RADICAL PROSTATECTOMY IMPROVES SURVIVAL IN N+ DISEASE 

NEW YORK (Reuters Health) Jun 07 - For prostate cancer patients with positive lymph nodes, radical prostatectomy, far from being futile, actually improves outcomes, a literature review suggests.

Aborting the surgery when nodes are positive "is no longer supported by current evidence, especially in patients with a limited lymph node tumor burden," conclude the authors of the report in European Urology, published online May 23.

Dr. Georgios Gakis, at Eberhard-Karls University Tubingen, Germany, and an international team say they undertook their study because emerging data have suggested that radical prostatectomy can have a benefit in this setting, and furthermore, that extended pelvic lymphadenectomy in lymph-node-positive prostate cancer may also be beneficial, based on experience with muscle-invasive bladder cancer.

They initially identified 857 relevant records, ultimately citing 69 studies in their paper. They point out that most studies were retrospective and therefore subject to selection bias, and that generally the level of evidence was not high.

Nonetheless, they concluded that radical prostatectomy does improve survival in lymph node (LN)-positive prostate cancer. In one study, for example, 10-year survival was 64% in patients who were treated with radical prostatectomy compared to 28% among those in whom the procedure was aborted - albeit that the groups were imbalanced in terms of the number of positive lymph nodes.

The team also concluded that evidence supports extended lymph node dissection in some patients with LN-positive prostate cancer. A recent prospective study found no difference in five-year progression-free survival for low-risk patients between those who underwent standard or extended pelvic LN dissection (90.1% vs 91.3%), whereas there was a significant difference for intermediate-risk patients (73.1% vs 85.7%; p=0.042) and high-risk patients (51.1% vs 71.4%; p = 0.036).

"Extended pelvic lymph node dissection including the common iliac arteries should be offered to intermediate- and high-risk patients in order to improve nodal staging with a possible benefit in PSA progression-free survival by removing significant metastatic load," Dr. Gakis advised in an email to Reuters Health.

He and his colleagues also found evidence that adjuvant local radiotherapy and androgen deprivation therapy have the potential to improve survival further after radical prostatectomy in LN-positive prostate cancer.

Also, Dr. Gakis noted, "Age is a critical parameter for survival, as cancer-specific mortality exceeds overall mortality in younger patients (aged <60 an="" and="" as="" be="" cancer="" high-risk="" impetus="" p="" possible.="" prostate="" should="" thoroughly="" to="" treat="" with="" years="">

"Altogether," he concluded, "our understanding of surgery of the primary tumor in lymph node-positive prostate cancer needs a conceptual change from a palliative option to the first step in a multimodal approach with a significant improvement of long-term survival and cure in selected patients."

SOURCE: http://bit.ly/11jNJDN

Eur Urol 2013

HER2 NAD BREAST CANCER STEM CELLS 

Cancer Res. 2013 Jun 5. [Epub ahead of print]

HER2 and Breast Cancer Stem Cells: More than Meets the Eye.

Korkaya H, Wicha MS.

Source

Authors' Affiliation: University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan.

Abstract

The development of HER2 targeting agents has dramatically altered the natural history of HER2-positive breast cancer and is often cited as a prime example of the effectiveness of molecularly targeted therapy. Emerging data suggest that the remarkable clinical efficacy of these agents may be related to their ability to target the breast cancer stem cell (CSC) population. A new study suggests that the regulation of BCSCs by HER2 may extend to breast cancers that do not display HER2 gene amplification. In these tumors, HER2 is selectively expressed in the CSC population, and this expression is regulated by the tumor microenvironment. In mouse models, trastuzumab blocked growth of these HER2-negative tumors when administered in the adjuvant setting but had no effect on established tumors. These studies provide a potential biologic explanation for retrospective analysis of clinical trials, which surprisingly suggest that the clinical benefits of adjuvant trastuzumab may extend to women currently classified as HER2-negative. In addition to having significant implications for breast cancer therapy, these studies suggest the need to reevaluate the role of HER2 in regulating CSCs in other tumor types. Furthermore, these studies suggest that effective adjuvant therapies may need to target the CSC population. Cancer Res; 73(12); 1-5. ©2013 AACR.

NO USE OF EVEROLIMUS IN COLORECTAL CANCER

Phase II Study of Everolimus in Patients With Metastatic Colorectal Adenocarcinoma Previously Treated With Bevacizumab-, Fluoropyrimidine-, Oxaliplatin-, and Irinotecan-Based Regimens.

Ng K, Tabernero J, Hwang JJ, Bajetta E, Sharma S, Del Prete SA, Arrowsmith ER, Ryan DP, Sedova M, Jin J, Malek K, Fuchs CS.

Source

Medical Oncology, Dana-Farber Cancer Institute.

Abstract

PURPOSE:

Dysregulation of the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway is seen in 40-60% of colorectal cancer (CRC) patients. Everolimus, an oral inhibitor of mTOR, demonstrated efficacy in metastatic CRC (mCRC) patients in phase I studies.

EXPERIMENTAL DESIGN:

In sequential phase II studies assessing 2 dosing schedules, mCRC patients refractory to bevacizumab-, fluoropyrimidine-, oxaliplatin-, and irinotecan-based regimens received everolimus 70 mg/week (N=99) or 10 mg/d (N=100). Primary endpoints were disease control rate (DCR) and objective response rate; secondary endpoints included progression-free survival (PFS), overall survival (OS), and duration of response or stable disease (SD). Tumor tissue was collected from all patients for predefined exploratory biomarker analyses.

RESULTS:

71 patients were included in the per protocol set for each cohort. DCRs of 31.0% and 32.4% (all SD) were seen in the weekly and daily schedules, respectively. Median duration of SD was 3.9 months in each cohort. Median PFS and OS were 1.8 months and 4.9 months and 1.8 months and 5.9 months, respectively, for the weekly and daily schedules. Among patients receiving daily everolimus, those with a KRAS mutation experienced significantly shorter median OS (P = .008) and lower DCR (P = .035) compared with those with wild-type KRAS in exploratory biomarker analyses.

