Additional Surgery after Breast-Conserving Surgery Varies Widely

A new study has found that the number of women who have one or more additional surgeries to remove suspected residual tumor tissue (re-excisions) following breast-conserving surgery (BCS) for breast cancer varies widely across surgeons and hospitals. Although researchers, led by Dr. Laurence E. McCahill from the Richard J. Lacks Cancer Center in Grand Rapids, MI, could not determine whether this variation affected rates of tumor recurrence, “the wide level of unexplained clinical variation itself represents a potential barrier to high-quality and cost-effective care,” the authors wrote in a report that appeared February 1 in JAMA.

The researchers pooled data on women with breast cancer diagnosed between 2003 and 2008 who had undergone a first BCS procedure at the University of Vermont or at one of three sites in the HMO Cancer Research Network (Group Health, Kaiser Permanente Colorado, and Marshfield Clinic). Of the 2,206 women eligible for inclusion in the study, 509, or 23 percent, had one or more breast surgeries after the initial BCS. Of these women, 190, or about 8.5 percent of those who underwent initial BCS, had a total mastectomy.

A total of 311 women, or 14 percent, had positive margins (some tumor cells left at the site of surgery, as determined by a pathologist) after their initial surgery, but only about 86 percent of those women underwent re-excision. “This finding is notable given that positive margins…have been correlated with a long-term increased risk of local recurrence,” the authors stated.

The percentage of women with positive margins who underwent re-excision differed among institutions, from 73.7 percent to 93.5 percent. The re-excision rates also varied substantially among individual surgeons, from zero percent to 70 percent. Whether these variations were influenced by pathological features of the tumors, clinical factors such as whether women received radiation therapy, or preferences of individual women could not be determined from the study.

Currently, the authors explained, there is no consensus about the appropriate size of a surgical margin around a tumor to be considered “clear.” As a result, in this study, nearly half of patients with pathologically clear margins that were less than 1 mm wide and one-fifth of patients with clear margins between 1 and 1.9 mm underwent re-excision.

“I think it’s clear that we have to do more clinical research to really understand what’s behind this variation: how much of it is clinically appropriate—including where patient preference may be driving some of that variation—and how much of it is really driven by factors that could be mediated by things like better education and better resources in the operating suites,” commented Dr. Steven Clauser, chief of the Outcomes Research Branch in NCI’s Division of Cancer Control and Population Sciences.

Comparing Prostate Cancer Treatments Shows Newer Isn’t Always Better

Two studies comparing the benefits and harms of different prostate cancer treatments show that newer, more expensive approaches may not produce better outcomes. The two comparative effectiveness research studies are among the first to compare newer therapies directly with older ones. The findings were presented at the 2012 Genitourinary Cancers Symposium.

Using the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database, Dr. Ronald Chen of the University of North Carolina at Chapel Hill and his colleagues compared data on more than 12,000 men with localized prostate cancer who had received one of three types of external-beam radiation therapy treatment: three-dimensional conformal radiation therapy, intensity modulated radiation therapy (IMRT), and proton therapy.

Compared with patients who received conformal radiation, patients who received IMRT had a 9 percent lower incidence of gastrointestinal side effects, were 20 percent less likely to have hip fractures, and were 19 percent less likely to receive additional cancer treatments. These differences suggest that IMRT offers better cancer control, Dr. Chen explained at a press conference at the symposium.

Compared with IMRT, proton therapy produced higher rates of gastrointestinal side effects and no improvement in cancer control, as measured by the need for additional cancer treatments.

“I think, based on these data, we can safely say…that there is no clear evidence that proton therapy is better than IMRT. And given the costs and potential increased toxicities [of proton therapy], we must continue to study this modality,” said Dr. Nicholas Vogelzang of the Comprehensive Cancer Centers of Nevada, who moderated the press conference.

In another study , Dr. Jay Ciezki of the Cleveland Clinic and his colleagues used SEER-Medicare data to compare the benefits and harms of external-beam radiation therapy, brachytherapy, and surgery for prostate cancer. The researchers found that external-beam radiation therapy was the most toxic, most expensive, and most commonly used of these techniques.

