the USPSTF report, the harms of unnecessary recall for additional imaging were emphasized, the authors note. However, "this harm can be mitigated if women elect real-time screening interpretation with same-visit diagnostic imaging offered at many [American] facilities, . . . but this option was not mentioned by the USPSTF report."

May Dissuade Payors

Because the new recommendations were made by a federal panel, they do have an effect on healthcare decisions, Dr. Hendrick said.

In fact, the guidelines could have dissuaded some women from having a screening mammography, and could influence reimbursement from Medicare, Medicaid, and private payors, he added.

The USPSTF recommendations have done potential damage to women's health by failing to seize the singular opportunity to both improve mammography in the United States and to increase screening mammography compliance," say the authors.

Dr. Hendrick reports being a consultant to GE Healthcare and serving on the medical advisory boards of the Koning Corporation and Bracco, both of which develop and manufacture diagnostic imaging systems. Dr. Helvie reports receiving grant support from GE Healthcare.

AJR Am J Roentgenol. 2011;196:W112-W116. Abstract

NEW GENE THERAPY FOR SYNOVIAL SARCOMA AND MELANOMA

NEW YORK (Reuters Health) Jan 31 - For the first time, scientists have been able to use cell transfer gene therapy to treat a common cancer other than melanoma, in a study reported online today in the Journal of Clinical Oncology.
"This provides a basis for extending this gene therapy to patients with common cancers," Dr. Steven A. Rosenberg from the National Cancer Institute, Bethesda, Maryland told Reuters Health in an email.
In the study by Dr. Rosenberg and colleagues, autologous lymphocytes genetically engineered to be reactive with the NY-ESO-1 cancer/testis antigen cause tumor regression in patients with metastatic synovial cell sarcoma and melanoma.
There were 17 patients altogether: six with metastatic synovial cell sarcoma and 11 with metastatic melanoma, all bearing tumors expressing NY-ESO-1.
"The patients described in this paper have had all available standard treatment and thus this experimental therapy was their last hope," Dr. Rosenberg said.
Four of the six patients with synovial cell sarcoma showed objective partial responses, with one lasting 18 months. Five of the 11 patients with metastatic melanoma experienced objective responses, including two complete responses (ongoing at 22 and 20 months) and 1 partial response (ongoing at 9 months).
One of six patients with synovial cell sarcoma and six of the 11 patients with melanoma showed significant anti-NY-ESO-1 antibody titers in pretreatment serum samples, but there was no association between pretreatment titers and response.
No toxicities associated with cell transfer were observed. The researchers note that this "contrasts with our previous observation of vigorous on-target toxicity in patients with melanoma treated with T cells engineered to express MART-1- and gp-100-reactive T-cell receptors."
"The antigen that we target (NY-ESO-1) is present on about one-third of common cancers," Dr. Rosenberg said. "Since patients with sarcoma and melanoma respond to this cell transfer gene therapy, we are now treating patients with common cancers that express NY-ESO-1, such as cancers of the breast, colon, and esophagus."
"As we treat more patients we hope to apply to the FDA to receive approval to more widely apply this treatment," Dr. Rosenberg added.
J Clin Oncol. Posted online January 31, 2011. Abstract

NEW POTENTIAL TARGET IN COLORECTAL CANCER

LONDON (Reuters) Jan 31 - British scientists said they have found a new target for treating advanced bowel cancer which could also be used to identify tumors that will respond to Bristol Myers Squibb's cancer drug Sprycel.
In a study published online January 31st in the Journal of the National Cancer Institute, researchers from the Institute of Cancer Research (ICR) found that Sprycel, known generically as dasatinib and already used in other cancers, reduced bowel cancer cell growth in the lab by blocking the effects of an enzyme called lysyl oxidase, or LOX.
"The enzyme LOX is the one that is important for the cancer to spread, and if you block that then you can stop the cancer from growing," Janine Erler, who led the study, said in an interview.
Erler said this followed previous work in which her team found LOX played a role in the spread of breast cancer, leading them to suspect it may also be key in other tumors.
The latest study confirmed LOX was also important in bowel cancer growth and spread, Erler said, and showed cell growth increases in tumor cells with high levels of LOX, while low levels of LOX lead to limited cell growth.
The team also showed LOX was activating a molecule called SRC to promote cancer growth and spread - a finding that led them to look at Sprycel, which is known to block SRC function and is already being used to treat patients with chronic myeloid leukemia, or CML.
"Our findings have revealed two potential new avenues for combating advanced bowel cancer - either with existing SRC inhibitor treatments or with drugs currently being developed to target LOX," Erler said.
She said experimental drugs to block LOX were only in the earliest stages of development and were not yet ready for testing beyond the laboratory. But she said the findings should open up a way to explore using Sprycel or other SRC inhibitors to help colon cancer patients.
Erler's study showed that a test for levels of LOX could be used to single out cancers whose SRC molecules are highly activated, therefore identifying patients most likely to benefit from treatment with Sprycel or other SRC inhibitors.
Pfizer's bosutinib, which is currently in late stage trials for CML, is also known to block SRC, as is Ariad's ponatinib, which is undergoing mid-stage testing.
Malcolm Dunlop of Britain's Medical Research Council (MRC), which funded the study, said finding a way to prevent the metastatic spread of tumors was crucial if doctors were going to be able to reduce the number of deaths from bowel cancer.
"The discovery that controlling the enzyme LOX could influence colorectal cancer cell growth is very encouraging," he said in a statement.
J Natl Cancer Inst. Posted online January 31, 2011. Abstract