CONCLUSIONS:

Everolimus 70 mg/week or 10 mg/day was well tolerated but did not confer meaningful efficacy in heavily pretreated mCRC patients. Future studies may consider evaluating everolimus in combination with other agents or in patients with dysregulation of the PI3K/Akt/mTOR pathway.

BE CAREFUL 

An oncologist at a top cancer center in the United States has allegedly poisoned a fellow oncologist at the center, with whom she was having a relationship.

Ana Maria Gonzalez-Angulo, MD, a principal investigator in a major breast cancer clinical trial and section head at the University of Texas M.D. Anderson Cancer Center in Houston, has been charged with the aggravated assault of a fellow staffer, oncologist George Blumenschein, MD.

Dr. Gonzalez-Angulo, 42, allegedly poisoned Dr. Blumenschein with ethylene glycol, a common lab chemical that is also an ingredient in antifreeze and can be fatal.

Dr. Gonzalez-Angulo's lawyer says that she is "completely innocent," according to a statement in multiple news reports.

The oncologist pair had a "casual sexual relationship," according to Dr. Blumenschein in an affidavit filed in the case on May 29.

When they were alone at her place on January 27, Dr. Gonzalez-Angulo served Dr. Blumenschein a cup of coffee that had an "odd taste," he stated in the complaint, which was published online last week in the Houston Chronicle.

Dr. Blumenschein, who prefers his coffee black, questioned Dr. Gonzalez-Angulo about the brew because it tasted "sweet."

She replied that it contained Splenda, an artificial sweetener, and later provided him with a second cup — but only after instructing him to "finish the first cup first."

Dr. Blumenschein, who is a lung cancer researcher and clinician, drank both cups.

Within 4 hours, he reportedly experienced slurred speech, poor balance, and loss of fine motor skills. About 16 hours after the coffee klatch, he was admitted to a hospital emergency department and was diagnosed with central nervous system depression, cardiopulmonary complications, and renal failure. He is under continued care for the kidney injury.

Lab testing revealed results "consistent with ethylene glycol poisoning." The chemical reportedly has a sweet taste.

A medical toxicology report cited in the affidavit said that the acute severe metabolic acidosis found in Dr. Blumenschein was "more likely than not due to ethylene glycol poisoning."

The affidavit also notes that ethylene glycol was not directly found in the blood or urine of Dr. Blumenschein. However, 2 experts quoted point out that the metabolism process would have cleared the substance in the amount of time that transpired between the alleged event and the hospitalization.

An administrator at M.D. Anderson confirmed that ethylene glycol is "present in all the labs" at the facility, according to the affidavit.

Dr. Gonzalez-Angulo, who attended medical school at the Universidad del Cauca in Colombia and moved to the United States to continue her training, has been at M.D. Anderson since 2003, when she was a Susan G. Komen Interdisciplinary Breast Cancer fellow.

Been in the Spotlight Before

Dr. Gonzalez-Angulo, who can be seen in a Komen for the Cure video that takes the viewer through a day in her clinical life, has a significant profile in the world of breast cancer research and clinical trials.

She has had research funded by the heavyweights of oncology: the National Cancer Institute (NCI), the American Society of Clinical Oncology, The Breast Cancer Research Foundation, Komen for the Cure, the American Association for Cancer Research (Stand Up To Cancer), and the Commonwealth Foundation for Cancer Research, according to online biographic information.

She is also the author of a blog entitled "31 Days of Impact" on the Komen Web site.

Dr. Gonzalez-Angulo is a principal investigator of a trial that has been described as seeking to "answer one of the most important scientific and clinical questions in breast oncology," according the Breast Cancer Research Foundation Web site.

The trial, known as RxPONDER S1007 (Rx for Positive Node, Endocrine Responsive Breast Cancer), is a phase 3 clinical trial led by the Southwest Oncology Group and carried out by the North American Breast Cancer Group.

The outstanding clinical question is whether chemotherapy benefits patients with node-positive breast cancer who have a low to intermediate Oncotype DX recurrence score.

At M.D. Anderson, Dr. Gonzalez-Angulo is chief of the section of clinical research and drug development in the Department of Breast Medical Oncology. She is also a tenured associate professor in the Department of Systems Biology.

She is a principal investigator of phase 1 clinical trial sponsored by the NCI of the experimental agent MK2206 (Merck) in locally advanced or metastatic solid tumors or metastatic breast cancer and of a phase 1 trial of the agent BYL719 (Novartis) in patients with advanced solid tumors who have an alteration of the PIK3CA gene.

Dr. Gonzalez-Angulo has 119 peer-reviewed published articles listed on her resume on the M.D. Anderson Web site.

Dr. George Blumenschein is an associate professor in the Department of Thoracic/Head and Neck Medical Oncology at M.D. Anderson. He has been at the cancer center since 2000, when he started as an instructor of medicine.

He is listed as a principal investigator on multiple clinical trials in lung cancer.

GENE PATENTS ARE FORBIDDEN 

In an highly anticipated decision, the Supreme Court has effectively invalidated the patents held by Myriad Genetics for the BRCA1 and BRCA2 genes.

However, the ruling is not all bad news for Myriad.

The Court unanimously ruled that although naturally isolated DNA is not patentable, synthetically created exon-only strands of nucleotides — complementary (c)DNA — is patentable.

In essence, the Court ruled that 5 of Myriad's claims covering isolated DNA are not eligible for patents. But according to Myriad, the company holds more than "500 valid and enforceable claims in 24 different patents conferring strong patent protection for its BRACAnalysis test."

The ruling was written by Justice Thomas, who was joined by Chief Justice Roberts and Justices Kennedy, Ginsberg, Breyer, Alito, Sotomayor, and Kagan; Justice Scalia concurred in part. The Court held that "a naturally occurring DNA segment is a product of nature and not patent eligible merely because it has been isolated, but cDNA is patent eligible because it is not naturally occurring."

