In this Issue
- Understanding PSA Screening – Pros and Cons for Patients
- Treatment Update for High-risk, Localized Prostate Cancer
- New Trial Tests Transplantation for Crohn’s Disease
- The Power of Translational Medicine at SCCA’s Liver Tumor Clinic
- FDA Approves Engineered T Cell Clinical Trial to Treat Leukemia and Lymphoma
- Now Recruiting: New Multi-center Trial Comparing Haploidentical and Cord Blood Transplants
- Welcome to New Director of UWMC Colorectal Surgery
- Continuing Medical Education Courses
By Ruth B. Etzioni, PhD
The U.S. Preventive Services Task Force recently recommended against routine prostate-specific antigen (PSA) screening for prostate cancer. The recommendation was based on evidence from two large screening trials conducted in the United States and Europe. The task force concluded that the benefits of PSA screening were likely to be very modest and that there was moderate certainty that they did not outweigh the harms.
What are the harms and benefits of PSA screening? Can these be adequately estimated from screening trials? These are questions that the statistical modeling group within Dr. Ruth B. Etzioni’s lab at Fred Hutchinson Cancer Research Center have been grappling with for at least 10 years.
Since PSA screening has been around in the population for more than 20 years, we have had an opportunity to learn from the population experience about its impacts — both positive and negative. Combining what we have learned from trials and population studies yields a far more nuanced picture than that provided by the task force. We would argue that the evidence is consistent with a significant long-term benefit of PSA screening and that we need to screen — and treat — smarter to reduce harms while preserving benefit.
History and results
The PSA test was introduced in the late 1980s for monitoring existing prostate tumors but became rapidly adopted for screening purposes. Since the early 1990s, prostate cancer deaths have dropped by 44 percent among men over 50, and by almost half among men aged 50 to 74. It is tempting to attribute the drop to changes in screening, but changes in treatment have also occurred. Radical prostatectomy rates increased through the 1980s and into the 1990s. Radiation therapy has evolved enormously, and hormonal therapies are now routinely being used as part of a primary treatment regimen for localized cases. We have concluded that screening and primary treatment changes together plausibly explain about two-thirds of the drop in prostate cancer deaths in this country. Screening alone, without treatment changes, explains one-third, accounting for about 10,000 lives saved in 2010.
At first glance, the task force’s conclusion that the benefits of screening are at most very modest would seem to be at odds with this finding. However, the task force based its conclusion on the absolute numbers of lives saved in the two trials. Although prostate cancer is the most common cancer in men, about three percent of men will actually die from the disease over their lifetimes in the absence of screening. In the trials which had limited follow-up, the number of deaths was considerably lower. In the trial in Europe, only five per 1,000 men enrolled died of prostate cancer in the control group. There was a significant, 20 percent reduction in the risk of dying of prostate cancer in the screened group, but with the low frequency of prostate cancer deaths, this only amounted to about one life saved per 1,000 men screened.
In the U.S. trial, the situation was similar in terms of the low frequency of deaths, but this was compounded by extensive screening in the control group, resulting in no difference in prostate cancer deaths between the two groups (in fact, the number of deaths was slightly higher in the screened group). So the U.S. trial was not able to inform about the benefits of screening versus no screening and the results from Europe almost certainly understated the lives saved over the long term. Taking these results at face value therefore produces an overly negative assessment of screening benefit.
Screening leads to over diagnosing
The relatively short-term results from the trials also produce a skewed assessment of screening harms, particularly overdiagnosis. This is the detection of tumors that would never have been diagnosed without screening. Most of these cases are low risk and can only be harmed by treatment. Prostate cancer treatments can lead to impotence, incontinence, and bowel problems. Different treatments have different side effects and rates of these side effects have been closely studied and are well-understood.
There is no question that any screening benefits that are seen in terms of reduced prostate cancer mortality have come at the cost of over-diagnosis and over-treatment of low-risk tumors, which now form the majority of prostate cancer diagnoses.
However, estimates of over-diagnosis used by the task force — primarily from the European trial — amount to at least 50 percent of screen-detected cases and the corresponding number of cases over diagnosed per life saved is 37. We have estimated that approximately one-fourth of screen-detected cases are over-diagnosed in the U.S. and, over the long term, the number over-diagnosed per life saved is seven. Both of these figures, which are based on U.S. population studies, are dramatically lower than the short-term, trial-based estimates from Europe.
In conclusion, we are concerned that a critically important policy decision may have been made by the U.S. Preventive Services Task Force on the basis of an incomplete picture of harms and benefits of PSA screening. We find ourselves in a situation in which we have a beneficial screening test that has likely saved many lives, but it uncovers many more cases that do not need to be treated. The realization that this is the case in contemporary practice has spurred a movement towards active surveillance — intensive monitoring of low-risk tumors — rather than immediate treatment of all newly-diagnosed cancers. We believe that we can also improve the harm/benefit profile of prostate screening by being more selective in referral to biopsy, particularly among older men who are at highest risk of overdiagnosis. The future of prostate screening will rest on our ability to successfully implement screening and treatment policies that are less invasive and less costly than our current practices which are undoubtedly causing a great deal of harm even while reducing prostate cancer morbidity and mortality.
