Long-term follow-up shows need for new chemotherapy strategies for rectal cancer

Results of EORTC trial 22921 at 10.4 years median follow-up

Appearing in Lancet Oncology, long term results of EORTC trial 22921 with 10.4 years median follow-up show that 5-FU (fluorouracil) based adjuvant chemotherapy after preoperative (chemo)-radiotherapy for patients with cT3-resectable T4 M0 rectal cancer does not improve survival or disease-free survival.

EORTC trial 22921 explored the value of adding chemotherapy to preoperative radiotherapy either concurrently, or as an adjuvant, or both for patients with cT3-resectable T4 M0 rectal cancer. Between April 1993 and March 2003, 1011 patients were randomized to four treatment arms, 252 patients received preoperative radiotherapy alone, 253 patients received preoperative radiotherapy – chemotherapy, 253 patients received preoperative radiotherapy followed by adjuvant chemotherapy, and 253 patients received preoperative radiotherapy and chemotherapy followed by adjuvant chemotherapy.

Prof. Jean-François Bosset of the CHRU de Besancon – Hopital Jean Minjoz in France and lead author of this study says, “When we looked at the results after five years median follow-up, we saw that chemotherapy, regardless of when it was administered, significantly improved local control. However, adjuvant chemotherapy did not improve survival or disease-free survival, but we noted that the curves by adjuvant treatment did diverge progressively starting from year four for overall survival and from year two for disease-free survival. This suggested a possible delayed benefit, and we wanted to resolve this. The long term follow-up results suggest that new treatment strategies incorporating neoadjuvant chemotherapy are required, because adjuvant chemotherapy does not demonstrate any significant long term benefit on overall survival or disease-free survival.”

Results of EORTC trial 22921 show that compliance with adjuvant chemotherapy was poor, and only 42.9%of the patients received the planned dose within the scheduled time frame. The 10-year overall survival rates were 51.8% (CI 47.0-56.4) for the patients receiving adjuvant chemotherapy and 48.4% (95% CI 43.6-53.0%) for those in the surveillance groups (HR=0.91, 95% CI 0.77-1.09, p=0.32). The 10-year disease free survival rates were 47.0% (CI 42.2-51.6%) for the patients receiving adjuvant chemotherapy and 43.7% (CI 39.1-48.2%) for those in the surveillance groups (HR=0.91, 95% CI 0.77-1.08, p=0.29).

Most relapses occur within five years, and at ten years local relapse rates were 22.4% (CI 17.1-27.6) with radiotherapy alone, 11.8% (7.8-15.8%) with neoadjuvant radiotherapy-chemotherapy, 14.5% (10.1-18.9%) with radiotherapy and adjuvant chemotherapy, and 11.7% (7.7-15.6%) with both adjuvant and neoadjuvant chemotherapy (p=0.0017).

There was no difference in cumulative incidence of distant metastases (p=0.52). The frequency of long term side effects did not differ between the four groups (p=0.22).

Bosset  et al., (2014). Fluorouracil-based adjuvant chemotherapy after preoperative chemoradiotherapy in rectal cancer: long-term results of the EORTC 22921 randomised study. Lancet Oncol., EPub Ahead of Print, doi:10.1016/S1470-2045(13)70599-0 [Abstract]

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Breast cancer in young women after treatment for Hodgkin’s disease

Girls treated for Hodgkin’s disease during adolescence acquire a considerable risk of developing breast cancer, as shown by an observational study published in the current issue of Deutsches Ärzteblatt International. The study, which was carried out by Günther Schellong and his colleagues in the German Working Group on the Long-Term Sequelae of Hodgkin’s Disease, has an unusually long follow-up time (average 17.8 years, maximum 33 years).

