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Friday, June 23, 2017

Women who receive HPV testing, in addition to a Pap smear, receive a faster, more complete diagnosis of possible cervical precancer, according to a study of over 450,000 women by Queen Mary University of London (QMUL) and the University of New Mexico (UNM) Comprehensive Cancer Center, Albuquerque.

HPV is a virus that can cause cervical, vaginal, penile, and anal cancers. More than 520,000 cases of cervical cancer are diagnosed worldwide each year (3,100 in the U.K.), causing around 266,000 deaths (800 in the U.K.). A common screening procedure for cervical cancer is the Pap smear, which tests for the presence of precancerous or cancerous cells on the cervix.

The study used data from the New Mexico HPV Pap Registry in the U.S. It is the first comprehensive evaluation of HPV testing on the long-term outcomes of women who had received a borderline abnormal Pap test result (JAMA Oncol 2017; doi:10.1001/jamaoncol.2017.1040).

A total of 457,317 women were included in the study. Of these, 20,677 women (4.5%) received a borderline abnormal result through a Pap smear and were followed in the study for 5 years. Some of the women with borderline abnormal Pap smear results had an HPV test.

HPV testing led to a 15.8 percent overall increase in the detection of cervical precancers and time to detection was much shorter (a median of 103 days versus 393 days).

Virtually all cervical precancers were detected in women who tested positive for HPV, suggesting HPV testing to be a good additional screening method after the Pap smear. Colposcopy could then be focused on women who would need it most: those with a positive HPV test.

At the same time, however, HPV testing of women resulted in 56 percent more biopsies and a 20 percent increase in surgical treatment procedures performed. Most of the additional biopsies were for low-grade lesions which could have regressed, indicating some overtreatment due to HPV testing.

Jack Cuzick, PhD, FRS, FMedSci, FRCP(hon), Director, Wolfson Institute of Preventive Medicine, and Head, Centre for Cancer Prevention at the QMUL said: "This study shows that knowing a woman's HPV status can help determine her likelihood of needing additional procedures, and prioritize immediate treatment and medical resources to the women who need them most."

Cosette Wheeler, Regents Professor, Pathology and Obstetrics and Gynecology, UNM Department of Pathology, noted: "The benefits of HPV testing outweigh the harms observed but it's important to understand and quantify the harms as well."

The authors warned that, as this was an observational study, the use of HPV testing was not randomized. So, it is also possible that there could be socioeconomic or other relevant differences among health care facilities that have not been measured.



Thursday, June 22, 2017

Rhabdomyosarcoma, a cancer made up of cells that normally develop into skeletal muscles, is the most common soft tissue cancer in children. If it is detected early and localized in certain areas, rhabdomyosarcoma is usually curable with traditional therapies like surgery, radiation, and chemotherapy. However, these treatments are fraught with side effects, especially for children.

A recent study points to a new treatment strategy that takes advantage of the body's own immune response.

Over the past decade, immunotherapy has become an important part of treating some cancers effectively and with fewer side effects than traditional therapies. One immunotherapeutic approach is oncolytic virotherapy, in which a virus is used to target cancer cells specifically. Oncolytic viruses infect and kill malignant, but not normal, cells.

In the new study, researchers from Nationwide Children's Hospital used a combination of immunotherapies in a mouse model of rhabdomyosarcoma (Sci Rep 2017; doi:10.1038/s41598-017-02503-8).

In addition to oncolytic virotherapy, the team also blocked the signaling of programmed cell death protein (PD)-1, which mediates the suppression of T-cells.

"Other researchers have recognized that if we can block the PD-1 checkpoint and unleash the T-cells a bit more, they might fight cancer better," said Timothy Cripe, MD, PhD, Chief of Hematology, Oncology, and Blood and Marrow Transplantation at Nationwide Children's Hospital; and senior author of the study.

"We thought that if a virus infection brings in more T-cells, and the PD-1 blockade allows those cells to fight cancer cells, then maybe the two therapies will work better together."

Combining the two immunotherapies delayed tumor growth and enhanced overall survival in a mouse model of rhabdomyosarcoma, noted the study's first author, Chun-Yu Chen, PhD, Research Scientist in the Center for Childhood Cancer and Blood Diseases at The Research Institute at Nationwide Children's Hospital.

"We used a mouse model to demonstrate that when we combine oncolytic therapy with PD-1 blockade, we see a better therapeutic outcome compared to either of the therapies individually," added Chen.

The researchers say the combination therapy is so effective because it marshals more of the T cells that attack infections and tumors to the site of the cancer without increasing the counterbalancing, regulatory T cells that suppress immune attacks.

Both oncolytic virotherapy and PD-1 blockade are FDA-approved for treating cancer; this new study provides preclinical data to support combining them in pediatric cancer patients.