Brachytherapy, although it was the least toxic and the least expensive, was used in only 12 percent of the patients. The limited use of brachytherapy may be due to the fact that it was initially thought to be suitable only for a small subset of men, but “I think people have gotten to the point where they’re more comfortable offering [brachytherapy],” said Dr. Ciezki.

See also: “Comparative Effectiveness Research Stirs Excitement as Well as Debate”

Oral HPV Infections May Explain Why Some Head and Neck Cancers are More Common in Men

The prevalence of human papillomavirus (HPV) infections in the oral cavity is significantly higher among men than women in the United States, according to a new study from researchers at Ohio State University and NCI’s Division of Cancer Epidemiology and Genetics (DCEG). Oral HPV infections have been associated with oropharyngeal cancer—a subset of head and neck cancers that arise in the back of the tongue, throat, and tonsils—rates of which have risen dramatically over the last several decades.

The study is the first to comprehensively document the prevalence of oral HPV infections in men and women in the United States. Overall, approximately 7 percent of people between the ages of 14 and 69 have an oral HPV infection, reported lead investigator Dr. Maura Gillison last week at the Multidisciplinary Head and Neck Cancer Symposium . (The prevalence of oral infections, however, is much lower than that of infections in the genital tract.) About 1 percent of the population has an oral infection with HPV 16, a type that is linked to cancer. The results were also published online January 26 in JAMA.

Using data from the National Health and Nutrition Examination Survey (NHANES), the researchers studied nearly 5,600 men and women ages 14 to 69, who provided an oral rinse and mouthwash gargle samples. The most common subtype of HPV in the oral cells of study participants was HPV 16, the HPV type that is responsible for more than half of all oropharyngeal cancer cases.

Oral HPV infections were three times more common in men than in women (10.1 percent versus 3.6 percent), with older men having the highest rates, Dr. Gillison said during a press briefing. Oral infections with HPV 16 were seen in 1.6 percent of men and 0.3 percent of women. The prevalence of HPV infections was highest among people who smoke at least a pack a day and those with more than 20 lifetime sexual partners.

HPV-related head and neck cancers are far more common among men than women, Dr. Gillison said. The higher oral HPV infection rates in men, “in particular the over fivefold higher prevalence of HPV 16 among men compared to women,” likely explains the discrepancy, she said.

As for why men are more likely to be infected, the available data, she said, “suggest that men are more prone to getting [HPV] infections…or, once infected, are more likely to have the infection persist.” It could also be a combination of both factors, she continued.

“These findings are particularly relevant because, in contrast to other head and neck cancers, HPV-associated oropharyngeal cancer rates have been on the rise in recent years,” commented senior author Dr. Anil Chaturvedi of DCEG’s Infections and Immunoepidemiology Branch. “The higher prevalence of both cigarette smoking and oral HPV infection in men helps complete our understanding of why men have higher rates of oropharyngeal cancer than women.”

See also: “Rising Oropharyngeal Cancer Rates Linked to HPV Infection”

Cancer Screening Rates Lag Behind National Target Levels

Screening rates for breast, cervical, and colorectal cancer remained lower in 2010 than national objectives set forth in Healthy People 2020, measures set by the Department of Health and Human Services to improve the health of Americans and gauge the impact of prevention activities. The findings appeared in the January 27 Morbidity and Mortality Weekly Report (MMWR).

2010 U.S. Cancer Screening Rates and Target Screening Rates for 2020

Based on findings from the National Health Interview Survey (NHIS), scientists from NCI’s Division of Cancer Control and Population Sciences (DCCPS) and from the Centers for Disease Control and Prevention (CDC) reported that from 2000 to 2010, “the population-based estimates in this report show a slight downward trend in the proportion of women up-to-date with screening for cervical cancer but no change over time in breast cancer screening rates,” Colorectal cancer screening rates for men and women increased substantially, the report showed, and by 2010 were generally the same for both sexes.

Rates of all three cancer screening tests were significantly lower among Asians than among whites and blacks, the report noted. Hispanics were less likely than non-Hispanics to be screened for cervical and colorectal cancer.

