Two studies examine long-term outcomes in childhood and young adult cancer survivors

JAMA Oncology published two studies and a related editorial focused on long-term outcomes in survivors of childhood or young adult cancer.

In the first study, Kathrine Rugbjerg, PhD, and Jørgen Olsen, MD, DMSc, of the Danish Cancer Society Research Center, Copenhagen, examined the risk for hospitalization up to 34 years after a diagnosis of adolescent and young adult cancer survivors. The study included 33,555 five-year cancer survivors diagnosed from 1943 through to 2004 with a comparison group from the general population. The authors identified 53,032 hospitalizations in cancer survivors for one or more of 97 disease categories.

Cancer survivors had an overall increased risk of hospitalization compared with those in the general population. Cancer survivors at highest risk for hospitalizations were leukemia, brain cancer and Hodgkin lymphoma survivors.

Survivors of adolescent and young adult cancers face persistent risks for a broad range of somatic diseases requiring hospitalization. The morbidity pattern, which is highly dependent on the type of cancer being treated, underscores the need for further implementation of strict evidence-based sex-, age- and cancer-specific follow-up plans for survivors, thereby increasing the likelihood for early detection and ultimately prevention of treatment-induced morbidities.

In the second study, Kevin Krull, PhD, of St. Jude Children’s Research Hospital, Memphis, and coauthors examined neurocognitive and patient-reported outcomes in adult survivors of childhood osteosarcoma, a type of bone cancer. The study included 80 survivors of osteosarcoma who were an average age of nearly 39 years and almost 25 years past diagnosis. The cancer survivors were compared with 39 community members unrelated to the cancer survivors. Long-term survivors had lower average scores in reading skills, attention, memory and processing speed. However, plasma concentration of methotrexate following high-dose intravenous administration during chemotherapy was not associated with neurocognitive outcomes at nearly 25 years after diagnosis.

Long-term survivors of osteosarcoma are at risk for neurocognitive impairment, which is related to current chronic health conditions and not to original treatment with high-dose methotrexate. … Our results demonstrate the need for increased attention in this diagnosis, with prospective studies to delineate the evolution of impairment over the course of therapy and long-term survival,” the authors conclude.

In a related editorial, Karen E. Effinger, MD, MS, and Michael P. Link, MD, of the Stanford University School of Medicine, California, write: “Advances in cancer therapy have led to increased survival; there are more than 9 million 5-year survivors of cancer in the United States. As this number continues to grow, focus on improved health and quality of life becomes a priority. … Going forward, we must apply our knowledge of late effects to improve monitoring and interventions for patients. While the progress made in the management of cancer in children and young adults has been gratifying, we must remember the words of Giulio D’Angio, who reminds us that ‘cure is not enough.'”Rugbjerg et al. Long-term Risk of Hospitalization for Somatic Diseases in Survivors of Adolescent or Young Adult Cancer. JAMA Oncol. Published online November 19, 2015. doi:10.1001/jamaoncol.2015.4393 [Article]Krull et al. Neurocognitive and Patient-Reported Outcomes in Adult Survivors of Childhood Osteosarcoma. JAMA Oncol. Published online November 19, 2015. doi:10.1001/jamaoncol.2015.4398 [Abstract]

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Young adult survivors most distressed after leukemia and lymphoma treatment

Two University of Colorado Cancer Center studies published in the Journal of Psychosocial Oncology show that young adult survivors (ages 18-39) of leukemia and lymphoma are more likely to report high distress than older survivors (ages 65+). Specifically, 45 percent of younger patients report moderate-to-high distress, whereas only 18 percent of older patients report similarly elevated levels. Interestingly, in both groups this distress was not affected by time since treatment – distress was just as likely to be high in survivors who had completed treatment four years prior as in survivors who were three months out of treatment.

Now that patients are living longer with cancer and after cancer, it is becoming more and more important to look at how survivors are living. What is their quality of life and how can we help make it better?” says Whitney Jones, PhD, the studies’ first author, working with data collected by Carly Parry, PhD, research scientist at Kaiser Permanente, California. Both Jones and Parry are family members of cancer survivors. Jones says, “It was natural – I just kind of fell into survivorship research.”