Ruth B. Etzioni, PhD; Member, Public Health Sciences Division, Fred Hutchinson Cancer Research Center. Dr. Etzioni is involved in the development and implementation of statistical methods for prostate cancer studies at the Hutchinson Center. She currently leads the biostatistics core for the Northwest Prostate Cancer Specialized Program of Research Excellence (SPORE) and is an active member of three national guidelines panels on early detection of prostate cancer.
By Bruce Montgomery, MD
Recent studies and revised guidelines make clear that many men with newly diagnosed, localized prostate cancer do not require therapy due to the natural history of low-grade, low-stage disease.
But what about the one in five men diagnosed with what is commonly referred to as “high-risk” localized prostate cancer? In these men, cure is achieved less than 50 percent of the time. This group accounts for the majority of the 27,000 annual deaths from prostate cancer seen in the U.S. every year.
To reduce overall mortality in this highly heterogeneous malignancy, new treatment strategies are focused on this subset of men with high-risk prostate cancer. These cancers have a propensity to spread—even when, by all clinical appearances, the disease is localized. The likely key to preventing and treating metastasis in this group is earlier and more effective systemic therapy.
Fortunately, more effective systemic therapies for hormone regulation are now in hand. These drugs are now starting to be used as early adjuncts to surgery or radiation for high-risk tumors. At Seattle Cancer Care Alliance, we are using novel combinations of these new drugs with hormonal agents in an attempt to control local and micrometastatic prostate cancer.
New generation of systemic agents
The efficacy of the most effective systemic therapy for prostate cancer — androgen deprivation therapy — has not changed substantially in 60 years.
Recently, a second generation of inhibitors of androgen receptor signaling has shown clinical promise in treating advanced prostate cancer. One of these agents blocks the ability of the tumor to metabolize androgens (abiraterone, or Zytiga®) and another prevents a tumor receptor from binding to androgens and translocating to the cancer cell’s nucleus (MDV3100, or enzalutamide).
These enhanced actions lead to a more powerful suppression of androgen receptor signaling in a manner that prolongs survival in patients with what was historically considered to be “hormone refractory prostate cancer.” Phase III studies show that these agents provide a significant overall survival advantage of four to five months in men with metastatic prostate cancer resistant to androgen deprivation and chemotherapy.[2,3] These results demonstrate that hormonal regulation remains a critical component of therapy across all phases of the disease. Ongoing studies indicate that these agents may also possess unique anticancer mechanisms involving apoptosis (programmed cell death).
Other agents that antagonize non-androgen dependent pathways (e.g., PI-3-kinase and MET-VEGF) also hold promise in improving prostate cancer outcomes.
Predicting high risk for relapse
The main choices for primary therapy of prostate cancer, radiation and prostatectomy, are associated with similar but uniformly poor cure rates in the high-risk population.[6,7] Several studies have found that the best predictive indicators of cure are pretreatment PSA, clinical stage, and Gleason score.[6, 8-12] Patients with clinically advanced pathology (stage 3 T2c), high-grade disease (Gleason 8-10), and pretreatment PSA > 20 ng/mL are considered at high risk of biochemical progression, regardless of primary therapy.[6,9,13] In one prostatectomy study, for example, 70 percent of the patients who relapsed and died had either high-grade or high-stage disease.
Neither imaging nor biopsy can reliably define whether relapses in these patients are local, systemic, or both. However, studies of radiation salvage treatment after relapse suggest that systemic disease accounts for the majority of biochemical recurrences and that, therefore, earlier systemic treatment will be critical to improving cure rates in high-risk, localized prostate cancer.
Rationale for earlier systemic therapy
The theoretical benefit of neoadjuvant therapy in solid tumors involves eradication of both local and micrometastatic systemic disease at a time when patients can still tolerate treatment. In prostate cancer, until recently, tests of this theory have had only marginal success. Combinations of radiation with androgen deprivation therapy (neoadjuvant, long-term, or short-term) have improved survival versus either treatment alone[17-21] but parallel results with surgery are lacking.[22,23] Many of these studies, it should be noted, included men at lower risk of relapse.
Could it be that the new more effective systemic agents, when targeted toward men with high-risk prostate cancer, would boost success rates?
Evidence from neoadjuvant therapy in other solid tumors indicates that the answer may be yes. Consider three other situations where identification of a systemic therapy that modestly improved survival in late-stage disease subsequently produced larger survival advantages when used earlier as neoadjuvant therapy.
- In metastatic non-small cell lung cancer, vinorelbine and cisplatin provided a two-month survival gain[24,25]; as adjuvant therapy for patients with surgically resected clinical localized (stage IB and II) disease, the chemotherapy regimen provided a 21-month survival advantage and a 15-month absolute improvement in five-year survival.