Cripe, also a Principal Investigator in the Center for Childhood Cancer and Blood Diseases at The Research Institute, said his team is working to determine whether they will move forward with clinical trials. They are also interested in figuring out how differences in immunogenicity might affect the success of the combination treatment.

"Our paper gives us some clues as to predictive biomarkers of who might respond best to this type of treatment," said Cripe, also a Professor of Pediatrics at The Ohio State University College of Medicine. "If we can identify patients who have a tumor that is recognized by the immune system better, we can individually select patients in which this combination treatment will work best.

"It has been shown that immunotherapy works for some adult cancers; the question is, what impact will it have on childhood cancers?" Cripe concluded. "We are fortunate to be at an institution that has all the resources that allow us to study this in the lab and in the clinical setting and find out its full potential."


Wednesday, June 21, 2017

A large study identified several new variants for lung cancer risk that will translate into improved understanding of the mechanisms involved in lung cancer susceptibility (Nat Genet 2017; doi:10.1038/ng.3892).

Using a genotyping platform developed by multiple cancer consortia, a recent aggregated genome-wide association study identified new susceptibility loci for lung cancer, the leading cause of cancer mortality worldwide. Although tobacco smoking is the main risk factor, past studies have shown heritability of lung cancer estimated at 18 percent. Previous genome-wide association studies have identified several lung cancer susceptibility loci, but most of its heritability remains unexplained. This study undertook additional genotyping of lung cancer cases and controls.

The study was co-led by Christopher Amos, PhD, Interim Director and Associate Director for Population Sciences, Norris Cotton Cancer Center, Lebanon, N.H.; James McKay, PhD, International Agency for Research on Cancer; and Rayjean Hung, PhD, Lunenfeld-Tanenbaum Research Institute and University of Toronto, along with many lung cancer investigators worldwide.

Researchers combined 14,803 cases and 12,262 controls of European descent with existing data, totaling 29,266 cases and 56,450 controls. Investigators then identified 18 susceptibility loci achieving genome-wide significance, including 10 new loci. The new loci highlight the striking variation in patterns of risk between lung cancer subtypes adenocarcinoma and squamous lung cancer, with four loci associated with lung cancer overall and six loci associated with lung adenocarcinoma. Variants in several genes related to telomere function were found to play an important role in contribution to adenocarcinoma risk but not squamous carcinoma risk.

"What is particularly exciting is the magnitude of the study along with the new findings of genes influencing lung cancer which have not previously been reported" said Amos. "This study definitely leads to new ideas about mechanisms influencing lung cancer risk. In particular, we identified several novel variants influencing telomere function that impact risk for lung adenocarcinoma.

"In addition, we found variation around a subunit of the nicotinic receptor that affects lung cancer risk and smoking behavior and appears to have a primary effect in the cerebellum, which has rarely been implicated in affecting addictive behaviors," he continued.

Further studies will provide a better understanding of the role of target genes in influencing lung cancer risk, smoking behavior, and smoking effects on brain biology.​

Wednesday, June 21, 2017

New data demonstrates that stereotactic body radiation therapy (SBRT) is a safe treatment option for early-stage lung cancer patients aged 80 or older. The recently released results are based on data from more than 1,000 patients across five institutions that comprise the Elekta Lung Research Group (ELRG) (Int J Radiat Oncol Biol Phys 2017 Jul 15;98(4):893-899).

The study evaluated safety and efficacy outcomes of 1,083 patient reports collected in a multi-institutional database. Patients were treated with SBRT for early-stage lung cancer between 2004 and 2014 and followed for a median of 1.7 years. The cohort included 305 patients under 70 years of age, 448 patients ages 70 to 79 years, and 330 patients aged 80 years or more (which included 16 patients aged 90 years or more). The median age was 75 years (range 41 to 94).

Study results show no significant differences among the three age groups with respect to 2-year local recurrence, regional recurrence, distant metastases, or the incidence of grade 3 or higher toxicity. Cause-specific survival was similar among all three age groups (90.3% to 90.6%). Two-year overall survival was lower in older patients, which is likely related to other medical issues. 

"Older patients are often not considered for radiation therapy due to concerns about their ability to tolerate treatment. The results of our study clearly support the use of SBRT for elderly patients, especially those who may not be able to tolerate longer courses of radiotherapy or more invasive treatment options," said Meredith Giuliani, MBBS, FRCPC, MEd, a radiation oncologist in the Cancer Clinical Research Unit at Princess Margaret Cancer Centre, University Health Network in Toronto, and lead study author. "Radiation oncologists need to work closely with our peers in other parts of the medical community to ensure that patients with diagnosed or suspected early-lung cancer are evaluated for potential treatment with SBRT regardless of age."