Jones explains the effect of age on distress using a framework called the Lifespan Perspective. Because there is an expected social, cultural and developmental course of a person’s life, an event (such as cancer) that is highly disruptive in one lifespan stage may be less disruptive in another.

For younger survivors, cancer is out of context,” Jones says. “When you’re under forty, you’re finishing your education, entering the workforce, starting a family, and cancer may be interpreted as disruptive and unexpected in that phase. On the other hand, some of our older survivors said things like, ‘Cancer isn’t the most difficult thing I’ve experienced in life.’ And they knew friends and family members who had dealt with similar cancer experiences,” she says.

One paper surveyed 477 cancer survivors, using a widely-used measure of distress after trauma and several items from a measure of quality of life in cancer survivors. These measures allowed Jones, Parry and colleagues to ask which factors of a cancer survivor’s life after treatment are the best predictors of persistent distress after treatment completion. Survivors under age 40 had the highest prevalence of distress, while a risk profile showed that a person’s fear of cancer recurrence was the best predictor of elevated distress – people who feared recurrence were most likely to also report high overall distress levels. High financial burden due to cancer treatment also predicted distress.

The second study used interviews with 51 leukemia survivors to explore the human side of these numbers and better understand the sources of distress as articulated by survivors themselves.

For example, this was before the Affordable Care Act, and we had one survivor who talked about having only the basic college student insurance when he was diagnosed. After treatment he discovered he had substantial medical debt and was uninsurable. It helped to hear survivors talk about their experiences in their own words. To hear them articulate it helped us understand the real struggles behind our data,” Jones says.

Interviews may also help explain why distress lingers even years after treatment ends.

A patient told us that, after lymphoma treatment, her doctor said that it would take two years to recover physically and mentally, and that almost all the gains would be in these two years,” Jones says. “She said something like, ‘I was really patient for two years, then after those two years passed, I didn’t feel any better and realized this is what I was going to be living with.'”

Distress detection and treatment is increasingly being seen as part of the standard of care for cancer patients and post-treatment survivors. For example, organizations like the National Comprehensive Cancer Network (NCCN) and the American College of Surgeons Commission on Cancer (ACS CoC) mandate distress screening and treatment in order to earn accreditation from these institutions.

Understanding which individuals are most likely to experience elevated distress,” for example young adult survivors who report fear of recurrence and financial strain due to cancer, “can be useful in targeting interventions to potential participants,” Jones says.

Jones et al. Understanding Distress in Post-Treatment Adult Leukemia and Lymphoma Survivors: A Lifespan Perspective. J Psycho Oncol. 2015; DOI:10.1080/07347332.2014.1002658 [Abstract]

Jones et al. Prevalence and Predictors of Distress in Post-Treatment Adult Leukemia and Lymphoma Survivors. J Psycho Oncol. 2015; DOI:10.1080/07347332.2014.992085 [Abstract]

Risk for leukemia after treatment for early-stage breast cancer higher than reported

The risk of developing leukemia after radiation therapy or chemotherapy for early stage breast cancer remains very small, but it is twice as high as previously reported, according to results of a new study led by researchers at the Johns Hopkins Kimmel Cancer Center.

The study team reviewed data on 20,063 breast cancer patients treated at eight U.S. cancer centers between 1998 and 2007 whose cancer recurrence and secondary cancer rates were recorded in a database kept by the National Comprehensive Cancer Network. In that group, 50 patients had developed some form of leukemia within 10 years after radiation therapy, chemotherapy or a combination of the two. That translates to roughly a cumulative risk of 0.5 percent.

Data from earlier randomized clinical trials, which typically include just a few hundred patients, found that about 0.25 percent of breast cancer patients develop leukemia as a late effect of chemotherapy, says Judith Karp, M.D., professor emerita of oncology at the Johns Hopkins University School of Medicine, who retired in 2013 as director of the Kimmel Cancer Center’s Leukemia Program. Results  were published online in the Journal of Clinical Oncology.

The frequency of bone marrow cancers such as leukemia is small, there’s no question about it,” Karp says. “However, the cumulative risk over a decade is now shown to be twice as high as we thought it was, and that risk doesn’t seem to slow down five years after treatment.”