- In metastatic colorectal carcinoma, fluorouracil plus levamisole had minimal survival advantages; when used as adjuvant therapy in resected stage III localized disease, there was 41 percent improvement in relapse-free survival and 33 percent reduction in mortality. Newer adjuvant regimens have led to even greater gains in response and survival rates.[28,29]
- In metastatic breast cancer, systemic therapy with anthracyclines and cyclophosphamide has limited, if any, impact on survival; when used as adjuvant chemotherapy for patients with any tumor over one cm in size, regardless of HER2 status, it has become the standard of care, associated with improvements of five to 15 percent in overall survival and 14 to 22 percent in disease-free survival.
Current studies at SCCA
Based on this established paradigm of neoadjuvant systemic therapy for other solid tumors, researchers at SCCA are now combining the newer, more effective systemic agents with radiation and prostatectomy in an attempt to cure prostate cancer in men with high-risk disease.
We have recently presented preliminary results demonstrating that novel combinations of hormonal agents and/or abiraterone prior to surgery can produce higher rates (30 to 35 percent) of complete or near-complete elimination of cancer in the prostate compared to previous studies (5 to 10 percent).[31,32]
Two ongoing SCCA studies that may be of interest to patients in the region are:
- With radiation therapy, use of abiraterone for men with high-risk localized prostate cancer. (In collaboration with SCCA Network Member, MultiCare Regional Cancer Center; contact Mark Konodi at (206) 359-5227 for more information.) www.seattlecca.org/clinical-trials/prostate-7048.cfm
- With surgery, use of MDV3100 (enzalutamide) with or without dutasteride and a LHRH agonist. (Contact Sara Teller at (206) 598-0854 for more information.) www.seattlecca.org/clinical-trials/prostatecancer-NCT01547299.cfm
Bruce Montgomery, MD; Associate Professor, Medical Oncology Division, University of Washington School of Medicine
By Dean Forbes
A new clinical trial testing bone marrow transplantation to cure severe cases of Crohn’s disease may provide a new treatment option to those who suffer from the chronic inflammatory condition of the gastrointestinal tract.
George B. McDonald, MD, a transplant researcher and gastroenterologist at Fred Hutchinson Cancer Research Center’s Clinical Research Division, leads the study, which is funded by an infrastructure grant from the Los Angeles-based Broad Foundation.
The initial goal of the Crohn’s Allogeneic Transplant Study (CATS) is to treat a small number of patients with treatment-resistant Crohn’s disease by transplanting matched bone marrow cells from a sibling or unrelated donor. The transplant replaces a diseased or abnormal immune system with a healthy one.
The idea of swapping out the immune system is based on evidence that Crohn’s is related to an abnormal immune response to intestinal bacteria and a loss of immune tolerance.
“There is strong evidence that genetic abnormalities in the immune regulatory system are linked to the disease,” McDonald says.
Although the CATS clinical trial represents a new direction for bone marrow transplantation, the procedure has precedent. The Hutchinson Center has used allogeneic transplants to cure patients who suffered from both leukemia and Crohn’s, with subsequent disappearance of the signs and symptoms of Crohn’s. Similar experiences have been reported from studies done in Germany.
While autologous stem cell transplants – in which the patient’s own hematopoietic cells are removed and then returned after high-dose chemotherapy is given to suppress the immune system – have been used to treat Crohn’s patients, the benefits have not always been permanent, probably because the risk genes for Crohn’s are still present.
“Autologous transplantation following chemotherapy beats the disease down but the Crohn’s tends to come back,” McDonald says.
Crohn’s disease is usually discovered in adolescents and young adults but can occur from early childhood to older age. The incidence of Crohn’s disease varies in different parts of the world with rates of four to nine persons per 100,000 people in North America. According to the Crohn’s and Colitis Foundation of America, a leading advocacy organization, Crohn’s may affect more than 700,000 Americans. Of those affected by Crohn’s, about 10 percent suffer from the most severe form for which no treatment is completely effective.
“The burden of this disease lays heavily on those who don’t respond to any therapy,” McDonald says.
More information about the study and a patient-eligibility questionnaire can be found at www.seattlecca.org/clinical-trials/transplant-NCT01570348.cfm.
The CATS investigator team includes transplant physicians, gastroenterologists, pathologists, and nurses from the Hutchinson Center, University of Washington, Seattle Children’s, and the Benaroya Research Institute. The bone marrow transplant procedures will be conducted at Seattle Cancer Care Alliance, University of Washington Medical Center, and Seattle Children’s Hospital.
By Paul Courter, Science Writer
Tumor boards are the multidisciplinary clinics where cancer specialists meet to discuss cases and decide on treatments. The Liver Tumor Clinic at Seattle Cancer Care Alliance brings together top liver cancer experts twice a week and engages patients—directly and urgently—with these specialists.
Patients are typically evaluated within days of referral to SCCA. Clinical and diagnostic evidence is reviewed and all treatments—old, new, and experimental— are considered. Once a therapy recommendation emerges from the brainstorming session, the patient meets the same day with the appropriate surgeon, oncologist, radiologist, interventionalist, or transplant expert.
“We bring seven specialties all together in one room,” says Raymond S.W. Yeung, MD, “to discuss the situation and basically leave no stone unturned to come up with a consensus recommendation. All that can be done within one visit to our clinic.”