The incidence figures for secondary breast cancer are based on long-term observation of 590 female patients in the German–Austrian pediatric treatment trials dating back to the years 1978 to 1995. The authors estimate that 19% of the girls treated with radiotherapy for Hodgkin’s disease develop secondary breast cancer within 30 years as a result of that therapy. Because of these findings, a structured screening program for breast cancer in this high-risk group has been set up in Germany, making use of existing structures put in place by the German Consortium for Hereditary Breast and Ovarian Cancer (Deutsches Konsortium für familiären Brust- und Eierstockkrebs).

The study authors recommend that, when supradiaphragmatic radiotherapy is necessary in girls over the age of 9, the part(s) of the chest exposed to the radiation should be kept as small as medically justifiable. This will allow the risk of breast cancer to be kept as low as possible.

Schellong et al., (2014). Breast cancer in young women after treatment for Hodgkin’s Disease during childhood or adolescence. Dtsch. Arztebl. Int.111:3–9 [pdf]

Physical activity seems to significantly extend lives of cancer survivors

Reduces mortality by up to 48 percent according to study

Physical activity significantly extends the lives of male cancer survivors, a new study of 1,021 men has found. During the period while the men were followed, those who expended more than 12,600 calories per week in physical activity were 48 percent less likely to die than those who burned fewer than 2,100 calories per week.

Kathleen Y. Wolin, PhD, of Loyola University Chicago Stritch School of Medicine, is co-author of the study, published in the Journal of Physical Activity & Health, the official journal of the International Society for Physical Activity and Health.

Many cancer survivors are living longer, due to earlier diagnosis and better treatment, and their numbers are increasing rapidly. “Thus physical activity should be actively promoted to such individuals to enhance longevity,” researchers concluded.

There has been extensive research showing that among generally healthy, cancer-free populations, physical activity extends longevity. But there has been relatively little such research on physical activity among cancer survivors.

Researchers examined data from the Harvard Alumni Health Study, an ongoing study of men who entered Harvard as undergraduates between 1916 and 1950. Researchers looked at 1,021 men (average age 71) who previously had been diagnosed with cancer. In questionnaires conducted in 1988, men reported their physical activities, including walking, stair-climbing and participation in sports and recreational activities. Their physical activities were updated in 1993, and the men were followed until 2008.

Compared with men who expended fewer than 2,100 calories per week in physical activity, men who expended more than 12,600 calories per week were 48 percent less likely to die of any cause during the follow-up period. This finding was adjusted for age, smoking, body mass index, early parental mortality and dietary variables. (By comparison, a 176-pound man who walks briskly for 30 minutes a day, five days a week burns 4,200 calories.)

There were similar findings for mortality from cancer and cardiovascular disease: the most physically active cancer survivors were 38 percent less likely to die of cancer and 49 percent less likely to die of cardiovascular disease during the follow-up period.

Lee et al., (2014). Physical activity and survival after cancer diagnosis in men. J. Phys. Act. Health.,11:85–90 [Abstract]

Breakthrough announced in treatment of patient with rare type of leukemia

University of Leicester researchers deploy ‘precision medicine’ to successfully target advanced form of leukaemia with skin cancer drug

A team of scientists from the University of Leicester has demonstrated a novel treatment for Hairy Cell Leukaemia (HCL), a rare type of blood cancer, using a drug administered to combat skin cancer. The research, which is published in the New England Journal of Medicine, indicates Vemurafenib, a BRAF inhibitor that has been approved as a treatment for advanced melanomas, is also successful in treating leukaemia. The study shows the treatment, which can be taken orally, cleared the malignant cells from the patient’s blood and led to a complete clinical recovery in a number of days. The study was led by the University of Leicester and involved treatment of a patient at the Leicester Royal Infirmary.

Dr Salvador Macip, from the University of Leicester’s Department of Biochemistry, explained: “A genetic study of the patient’s blood cells allowed us to identify a mutation in the BRAF gene that is commonly found in skin cancers. This knowledge enabled us to combat the cancer cells with Vemurafenib, which has had proven success as a BRAF inhibitor in melanomas, and showed similar success for this patient who had exhausted all other treatment options, which is fantastic.”