It notes that "Myriad's principal contribution was uncovering the precise location and genetic sequence of the BRCA1 andBRCA2 genes." Although this was an important contribution, "Myriad did not create or alter either the genetic information encoded in the BCRA1 and BCRA2 genes or the genetic structure of the DNA."

In the decision, Justice Thomas notes that Myriad's claims were not "saved by the fact that isolating DNA from the human genome severs chemical bonds and thereby creates a non-naturally occurring molecule." This is because the claims are "simply not expressed in terms of chemical composition, nor do they rely in any way on the chemical changes that result from the isolation of a particular section of DNA."

However, the decision leaves the door somewhat open on gene patenting because it distinguishes natural from synthetic DNA. The Court noted that "cDNA does not present the same obstacles to patentability as naturally occurring, isolated DNA segments."

More specifically, Justice Thomas points out that "cDNA retains the naturally occurring exons of DNA, but it is distinct from the DNA from which it was derived." Thus, this form of DNA is "not a 'product of nature' and is patent eligible under §101."

Long and Convoluted Journey

Today's decision puts an end to what has been a long and protracted case. Myriad acquired patents on the 2 genes in the mid-1990s. Since that time, it has become the sole commercial provider of testing services for BRCA1 and BRCA2 in the United States.

On May 12, 2009, the American Civil Liberties Union and the Public Patent Foundation filed a lawsuitagainst the US Patent and Trademark Office, Myriad Genetics, and the University of Utah Research Foundation, which hold the patents on the BRCA1 and BRCA2 genes. It charged that patents on human genes violate the First Amendment and patent law because genes are "products of nature," and therefore cannot be patented.

The coplaintiffs in the case, including several medical organizations, physicians, academic researchers, cancer survivors, and patient advocates, represented 150,000 geneticists, pathologists, and laboratory professionals.

On March 29, 2010, a New York federal court ruled against Myriad, finding that patents on the BRCA1and BRCA2 genes were invalid. Myriad appealed the case, and it was heard by the US Court of Appeals for the Federal Circuit in April 2011. Three months later, the appeals court ruled in Myriad's favor, finding that companies can obtain patents on specific genes.

In March 2012, the US Supreme Court instructed the appeals court to reconsider the case after a unanimous ruling invalidated 2 patents on a blood test that determines drug dosages, which had been licensed to Prometheus Laboratories.

In August 2012, a divided federal appeals court (2 to 1) ruled in favor of Myriad and gene patents in general. However, the Court invalidated patents on methods used to compare gene sequences. A month later, the plaintiffs once again asked the Supreme Court to hear the challenge to Myriad's patents. In November 2012, the Supreme Court agreed to hear it.

Today's decision is likely to have far-reaching implications for the biotechnology industry, and will undoubtedly raise questions about the validity of thousands of other patents that are currently in force.

Victory for Both Sides?

Both sides of the court battle see the ruling as a victory. The American Society for Clinical Pathology (ASCP) and Breast Cancer Action, both plaintiffs in the case, have expressed satisfaction with the ruling in press releases.

"Isolated DNA is a product and law of nature, not an invention, so it is not open to patent protection," said Steve Kroft, MD, FASCP, president-elect of the ASCP, in a statement. "Gene patents hinder advances in patient care and make the process slower and more expensive for women to find out if they have certain gene mutations that could adversely affect their health."

According to the ASCP, the cost of BRCA testing will be considerably lower without patent protection, and laboratories nationwide will be able to conduct the tests. In addition, patients will be able to obtain a second opinion, which Myriad Genetics has not allowed.

Breast Cancer Action, a nonprofit advocacy group, called the decision a "tremendous win for women's health — and for all our health!" They echoed the sentiments of the ASCP, in that "Myriad's monopoly is broken and other labs can conduct testing, perform vital research, and develop treatments using the human BRCA1 and 2 genes."

Myriad also claimed victory because the Court upheld its claims on cDNA, and pointed out that the Court noted that many of Myriad's unchallenged claims are method claims applying knowledge about the BRCA1 and BRCA2 genes.

"We believe the Court appropriately upheld our claims on cDNA, and underscored the patent eligibility of our method claims, ensuring strong intellectual property protection for our BRACAnalysis test moving forward," said Peter D. Meldrum, president and CEO of Myriad. "More than 250,000 patients rely on our BRACAnalysis test annually, and we remain focused on saving and improving peoples' lives and lowering overall healthcare costs.

BENEFIT OF CYTOREDUCTIVE SURGERY-HIPEC FOR PERITONEAL CARCINOMATOSIS 

Cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy (CS/HIPEC) appears to be safe and effective for select patients with advanced abdominal cancers, according to a retrospective analysis published in the June issue of Cancer Medicine.

"There has been much discussion as to whether there is a benefit with this procedure, and historically it has been associated with a lot of risk," senior author Joseph J. Skitzki, MD, a surgical oncologist at Roswell Park Cancer Institute in Buffalo, New York, said in a news release. "However, reviewing our data in patients treated with CS/HIPEC over the last decade showed a statistically significant benefit in terms of survival, with low morbidity and low mortality."

It is thought that candidates for CS/HIPEC are patients with appendiceal, colorectal, or mesothelioma tumors that are refractory to standard chemotherapy and/or previous surgery. With this approach, all visible metastases to the peritoneum are removed surgically and then high doses of heated chemotherapeutic agents are perfused throughout the abdomen to eradicate any remaining cancer cells. To limit systemic toxicity, the chemotherapy is administered only to the targeted area and is washed out after 90 minutes. The entire procedure takes 8 to 18 hours.

"HIPEC is an extremely invasive procedure that an increasing number of cancer centers across the United States offer," Dr. Skitzki said. "Our research shows that when it's used for appropriate candidates as part of a multidisciplinary treatment approach in an experienced setting, outcomes will be favorable, compared with standard combination therapy, with the added benefit of shorter-term side effects."