Tuesday clinics are devoted to secondary tumors and Wednesday clinics, which include transplant experts and hepatologists, are for patients with primary liver tumors. Yeung and his colleagues see between 400 and 500 patients each year.
Increased referrals to the Liver Tumor Clinic are the result of community oncologists and surgeons being able to detect tumors earlier, as well as the growing demand for new treatments for hepatobiliary tumors offered at SCCA, including minimally-invasive procedures and clinical trials with novel agents.
Robotic surgery for liver tumors
Yeung and his colleague James O. Park, MD, offer two of the newest treatment options for liver tumors. While open or laparoscopic resection remains effective for many patients, Yeung and Park are among the few surgeons in the nation to offer robotic-assisted partial and major liver resections, including lobectomies.
“It’s not just about making smaller incisions,” says Park. “Compared to open procedures, use of the robot leads to less pain, less blood loss, fewer transfusions, and fewer days in the hospital for our patients. When they recover faster and avoid complications, we can start the next phase of treatment, adjuvant chemotherapy, sooner. This can be critical to improving the patient’s overall outcome.”
Park says the robotic technique is superior to standard laparoscopy in certain situations. “The 3-D stereotactic vision provides depth perception,” he says, “allowing greater precision and accuracy. Also, the wristed robotic instruments give the surgeon much greater range of motion. This means we can perform challenging tasks—such as rapidly suturing bleeding hepatic vessels in a tight spot to control the hemorrhage—that with a standard laparoscopic procedure might require conversion to an open procedure. In our first 25 liver cases with the robot, we had one conversion.”
Irreversible electroporation – punching holes in cancer cells
The other new treatment that Yeung, Park, and their SCCA radiology colleagues now offer patients is irreversible electroporation (IRE), commonly called NanoKnife®. This technique is an alternative to thermal ablation. Instead of using radiofrequency (RF) or microwave energy to heat and destroy the tumor, electroporation shrouds cancer cells in a pulsatile electric current that weakens their cell membrane. This triggers a sudden influx of fluid and chemicals that kills the cell. The electricity is delivered by chopsticks-like probes inserted by the interventional radiologist (guided by ultrasound or CT scan) or by the surgeon via a laparoscopic or open surgical procedure (guided by ultrasound).
“IRE isn’t a replacement for RF ablation,” explains Park, “but it is useful when thermal ablation is less effective or contraindicated, for example a tumor abutting a large blood vessel. If you try to burn such a tumor with RF, the tumor edge nearest the vein may not be destroyed due to cooling by the flowing blood, resulting in local recurrence. With IRE, all the tumor tissue can be destroyed.”
A tumor next to a bile duct is another situation where IRE might be preferred. “We shy away from doing RF or microwave ablation here,” says Park, “because we risk burning the duct and causing a stricture or leaks.” IRE allows more targeted tumor destruction because the bile ducts or blood vessels can recover from electroporation but the tumor cells cannot.
Nexus for research-based treatment
The principal investigator for most of liver cancer clinical trials is gastrointestinal medical oncologist William P. Harris, MD, who is a regular participant in the Wednesday SCCA Liver Tumor Clinic. A specialist in liver and pancreatic cancers, Harris says SCCA is uniquely positioned because of its combination of extensive clinical expertise in liver tumor treatment and substantial research infrastructure providing patients access to promising clinical trials.
“I help my patients gain access to several clinical trial options and help them select the most appropriate option based upon their specific situation,” he says. “Good communication within our liver tumor group ensures that our patients get optimal care, whether or not they are being treated with novel agents.”
Liver tumor clinicians perform basic and translational research at SCCA as well, which often intersects with Tuesday and Wednesday morning clinics. In an example of just one collaboration, Yeung analyzed his large repository of liver tissue specimens to explore molecular pathways for liver cancer while Park worked with the Materials Sciences Engineering group at UW Medicine to create nanoparticles that deliver short interfering RNAs to block those exact pathways.
“It’s a potent way to knock down multiple cancer pathways at once,” says Park. “To do so using systemic agents would be too toxic. We deliver the loaded nanoparticles via the hepatic artery, further enhancing the uptake by tumor cells.”
Park says it’s the unprecedented amount of time that SCCA liver specialists spend together in the Liver Tumor Clinics that fosters such creative and cross-disciplinary thinking.
“Sometimes,” he says, “our hospital administrators tell us it doesn’t make much financial sense to have all these specialists spending so many hours together in the Liver Tumor Clinic. But these are all very patient-invested clinicians. Our clinic coordinators are highly skilled and experienced. All of this is a huge benefit for patients who come here. And on the research side, the model creates an environment of collaboration. There really is no other liver tumor clinic like it.”
The Liver Tumor Clinic has become a hub for planning new clinical trials. Go to www.seattlecca.org/clinical-trials/livercancer-list.cfm for a complete listing.
To schedule an appointment for patients at the SCCA Liver Tumor Clinic, call Jan Thomas or Stacy Tomich at (206) 598-0539.
By Paul Courter, Science Writer
Cancer researchers at Seattle Cancer Care Alliance received approval from the U.S. Food and Drug Administration (FDA) to begin a new clinical trial using immunotherapy with genetically engineered T cells for leukemia and lymphoma patients.
