Onco’Zine reports about current research and development in hematology and oncology and includes comments on peer-reviewed reports and congress reports from international medical meetings.
Researchers using the OncoVue® (InterGenetics Inc,655 Research Parkway, Suite 300, Oklahoma City, OK 73104) clinical breast cancer model for assessing genetic risk had much higher accuracy when compared with the more commonly used Gail model, according to data presented at the 31st Annual CTRC-AACR San Antonio Breast Cancer Symposium (SABCS, December 10 - 14, 2008).
By using a combination of a questionnaire and a saliva test, the OncoVue® model takes into account genetic variation in single nucleotide polymorphisms, or SNPs, that the traditional Gail model, which bases risk calculation primarily on traditional risk factors like woman's own personal medical history (number of previous breast biopsies and the presence of atypical hyperplasia in any previous breast biopsy specimen), her own reproductive history (age at the start of menstruation and age at the first live birth of a child), and the history of breast cancer among her first-degree relatives (mother, sisters, daughters) to estimate her risk of developing invasive breast cancer over specific periods of time, does not.
The single nucleotide polymorphisms or SNPs used by the OncoVue model, are small genetic changes within DNA that underlie individuality, including disease risk.
The initial research considered 117 common SNPs as candidates, but during test development the list was ultimately narrowed to 22 SNPs in 19 genes that proved to be most informative in estimating a woman’s individualized risk of developing breast cancer.
‘Women are clamoring for genetic tests like this one. The traditional Gail model looks at personal and clinical risk factors, but not at the inherited genetic variation in SNPs,’ explained lead investigator Kathie Dalessandri, M.D., a physician scientist who led the research team along with colleagues at the University of California, San Francisco, and the Buck Institute for Age Research.
Buccal cell DNA had been collected from 177 women without breast cancer who comprised the control group and 169 women diagnosed with breast cancer between 1997 and 1999 in Marin County, California. This region has been recognized for many years as having higher than average breast cancer incidence and mortality rates. Despite their elevated risk, Marin women who develop breast cancer have similar risk factors as Marin women who do not develop breast cancer when assessed by the classical Gail model characteristics. The researchers theorized that the OncoVue model which integrates the influence of genetic variation along with personal and clinical information would be able to more accurately estimate risk for these Marin women.
DNA was genotyped for 22 SNP variants, and the researchers assessed the fraction of case and control patients who were assigned an OncoVue risk score greater than 1.5 times average likelihood of developing breast cancer between ages 30 and 69. In this blinded analysis, the OncoVue® score proved 2.4 times (p=0.036) more accurate than the Gail model characteristics in accurately identifying the Marin cases with their increased risk from Marin controls with their reduced risk.
In this blinded validation study OncoVue exhibited significantly improved performance, compared to the Gail model alone, in estimating individual risk among Marin County, California women. The improved performance of OncoVue was similar to that observed in two previous independent validation sets, thus, supporting the clinical utility of OncoVue for more accurate individualized breast cancer risk estimation.
Additionally, OncoVue exhibited a 51 percent improvement over the Gail model in assigning an elevated risk score to cases. The improvement in risk estimation is significant and Dalessandri believes the OncoVue model will soon become standard clinical practice for evaluating breast cancer risk. ‘Within the next few years there is going to be a definite paradigm shift toward prevention by analysis of genetic material rather than traditional risk factors,’ Dalessandri noted. ‘As these tests become more commonplace we will be able to more effectively target prevention and early intervention to those at highest risk.’
NCI– National Cancer Institute: Breast Cancer Risk Assessment Tool, based on a statistical model known as the ‘Gail model,’ named after Dr. Mitchell Gail, Senior Investigator in the Biostatistics Branch of NCI's Division of Cancer Epidemiology and Genetics.
HER2, human epidermal growth factor receptor 2, is a protein found on the surface of breast cancer cells. When functioning normally, HER2 is a key component in regulating cell growth. However, when altered, extra HER2 protein receptors may be produced.
This overexpression of HER2 is considered a negative prognostic factor and associated with increased cell growth and reproduction, often resulting in a more aggressive form of breast cancer with increased disease recurrence and worse prognosis. Studies show that HER2/neu is overexpressed in approximately 15-20% of invasive breast cancers. Because HER2+ tumors tend to grow and spread more quickly than tumors that are not HER2+, accurate and timely diagnostic procedures are crucial.