Because most reports of CS/HIPEC use in the United States come from a very few high-volume centers, "the applicability of CS/HIPEC among a broader spectrum of providers has been questioned," said Jan Franko, MD, PhD, from Mercy Medical Center in Des Moines, Iowa. He was asked byMedscape Medical News to comment on the analysis.

The study "provides increasing support of the technical safety of CS/HIPEC in proper settings," Dr. Franko noted in an email. "The data demonstrate that CS/HIPEC can be safely implemented outside of traditional high-volume centers."

History of Peritoneal Carcinomatosis Treatment

The average life expectancy for a patient with peritoneal carcinomatosis (PC) from nongynecologic adenocarcinomas has historically been 6 months. Surgical cytoreduction to remove all visible tumor was first reported in the 1930s for ovarian cancer, and was eventually accepted for nongynecologic PC, with proven survival benefit. CS/HIPEC was introduced several decades later, with accumulating evidence supporting clinical efficacy, Dr. Skitzki and colleagues explain.

They note that in 11 phase 2 studies of colorectal PC treated with CS/HIPEC, the 5-year overall survival rate ranged from 25% to 47% (J Clin Oncol. 2003;21:3737-3743). They also cite a phase 3 randomized controlled trial in this population that showed that overall survival was significantly better with CS/HIPEC than with standard therapy alone (21.6 vs 12.6 months), as was the 6-year survival rate (20% vs 5%). For patients in that study who achieved complete cytoreduction, 5-year survival was 45%; for those with incomplete cytoreduction, median survival was less than 1 year (Cancer J. 2009;15:212-215).

Caveats include potential selection bias and high morbidity. In many studies, perioperative complication rates range from 27% to 56% and mortality rates range from 8% to 11%.

Study Design and Findings

Dr. Skitzki and colleagues retrospectively reviewed 112 patients undergoing CS/HIPEC from 2003 to 2011. The mean age was 53 years, and half of the patients had received systemic chemotherapy.

Morbidity associated with CS/HIPEC was similar to that associated with other major surgical oncology procedures. None of the patients died during surgery or within 30 days; the 60-day mortality rate was 2.7%, the researchers report.

That 60-day mortality rate "is extremely low," Dr. Franko noted. "It is similar to other high-volume centers and directly comparable to the 60-day mortality of current cytotoxic chemotherapy for metastatic colorectal cancer." This study validated the association between CS-HIPEC and low mortality and acceptable morbidity in proper settings, and "is best viewed as an important confirmatory and validating report," he explained.

Dr. Skitzki and colleagues note that an increasing number of bowel resections is associated with an increased incidence of abscess, enterocutaneous fistula, deep surgical-site infection, and the need for repeat surgery. Reoperation is linked to lower overall and progression-free survival.

"Akin to other reports of worsened overall and disease-free survival among those with surgical complications, this study demonstrated inferior overall survival and progression-free survival among those suffering from complications," Dr. Franko said.

Site of tumor origin and histology predicted 5-year overall survival rates, which were 91.3% for disseminated peritoneal adenomucinosis, 80.8% for mesothelioma, 38.7% for appendiceal adenocarcinoma, and 38.2% for colorectal adenocarcinoma.

In other words, more than 1 of 3 patients with stage IV colon cancer treated with CS/HIPEC survived for at least 5 years, and some never had a recurrence. In contrast, historic survival rates for peritoneal colorectal carcinoma have typically been measured in months, with 5-year overall survival rates approaching zero, Dr. Skitzki and colleagues point out.

"With an acceptable morbidity and mortality rate, CS/HIPEC should be included as an effective treatment modality in the multidisciplinary care of select patients with peritoneal metastases," they write.

Study Limitations and Implications

Study limitations include the retrospective design of the analysis (leading to possible selection bias), the lack of inclusion of patients receiving only systemic chemotherapy, the relatively small sample size, the limited generalizability of the results, and the inclusion of a variety of tumor types.

"It is difficult to analyze the survival data provided by the authors, because a great variety of histology was included. Clearly, survival analysis was not the primary objective," Dr. Franko said.

In addition, the Peritoneal Cancer Index (PCI), a marker of the extent and location of disease in the abdominal cavity, was not scored intraoperatively. In many patients, pretreatment with systemic chemotherapy prevents the calculation of the true PCI score, he pointed out.

Dr. Franko suggested that future research should focus on specific histologies and analyze subgroups of colorectal carcinomatosis and peritoneal mesothelioma separately, and should identify the best sequencing and combination of intraperitoneal and systemic chemotherapy.

The National Cancer Institute funded this study in part. The study authors and Dr. Franko have disclosed no relevant financial relationships.

Cancer Med. 2013;2: 334-342. Abstract

ONCOFETAL GENE AS MARGER OF HCC AGGRESSIVENESS 

The discovery that an oncofetal gene, SALL4, appears to be a marker for aggressive liver cancer has ignited hope that it can be used to screen patients and that it will offer a new target for drug development.

"Hepatocellular carcinoma is the third leading cause of cancer-related deaths worldwide," Kol Jia Yong, BSc, from the Cancer Science Institute of Singapore and the National University of Singapore, and colleagues write in their report published in the June 13 issue of the New England Journal of Medicine.

"In the heterogeneous group of hepatocellular carcinomas, those with characteristics of embryonic stem-cell and progenitor-cell gene expression are associated with the worst prognosis. The oncofetal gene SALL4, a marker of a subtype of hepatocellular carcinoma with progenitor-like features, is associated with a poor prognosis and is a potential target for treatment," they note.

The investigators screened specimens from patients with primary hepatocellular carcinoma to detectSALL4 expression. They then conducted loss-of-function studies to determine the role of SALL4 in hepatocarcinogenesis and its potential as a molecular target for therapy. In vitro functional and in vivo xenograft assays allowed them to evaluate the therapeutic effects of a peptide targeting SALL4.

The stem-cell factor SALL4 was expressed in the human fetal liver but not in the healthy adult liver. However, in a subgroup of patients with hepatocellular carcinoma and an unfavorable prognosis, theSALL4 oncofetal protein was re-expressed.