LIFETIME RISK OF AUTOIMMUNE DISEASE

January 31, 2011 — The first study to determine lifetime risk for inflammatory autoimmune rheumatic disease reports that 1 in 12 women and 1 in 20 men will develop such disorders, and 1 in 28 women and 1 in 59 men will develop rheumatoid arthritis (RA).
The research team, from the Mayo Clinic, Rochester, Minnesota, estimated the lifetime risk for rheumatic disease for both sexes — something that had not been done before. First author Cynthia Crowson, MS, said that prevalence and incidence rates exist, but prevalence figures underestimate individual risk, and incidence rates express only a yearly estimate. The researchers were looking for an accurate basis to offer an easy-to-understand average risk during a person's lifetime, knowing that risk changes at almost every age.
"We were surprised that the lifetime risk is this high," Crowson told Medscape Medical News. "Many people erroneously equate prevalence with lifetime risk, but they are not the same. The prevalence of RA is 1 in 100. These are the first estimates of lifetime risk of RA, so prior to this, the lifetime risk was unknown. However, it was thought to be much smaller." Crowson is a biostatistician at the Mayo Clinic's Department of Health Sciences Research.
The study, reported online December 28, 2010, in Arthritis & Rheumatism, was based on data from the Rochester Epidemiology Project, a long-term epidemiology resource based on patients in Olmsted County, Minnesota. The cohort of 1179 patients diagnosed with any of 7 inflammatory autoimmune diseases between 1955 and 2007 allowed the team to extrapolate the nationwide estimates.
The diseases studied were RA, polymyalgia rheumatica, systemic lupus erythematosus, giant cell arteritis, psoriatic arthritis, primary Sjögrens syndrome, and ankylosing spondylitis.
Table.

Disease	Women	Men
RA	3.6%	1.7%
Polymyalgia rheumatica	2.4%	1.7%
Systemic lupus erythematosus	0.9%	0.2%
Giant cell arteritis	1.0%	0.5%
Psoriatic arthritis	0.5%	0.6%
Primary Sjögrens syndrome	0.8%	0.04%
Ankylosing spondylitis	0.1%	0.6%

"Knowledge of the lifetime risk of RA and of rheumatic diseases is useful because it helps to put the risk of these diseases in context relative to the risks for other diseases," Crowson said. "Clinicians should take note of these numbers in order to provide accurate information to their patients. If patients are concerned about these risks, they may consider lifestyle changes, such as smoking cessation, to lower their risks."
The authors said that these data "have important implications for disease awareness campaigns such as those of the Arthritis Foundation."
Arthritis Foundation President and chief executive officer Jack H. Klippel, MD, told Medscape Medical News that the Crowson study will change the foundation's approach to disease awareness campaigns and should change primary care clinical practice.
"The Arthritis Foundation will use this information as part of our standard messaging. In addition to saying that 1.3 million people in this country have RA, we will be pointing out that the risk [for an autoimmune inflammatory disease] is 1 in 12 for women and 1 in 20 for men. Of course, that risk rises substantially if you smoke or have a family history, and for women begins to approach the risk for breast cancer, which is 1 in 8," Dr. Klippel said.
According to Dr. Klippel, the lifetime risks identified in the Crowson study also suggest that primary care physicians should be considering changes in their approach to RA and related diseases.
"The primary care physician is nearly always the first medical contact for patients with RA, but many (if not most) primary care physicians will tell you that they see few cases of RA. The numbers in this study suggest that early RA is being under-recognized in this setting," Dr. Klippel said.
Dr. Klippel also noted that the 1 in 12 (women) and 1 in 20 (men) baseline risks give physicians a powerful tool for convincing smokers to stop, especially if they also have family histories of RA or related diseases.
Perhaps the most important study limitation, also noted by the researchers, is that the population of Olmstead County is overwhelmingly white, which might limit generalizability to more diverse populations. Dr. Klippel pointed out that this might account for the high risk for polymyalgia rheumatica.
"These risks might reflect both the relatively large number of people of Scandinavian descent, since PMR is more common among Scandinavians, and some degree of referral bias, since the Mayo Clinic is known to have a special interest in PMR," Dr. Klippel commented.
The study was supported in part by a grant from the National Institutes of Health. Ms. Crowson and Dr. Klippel have disclosed no relevant financial relationships.
Arthritis Rheum. Published online December 28, 2010.