High Risk There are a number of different kinds of breast cancer and each is treated differently. Patients with Her2+ breast cancer are generally classified as high risk. As a result, current treatment guidelines recommend adjuvant trastuzumab (Herceptin®, Genentech, 1 DNA Way South San Francisco, CA 94080-4990, co-marketed by F. Hoffmann-La Roche, Grenzacherstrasse 124, CH-4070 Basel, Switzerland) and chemotherapy as the best treatment option for all HER2-positive breast cancer patients at high risk of relapse, increasing their chance of living longer. At the same time, results from the HERA-trial (HERceptin Adjuvant), a randomized, two-arm, open label study of the efficacy, safety and tolerability of trastuzumab compared to observation in women who have completed standard adjuvant treatment of HER2 positive primary breast cancer, showed that 74% of patients remained distant recurrence-free at 3 years without trastuzumab.
A highly sensitive prognostic tool Dr. Michael Knauer, MD, from the Netherlands Cancer Institute presented the results from a study investigating the benefits of a highly sensitive diagnostic assay during the 2008 San Antonio Breast Cancer Symposium (SABCS). In the study, researchers used MammaPrint®, (Agendia BV, Amsterdam Science Park, Kruislaan 406, NL-1098 SM Amsterdam, The Netherlands), a prognostic genomic test developed with micro-array technology that has the potential to greatly improve risk assessment and treatment decision making for early breast cancer, to identify a subgroup of patients with low risk and favorable outcome. This test looks at the expression of 70 genes linked to breast cancer with an accuracy level of 96.7% as determined by a study published in the New England Journal of Medicine. This prognostic signature of genetic 'fingerprint' is validated as an independent prognostic indicator for patients with up to three positive lymph nodes.
Knauer showed that the highly accurate MammaPrint was able to differentiate between patients at high risk for recurrence and a low risk subgroup of HER2+ patients. The assay helped uncover a substantial group of traditionally miscategorized low risk HER2+ patients.
Study results In the study population of 169 HER2+ patients, Mammaprint, the first ‘in vitro diagnostic multivariate index assay’ (IVDMIA) cleared by the U.S. Food and Drug Administration (FDA) designed to identify patients with early metastasis, classified 16 percent of patients as having a good prognosis signature with a 10-year distant disease-free survival (DDFS) of 89 percent, even in the absence of (neo)adjuvant trastuzumab and chemotherapy, compared to 84 percent of patients classified as having a poor prognosis signature with a DDFS of 64 percent. Additionally, in a subgroup of highly endocrine responsive HER2/neu positive patients, MammaPrint low risk patients had no relapse.
All 169 patients with HER2-positive breast cancer were selected from a pooled dataset of 1280 patients with known HER2-status. Patients had a unilateral T1-3, N0-1 tumor and were treated with either breast-conserving therapy or mastectomy. Samples were analyzed and classified by the 70-gene signature as good or poor prognosis by Agendia Laboratories.
The strength of the assay is underscored by the 70 gene panel unique to the test and a resulting gene profile that covers all molecular pathways associated with breast cancer.
Personalized medicine MammaPrint accurately identified a subgroup of patients with a good clinical outcome in HER2+ early breast cancer. These patients will be further studied in the ongoing MINDACT-trial (EORTC 10041/ BIG 3-04), a multicentre, prospective, phase III trial coordinated by the EORTC (European Organisation for Research and Treatment of Cancer) and run under the BIG and TRANSBIG network, which will accrue 6000 node-negative patients designed to determine the prospects of withholding chemotherapy and/or trastuzumab in HER2+, MammaPrint low risk patients.
This study compares MammaPrint to traditional clinical-pathological methods to assess the risk of breast cancer recurring in women with lymph node negative disease. Since breast cancer tumors with similar clinicopathological characteristics can have strikingly different outcomes, the traditional selection for adjuvant chemotherapy is far from accurate.
Based on the initial results with MammaPrint, it is hypothesized that using the genomic test in addition to traditional methods will result in more accurate risk assessment. It is expected that 10% to 20% of patients with node negative breast cancer will, in the future, safely be able to avoid chemotherapy and its potential side effects.
The current trend in research cancer is to develop ways of individualizing breast cancer treatment. This goal toward ‘personalized medicine’ requires better identification of type of systemic treatment and better identification of patients who are highly likely to develop distant metastases, and therefore, may benefit the most from adjuvant chemotherapy.
MammaPrint may be one of the tools helping to realize these goals.