Gene-expression analysis revealed that in SALL4-positive hepatocellular carcinomas, progenitor-like gene signatures are enriched and proliferative and metastatic genes are overexpressed. SALL4 is essential for cancer cell survival and tumorigenicity, according to loss-of-function studies.

In xenograft models in vivo, blocking SALL4–corepressor interactions released suppression of the phosphatase and tensin homolog protein and inhibited tumor formation. These findings add biologic credibility to SALL4 as a prognostic marker and suggest that targeting this pathway could be of therapeutic value.

Study Limitations and Implications

"The discovery of a role for SALL4 in hepatocellular carcinoma, its association with prognosis, and the antitumor effects of a newly identified peptide blocker targeting it have potential therapeutic significance," the investigators conclude. "Testing for the presence of SALL4 at diagnosis may be helpful not only for determining the prognosis but also for identifying patients who are likely to have a response to treatment. Given the expression of SALL4 in hepatocellular carcinoma cells but not in normal adult hepatocytes, treatment with SALL4 peptide may have less tissue toxicity, which is especially beneficial in patients with underlying cirrhosis whose baseline liver function is already compromised."

Limitations of this study include the retrospective design. The investigators recommend prospective clinical trials to verify the prognostic value of SALL4 and to determine whether it has synergistic potential with sorafenib or other molecular therapies that act on parallel nonoverlapping pathways.

In an accompanying editorial, Jens U. Marquardt, MD, from the National Cancer Institute in Bethesda, Maryland, and colleagues note that hepatocellular carcinoma is the most common and deadly cause of primary liver cancer. Most patients with hepatocellular carcinoma still present at advanced stages, when there are limited curative options.

"Currently, the standard-of-care treatment for advanced liver cancer is limited to the multiple receptor tyrosine kinase inhibitor sorafenib," the editorialists write. "Furthermore, development of new therapies is often hampered by the molecular complexity of hepatocellular carcinoma, as well as associated inflammatory and fibrotic liver disease. Results of ongoing clinical trials are discouraging overall, and they highlight the urgent and unmet need for innovative treatment approaches in patients with advanced stages of hepatocellular carcinoma."

Therapeutic Potential of Targeting SALL4

The editorialists call the study findings "convincing," but insufficient to determine whether the targeting of SALL4 alone has enough antitumor activity to prevent recurrent disease, or whether inhibition of the associated transcriptomic programs is also required.

"Another open question is whether responses to SALL4 inhibition in stemness-associated tumors vary according to the patient's ethnic origin and the cause of the hepatocellular carcinoma (e.g., hepatitis B virus, hepatitis C virus, and alcohol); this variability has been repeatedly observed in other targeted therapies," Dr. Marquardt and colleagues write. "Also, the present data do not resolve whether tumors that overexpress SALL4 are derived from reprogrammed hepatocytes or rare stem cells; the latter might have a major effect on the regenerative capacity of the liver and should be considered in a therapeutic context."

Interim results from an ongoing phase 2 trial of the HDAC inhibitor resminostat appear to be promising and may now warrant further subgroup analyses according to SALL4 status.

Similarly, these findings support those from a phase 2 trial of the c-MET inhibitor tivantinib, which demonstrate that biopsies are mandatory for molecular subclassification in patients with advanced hepatocellular carcinomas.

The study findings "elegantly show the benefit of innovative treatment strategies in hepatocellular carcinoma, including the targeting of genes with stem-cell features such as SALL4," the editorialists conclude. "Clinical translation of these important findings is urgently needed to achieve individualized therapies and ultimately improve the poor outcome in patients with hepatocellular carcinoma."

A press release from the National University of Singapore notes that 2 patents have already been filed on this research. It also notes that, because SALL4 is associated with other types of cancers, such as leukemia and solid tumors (including ovarian, endometrial, gastric, breast and lung cancers), the findings could contribute to an improvement in the treatment of such diseases.

The Singapore National Medical Research Council and grants from the Singapore Ministry of Education, National Research Foundation, and the National Institutes of Health funded this study.

N Engl J Med. 2013;368:2266-2276, 2316-2318. 

DUAL HER2 BLOCKADE DO NOT INCREASE CARDIOTOXICITY 

NEW YORK (Reuters Health) Jun 10 - Dual HER2 blockade didn't increase heart problems in a meta-analysis of data from patients with HER2-positive breast cancer.

"The combination of dual HER2 blockade is so far as safe as anti-HER2 monotherapy in terms of cardiotoxicity," Dr. Antonis Valachis told Reuters Health by email. "As a result, the clinicians who choose such combinations for the treatment of their patients or propose a clinical study to their patients with combination should not be worried about increased cardiac toxicity."

As reported May 29 online in the International Journal of Cancer, Dr. Valachis of the University of Uppsala, Sweden, and colleagues conducted a meta-analysis of six randomized trials. Overall, 1,142 patients received combined anti-HER2 therapy and 1,473 received anti-HER2 monotherapy.

In fact, the incidence of congestive heart failure (CHF) was 0.88% in the combination group and 1.49% in monotherapy patients (odds ratio 0.58).

Corresponding rates of left ventricular ejection fraction (LVEF) decline to less than 50% or 10% below baseline were 3.1% and 2.9% (odds ratio 0.88).

Subgroup analyses showed no association between combination therapy and CHF or LVEF, neither in the two trials in the metastatic setting nor in the four trials in the adjuvant setting.

In fact, say the investigators, "we could not find a subgroup in which dual anti-HER2 blockade was associated with excess cardiac toxicity."

Still, they caution, "Appropriate patient selection and cardiac monitoring are essential to prevent and manage potential cardiac adverse events."

As they stand, pending further study, the results "are valid for patients with adequate cardiac function at baseline (namely before the start of combination therapy)," Dr. Valachis said.

SOURCE: http://bit.ly/106kQRz

Int J Cancer 2013.