The modified receptors on these T cells recognize a specific antigen on the surface of cancerous blood cells. When infused into a patient, the engineered lymphocytes bind to the tumor antigen and trigger potent cytotoxic effects that lyse the cancer cells.
The SCCA trial, led by Cameron J. Turtle, MD, PhD aims to reduce relapse rates in patients having allogeneic bone marrow transplantation (BMT) for acute lymphoblastic leukemia (ALL), advanced chronic lymphocytic leukemia (CLL), and diffuse large cell lymphoma. Even with current best practices, nearly half of patients with these advanced forms of cancer will eventually relapse after BMT.
“The results of allogeneic BMT have improved, but recurrence of the cancer remains a significant problem,” says Stanley R. Riddell, MD, oncologist and immunology researcher at Fred Hutchinson Cancer Research Center. “The graft-versus-leukemia effect that occurs with an allogeneic transplant is simply not sufficient to eliminate all of the tumor in all patients. The primary goal of administering engineered T cells is to boost the graft-versus-tumor effect and reduce leukemia and lymphoma relapse rates after transplant.”
The quest for improved cancer immunotherapy
To create this promising immunotherapy, Turtle and Riddell have partnered with Michael Jensen, MD, pediatric cancer researcher at Seattle Children’s Hospital, and several other SCCA researchers. This trial culminates years of work. The Seattle team is not the first to engineer T cell receptors in an attempt to sharpen these spearheads of the immune system against cancer. In late 2011, a report of complete remissions in two of three patients with refractory CLL who were treated with this approach at the University of Pennsylvania (Porter et al. N Engl J Med 2011;365:725-733; Kalos et al. Sci Transl Med 2011;3:95ra73) generated headlines and raised hopes that years of laboratory research into developing immunotherapy will soon benefit patients with cancer.
Fighting cancer with the immune system has become a goal for many clinician-researchers. Harnessing the body’s own immune mechanisms theoretically targets malignant cells for a relentless search-and-destroy mission. If immunotherapy becomes a reality, the side effects of chemotherapy and radiation might be lessened or avoided entirely. But the immune system is incredibly complex. So far, researchers have exploited only a fraction of its potential protective energy. Most victories using cancer immunotherapy—cytokines, monoclonal antibodies, cancer vaccines—have been partial at best. That’s why preliminary evidence of efficacy with engineered T cell receptors has spawned so much excitement.
The engineered chimeric antigen receptor: why it may work better
In most previous attempts at adoptive T cell transfer immunotherapy, lymphocytes with anti-tumor activity were isolated from a patient, stimulated to grow in the laboratory, and re-introduced into the patient. Although helpful in certain diseases (e.g., melanomas), this approach is limited by the difficulty of isolating the ideal antitumor cells and because the T cells still require the proper HLA (human leukocyte antigen) molecule to present the tumor antigen before triggering cytotoxicity.
To get around these problems, Riddell and Jensen armed donor T cells obtained easily from the blood with a chimeric antigen receptor—half monoclonal antibody and half T cell receptor. The extracellular tip of the receptor is a portion of a monoclonal antibody specific for CD19, a molecule expressed exclusively on B cells (both malignant and normal). This antibody fragment is fused to a cluster of normal T cell receptor signaling components, which remain positioned inside the cell.
Combining these two immune features into one membrane-spanning receptor, explains Riddell, overcomes the inherent limitations of each separate element, removing the requirement for HLA, and still triggering killing of tumor cells.
“We know that monoclonal antibody therapies have been very useful in treating B cell tumors,” Riddell says. “These antibodies given passively will target the tumor but they can be ineffective in killing all of the tumor cells.” Rituximab, which targets CD20 on B lymphocytes, is one classic example of monoclonal antibody therapy that zeros in on the tumor. While the agent is clinically effective and has now been used by more than a million patients with lymphoma, it is thought to produce its cytotoxic activity via antibody-dependent or complement pathways—which are considered relatively weak or indirect antitumor mechanisms.
By contrast, a monoclonal antibody linked directly to the T cell receptor requires no activation of immune mediators or attraction of other immune cells to trigger cytotoxicity. When the antibody is hard-wired in the chimeric receptor, binding to the tumor cell automatically flips the switch on the lethal effector functions inside the T cell. This leads to the release of molecules that poke holes in the target cell membrane and cause it to explode.
A further advantage of arming the T cell with a monoclonal antibody in this fashion is that T cell activation no longer requires recognition of the HLA molecule on the target cell. “Recognition and signaling is based only on the surface tumor antigen,” says Riddell. “The patient’s HLA allele doesn’t matter.” This absence of major histocompatibility complex (MHC) restriction makes it easier to use a single pre-engineered receptor to target tumor cells in a variety of patients displaying a diversity of MHC patterns.
“What we are doing,” explains Riddell, “is coupling the exquisite specificity of the antibody to the potent effector function of the T cell. We target the tumor with the antibody and kill it with the T cell. Moreover, since this is a living therapy, the engineered cells can grow in the patient until the tumor is eradicated.”