With more than 108,000 new cases of colon cancer and more than 40,000 new cases of rectal cancer, colorectal cancer is the fourth most common cancer in men and women in the United States and the second leading cause of cancer-related deaths. The symptoms can remain undetected for many years and in most cases will develop quite slowly. However, as a result of better detection and treatment, the death rate from colorectal cancer has been dropping. Caught early, colorectal cancer is often curable.
The new assessment tool is designed for people 50 years of age and older and based on data collected from two large US population-based case control studies of colon and rectal cancer, data from 13 NCI Surveillance, Epidemiology and End Result Registries (SEER data), and the US national mortality rates.
How it works The Colorectal Cancer Risk Assessment Tool uses the respondent’s answers about risk and preventive factors to calculate that person’s absolute risk for developing colorectal cancer for a specific time period. The online test is interactive, simple and straightforward and takes only 5-8 minutes to complete. After answering the questions, the tool will calculate an individual’s risk for colorectal cancer.
To validate the accuracy, the model was tested in a large population. The results show that the tool is accurate in predicting absolute risk. Because the majority of participants in the case-control studies were non-Hispanic white males and females, relative risks for other racial or ethnic groups could not be estimated. Researchers are in the process of updating the tool by using SEER rates for minority populations to allow the tool to produce more accurate results for men and women in these populations. When available, the expanded functionality will include additional ages and racial/ethnic groups.
The risk calculator will be updated periodically as new data or research become available. In addition, the tool may prove useful to researchers who are designing research intervention studies.
Man and Women To help assess the risk for, the tool is gender specific. For men, the model included a cancer-negative sigmoidoscopy/colonoscopy in the last 10 years, polyp history in the last 10 years, a history of colorectal cancer in a first-degree relatives, use of aspirin and nonsteroidal anti-inflammatory drug (NSAID), cigarette smoking, body mass index (BMI), current leisure-time vigorous activity, and vegetable consumption.
For women, the model included sigmoidoscopy/colonoscopy, polyp history, a history of colorectal cancer in a first-degree relatives, aspirin and NSAID use, BMI, leisure-time vigorous activity, vegetable consumption, hormone-replacement therapy (HRT), and estrogen exposure on the basis of menopausal status.
Better Understanding The tool is designed to assist health care providers in counseling their patients. A better understanding of the risk will help patients and their doctor make more informed choices about how to screen and which screening tests they should take to detect signs of cancer before symptoms appear.
Although the questionnaire is suitable for 'self-administrations', researchers stress that it’s important that patients talk with their primary health care provider about the results. Commenting of the test they claim ‘The test is designed to be used by health professionals and their patients. If patients are using the tool at home, we encourage them to discuss the results, and their individual risk of colorectal cancer with their healthcare provider.’
Data from a Phase I investigator-sponsored trial of the investigational cancer vaccine vitespen (Oncophage®, Antigenics Inc, 3 Forbes Rd, Lexington, MA 02421), an investigational patient-specific vaccine designed to treat cancer with the intent of minimizing adverse events of toxicities in recurrent, high-grade glioma, showed a considerable survival advantage for patients with this disease.
Vaccination with the new cancer vaccine following brain cancer surgery increased overall median survival to approximately 10.5 months with four patients surviving beyond 12 months and one patient surviving almost 2.5 years. This is compared to a historical median survival of only 6.5 months post surgery. All patients enrolled into the trial had at least one recurrence of brain cancer.
The trial was conducted at the Brain Tumor Research Center at the University of California, San Francisco, CA, a center which is internationally recognized as a major research and treatment center for adults and children with tumors of the brain and spinal cord. The data was presented in November 2008 during the Society for Neuro-Oncology’s 13th Annual Scientific Meeting in Las Vegas.
‘These are the most challenging patients to treat because their survival is typically three to six months,’ explained Andrew T. Parsa, MD, PhD, associate professor in the department of neurological surgery at the University of California, San Francisco. ‘These preliminary results suggest a possible impact on survival as well as a very favorable safety profile.’
In addition to survival data, the study also observed a correlation between immune response and overall survival as a result of vaccination with vitespen (n=12; P < .001). These responses were validated by using three separate immune techniques and showed that vitespen evoked a tumor-specific immune response by producing activated T-cells and natural killer cells that can destroy tumor cells. ‘Gliomas develop built-in immunoresistant pathways which play an important role in tumor progression,’ Parsa explained. ‘This study demonstrated significant tumor-specific immune responses leading to a proliferation of T-cells which did not exist in these patients before vaccination with Oncophage. We look forward to completing the Phase II portion of this study and presenting results next year.’