PET/CT 3 MONTHS AFTER LIVER METASTATECTOMY 

VANCOUVER, British Columbia — Early positron emission tomography and computed tomography (PET/CT) imaging is effective at identifying local-site recurrences of colorectal liver metastases after radiofrequency ablation. Although there are no guidelines for the timing or interpretation of images, they are best used 3 to 12 months after radiofrequency ablation, according to a new study.

Liver metastases are common in patients with colorectal cancer. In some cases, the lesions can be effectively treated with radiofrequency ablation. If local-site recurrences are caught early enough, they can also be treated with radiofrequency ablation.

"Most physicians use contrast-enhanced CT or MRI to do follow-up on these patients, although there is literature that suggests a beneficial role for PET/CT because of the added metabolism factor that you have with PET," said Karin Nielsen, MD, a PhD student at the VU University Medical Centre in Amsterdam, the Netherlands.

Dr. Nielsen presented the research here at the Society of Nuclear Medicine and Molecular Imaging 2013 Annual Meeting.

"We know that the sensitivity and specificity between normal CT and PET/CT differs by 10% to 15%," so you miss a significant number of local-site recurrences, Dr. Nielsen told Medscape Medical News. When you see them in follow-up scans, they could be too large for repeated treatment, she noted.

The researchers set out to develop criteria for PET/CT image interpretation after radiofrequency ablation and to determine a timetable for follow-up analyses.

The study involved patients who underwent radiofrequency ablation for colorectal liver metastases and then underwent PET/CT in the 12 months after treatment. They defined local-site recurrences as increased fluorodeoxyglucose uptake in the ablated region or adjacent to it.

Dr. Nielsen and colleagues analyzed 170 scans from 79 patients with 179 ablated regions. Of those patients, 72.2% were scanned in the 6 months after treatment. Of the 30 patients who developed a local-site recurrence, 90.0% occurred in the 9 months after treatment and 96.7% occurred in the 12 months after treatment.

"The problem of incomplete ablation is notorious; that's why follow-up is so important after that treatment," said Dr. Nielsen. "PET is absolutely important in the first year after ablation, but not before 3 months," she added. Just 2% of lesions smaller than 1 cm and 4% of lesions smaller than 2 cm showed a local-site recurrence.

These findings should be clinically useful, according to Darko Pucar, MD, from Georgia Regents University in Augusta, who attended the session.

"In clinical practice, you need to apply very firm criteria, but something that is easy to apply, not only for academic doctors, but also for practitioners. What I like about this study is that they provide relatively clear guidelines," Dr. Pucar told Medscape Medical News. "Sometimes, if something is very complicated, physicians don't act immediately. This is simple and actionable."

Dr. Nielsen and Dr. Pucar have disclosed no relevant financial relationships.

Society of Nuclear Medicine and Molecular Imaging (SNMMI) 2013 Annual Meeting: Abstract 67. Presented June 9, 2013.

1 mm MARGIN OK FOR LIVER METASTATECTOMY 

NEW YORK (Reuters Health) Jun 12 - When resecting colorectal liver metastases, a 1-mm margin should be the standard of care, instead of a 1-cm margin, according to researchers at two major liver resection centers in the UK.

This study, the investigators say in their report, "rejects the null hypothesis that a 1-mm margin is not sufficient for cure of patients with resectable colorectal liver metastases. It supports previous studies that the width of cancer-free resection margin is not important in modern liver resection practice."

Their conclusion is drawn from data on 2,715 consecutive patients who had primary liver resection for colorectal metastases, under similar assessment and resection protocols.

"There is consensus that a histological positive resection margin is a predictor of disease recurrence after resection of colorectal liver metastases," Dr. Zaed Hamady of St. James's University Hospital, Leeds and colleagues say. Yet, there is ongoing debate over the appropriate width of a cancer-free resection margin.

In a paper online now in Annals of Surgery, they say a "handful" of observational studies in the last decade have argued for or against a 1-cm margin as the minimum for curative resection.

Some studies have suggested that a 1-mm microscopic cancer-free resection margin is sufficient for a curative resection and for achieving long-term survival matching that of a 1-cm cancer-free resection margin. But others have argued that patients with less than a 1-cm margin have poorer outcomes.

That's not what Dr. Hamady and colleagues found.

In their series, a 1-mm cancer-free resection margin was sufficient to achieve 33% five-year overall disease-free survival, and extra margin width did not further boost disease-free survival.

Also, in a propensity score case-matched analysis, there was no statistical difference in disease-free survival between patients with negative narrow and wider margin clearance. The hazard ratio was 1.0 at a cutoff of 5-mm and 1.1 at a cutoff of 10-mm.

"Our study represents the strongest evidence up to date in support of the concept that a narrow (and clear) margin of tumor clearance is sufficient," the researchers say.

But, the paper says, patients with extrahepatic disease and positive lymph node primary tumor had an "extremely short survival time after what was assumed to be curative resection, even if the resection margin was clear and more than 1-mm. This may indicate that tumor biology is a more important factor in disease-free survival than surgical margin clearance."

The authors did not respond to a request for comment.

ASCO RAISES THE BAR FOR CLINICAL TRIALS 

CHICAGO — As technology and therapies evolve, so must the design of clinical trials, which provide the evidence base used to improve cancer treatments. To "raise the bar" on clinical trial standards, the American Society of Clinical Oncology (ASCO^®) has issued draft recommendations for the design of trials that provide "clinically meaningful outcomes."

During a session here at the 2013 Annual Meeting of ASCO, Lee Ellis, MD, explained why the ASCO cancer research committee decided to put together these guidelines.

"First, we owe it to our patients to do better," said Dr. Ellis, who is committee chair and director of the colorectal cancer translational research program at the University of Texas M.D. Anderson Cancer Center in Houston.

Second, in the current era, "tumors can be defined by their molecular drivers and we have a better understanding of cancer biology. Immune therapy is working, and we need to exploit this and look for biomarkers," he noted.

Third, "with only so much money in the bank" because of economic restraints from funding agencies, there is a choice between doing a few large trials or many small trials. But the small trials need to be smarter, so we have to raise the bar.