For this trial, T cells were engineered from donor blood cells. “A lentiviral vector inserts the gene that encodes the chimeric receptor,” Riddell says. “The receptor is then expressed on the T cell’s surface, retargeting it to the CD19 molecule.”
The whole process for making the T cells takes a few weeks. The patient receives the engineered cells after the allogeneic BMT. For those patients who have relapsed after a previous transplant, stored cells from the original donor can be retrieved, engineered, and then given as a donor lymphocyte infusion.
“This study uses our sophisticated GMP facility to generate the cells very quickly,” says Riddell. “Our first goal is to show safety; however, we also hope to see antitumor activity. Because tumors are susceptible to mutation, we also need to see if the tumors lose expression of the molecule we’re targeting.”
Anticipated side effects are related mainly to depletion of normal B cells along with the tumor cells. The resulting tumor lysis syndrome and longer-term lymphopenia are expected to be manageable.
While the challenges and complexities of the trial are clear, Riddell and Turtle are hopeful and already looking ahead. “In animal models these cells are extremely effective and completely eliminate tumors,” Turtle says. “If proven effective in trials, this is a treatment that could expand very rapidly to help patients who are unable or choose not to receive a transplant.”
More information about this study is on the SCCA website at: www.seattlecca.org/clinical-trials/transplant-NCT01475058.cfm.
This new trial will randomize patients between two alternative donor stem cell protocols in a comparison: haploidentical (HLA-mismatched) family members (including parents, children, and about half of a patient’s siblings) versus unrelated umbilical cord blood.
“Patients who may not have had a chance at a matched donor transplant will have more opportunities through the growth of these alternative donor options,” says Paul O’Donnell, MD, PhD, medical director of the Adult Stem Cell Transplant Service at SCCA. In some cases, patients of mixed ethnic heritage can have the most difficulty finding matches, and may benefit the most from these studies.
Looking for alternatives
Only 30 percent of bone marrow transplant patients have matched sibling donors. Another 35 percent will find matched unrelated donors, leaving the remaining 35 percent looking for alternatives. “For a long time, matched unrelated donors have been the alternative donors of choice,” O’Donnell says. “Our outcomes using such donors consistently outperform many other centers. But now we are able to offer patients who can’t find a matched unrelated donor the option of transplant using a haploidentical donor or unrelated cord blood.”
Across the country, findings indicate that transplant outcomes using haploidentical or cord blood donors are very similar to matched donors, according to O’Donnell. “The incidences of acute or chronic graft versus host disease (GVHD) are surprisingly similar or less than matched donors using current protocols,” he says.
O’Donnell is one of three principal investigators and the trial will include about 40 centers around the nation enrolling 410 leukemia and lymphoma patients. Coordinated nationwide by the Blood and Marrow Transplant Clinical Trials Network, the trial will be open for four years and patients will be followed for three years after their transplant.
More information about this trial is on the SCCA website at: www.seattlecca.org/clinical-trials/transplant-NCT01597778.cfm.
Watch Dr. O’Donnell’s video where he discusses this new, exciting opportunity for hard-to-match transplants.
Watch two SCCA patients talk about their experience with this treatment.
Alessandro Fichera, MD, a nationally renowned, board certified colorectal surgeon specializing in the latest surgical techniques and research, joined UW Medicine in July to lead and further develop the Colorectal Surgery and Surgical Oncology Programs. He spent the last 10 years at the University of Chicago Medical Center, where he started and then directed the Colon and Rectal Surgery Residency Training Program.
Trained at the Catholic University of Rome in Italy, Fichera received his doctorate degree with academic honors. He completed his internship and residency in general surgery at the 2nd University of Rome and at the University of Chicago, followed by fellowship training in colorectal surgery at Mt. Sinai in New York.
In addition to his surgical expertise in all types of colorectal disorders, Fichera has a strong interest in inflammatory bowel disease (IBD) and pelvic floor disorders. His research interests focus on IBD, minimally-invasive and robotic surgery, prevention and treatment of colorectal cancers, and the management of a wide variety of digestive diseases. His long-term goals include the development of multidisciplinary programs for IBD, rectal cancer, and pelvic floor disorders.
Comprehensive Oncology Review Course
September 22–25, 2012 • Location: W Hotel, Seattle
Returning in 2012, SCCA and two of its founding organizations, Fred Hutchinson Cancer Research Center and UW Medicine, are offering this four-day program that will incorporate data supporting guideline-based recommendations and recent advances regarding therapeutic options for patients with malignant solid tumor disorders. At the end of the course, physicians will leave with a comprehensive syllabus, a self-assessment, and a deeper understanding of the pathogenesis, diagnostic evaluation, and therapeutic modalities available for common solid tumor malignancies.
There will be a case-based review session and discussions. The course will be designed to help prepare physicians for certifying and re-certifying exams as applicable. Don’t miss the most informative CME of the year!
For more information or to register online, click here.