Study Design and Findings This investigator-sponsored Phase I/II study was designed to evaluate the feasibility, safety and activity of vaccination with vitespen in patients with recurrent, high-grade glioma. Patients were monitored for immune response before and after vitespen treatment using three different techniques.
According to investigators, no adverse events or toxicities identified were considered attributable to the vaccine. A tumor-specific immune response was detected after vaccination in all 12 patients.
Current Regulatory Status Vitespen is approved in Russia for the adjuvant treatment of kidney cancer patients at intermediate risk for disease recurrence. Outside Russia, vitespen is being evaluated in clinical trials. The drug has been granted fast track and orphan drug status from multiple regulatory bodies, including the US Food and Drug Administration and the European Medicines Agency (EMEA), for the treatment of renal cell carcinoma and metastatic melanoma.
Glioma Gliomas are the most common type of brain tumor and is currently a fatal disease impairing areas such as thinking, personality and movement. The National Cancer Institute estimates that about 19,000 cases are diagnosed every year in the U.S and according to historical estimates, the median survival of patients with previously treated glioma is typically three to six months. The outlook for patients with gliomas is generally poor. The median survival for patients with moderately severe or grade III gliomas is 3 - 5 years. The median survival for patients with grade IV glioma, the most severe and aggressive form of the disease also called glioblastoma multiforme, is less than a year.
Personalized medicine Vitespen offers a unique, personalized, opportunity for the treatment of individual patients. Derived from each individual’s tumor, the vaccine consists of purified complexes of tumor-derived HSPs linked to tumor antigen peptides which consists the ‘antigenic fingerprint’ of the patient’s particular cancer. This ‘antigenic fingerprint’ is designed to reprogram the body’s immune system to target only cancer cells bearing this specific fingerprint.
When these purified complexes are re-administered to a patient antigenic tumor peptides are expressed on the surface of potent antigen-presenting cells of the immune system, such as macrophages and dendritic cells. This stimulates a more powerful anti-tumor immune response than that generated by expression of the same antigens by the tumor cell. The result is that activated T-cells directly target and destroy cancer cells bearing the specific ‘fingerprint’.
Vitespen is designed to target only cancerous cells and to leave healthy tissue unaffected. As a result, vaccination with this cancer drug limits the toxicities and debilitating side effects typically associated with traditional cancer treatments such as broad-acting cancer chemotherapy and radiation therapy.
Mode of Action Heat-shock proteins (HSPs) also called stress proteins, are the most abundant and ubiquitous soluble intracellular proteins. They are present in all cells in all life forms and induced when a cell undergoes various types of environmental stresses like heat, cold and oxygen deprivation. Despite the obvious importance of stress responses, heat shock proteins have only recently been examined for the role they play in the control of disease pathology and in the survival and virulence of pathogens. For example, research has shown that a number of heath shock proteins protect against oxidative damage, conveys peptide antigens for presentation to the immune system, and can protect against cardiac failure.
Various forms of heat shock proteins are involved in binding and stabilizing proteins at intermediate stages of folding (essential for protein function), assembly and translocation and degradation. They interact with antigen-presenting cells (APCs) through CD91 and other receptors, eliciting a cascade of events that includes representation of HSP-chaperoned peptides MHC, translocation of NF-kappaB into the nuclei, and maturation of dendritic cells. The key role heath shock proteins play in fundamental immunologic phenomena allow them to be used for immunotherapy of cancers and infections in new and exciting ways.
NOB/Neuro-Oncology Branch. A trans-institute program of the National Cancer Institute and National Institute of Neurologic Diseases and Stroke of the National Institutes of Health. About brain cancer.
Dr. Glen Weiss, Director of Thoracic Oncology at TGen Clinical Research Services TCRS at Scottsdale Healthcare, said the new drug appears promising and may be more effective and less toxic to healthy tissues than conventional drugs.
‘TH-302 is a new, novel, small molecule that is activated under a metabolic condition characteristic of cancer cells — hypoxia. The drug candidate may provide an opportunity to treat slowly dividing tumor cells within hypoxic regions that generally evade traditional chemotherapeutic agents and ultimately contribute to relapse,’ Dr. Weiss explained.
Phase I and Phase I/II trials are underway to investigate the safety and activity of TH-302 in patients with advanced solid tumors. After evidence of tumor activity was observed in the Phase I trial in patients with advanced melanoma – both non-small cell lung cancer and small cell lung cancer – the study was expanded to further investigate TH-302 anti-tumor activity in these tumors. Both Phase I and I/II trials continue to enroll patients with other solid tumors. If successful, Phase II and III clinical trials will confirm the drug's effectiveness on solid tumors.