Dr. Ellis emphasized that these are only draft recommendations, and the committee continues to receive feedback from the community. "These are not rules, so if you don't meet all of them, it doesn't mean that your clinical trial is not useful," he said. "But we have to set the bar in order to do better, to use the foundation of genomic medicine and what we know about immunology to improve outcomes."

He noted that these guidelines will not please everyone and, in a way, "that's good." There are many valid arguments for various viewpoints, he said.

We believed if we aimed too high or too low, "no one would pay attention," Dr. Ellis explained. "We worked really hard to hit that midpoint, where we would get people intrigued by our recommendations."

Draft Recommendations for Pancreatic Cancer

The committee looked at 2 disease states — metastatic pancreatic cancer and locally advanced disease — and 2 treatments — FOLFIRONOX (irinotecan, oxaliplatin, leucovorin, and 5-fluorouracil) and gemcitabine.

It is recommended that clinical trials aim to improve overall survival by ~50% and that toxicity and quality of life specific to pancreatic cancer be taken into consideration.

For the FOLFIRONOX group, a meaningful benefit in median overall survival would be 4 to 5 months; for gemcitabine, it would be 3 to 4 months.

Draft Recommendations for Lung Cancer

The committee looked at 2 subpopulations of patients with advanced metastatic (stage IV) nonsmall-cell lung cancer — those with squamous cell disease and those with nonsquamous cell disease.

Patients with EGFR and ALK mutations were excluded because there has been some degree of success with those.

It is recommended that clinical trials aim to improve overall survival by ~25% to 30%, with a minimal increase in toxicity. For squamous cell disease, that benefit would be an increase of 2.5 to 3.0 months (target hazard ratio [HR], 0.77 - 0.80); for nonsquamous cell disease, it would be 3.25 to 4.00 (target HR, 0.76 - 0.80).

Draft Recommendations for Breast Cancer

Dr. Ellis noted that the discussion was livelier and the opinions more diverse for breast cancer than for the other cancers.

The committee selected metastatic triple-negative breast cancer that was previously untreated for metastatic disease. In this population, survival is poor, there is an absence of validated targeted therapies, and there is an urgent need for better treatment options.

Currently, the median overall survival in this population is 18 months, and cytotoxic therapies provide only a short benefit (2 to 3 months). The general consensus for a meaningful benefit in median overall survival was 4.5 months, said Dr. Ellis. "This encourages bold approaches."

Draft Recommendations for Colorectal Cancer

Subpopulations are difficult to define in colorectal cancer, and treatment is a continuum, not an orderly progression from first- to second-line therapies. In addition local/regional approaches confound the analysis of common end points. Therefore, the committee focused on patients who have progressed on first- or second-line therapy or who are not candidates for standard therapies, and excluded those with BRAF-mutated tumors.

It is recommended that clinical trials aim to improve overall survival by ~50% in patients who have progressed on standard treatments, and the increase in toxicity should be minimal. The general consensus for a meaningful benefit in median overall survival was 3 to 5 months.

The To-Do List

There is still a to-do list to complete for these draft recommendations, Dr. Ellis noted.

The 1- and 2-year survival recommendations need to be revisited, and progression-free survival needs to be added to tables, where appropriate, he explained. Statistics need to be revised and tables need to be added that define the number of patients needed for the ranges provided in specific tables.

"Once we respond to comments from the ASCO membership and refine our paper, we'd like to submit it for peer reviewed publication," he added.

2013 Annual Meeting of the American Society of Clinical Oncology. Presented June 2, 2013.

VISMODEGIB APPROVE DIN SWITZERLAND 

ZURICH (Reuters) Jun 11 - Roche Holding AG has received Swiss approval for vismodegib (Erivedge) for treatment of advanced forms of basal cell carcinoma.

Erivedge is designed to selectively inhibit abnormal signaling in the Hedgehog pathway, which is an underlying molecular driver of basal cell carcinoma, Roche notes in a statement.

Erivedge is an oral drug taken three times daily.

The drug was approved in the United States earlier in January and recommended for approval by European regulators in April.

According to Roche, the most common side effects of Erivedge are muscle spasms, hair loss, change in how things taste or loss of taste, weight loss, tiredness, nausea, diarrhea, decreased appetite, constipation, vomiting and joint aches.

Other side effects may include missed monthly periods in women of childbearing age, low levels of sodium in the blood, low potassium levels, and a higher than normal blood level of urea or other nitrogen containing compounds in the blood.

XGEVA APPROVED FOR GIANT CELL TUMOR 

The US Food and Drug Administration (FDA) today expanded the approved use of denosumab (Xgeva, Amgen) to include the treatment of adults and some adolescents with giant cell tumor of the bone (GCTB), a rare condition that is usually noncancerous.

Denosumab is intended for use in adults when GCTB is unresectable or when surgery is likely to result in severe morbidity. It is only indicated for adolescents whose bones have matured.

The drug becomes the first systemic therapy for this condition, which typically does not metastasize but causes pain, limited range of motion, and bone fractures. Only rarely does GCTB transform into a cancerous tumor, which in turn can spread to the lungs.

Denosumab, which was first approved by the FDA in June 2010 for the treatment of osteoporosis, was approved later that year for use in preventing skeletal-related events in adults with solid tumors and bone metastases. It is also approved in Europe for the same use.

Denosumab is a fully human monoclonal antibody that targets the receptor activator of the nuclear factor-kappa-B ligand (RANKL) protein, which contributes to bone maintenance. That protein is present in GCTB.

News of the drug's promise in GCTB was widely covered in 2010.

"Today's approval of denosumab provides a needed treatment option for patients with GCTB who are not surgical candidates or who would otherwise have to undergo extensive, life-altering surgery," said Richard Pazdur, MD, director of the Office of Hematology and Oncology Products at the FDA Center for Drug Evaluation and Research, in a press statement.

Of 305 adult or adolescent patients in clinical trials, 187 had measurable tumors, 47 of whom had a reduction in tumor size after an average of 3 months. Only 3 of the responding patients had regrowth of GCTB during follow-up (median duration, 20 months).