ELRG is an international collaboration of physicians and physicists that is evaluating clinical outcomes in early-stage non-small cell lung cancer patients. To date, they have accumulated data on close to 1,200 such patients and identified medical and technical factors that affect tumor control and toxicity. Their collective experience is among the largest multinational series of patients treated with image-guided SBRT to date.

Participants include, William Beaumont Hospital in Royal Oak, Mich.; Princess Margaret Cancer Centre; Thomas Jefferson University in Philadelphia; Julius-Maximilians University of Würzburg in Würzburg, Germany; and The Netherlands Cancer Institute-Antoni van Leeuwenhoek hospital in Amsterdam.

"This study is the largest series of its type to evaluate SBRT outcomes in patients aged 80 years and older," concluded Joel Goldwein, MD, Senior Vice President, Medical Affairs for ELRG. "In addition to providing important support for using SBRT to treat early-stage lung cancer in elderly patients, these findings highlight the value of multi-institutional collaborations and large data sets that can provide statistically meaningful answers to critical questions about treatment outcome and guide clinical decision-making." ​

Wednesday, June 21, 2017

A late breaking subanalysis of the phase III CONVERT trial presented at the European Lung Cancer Conference shows that white blood cell boosting drugs are safe during concurrent chemo-radiotherapy of small cell lung cancer (SCLC) (Abstract LBA2_PR).

"The optimal treatment for limited-stage SCLC is concurrent chemo-radiotherapy," said Fabio Gomes, PhD, the study's lead author and a medical oncologist at the Christie NHS Foundation Trust, Manchester, U.K. "The efficacy of this intensive treatment is balanced by more toxicity, mainly hematological but also esophageal and pulmonary. Meaning this is not a treatment to be considered for every patient and many more will struggle to stay on track with the planned treatment."

Granulocyte colony-stimulating factors (G-CSF) are commonly used as a supportive measure to boost the survival, proliferation, and differentiation of neutrophils. The expected neutropenia is less severe and patients recover more quickly, reducing their risk for infectious complications. However, its use during concurrent chemo-radiotherapy in SCLC is controversial and ASCO recommends against its routine use (J Clin Oncol 2015;33(28):3199-3212). This is due to a randomized trial with 215 eligible patients performed between 1989 and 1991, which showed a significant increase in severe thrombocytopenia, severe anemia, pulmonary complications, and toxic deaths when granulocyte-macrophage CSF (GM-CSF) were used during concurrent chemo-radiotherapy (J Clin Oncol 1995;13(7):1632-1641).

"There have been two major changes since this trial was published in 1995 which may affect the safety of CSF in this context. First, the trial tested GM-CSF, which acts on more than one blood cell lineage and are not commonly used nowadays. Instead, we use G-CSF, which is more specific and aims for the neutrophil lineage only. Second, modern radiotherapy techniques have evolved significantly since then and are more precise, which reduces the risks of toxicity," said Gomes.

The phase III CONVERT trial enrolled 547 patients with limited-stage SCLC for concurrent chemo-radiotherapy who were randomized to once-daily or twice-daily radiotherapy. There was no difference in overall survival between the two groups.

The trial protocol allowed the use of G-CSF, and around 40 percent of patients received it at some point during the treatment. For the analysis presented today, the researchers compared the toxicities and outcomes between patients who received G-CSF during concurrent chemo-radiotherapy and those who did not.

They confirmed that the chance of severe thrombocytopenia or anemia during treatment almost doubled in patients given G-CSF to around 30 percent and 20 percent, respectively, however these were lower than previously reported. That was followed by a significantly higher use of further supportive measures, such as platelets and blood transfusions. However, there was no difference in the incidence of pulmonary complications or in survival. "G-CSF had no significant negative impact on the outcomes of these patients, which is a very comforting result. The higher hematological toxicity was balanced by an appropriate supportive care throughout treatment," noted Gomes.

"We can conclude from this analysis that the use of G-CSF during thoracic radiotherapy is safe and should support patients to receive the full planned course of concurrent chemo-radiotherapy and achieve the best possible benefit," he continued. "These findings should give clinicians the confidence to use G-CSF when needed in this context. We aim to publish a complete analysis later this year which may hopefully help change the current guidelines."

Commenting on the findings, Stefan Zimmermann, MD, Senior Consultant, Medical Oncology Department, HFR - Hôpital Cantonal, Fribourg, Switzerland, said: "Oncologists do need G-CSF to mitigate neutropenia and increase chemotherapy delivery and compliance, but want the beneficial effect of timely concurrent therapy to outweigh the toxic risks.

"In this analysis, the use of G-CSF did not result in an increased risk of pneumonitis, but the incidence of severe thrombocytopenia is a concern," he concluded. "The use of G-CSF was not detrimental to progression-free survival or overall survival. We can conclude that primary or secondary prophylaxis of febrile neutropenia with G-CSF is justified, but patients at higher risk for thrombocytopenia should be treated with caution."​