“What was most surprising was that the drug did not work in the way we expected it to. Whilst it successfully blocked BRAF and killed the cancerous cells, there was no ability to block the downstream cascade of signals. Therefore more research is required to better understand how this drug works to ensure we are able to use it in the best possible way.”

“This is one of the first clinical examples of this treatment for HCL and we are the first researchers to do a biochemical study of the samples and discover that the drug does not do what it’s supposed to be doing.”

This approach to targeting cancer is an example of precision medicine with clinicians and research scientists working side-by-side to ensure the best treatment, tailored to the individual patient, was provided.

Professor of Haemato-Oncology at the University of Leicester, Professor Martin Dyer, who is Honorary Consultant Physician, Department of Haematology at Leicester’s Hospitals, said: “Precision medicine in which clinicians and basic scientists collaborate to deliver novel and rapid personalised therapies to cancer patients like this is essential.”

“We drew blood from the patient on a daily basis which was analysed back in the lab to monitor the effects of the drug. The more understanding we have of how treatments such as Vemurafenib kill cancer cells, the more effective and targeted treatments can be.”

Professor Dyer is based in the University of Leicester’s Department of Cancer Studies and Molecular Medicine and the treatment of the patient took place at the Leicester Royal Infirmary. This research shows that drugs currently used to target certain cancers could be applied in other malignancies that share similar genetic backgrounds.

University of Leicester Pro-Vice-Chancellor and Head of the College of Medicine, Biological Sciences and Psychology, Professor David Wynford-Thomas, said: “The importance of the close working partnership between the University of Leicester and Leicester’s Hospitals is highlighted in advances such as this. World-class research at the University brings direct benefits to patients in Leicester’s hospitals in diverse areas including cardiovascular health, kidney research, lung health, diabetes, cancer research and many other areas.”

“I am delighted that our research has had such a direct benefit locally – it is another first for the University of Leicester and Leicester Royal Infirmary.”

Samuel et al., (2014). Efficacy of Vemurafenib in Hairy-Cell Leukemia. N. Engl. J. Med., 370:286-288 DOI: 10.1056/NEJMc1310849 [Article]

New analysis shows fewer years of life lost to cancer

Since the enactment of the National Cancer Act in 1971, the U.S. has spent hundreds of billions of dollars in cancer research and treatment. And yet, the cancer mortality rate – the historic benchmark of progress – has only declined modestly while the mortality rates of other leading causes of death have declined substantially. This difference has led many to question whether we’ve made progress in the ‘War on Cancer’. The answer is definitively yes according to Norris Cotton Cancer Center research published Monday in the Journal of Clinical Oncology.

“Our findings show that we have made steady progress against the burden of many cancers for decades,” said lead author Samir Soneji, PhD, assistant professor for Geisel School of Medicine at Dartmouth and the Dartmouth Institute for Health Policy and Clinical Practice. “We have underestimated the progress because, as fewer and fewer people die from heart disease, stroke, and accidents, more and more people are living longer and having more years in which to develop and die from cancer.”

According to Soneji the accuracy of existing measurements for the nation’s progress against the burden of cancer are limited because they reflect progress against other diseases. Soneji and his colleagues Hiram Beltrán-Sánchez, PhD, and Harold C. Sox, MD, measured the effect of cancer prevention, screening, and treatment on the burden of cancer mortality while taking account of the increased incidence of cancer because people are living longer as a result of progress against other leading causes of death.

To solve a problem first identified by the National Cancer Institute (NCI) 20 years ago, Dartmouth cancer researchers started with a measure of the burden of cancer mortality called the years of life lost due to cancer, which reflects how much longer we might expect to live if cancer did not exist. They then separated the favorable effect of advancements in cancer care from the unfavorable effect on cancer incidence due to advancements in the care of other diseases, notably cardiovascular disease.