STATIN BENEFITS IRRESPECTIVE OF CRP LEVEL

January 28, 2011 (Oxford, United Kingdom) — The idea that C-reactive protein (CRP) levels can be used to guide statin therapy has taken another knock, with the publication of an analysis from the large-scale Heart Protection Study (HPS) showing that statin treatment was associated with a similar reduction in vascular events irrespective of baseline concentrations of CRP [1].
In the analysis, published online in the Lancet on January 27, 2011, the reduction in vascular events with statin therapy remained consistent even in individuals with low concentrations of both CRP and LDL cholesterol.
Fueling the CRP Debate
The authors conclude: "The results do not lend support to the suggestion that the beneficial effects of statin therapy are affected by baseline CRP concentration or, more generally, by inflammation status." They add that the results could be applicable to all statins and to a wide range of people with and without preexisting vascular disease.
However, CRP advocate Dr Paul Ridker (Brigham and Women's Hospital, Boston, MA) argues that the HPS trial was conducted in a mainly secondary-prevention population and so these data should not be used to pass judgment on the usefulness of CRP measurements in a primary-prevention population, where, he says, "CRP measurement has been shown to provide as much incremental information on vascular risk as does total or HDL cholesterol and where CRP evaluation is recommended as a method to detect patient groups who benefit from statin therapy but otherwise would not qualify for treatment based on levels of LDL cholesterol."
Asked for his opinion on the study,Dr Roger Blumenthal (Johns Hopkins Medical Institute, Baltimore, MD) told heartwire : "These results are disappointing, in that some of us felt that [high-sensitivity] hs-CRP may be useful in the secondary-prevention setting. It clearly is not, based on these data." But he pointed out that CRP levels were still a predictor of absolute risk in HPS. "For now, I will continue to use hs-CRP and coronary calcium measurements selectively in patients in whom the decision to treat with lifelong statin and aspirin is unclear or if the patient qualifies for treatment but is inclined not to take it," he added.
The HPS trial randomized 20 536 men and women at high risk of vascular events to simvastatin 40 mg daily or placebo for a mean of five years. Overall, allocation to simvastatin resulted in a significant 24% proportional reduction in the incidence of first major vascular event.
For the purposes of the current analysis, patients were categorized into six baseline CRP groups (<1.25, 1.25–1.99, 2.00–2.99, 3.00–4.99, 5.00–7.99, and >8.00 mg/L). Results showed no evidence that the proportional reduction in the primary end point (the composite of coronary death, MI, stroke, or revascularization) or its components varied with baseline CRP concentration. Even in participants with baseline CRP concentration less than 1.25 mg/L, major vascular events were significantly reduced by 29%. There was also no significant heterogeneity in the relative risk reduction between the four subgroups defined by the combination of low or high baseline concentrations of LDL cholesterol and CRP. In particular, there was clear evidence of benefit (27% reduction) in those with both low LDL cholesterol and low CRP.
Lead author of the current paper, Dr Jonathan Emberson (Clinical Trial Service Unit, University of Oxford, UK), explained to heartwire that there had been confusion in the past as to whether a patient's baseline CRP level would affect the benefits of statins, with the suggestion that statins may be more effective in patients with high levels of CRP. Such an observation has been seen in a couple of post hoc analyses of studies, including the AFCAPS/TEXCAPS and CORONA trials. But Emberson noted that these trials did not have enough events to reach definitive conclusions.
He added: "These studies raised a hypothesis that statins may not be so effective in patients with low CRP levels. We tested that hypothesis in the much larger HPS trial and found that it is not the case."
What About JUPITER?
Emberson said these latest results from HPS were not inconsistent with those from the JUPITER trial, which showed a reduction in cardiovascular event rate with rosuvastatin vs placebo in primary-prevention patients with raised levels of CRP. Emberson pointed out that in the JUPITER trial, there was also no differential effect of rosuvastatin in patients with different CRP levels, although in that study all patients had levels above 2 mg/L.
"In the HPS study, we've shown that the benefits of statins also extend to lower CRP levels, right down to patients with levels below 1 mg/L," he added.
Emberson agreed that the patient population in HPS was probably higher risk than that in JUPITER, but he pointed out that the recent primary-prevention meta-analysis conducted by the Oxford group showed that the benefit of statins continued right down to very low-risk populations.
Asked how the JUPITER trial and the current HPS analysis can be interpreted together in terms of clinical practice, Emberson said: "JUPITER has shown that measuring CRP might be one way of identifying primary-prevention patients who may benefit from a statin. We are not arguing with that. But our take is that patients should be assessed for statin treatment by their overall absolute risk of vascular disease, and while CRP may be one factor in identifying those at higher risk, there are also other, perhaps easier, ways to assess risk such as age, smoking status, blood pressure, etc."
CRP: A Shining Star or a Dimming Light?
In a comment accompanying the paper, Dr Jean-Pierre Després (Université Laval, Quebec, QC), points out that the drivers of CRP concentrations and the relative weight of CRP to the global risk of cardiovascular disease might differ in different populations [2]. He also notes that although all subgroups benefited from statin therapy in HPS, both LDL-cholesterol and CRP concentrations were clearly associated with absolute major vascular-event rates, adding: "CRP is a cheap and convenient marker of inflammation related to risk of cardiovascular disease."
He concludes: "As for other controversies in cardiovascular medicine, it is with robust experimental and clinical evidence together with constructive criticism that CRP will appropriately position itself in the galaxy of simple CVD risk markers--as a shining star or a dimming light."
More Arguments From Ridker
Other points made by Ridker included the observation that while baseline CRP did not modify the vascular benefits of statin therapy in HPS, neither did baseline LDL. He reiterated Despres's argument: "CRP levels track directly with absolute risk in HPS; thus, these data confirm the ability of CRP to predict high risk."
Ridker also says that the HPS investigators chose not to address the hypothesis that on-treatment levels of CRP associate with the risk reduction attributable to statins, which he says has been seen in many prior statin trials. "The authors make the claim that such an analysis should not be done as it is nonrandomized, yet they go on to conclude that the benefits of statin therapy accrue solely to on-treatment LDL, an analysis that suffers equally from the same nonrandomized limitations."
Kaul: An Evidence Vacuum
Commenting on the debate for heartwire , Dr Sanjay Kaul (Cedars Sinai Medical Center, Los Angeles, CA) said that while the HPS did have the advantage of size and a wide range of CRP values, it was still a post hoc analysis and as such could not be considered definitive. "This study doesn't change much for me. Yes, it provides more ammunition for the detractors of the CRP hypothesis to stake their claim, but we are stuck in an evidence vacuum in this debate, without the quality of data we need to progress the arguments," he added.
But this may change if Ridker gets his way. He notes that the only way to test the inflammatory hypothesis of atherosclerosis is to directly randomize patients to targeted anti-inflammatory therapies, and his group hopes to launch two such trials this year.