Most medical oncologists have come to think that the risk is early and short-lived,” says Karp. “So this was a little bit of a wake-up call that we are not seeing any plateau of that risk, and it is higher.”

Antonio Wolff, M.D., a professor of oncology at the Johns Hopkins University School of Medicine, says the study could help early-stage breast cancer patients and their physicians think more carefully about the use of chemotherapy for “just-in-case” reasons, especially when patients have a low risk of cancer recurrence.

Our study provides useful information for physicians and patients to consider a potential downside of preventive or adjuvant chemotherapy in patients with very low risk of breast cancer recurrence,” says Wolff. “It could be a false and dangerous security blanket to some patients by exposing them to a small risk of serious late effects with little or no real benefit from the treatment.”

In recent years, oncologists have learned that postsurgical chemotherapy for breast cancer mostly benefits a small and select group of patients. The National Comprehensive Cancer Network clinical guidelines no longer recommend it for all patients with stage 1 breast cancers, the term for invasive breast cancers no larger than 2 centimeters that have not spread to nearby lymph nodes.

Wolff says that each patient’s treatment plan for early-stage cancer could differ depending on a variety of factors, including the size of the tumors; whether the cancer has spread to the lymph nodes; and whether the tumor tests positive for certain breast cancer-related hormone and growth receptors, such as estrogen receptors (ER) and human epidermal growth factor receptor 2 (HER2).

The study team, led by Johns Hopkins researchers, also included a hypothetical case to put the risks of early-stage breast cancer and chemotherapy treatment in perspective. She was a 60-year-old woman in average health, diagnosed with stage 1 breast cancer that was rapidly growing and ER-positive, and who is calculated to have a 12.3 percent risk of dying of breast cancer after 10 years. She could improve her 10-year survival rate by 1.8 percent with four cycles of chemotherapy, but she would also increase her risk of leukemia over that same time by 0.5 percent.

The good news is that the majority of patients with stage 1 breast cancer will survive their breast cancer diagnosis,” he adds, “and of all the solid tumors, breast cancer is among the most curable of them.”

Wolff says it isn’t yet clear whether the increased risk of leukemia after post surgical chemotherapy applies to patients with other kinds of solid tumors, especially since the drug regimens used in breast cancer differ from those used for other cancers.

Boileau et al. Sentinel node biopsy after neoadjuvant chemotherapy in biopsy-proven node-positive breast cancer: The SN FNAC study. J Clin Oncol. 2014; Epub ahead of print. doi:10.1200/JCO.2014.55.7827 [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]

Breakthrough in treating leukemia, lymphoma with umbilical cord blood stem cells

Study finds that growing stem cells in lab before transplant boosts survival

Donated umbilical cord blood contains stem cells that can save the lives of patients with leukemia, lymphoma and other blood cancers. Now a study lead by a Loyola University Medical Center oncologist has found that growing cord blood stem cells in a laboratory before transplanting them into patients significantly improves survival.

The cell-expansion technology potentially could boost the number of patients who could benefit from life-saving transplants of stem cells derived from umbilical cord blood, said Patrick Stiff, MD, lead author of the study. Stiff, director of Loyola’s Cardinal Bernardin Cancer Center, presented findings at the 2013 annual meeting of the American Society of Hematology.

The ASH meeting is the preeminent annual event for physicians and scientists in hematology. Data from more than 5,300 abstracts were presented, and Stiff’s abstract was selected as one of the 2013 meeting’s top submissions.

Stem cell transplants can save lives of patients who have no other options. Patients receive high-dose chemotherapy, and in some cases, high-dose radiation as well. The treatment, unfortunately, kills healthy blood cells along with the cancerous cells. To rebuild the stores of healthy cells, the patient subsequently receives a transplant infusion of immature stem cells. Over time, these stem cells develop into new blood cells.

Stem cells are produced in the bone marrow. In many cases, patients receive bone marrow stem cells donated by family members or Good Samaritans who have signed up with a bone marrow registry.