Tumor hypoxia Hypoxia is a condition in which there is a decrease in the oxygen concentration in tissue. In cancer, as a tumor grows, it rapidly outgrows its blood supply, leaving portions of the tumor with regions where the oxygen concentration is significantly lower than in healthy tissues. This condition is called tumor hypoxia. Several studies have shown that higher levels of tumor hypoxia correlate with poor treatment outcomes for a variety of solid tumors. It is believed that hypoxia may severely limit the curability of tumors.
This lack of oxygen in cancer cells compared to normal cells is exploited by Threshold’s Hypoxia-Activated Prodrug (HAP) platform. In time, this breakthrough technology platform may provide an opportunity to treat slowly dividing tumor cells within hypoxic regions that generally evade traditional chemotherapeutic agents and ultimately contribute to relapse.
A New Class of Drug TH-302 is converted selectively in the presence of hypoxia to the drug’s active form, bromo-isophosphoramide mustard, a potent DNA alkylator. TH-302 targets levels of hypoxia that are common in tumors but are rare in normal tissues – this is how selective targeting of the tumor occurs. After conversion to the active form of the drug, the more resistant hypoxic cells are exposed to high concentrations of released cytotoxic agent, which can also diffuse into the oxygenated regions of a tumor cell. The Phase I/II trials are investigating the safety and activity of TH-302 in combination with a number of conventional chemotherapies that are believed to be effective in the non-hypoxic regions of solid tumors.
The clinical trial at TCRS at Scottsdale Healthcare will investigate the safety and pharmacology of multiple doses of TH-302 in patients with late-stage cancer.
The initial phase I clinical trial of TH-302 started in July 2007. In July 2008, interim results were presented. This trial was designed with an initial accelerated titration design followed by a standard dose escalation schema. The trial completed the accelerated titration design component and has enrolled the eighth dosing cohort. The weekly dose had been escalated from the initial dose of 7.5 mg/m2 to 670 mg/m2. None of the 20 patients enrolled at the time of the presentation has experienced any dose limiting toxicities (DLTs). One patient with refractory small cell lung cancer metastatic to the liver had a partial response at their initial response assessment with a greater than 45% reduction in target lesion diameters. The patient, who had received two cycles of TH-302, was being followed by RECIST (Response Evaluation Criteria In Solid Tumors) criteria. Other anti-tumor activity observed include one patient with non-small cell lung cancer with tumor shrinkage lasting over 6 months.
In August 2008, an additional clinical trial of TH-302 was initiated. The design of this trial included three separate treatment arms that will each examine TH-302 in combination with either gemcitabine, docetaxel or pemetrexed.
Approximately 50 patients with advanced solid tumors are planned to enroll in the Phase I/II, open-label, dose-escalation portion of the clinical trial. Up to six patients per dose level will participate in the dose escalation phase of the trial. Once the maximum tolerated dose (MTD) has been reached, the Phase II portion of the trial will enroll an additional 12 patients at the MTD within each treatment arm including gemcitabine in advanced pancreatic cancer patients, docetaxel in patients with castrate-resistant prostate cancer (CRPC) and pemetrexed in patients with non-small cell lung cancer.
Researchers expect that within the next several years a number of development candidates will arise from the hypoxia-activate prodrug platform.
For more information:
Curd J, Sun J, Liu Q, et al, Targeting Tumor Hypoxia with TH-302 and Complementary Chemotherapy; 2nd American Association for Cancer Research (AACR) Conference on Translational Medicine, July 20-23, 2008; Monterey, CA. Drug Development/New Technologies: Poster Presentations - Proffered Abstracts, Abstract A5.
Hart C, et al., Discovery of TH-302: an achiral hypoxia-activated cytotoxic prodrug, American Society of Clinical Oncology (ASCO) Annual Meeting, June 2007.
The new version of RECIST (version 1.1) has been presented at the 20th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics in Geneva, Switzerland (21-24 October 2008) and will be published in a special edition of the European Journal of Cancer in the first quarter of 2009.
The European Union’s Committee on Human Medicinal Products (CHMP), on January 22, 2009, issued a positive recommendation for the use of rituximab, (MabThera®, F. Hoffmann-La Roche, Grenzacherstrasse 124, CH-4070 Basel, Switzerland / Rituxan®, co-marked in the United Sates by Genentech, 1 DNA Way South San Francisco, CA 94080-4990 and Biogen Idec , 14 Cambridge Center, Cambridge, MA 02142), with any chemotherapy combination as a first-line treatment for chronic lymphocytic leukemia (CLL), the most common form of adult leukemia. This recommendation is considered an important step towards license extension for rituximab in combination with chemotherapy as initial treatment.