“We estimate how the years of life lost from cancer are directly affected by cancer mortality and indirectly affected by increased cancer incidence because of greater longevity due to improvements in primary prevention, detection, and treatment of other disease,” said Soneji. With this approach cancer control researchers at Norris Cotton Cancer Center were able to measure how much progress the U.S. has made against the burden of cancer mortality in America.

Soneji’s research concluded that the decrease in lung cancer mortality rates between 1985 and 2005 tripled their contribution to reducing the years of life lost due to cancer. Yet not all of this progress was actually realized because other-cause mortality rates also decreased. The resulting increase in life expectancy and its consequent increase in lung cancer incidence partially offset this progress. “The decline in cigarette smoking, which began in the 1960s, is almost certainly the main reason the burden of lung cancer mortality declined,” said Soneji.

Authors Soneji, Beltrán-Sánchez, and Sox also found consistent progress in reducing the burden of colorectal cancer mortality since 1985. More recent, but less consistent, progress has been made in reducing the burden on prostate and breast cancer deaths.

“Our approach reveals more accurately the aggregate contribution of cancer prevention, screening, and treatment on progress against cancer,” said Soneji.

To date, survival time and mortality rates have been the leading population-level measures of cancer burden. These measures assess the effect of prevention, screening, and treatment on cancer, but they fail to account for changes in other-cause mortality rates. In contrast, Soneji and his colleagues used a more comprehensive measure that accounts for both changes in cancer mortality rates and changes in other-cause mortality rates. By accounting for progress against other leading causes of death, researchers can now more accurately assess progress against cancer. Whether historical progress in cancer continues in the future depends, in large part, on whether cigarette smoking continues to decline and effective screening detects earlier and more treatable stages of cancer.

Soneji et al., (2014). Assessing Progress in Reducing the Burden of Cancer Mortality, 1985-2005. J. Clin. Oncol., EPub Ahead of Print, doi: 10.1200/JCO.2013.50.8952 [Abstract]

Most women undergoing surgery for vulvar cancer maintain healthy body image and sex life

A new study finds that most women who undergo conservative surgery for vulvar cancer experience little to no long-term disruption to sexuality and body image. Published early online in the Journal of Advanced Nursing, the study also reveals factors that can increase women’s risk of feeling negative emotions after surgery.

Women diagnosed with vulvar cancer are often treated with surgery that involves the removal of substantial sections of the external genitalia. Because survival rates are extremely high for women with early stages of the disease, it is important to understand the psychosocial issues that women experience following treatment.

Ellen Barlow, RN, of The Royal Hospital for Women in Australia, and her colleagues interviewed 10 women who had previously been treated for early stage vulvar cancer, with a focus on investigating the women’s experiences of sexuality and body image.

The researchers found that the majority of women experienced little to no long-term disruption to sexuality and body image following conservative surgery to treat their cancer. Women’s sexual satisfaction was affected more by intimacy and relationship status than physical arousal. Women tended to feel negative emotions if they experienced more radical vulvar excision, multiple vulvar procedures, and/or swelling of the lower limbs (a potential complication of surgery). Some women expressed fear of possible removal of their clitoris, and all sexually active women expressed fear of pain on resumption of sexual intercourse.

“The findings indicate surprisingly good outcomes for sexuality and body image in women having conservative surgery for early stage vulvar cancer and support the concept of performing the most conservative vulvar resection consistent with cure of their disease,” said Barlow. The authors noted a need for improved communication about sexuality and body image, specifically about resumption of sexual intercourse. They also stressed that women should be counselled on how to prevent or alleviate sexual issues that may arise as a consequence of their treatment.