Updates in Oncology and Blood/Marrow Transplantation: A Spotlight on Seattle Cancer Care Alliance
October 15–16, 2012 • Location: The Westin, Seattle
This two-day multidisciplinary conference will highlight the latest updates in science and clinical practice for oncology, hematology and blood/marrow transplantation. A panel of experts will discuss the most recent clinical innovations and emerging therapies in their respective fields. The goal is to provide attendees with a greater understanding of the advancements and clinical research in the field of oncology to ensure they are providing the best possible adult and pediatric patient care. The conference is for physicians, case managers, managed care professionals, nurses/oncology nurses, nurse practitioners, medical directors, medical management staff, physician assistants, reinsurance managers, utilization review staff, and other healthcare professionals committed to managing and improving patient care.
For more information or to register online, click here.
- Cooperberg MR, Moul JW, Carroll PR: The changing face of prostate cancer. J Clin Oncol 2005, 23(32):8146-8151.
- de Bono JS, Logothetis CJ, Molina A, Fizazi K, North S, Chu L, Chi KN, Jones RJ, Goodman OB, Jr., Saad F et al: Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med 2011, 364(21):1995-2005.
- Scher HI, Fizazi K, Saad F, Taplin M, Sternberg C, Miller K, De Wit R, Mulders P, Hirmand M, Selby B et al: Effect of MDV3100, an androgen receptor signaling inhibitor (ARSI), on overall survival in patients with prostate cancer postdocetaxel: Results from the phase III AFFIRM study. Proc Am Soc Clin Onc 2012, .
- Scher HI, Beer TM, Higano CS, Anand A, Taplin ME, Efstathiou E, Rathkopf D, Shelkey J, Yu EY, Alumkal J et al: Antitumour activity of MDV3100 in castration-resistant prostate cancer: a phase 1-2 study. Lancet 2010, 375(9724):1437-1446.
- Cooperberg MR, Broering JM, Litwin MS, Lubeck DP, Mehta SS, Henning JM, Carroll PR: The contemporary management of prostate cancer in the United States: lessons from the cancer of the prostate strategic urologic research endeavor (CapSURE), a national disease registry. J Urol 2004, 171(4):1393-1401.
- D'Amico AV, Whittington R, Malkowicz SB, Schultz D, Blank K, Broderick GA, Tomaszewski JE, Renshaw AA, Kaplan I, Beard CJ et al: Biochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancer [see comments]. Jama 1998, 280(11):969-974.
- Potters L, Klein EA, Kattan MW, Reddy CA, Ciezki JP, Reuther AM, Kupelian PA: Monotherapy for stage T1-T2 prostate cancer: radical prostatectomy, external beam radiotherapy, or permanent seed implantation. Radiother Oncol 2004, 71(1):29-33.
- Roberts WW, Bergstralh EJ, Blute ML, Slezak JM, Carducci M, Han M, Epstein JI, Eisenberger MA, Walsh PC, Partin AW: Contemporary identification of patients at high risk of early prostate cancer recurrence after radical retropubic prostatectomy. Urology 2001, 57(6):1033-1037.
- Kattan MW, Wheeler TM, Scardino PT: Postoperative nomogram for disease recurrence after radical prostatectomy for prostate cancer. J Clin Oncol 1999, 17(5):1499-1507.
- Bauer JJ, Connelly RR, Sesterhenn IA, Bettencourt MC, McLeod DG, Srivastava S, Moul JW: Biostatistical modeling using traditional variables and genetic biomarkers for predicting the risk of prostate carcinoma recurrence after radical prostatectomy. Cancer 1997, 79(5):952-962.
- Amling CL, Bergstralh EJ, Blute ML, Slezak JM, Zincke H: Defining prostate specific antigen progression after radical prostatectomy: what is the most appropriate cut point? J Urol 2001, 165(4):1146-1151.
- Garcia-Rocha M, Avila J, Lozano J: The zeta isozyme of protein kinase C binds to tubulin through the pseudosubstrate domain. Exp Cell Res 1997, 230(1):1-8.
- Kupelian P, Katcher J, Levin H, Zippe C, Suh J, Macklis R, Klein E: External beam radiotherapy versus radical prostatectomy for clinical stage T1-2 prostate cancer: therapeutic implications of stratification by pretreatment PSA levels and biopsy Gleason scores. Cancer J Sci Am 1997, 3(2):78-87.
- D'Amico AV, Chen MH, Roehl KA, Catalona WJ: Preoperative PSA velocity and the risk of death from prostate cancer after radical prostatectomy. N Engl J Med 2004, 351(2):125-135.
- Leventis AK, Shariat SF, Kattan MW, Butler EB, Wheeler TM, Slawin KM: Prediction of response to salvage radiation therapy in patients with prostate cancer recurrence after radical prostatectomy. J Clin Oncol 2001, 19(4):1030-1039.
- Stephenson AJ, Shariat SF, Zelefsky MJ, Kattan MW, Butler EB, Teh BS, Klein EA, Kupelian PA, Roehrborn CG, Pistenmaa DA et al: Salvage radiotherapy for recurrent prostate cancer after radical prostatectomy. Jama 2004, 291(11):1325-1332.
- Warde P, Mason M, Ding K, Kirkbride P, Brundage M, Cowan R, Gospodarowicz M, Sanders K, Kostashuk E, Swanson G et al: Combined androgen deprivation therapy and radiation therapy for locally advanced prostate cancer: a randomised, phase 3 trial. Lancet 2011, 378(9809):2104-2111.