Rituximab is a chimeric monoclonal antibody (mAb) against the protein CD20+ B-cell antigen used to treat previously untreated patients with stage III-IV follicular lymphoma in combination with chemotherapy, as maintenance therapy for patients with relapsed/refractory follicular lymphoma responding to induction therapy with chemotherapy with or without rituximab, for the treatment of patients with CD20 positive diffuse large B cell non-Hodgkin’s lymphoma in combination with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) chemotherapy and as monotherapy for treatment of patients with stage III-IV follicular lymphoma who are chemoresistant or are in their second or subsequent relapse after chemotherapy.
Early predictions, great potential
The FDA approved rituximab in 1997 as the first antibody approved for the treatment of patients with non-Hodgkin's lymphoma (approval in Europe followed in 1998). The launch of rituximab as a therapeutic agent fulfilled predictions dating back to the early 1900s regarding the therapeutic effect of antibodies and their potential in medicine.
In 1895 Charles Robert Richet (1850 – 1935) and Jules Héricourt described the first attempts of a novel anti-cancer treatment. Their approach was a radical departure from the standard cancer treatments available at that time. Instead of surgery, Richet and Héricourt immunized dogs with a human sarcoma and then transferred the serum to patients with advanced cancer. The idea was to raise an antiserum for treating the patient.
These bold scientists believed that a mechanism to target diseases selectively, know today as ‘passive serotherapy’, which was realized only a few years earlier when scientists discovered that resistance to infectious disease (diphtheria) could be transferred from one animal to another through their serum, would also work in treating cancer. Their pioneering work was the forerunner of the ‘magic bullet’ concept, later developed by the German scientist Paul Ehrlich (1854-1915), believed that ‘toxins’ could be targeted to cancer and other diseases.
The results of these initial attempts seemed very promising. And while several patients with different types of advanced cancer were treated and showed significant improvements in their symptoms, none of them were actually cured. These trials were repeated during the early 1900s, but, again, did not yield the results hoped for. Problems were readily acknowledged. Inconsistent and contradictory results, lack of specificity and reproducibility, lack of purity and xenogeneic immune responses ultimately led to disappointing conclusion that ‘nothing may be hoped for at present in respect to a successful therapy from this direction’.
The science of the times was not yet ready for a proper understanding of idea of a ‘magic bullet’ proposed by Ehrlich in 1908. More than a half-century passed before antibodies were identified as the substance in serum responsible for the effects initially observed by Richet, et al. Ultimately, Ehrlich’s concept of a ‘magic bullet’ was fully realized with the development of monoclonal antibodies (mAbs) in the 1970s.
The great leap forward In 1975 Georges Jean Franz Köhler (1946 -1995) César Milstein (1927 – 2002) and Niels Kaj Jerne ( 1911 – 1994), started major developments in the field of monoclonal antibodies (mAbs) for which they were awarded the 1984 Nobel Prize in Physiology for Medicine.
Köhler’s and Milstein’s development of the hybridoma technique, the first practical method for mass-producing monoclonal antibodies, is considered one of the most important advances in medicine during the 1970s. This technique has, in less than a decade, revolutionized the use of antibodies in health care and research.
During the following two decades, potential monoclonal antibodies as laboratory tools were rapidly exploited for biotechnology and biomedical applications. Today, mAbs represent over 30% of all biological proteins undergoing clinical trials and are the second largest class of biodrugs after vaccines. With the help of antibody engineering, mAbs have been reduced in size, rebuilt into multivalent molecules, and conjugated with drugs, toxins, or radioisotopes for the treatment of cancer, autoimmune disorders, graft rejection, and infectious diseases. Additionally, in the past few years, important advances have been made in the design, selection, and production of new types of engineered antibodies.
Impact Since the introduction of rituximab, hundreds of thousands of patients have been treated with the drug. In 2002, rituximab became the number one anticancer drug worldwide. During its first decade of use (1993-2003), rituximab has had an important impact on treatment strategies for lymphoma and other hematologic malignancies. During the 5 years following approval, its applications expanded beyond non-Hodgkin's lymphoma to a variety of malignant and non-malignant B-cell disorders. Also, as a result of its early clinical trials, initiatives came about that eventually led to the development of the new international response criteria for non-Hodgkin's lymphoma. Rituximab has been characterized as the most important therapeutic development of the decade.