“Higher screening rates were positively associated with education, availability and use of health care, and length of U.S. residence,” the researchers added.  For breast cancer, “immigrant women who had been in the United States for 10 or more years were almost as likely as U.S.-born women to report having had a mammogram within the past 2 years (70.3 percent and 73.1 percent, respectively),” the article stated, “whereas only 46.6 percent of immigrants [who had been] in the United States for less than 10 years reported being screened in the past 2 years.”

“Healthy People objectives are important for monitoring progress toward reducing the burden of cancer in the United States,” said Dr. Carrie Klabunde, an epidemiologist with DCCPS and a co-author of the study. “Our study points to the particular need for finding ways to increase the use of breast, cervical, and colorectal cancer screening tests among Asians and Hispanics, as well as among adults who lack health insurance or a usual source of health care.”

HPV Testing with Self-Collected Samples May Be Valid Cervical Cancer Screening Method

Data from five large studies carried out in China demonstrate that self-HPV testing—in which a woman collects a sample of her own cervical-vaginal cells for human papillomavirus (HPV) DNA testing—is as sensitive as the standard liquid-based Pap test for cervical cancer screening. This method has the potential to make cervical cancer screening available to women in rural or low-resource areas who do not have ready access to cytology screening services. The results were published online January 23 in the Journal of the National Cancer Institute.

Pap screening is often unavailable in low-resource areas. Instead, health care providers sometimes use visual inspection with acetic acid (VIA) to look for abnormal cervical cells that can be treated before they progress to cancer. However, VIA is not very accurate, and women still need the time and means to attend appointments with a health provider.

The researchers pooled data from cervical screening studies conducted in China between 1999 and 2007 that included more than 13,000 women between the ages of 17 and 56. The participants underwent an HPV test on a self-collected cervical specimen, VIA, HPV test on a physician-collected cervical specimen, and liquid-based Pap test. Women with positive results on any screening test received a colposcopy and a biopsy of any cervical lesion. By comparing the test and biopsy results, the researchers were able to determine the sensitivity and specificity of each screening method.

Although self-HPV testing proved less sensitive than clinician sampling, self-HPV testing was more sensitive than VIA and as sensitive as the Pap test at identifying cervical precancer or cancer. However, the self-collected samples produced more false-positive results than the Pap test or VIA, meaning that more women who did not have cervical precancer or cancer underwent a colposcopy and biopsy. The researchers showed that conducting follow-up VIA or Pap tests on women whose self-collected sample tested positive could reduce the colposcopy rate from around 16 percent to less than 5 percent but would result in some loss of sensitivity for diagnosing abnormalities.

While acknowledging that self-HPV testing “is not specific enough to be a stand-alone test,” the authors point out that it “provides sensitive results without pelvic exams, medical professionals, or health-care facilities and thus has the potential to serve as a primary cervical cancer screening method for women, regardless of their geographic location or access to health care. Limited resources can then be focused on the clinical follow-up of the smaller percentage of women who tested positive.”

The authors of an accompanying editorial contend that more research is needed before self-HPV testing can be used outside of a research setting. Both the editorialists and the authors noted that the study participants received physician instruction on sample collection, and it is unclear whether the same results would be obtained by women who did not receive this instruction. Women’s willingness to participate in this type of screening and their ability to access follow-up care also need to be investigated.

Genetic Studies Uncover Clues to Childhood Brain Cancers

Two genetic studies of brain tumors in children have identified a new suspect in these deadly cancers. In each study, researchers found recurrent mutations in a protein that helps package DNA in the cell nucleus. Changes to this process may alter the activity of genes and contribute to cancer, the researchers reported.

In one study, published online January 29 in Nature, researchers sequenced the entire exome (all protein-coding DNA) of tumors from 48 children with glioblastoma multiforme (GBM), an aggressive form of brain cancer. The sequencing revealed two recurrent mutations in a gene called H3F3A, which encodes a histone protein (H3.3).

Histones assemble into structures called nucleosomes, around which long strands of DNA wrap, resulting in a tightly packaged complex called chromatin. Because histones interact so closely with DNA, structural modifications to histone proteins can also control gene activity.

Two recent studies (here and here) have found evidence that mutations in genes whose products modify histones may be involved in cancer. The Nature study, however, is the first to describe mutations in a histone gene in tumors. “Histones are, in a way, the guardians of our genetic information,” said Dr. Nada Jabado of McGill University, who led the research.