All the clinical trial participants had confirmed cases of GCTB that were recurrent, unresectable, or vulnerable to severe morbidity upon surgery.

The common adverse effects of denosumab reported in the clinical trials include arthralgia, headache, nausea, fatigue, back pain, and extremity pain. The most common serious adverse effects were osteonecrosis of the jaw and osteomyelitis. The FDA notes that women of reproductive potential should use highly effective contraception while taking denosumab because of potential fetal harm.

The FDA reviewed denosumab as an orphan product under its priority review program.

"Advances in our understanding of the underlying biology of this rare disorder have allowed Amgen to generate compelling clinical evidence to address the medical need of patients and their healthcare providers," said Sean E. Harper, MD, executive vice president of research and development at Amgen, in a press statement.

AN ALTERNATIVE REGIMEN THAT LOWERS PSA 

CHICAGO, Illinois — A commercially available food supplement that contains pomegranate, broccoli, green tea, and turmeric significantly lowers prostate-specific antigen (PSA) levels, compared with placebo, in patients with prostate cancer, a double-blind placebo-controlled randomized trial has shown.

The study results, presented here at the 2013 Annual Meeting of the American Society of Clinical Oncology (ASCO^®), made headlines around the world and caused the polyphenol-rich supplement, known asPomi-T (nature Medical Products), to sell out within hours.

This is a "promising new therapy," said Tomasz Beer, MD, professor of medicine and director of the prostate cancer research program at the Oregon Health and Science University in Portland, during a "highlights of the day" session.

"We have been staggered by the level of interest...from medical professionals and the public," Marcus Williams, owner and director of nature Medical Products, told Medscape Medical News. As soon as the results of this study were released, the company, based in Porthcawl, South Wales, United Kingdom, received a rush of orders from customers in Australia, Canada, the United Kingdom, and the United States.

"It's awesome," the study's lead investigator, Robert Thomas, MD, a consultant oncologist at Bedford Hospital and Addenbrooke's Hospital, in the United Kingdom, told Medscape Medical News.

"We didn't expect such a big response. People are seeing that this can change practice...because men and their doctors do look at their PSA as a deciding factor in whether to stop active management," he explained.

Significantly Different Than Placebo

The study involved 203 men (average age, 74 years) with a PSA relapse after radiotherapy or surgery for localized prostate cancer. The men, who were being managed with active surveillance, were randomized to receive the supplement 3 times a day for 6 months or placebo.

At 6-month follow-up, the median increase in PSA was 63.8% lower in the supplement groups than in the placebo group (14.7% vs 78.5; P =.0008). In addition, PSA levels were stable or lower than baseline more often in the supplement group (46% vs 14%; P = .00001).

Fewer men in the supplement group than in the placebo group went on to receive brachytherapy, radiotherapy, surgery, or androgen-deprivation therapy (7.4% vs 26.0%; P = 0.01).

At the end of the study, more men in the supplement group than in the placebo group continued on active surveillance (92.6% vs 74.0%). "This is an end point we feel is important: more men were choosing to stay on treatments with less toxicity," Dr. Thomas noted.

There were no differences between the supplement and placebo groups for baseline and serial measurements of cholesterol, blood pressure, serum glucose, C-reactive protein, or adverse events.

"Pomi-T was well tolerated," he said. "More men experienced nonsignificant bloating or diarrhea, but 15% of men reported beneficial effects, including better digestion and improvement of urinary symptoms."

Previous research has shown that the polyphenols and antioxidants in pomegranate, broccoli, green tea, and turmeric have individual anticancer properties, but "we believe there's a synergistic effect in the supplement," said Dr. Thomas.

In addition, the fact that each ingredient originates from a separate food category (fruit, vegetable, herb, and spice) might prevent potential adverse effects from the overconsumption of one particular type of polyphenol, he noted.

In the lab, polyphenols have been shown to have antiproliferative, antiangiogenic, proadhesion, antimetastatic, and proapoptotic properties, and notably, they have no phytoestrogenic or hormonal effects. "We specifically chose to steer away from anything that might have a hormonal effect."

Because of the supplement's effect is likely not hormonal, future trials will involve men with different stages of prostate cancer and those receiving androgen-deprivation therapy, he said. In addition, the researchers hope to look at the impact of the supplement on other slow-growing cancers and even on cancer prevention.

The study received no funding from the manufacturer of the supplement; however, the company worked very closely with the research team to develop the product, said Williams. "Unlike other nutritional supplement products, the manufacture of this supplement was significantly more time-consuming because Dr. Thomas and colleagues, for whom this was initially made, insisted on a great deal of quality assurance, over and above that normally required by the US Food and Drug Administration or European Commission, particularly in terms of purity and authenticity."

He said the study signals "a new era for the nutritional supplement industry, which has previously relied on advertising and marketing rather than evidence of benefit. Clearly, it's the latter that the public wants."

Dr. Beer noted that the product's significant effect on adherence to active surveillance is "potentially clinically meaningful... If this can be confirmed, this is really interesting," he said, although he added that "these patients were more severe than the sort of patients that we would follow [with active surveillance] here in the United States."

Prostate Cancer UK reacted more cautiously to the news, releasing a statment saying that "there is not yet enough evidence that Pomi-T food supplements have a significant impact."

Kate Holmes, MD, head of research at Prostate Cancer UK, said in a statement that "there is increasing evidence showing that men who have a healthy lifestyle, including a balanced diet and regular exercise, have better prostate cancer outcomes than those who do not. At this stage, however, we simply do not have enough evidence to suggest that any particular foods or supplements have a significant impact and these should certainly not be substituted for conventional treatments."

"We would not encourage any man with prostate cancer to start taking Pomi-T food supplements on the basis of this research. Anyone with any concerns about prostate cancer should discuss them with their doctor or call Prostate Cancer UK's helpline," she added.

The authors have disclosed no relevant financial relationships.

2013 Annual Meeting of the American Society of Clinical Oncology. Abstract 5008. Presented June 3, 2013.