Mechanism of Action Rituximab effectively eradicates CD20+ cells in lymphoma patients by several unique and distinct mechanisms, including complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC) and apoptosis. It binds to CD20 on the surface of normal and malignant B-cells and then recruits the body's natural defenses to attack and kill the marked B-cells. B-cell progenitors in bone marrow lack the CD20 antigen, allowing healthy B-cells to regenerate after treatment and return to normal levels within several months.
Label extension
The label extension which will be possible as a result of CHMPs positive recommendation for the use of rituximab, is based on the impressive, highly significant results of the international CLL-8 study which showed that the median time until patients progressed with their disease, experienced a relapse or died was 40 months if patients were given rituximab plus chemotherapy compared to just 32 months for those that received chemotherapy alone.
Pending the final approval by the EU authorities, physicians will soon be able to prescribe rituximab to CLL patients in combination with their preferred chemotherapy regimen.
‘Treatment with MabThera achieved significantly better outcomes for the patients than chemotherapy alone. This provides hope for the future treatment of a disease that remains life-threatening and incurable,’ said William M. Burns, CEO of the Pharmaceuticals Division of Roche.
Incidence of CLL Chronic lymphocytic leukemia (CLL) is the most common type of leukemia in adults, accounting for approximately 25-30% of all forms of leukemia. Overall incidence of CLL is around three per 100,000 and is twice as common in men compared to women. It mainly affects the elderly with up to 95% of patients diagnosed after the age of 55 and the median age for diagnosis believed to be approximately between 65 and 70 years of age. Despite the fact that the incidence has been reported to increase in younger patients, with about one-third of CLL patients younger than 55 years, the overall incidence of CLL has decreased during the past 15 years.
While CLL is generally considered a disease that is slow to progress, a significant proportion of patients have rapidly progressing forms of the disease.
Two pivotal trials
Significant new data from two pivotal phase III studies, presented at the 50th Annual Meeting of the American Society of Hematology in San Francisco (December 6 – 9, 2008), showed that patients with chronic lymphocytic leukemia (CLL) treated with rituximab in combination with chemotherapy live considerably longer without their disease progressing, compared to patients treated with chemotherapy alone.
The first trial, the CLL-8 study, an international study conducted by the German CLL Study Group and Professor Michael Hallek (Klinik I für Innere Medizin, Universitaet zu Koeln, Joseph-Stelzmann-Str. 9, Cologne, D-50924, Germany) in collaboration with F. Hofmann La Roche, included 817 patients with CLL receiving first-line treatment. The study was conducted at 191 study sites across 11 countries. In this randomized study, patients received either rituximab in combination with chemotherapy (fludarabine and cyclophosphamide) or chemotherapy alone. The primary endpoint of the study was progression-free survival. No new or unexpected safety signals were observed.
Results from the CLL-8 study showed that at two years, more than three quarters (76.6%) of patients receiving rituximab plus chemotherapy lived without their disease progressing compared to 63.3 % of those treated with chemotherapy alone.
The second trial, the REACH study, a randomized international study that included 552 patients with relapsed or refractory CLL, was conducted at 88 study sites across 17 countries. The study was set up to investigate whether treatment of patients with relapsed or refractory CLL with rituximab in combination with chemotherapy (fludarabine and cyclophosphamide) was more beneficial than treatment with chemotherapy alone. The primary endpoint of the study was to show an increase in terms of median progression-free survival.
After analyzing the data, the REACH study demonstrated that with rituximab, patients who had relapsed lived an average 10 months longer without their disease progressing compared to those receiving chemotherapy alone (30.6 months vs 20.6 months).
‘The positive results from both of these trials is very encouraging news for patients suffering from a disease that remains life-threatening and incurable ,’ noted Roche's Burns. ‘The outcome of these trials clearly demonstrates the important role MabThera will have in the treatment of this devastating disease.’
‘Rituximab has already revolutionized the treatment of people living with non-Hodgkin's lymphoma’, explained Professor Tadeusz Robak, Medical University of Lodz, Poland, and principle investigator for the REACH trial. ‘These results add to a growing body of evidence that underscores the important role MabThera has to play in the management of CLL, which currently remains a life-threatening and incurable disease.’