She and her colleagues also found that some GBM tumors had mutations in genes that are involved in chromatin remodeling, a process in which chromatin “opens” so that transcription factors can gain access to DNA, allowing previously silent genes to be transcribed. Defects in the chromatin remodeling pathway may be common in pediatric GBM and could be the basis for exploring much-needed new treatments for the disease, the study authors concluded.

“We now have a starting point for investigating the biological basis of this disease,” Dr. Jabado continued. “Until now, we essentially have been working in the dark.”

In a separate study, researchers with the Pediatric Cancer Genome Project also found the same mutations in H3F3A or a closely related gene, HIST1H3B, in 78 percent of tumors from 50 children with a cancer known as diffuse intrinsic pontine glioma (DIPG). The findings were reported online in Nature Genetics on January 29.

“It’s not often that you find a mutation that affects such a high proportion of [patient samples],” said senior author Dr. Suzanne Baker of St. Jude Children’s Research Hospital. “This tells us that anything we learn about this mutation will reveal something important about the biology of this disease.”

The finding also adds weight to the idea that epigenetic processes are being undermined in some cancers, Dr. Baker added. “I expect that significant resources will now be devoted to understanding how and why alterations in the histone proteins contribute to cancer.”

Source:NCI bulletin.

Studies Highlight Complexities of Treating Advanced Head and Neck Cancer

In a large randomized European clinical trial, accelerated radiation therapy for locally advanced, inoperable head and neck cancer—given either with or without chemotherapy—did not prolong the time to disease progression compared with standard radiation therapy plus concurrent chemotherapy (chemoradiotherapy), which has been the standard of care in Europe and the United States. Results from the study were published online January 18 in Lancet Oncology.

Another trial published in 2010, by the U.S. Radiation Therapy Oncology Group (RTOG), showed similar results, but the two research teams have drawn different conclusions, which will affect ongoing clinical trials and, potentially, future research collaborations.

The researchers, from the European Groupe d’Oncologie Radiothérapie Tête et Cou (GORTEC), compared two experimental regimens with standard chemoradiotherapy in the trial, called GORTEC 99-02. All participating patients had stage III or stage IV head and neck squamous-cell carcinoma that had not metastasized but that could not be removed surgically.

The 244 patients in the conventional chemoradiotherapy arm received three cycles of chemotherapy with the drugs carboplatin and fluorouracil plus 70 Gy of radiation given over the standard 7 weeks.

In one experimental arm, 245 patients received “accelerated chemoradiotherapy,” which consisted of two cycles of the same chemotherapy drugs plus radiation therapy accelerated by 1 week. In the second experimental arm, 242 patients received only “very accelerated” radiation therapy, which consisted of a total dose of 64.8 Gy given over 3.5 weeks. (See the tables below.)

Treatment Groups in the GORTEC 99-02 Trial

Treatment Groups in the RTOG-0129 Trial

On the basis of promising earlier studies of accelerated radiation, the authors hypothesized that the more intense dose of radiation would improve progression-free survival and disease control.

Instead, the trial “showed that there was no such benefit and that acceleration of radiotherapy by 1 week, concomitant to chemotherapy, did not add any benefit when compared with conventional concomitant chemoradiotherapy,” wrote the authors. Three years after treatment, 37.6 percent of patients in the conventional chemoradiotherapy arm were alive without progression of their disease, compared with 34.1 percent of those in the accelerated chemoradiotherapy arm.

The very accelerated radiation regimen provided inferior disease control compared with conventional chemoradiotherapy, with 32.2 percent of patients in that group alive and free of disease progression 3 years after treatment. These results were another surprise: “We expected ‘very accelerated’ radiotherapy to be at least as good as conventional chemoradiotherapy,” stated the authors.

Same Results, Divergent Conclusions

The GORTEC trial results are somewhat difficult to interpret because the trial “didn’t change just one variable, it changed two—in addition to the radiation regimen, it also changed the chemotherapy,” explained Dr. Bhadrasain Vikram, chief of the Clinical Radiation Oncology Branch of the Radiation Research Program in NCI’s Division of Cancer Treatment and Diagnosis.