SCREENING FOR THYROID CANCER IN PATIENTS WITH FAP

NEW YORK (Reuters Health) Jan 25 - Ultrasound screening can detect potentially curable thyroid cancer in patients with familial adenomatous polyposis (FAP), researchers report online in the January Annals of Surgery.
"While patients with FAP (especially women) are known to be at increased
risk for thyroid cancer, there has been no concerted effort to provide screening," Dr. James M. Church told Reuters Health by email.
To investigate the yield from ultrasound thyroid screening in patients with this rare cancer predisposition syndrome, the researchers from the Cleveland Clinic in Ohio employed the approach in 192 patients undergoing annual gastrointestinal surveillance from August 2008 to December 2009.
In all, 72 (38%) had thyroid nodules, none of which were palpable, and 5 (2.6%) had thyroid cancer. Four of the patients had the multifocal papillary type with a mean size of 15 mm. Three of the patients with cancer were women.
None of the cancers were detected based on clinical history or neck examination.
The 2.6% incidence of thyroid cancer is significantly higher than the 0.2% historically reported for the general population.
The fact that the thyroid cancers detected were small and asymptomatic, say the investigators, "Gives credibility to the notion that ultrasound screening can lead to diagnosis and treatment of earlier-stage thyroid cancers."
"This study shows that simple neck ultrasound screening is effective in detecting asymptomatic, unsuspected, curable thyroid cancer. The thyroid cancer risk in FAP is high enough that such screening should be offered to all patients." Dr. Church concluded.
Ann Surg. Posted January 4, 2011. Abstract