But fewer than 50 percent of eligible patients can find a matching bone marrow donor. In such cases, stem cells derived from umbilical cord blood can be an effective alternative because these cells do not require perfect matches.The cord blood is donated by parents of newborns, and frozen in a cord blood bank. Each donation contains only about one ounce of blood, which usually is enough for only a child or very small adult. Many adults, therefore, receive a double dose of cord blood stem cells donated by two newborns.

The study examined a new technology called StemEx®, which grows cord blood stem cells in an outside laboratory. After 21 days, there’s a roughly 14-fold increase in the number of stem cells available for transplant. The study included 25 centers in the United States, Europe and Israel. Researchers used the StemEx technology for cord blood transplants in 101 leukemia and lymphoma patients. These patients were compared with a historical control group of 295 patients who each received a double dose of cord blood stem cells.

After 100 days, the overall survival was significantly higher in the StemEx group ( 84.2 percent) than in the control group (74.6 percent). The StemEx transplants also were quicker to engraft, i.e., develop into a sufficient number of blood cells. In the StemEx group, engraftment of neutrophil blood cells took a median of 21 days, compared with 28 days in the control group. Engraftment of platelets took a median of 54 days in the StremEx group and 105 days in the control group. (Neutrophils are infection-fighting white blood cells; platelets are small blood components that help the clotting process.) The faster neutrophils and platelets are engrafted, the less time patients are vulnerable to infections and bleeding.

The StemEx process has not been approved by the Food and Drug Administration, and is not available to patients except in clinical trials.

2013 ASH Annual Meeting and Exposition, December 7-10, New Orleans, LA

Technique filters cancer where chemo can’t reach

A cancer therapy that removes malignant cells from a patient’s cerebrospinal fluid may soon be available to prevent metastases and decrease complications of cancers involving the brain, according to Penn State medical researchers.

Many cancer types metastasize to the brain — including breast cancer, pancreatic cancer, prostate cancer and leukemia — but by filtering these malignant cells out of the cerebrospinal fluid (CSF), the researchers hope to decrease the chance of cancer spreading toward and away from the brain.

The brain and spinal cord are surrounded by cerebrospinal fluid, separated from the blood circulating throughout the rest of the body by a cellular lining known as the blood-brain barrier.

“Most chemotherapies have a difficult time crossing the blood-brain barrier, but cancer cells can if they have the right instructions,” said Joshua E. Allen, postdoctoral fellow at the Penn State Hershey Cancer Institute.

The researchers have devised a way to move CSF through a filter outside the body that catches the cancer cells and then allows the CSF to flow back into the patient, tumor cell-free.

“Currently nothing exists that can filter cerebrospinal fluid — which, in some patients, contains malignant active cancer cells,” said Akshal S. Patel, neurosurgery resident at the Penn State Milton S. Hershey Medical Center. “This therapy filters all cerebrospinal fluid.”

Many treatments, including chemotherapy, increase therapeutic resistance of cancer cells, Allen noted. However, filtering cells out does not offer the malignant cells an opportunity to develop therapeutic resistance.

Treatment providers can count the cells captured in the filter and use that to measure the severity of metastasis, another benefit to using this method.

Approximately 15 to 20 percent of metastatic breast cancer patients eventually develop brain metastases, according to the researchers.

“There is a high likelihood of breast cancer patients getting cancer cells in their cerebrospinal fluid,” said Patel.

The researchers monitored the number of tumor cells in nine breast cancer patients with confirmed metastatic spread to their central nervous system. They counted both the number of tumor cells in the bloodstream and in the CSF.

Approximately half of these patients had tumor cells that moved through the blood-brain barrier. Allen and Patel found that this movement of tumor cells is not necessarily restricted to later phases of breast cancer, as previously thought.

With this new knowledge in mind, the researchers’ proposed method can help treat breast cancer — and other metastasizing cancers — earlier and with potentially fewer drugs. This filtering of body fluid is similar to that used as standard care for leukemia, and offers potentially increased cure rates.

“The minimum this therapy would provide is straining the tumor cells out,” said Allen. “But we could also include other therapies when returning the CSF to the body.”

A provisional patent application for this method described by the inventors has been filed.