Because patients in the accelerated chemoradiotherapy group received two, rather than three, cycles of chemotherapy (although those two cycles were longer in duration), they received 17 percent less chemotherapy overall than patients in the conventional chemoradiotherapy group.

The RTOG trial that showed similar results (RTOG-0129) also reduced the amount of chemotherapy given, and not just because of fears of toxicity, explained Dr. Maura Gillison, RTOG investigator and professor of medicine at the James Comprehensive Cancer Center at Ohio State University.

“All of the studies have shown that it’s critical to give the chemotherapy with the radiation,” she stressed. Chemotherapy given alone does not have as potent an antitumor effect in head and neck cancer, and in the accelerated chemoradiotherapy arms of the two trials, shortening the duration of radiation therapy did not leave enough time for a third cycle of chemotherapy.

Because only about 60 percent of patients with advanced head and neck cancer are healthy enough to complete the third cycle of chemotherapy with conventional chemoradiotherapy, and because the patients in RTOG-0129 who received conventional and accelerated chemoradiotherapy survived for a similar length of time, “we thought that to some extent our results are an advance,” Dr. Gillison said. “You can shorten the treatment to 6 weeks instead of 7, and shortening the treatment means you don’t have to give that third cycle of chemotherapy, with all its associated toxicities.”

While the GORTEC investigators did not see a benefit from accelerated chemoradiotherapy, the RTOG investigators have chosen to use an accelerated chemoradiotherapy regimen as the standard of care in their trials of advanced head and neck cancer.

This decision for trials in the United States was also influenced by changes in modern radiation therapy technology, explained Dr. K. Kian Ang, professor of radiation oncology at the University of Texas M. D. Anderson Cancer Center and former chair of RTOG’s Head and Neck Committee. The more widespread availability of intensity modulated radiation therapy (IMRT) has allowed radiation oncologists to reduce the number of visits required for irradiation even further than in the RTOG-0129 trial, which makes it more practical for patients to complete therapy, added Dr. Ang.

HPV Status Makes a Difference

The recent understanding of the importance of human papillomavirus (HPV) as a cause of oropharyngeal cancer also limits the application of the GORTEC results to current practice, added Dr. Vikram. That trial began “before the huge importance of HPV status [in head and neck cancer] was recognized. One would expect about 40 to 50 percent of the tumors in this trial to have been HPV-positive, but the paper unfortunately has no information on that, so we have no idea from this trial if one of the regimens tested might work better for subsets of patients with HPV-positive or HPV-negative tumors,” he explained.

The recent understanding of the importance of HPV as a cause of oropharyngeal cancer also limits the application of the GORTEC results to current practice.

Dividing patients into those whose tumors are HPV-positive versus HPV-negative will be increasingly important in future trials for head and neck cancer, as the rate of oral HPV infection continues to rise. In the RTOG-0129 trial, people whose oropharyngeal tumors contain the HPV virus were found to respond much better to treatment than patients with HPV-negative tumors.

“After so many years, we’ve really started to understand that, although [HPV-positive and HPV-negative tumors] are located in the same small anatomical region, we are dealing with different types of cancers,” said Dr. Ang. “Because HPV-positive patients do relatively well on current treatments, one of our main goals now is to reduce toxicity. And for HPV-negative patients, because they do so badly with what we have now, we want to know how we can intensify treatment in order to improve outcomes.

“With these completely different objectives, we don’t think we can put [these two groups] in the same protocol—we need to do separate trials,” he continued. RTOG recently launched its first trial for HPV-positive patients only (RTOG-1016), to see if using the targeted drug cetuximab instead of cisplatin can reduce the side effects of treatment while controlling tumors.

A big challenge, added Dr. Ang, is that “head and neck cancer is relatively rare, and now we’re dividing it into smaller and smaller subsets. International trials will be a necessity to enroll enough patients.”

And along with the normal challenges of cross-border funding, quality control, and tumor sample transportation, what should actually be tested will also have to be agreed upon. “Investigators will need to agree on what are the best scientific questions to ask,” concluded Dr. Ang.

Source:NCI bulletin.