- Widmark A, Klepp O, Solberg A, Damber JE, Angelsen A, Fransson P, Lund JA, Tasdemir I, Hoyer M, Wiklund F et al: Endocrine treatment, with or without radiotherapy, in locally advanced prostate cancer (SPCG-7/SFUO-3): an open randomised phase III trial. Lancet 2009, 373(9660):301-308.
- Bolla M, Gonzalez D, Warde P, Dubois JB, Mirimanoff RO, Storme G, Bernier J, Kuten A, Sternberg C, Gil T et al: Improved survival in patients with locally advanced prostate cancer treated with radiotherapy and goserelin. N Engl J Med 1997, 337(5):295-300.
- D'Amico AV, Manola J, Loffredo M, Renshaw AA, DellaCroce A, Kantoff PW: 6-month androgen suppression plus radiation therapy vs radiation therapy alone for patients with clinically localized prostate cancer: a randomized controlled trial. Jama 2004, 292(7):821-827.
- Jones CU, Hunt D, McGowan DG, Amin MB, Chetner MP, Bruner DW, Leibenhaut MH, Husain SM, Rotman M, Souhami L et al: Radiotherapy and short-term androgen deprivation for localized prostate cancer. N Engl J Med 2011, 365(2):107-118.
- Gleave ME, Goldenberg SL, Chin JL, Warner J, Saad F, Klotz LH, Jewett M, Kassabian V, Chetner M, Dupont C et al: Randomized comparative study of 3 versus 8-month neoadjuvant hormonal therapy before radical prostatectomy: biochemical and pathological effects. J Urol 2001, 166(2):500-506; discussion 506-507.
- Soloway MS, Pareek K, Sharifi R, Wajsman Z, McLeod D, Wood DP, Jr., Puras-Baez A: Neoadjuvant androgen ablation before radical prostatectomy in cT2bNxMo prostate cancer: 5-year results. J Urol 2002, 167(1):112-116.
- Rapp E, Pater JL, Willan A, Cormier Y, Murray N, Evans WK, Hodson DI, Clark DA, Feld R, Arnold AM et al: Chemotherapy can prolong survival in patients with advanced non-small-cell lung cancer--report of a Canadian multicenter randomized trial. J Clin Oncol 1988, 6(4):633-641.
- Ranson M, Davidson N, Nicolson M, Falk S, Carmichael J, Lopez P, Anderson H, Gustafson N, Jeynes A, Gallant G et al: Randomized trial of paclitaxel plus supportive care versus supportive care for patients with advanced non-small-cell lung cancer. J Natl Cancer Inst 2000, 92(13):1074-1080.
- Winton T, Livingston R, Johnson D, Rigas J, Johnston M, Butts C, Cormier Y, Goss G, Inculet R, Vallieres E et al: Vinorelbine plus cisplatin vs. observation in resected non-small-cell lung cancer. N Engl J Med 2005, 352(25):2589-2597.
- Moertel CG, Fleming TR, Macdonald JS, Haller DG, Laurie JA, Goodman PJ, Ungerleider JS, Emerson WA, Tormey DC, Glick JH et al: Levamisole and fluorouracil for adjuvant therapy of resected colon carcinoma. N Engl J Med 1990, 322(6):352-358.
- Efficacy of adjuvant fluorouracil and folinic acid in colon cancer. International Multicentre Pooled Analysis of Colon Cancer Trials (IMPACT) investigators. Lancet 1995, 345(8955):939-944.
- Andre T, Boni C, Mounedji-Boudiaf L, Navarro M, Tabernero J, Hickish T, Topham C, Zaninelli M, Clingan P, Bridgewater J et al: Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med 2004, 350(23):2343-2351.
- Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet 2005, 365(9472):1687-1717.
- Mostaghel EA, Nelson P, Lange PH, Lin DW, Taplin M, Balk SP, Ellis WJ, Penning T, Marck B, True LD et al: Neoadjuvant pathway suppression prior to prostatectomy. Proc Am Soc Clin Onc 2012.
- Taplin M, Montgomery RB, Logothetis C, Bubley GJ, Richie J, Dalkin BJ, Sanda M, Loda M, True L, Troncoso P et al: Effect of neoadjuvant abiraterone acetate (AA) plus leuprolide acetate (LHRHa) on PSA, pathological complete response (pCR), and near pCR in localized high-risk prostate cancer (LHRPC): Results of a randomized phase II study. Proc Am Soc Clin Onc 2012.
The SCCA Adult Bone Marrow Transplant News is a publication presenting the latest information on bone marrow transplant research at SCCA, providing up-to-date information for all health care professionals caring for transplant patients.
Read about important outcomes research at the Fred Hutch that may benefit your patients.
Each issue of Clinical Trials Monthly highlights several of the more than 200 clinical trials that are currently recruiting patients at SCCA.
Each quarterly Leading Edge newsletter will highlight a new topic to give you the latest news on leading-edge therapies that SCCA physicians are offering.