Barlow et al., (2014). Sexuality and body image following treatment for early-stage vulvar cancer: a qualitative study. J. Adv. Nurs., EPub Ahead of Print, DOI: 10.1111/jan.12346 [Abstract]

Antipsychotic drug exhibits cancer-fighting properties

In zebrafish model, perphenazine activates therapeutic pathway for intractable leukemia, may hold promise for other tumor

In a prime example of finding new uses for older drugs, studies in zebrafish show that a 50-year-old antipsychotic medication called perphenazine can actively combat the cells of a difficult-to-treat form of acute lymphoblastic leukemia (ALL). The drug works by turning on a cancer-suppressing enzyme called PP2A and causing malignant tumor cells to self-destruct.

The findings suggest that developing medications that activate PP2A, while avoiding perphenazine’s psychotropic effects, could help clinicians make much-needed headway against T-cell ALL, and perhaps other tumors as well. A study team led by Alejandro Gutierrez, MD, and A. Thomas Look, MD, of Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, and Jon Aster, MD, PhD, of Dana-Farber Cancer Institute and Brigham and Women’s Hospital, reported the results Jan. 9 in the Journal of Clinical Investigation.

T-ALL is rarer and more aggressive than the B-cell form of ALL, and it has a relatively poor prognosis. Despite improvements in the treatments available, 20 percent of children and more than 50 percent of adults diagnosed with T-ALL succumb to it. To identify possible new treatment options, Gutierrez, Look and their collaborators screened a library of 4,880 compounds—including FDA-approved drugs whose patents had expired, small molecules and natural products—in a model of T-ALL engineered using zebrafish.

Strategies that identify new uses for existing drugs have grown in popularity in recent years as a way of quickly developing new disease therapies. Zebrafish models are cost-effective platforms for rapidly conducting drug screens, as well as basic stem cell, genetic, cancer and developmental research.

“We wanted to see if there were drugs or known bioactive molecules that are active against T-ALL that hadn’t been tested yet,” Look explained. “There may be drugs available for other indications that could be readily repurposed if we can show activity.”

One of the strongest hits in the zebrafish screen was the drug perphenazine. It is a member of the phenothiazines, a family of antipsychotic medications used for 50 years, because they can block dopamine receptors.The team verified perphenazine’s anti-leukemic potential in vitro in several mouse and human T-ALL cell lines. Biochemical studies indicated that perphenazine’s anti-tumor activity is independent of its psychotropic activity, and that it attacks T-ALL cells by turning on PP2A. The fact that perphenazine works by reactivating a protein shut down in cancer cells is itself novel in the drug development field.

“We rarely find potential drug molecules that activate an enzyme,” Gutierrez explained. “Most new drugs deactivate some protein or signal that the cancer cell requires to survive. But, here, perphenazine is restoring the activity of PP2A in the T-ALL cell.”

Gutierrez and Look, along with their collaborators, are now working to better understand the interactions between PP2A and perphenazine. They also want to search for or develop molecules that bind to and activate the enzyme more tightly and specifically to avoid perphenazine’s psychiatric effects.

“The challenge is to use medicinal chemistry to develop new PP2A inhibitors similar to perphenazine and the other phenothiazines, but to dial down dopamine interactions and accentuate those with PP2A,” Look said.

The researchers see future PP2A inhibitors not as magic bullets but as potentially important additions to the oncologist’s arsenal when treating patients with T-ALL.

” T-ALL patients are often on the borderline between a long remission and a cure,” Look said. “If we can push the leukemia cells a little harder, we may get more patients who are actually cured. In this way, PP2A inhibitors may, in combination with other drugs, make a real difference for patients.”

It may be that the benefits of PP2A-activating drugs could extend beyond T-ALL. “The proteins that PP2A suppresses, such as Myc and Akt, are involved in many tumors,” Look noted. “We are optimistic that PP2A activators will have quite broad activity against different kinds of cancer, and we’re anxious to study the pathway in other malignancies as well.”

Gutierrez et al., (2014). Phenothiazines induce PP2A-mediated apoptosis in T cell acute lymphoblastic leukemia. J. Clin. Invest., doi:10.1172/JCI65093 [Article]