A new Standard of Care
Based on the results of both trials, the researchers involved feel that rituximab is set to change the face of chronic lymphocytic leukemia management. Commenting on the results of the CLL-8 trial, professor Hallek, who led the German CLL Study Group (GCLLSG) in conducting the study, said, ‘With new therapies emerging, the management of CLL is set to change markedly, with physicians having more options and greater treatment expectations for their patients. These data, which come from the largest randomized clinical trials ever reported in CLL, suggest that rituximab used in combination with chemotherapy has the potential to become the new standard of care for CLL patients.’
European Summary of Product Characteristics (only for healthcare professionals outside the Unites States of America). The ESPC provides comprehensive clinical, pharmacological and prescribing information about MabThera. Detailed information about the safety experience with MabThera can be found in the ESPC.
Additional references:
Hericourt J, Richet CH. ‘Physologie pathologique’ - de la serotherapie dans la traitement du cancer. Comptes Rendus Hebd Seanc Acad Sci (Paris) 1895; 120: 567–569
Himmelweit F. The Collected Papers of Paul Ehrlich. Vol. 3. London: Pergamon; 1960: 59.
Researchers have identified specific mutations in the epidermal growth factor (EGF) gene that are associated with increased esophageal cancer risk in people with gastroesophageal reflux disease (GERD). This is the first study to examine EGF mutations as predictors of esophageal cancer risk in patients with GERD.
‘We’ve known for some time that GERD is a risk factor for esophageal cancer, but our findings are the first to identify specific genetic markers that are linked with increased cancer risk in patients with GERD,’ said Winson Y. Cheung, MD, a clinical research fellow working with the University of Toronto and the Harvard School of Public Health, and the lead author of the study.
‘While our findings will need to be validated in larger and more diverse patient groups, this is a first step in the right direction toward developing a test to identify which patients are at highest risk of esophageal cancer and would benefit from more aggressive screening. And because GERD is a common condition, the ability to single out patients at high risk of cancer could lead to better outcomes and significant cost savings.’
Incidence and cause of GERD Gastroesophageal reflux disease (GERD), also referred to as heartburn, is reflux and regurgitation of the contents of the stomach into the esophagus. The disease is quite common, can affect everyone, from newborn infants to adults, and is often frequent and severe enough to impact daily life. In the United States it is estimated that nearly 60 million people experience symptoms at least once a month. Over 60% of the elderly have frequent GERD, and over 14 million Americans have GERD so frequently and severely that they experience symptoms every single day.
In general, the presence of gastroesophageal reflux implies lower esophageal sphincter (LES) incompetence. Located at the very bottom of the esophagus, where the esophagus joins the top of the stomach, the esophageal sphincter is a ‘high pressure zone’ between the esophagus and stomach. After swallowing, food moves down the esophagus by esophageal contraction. Then esophageal sphincter relaxes to allow food to pass into the stomach, and then closes again to prevent reflux of the stomach content, including food and digestive juices, back into the esophagus. Another important contributor to GERD is the failure of the antireflux barrier (ARB) and its primary component, the gastroesophageal valve (GEV).
Although the lower esophageal sphincter plays a major role in the occurrence of GERD, researchers recently started to focus more on the gastroesophageal valve as the largest contributor to the anti-reflux barrier. In healthy individuals, the Angle of His, the angle at which the esophagus enters the stomach, is intact creating a valve that prevents duodenal bile, enzymes, and stomach acid from traveling back into the esophagus where it can cause burning and inflammation of the sensitive esophageal tissue. In gastroesophageal reflux disease, the ‘valve’ is damaged, weakened or absent. This causes the acidic digestive juices from the stomach to flow back (or reflux) into the esophagus. This often creates a burning pain in the center of the chest that starts in the upper abdomen and sometimes spreads into the neck.
There are a number of factors contributing to the development of GIRD. These may include weight gain, fatty foods, caffeinated or carbonated beverages, alcohol, tobacco smoking, and drugs, including anticholinergics, antihistamines, tricyclic antidepressants, Ca channel blockers, progesterone, and nitrates.
Complications In severe or chronic GERD, regurgitation occurs regularly, spilling acid, bile, and other stomach contents not only into the esophagus but also into the lungs, mouth, pharynx and even the nose. This can lead to a variety of complications including esophagitis, anemia, esophageal stricture, peptic esophageal ulcer, and Barrett's esophagus, a condition that develops in the lining of the lower esophagus.
Uncontrolled regurgitation has also been associated with a number of atypical symptoms, including a chronic sore throat, cough, laryngitis, dental erosions, discomfort in the ears and nose, recurrent bronchitis, asthma like symptoms and sleep disturbance. Cell damage of the lower part of the esophagus has been linked to the development of esophageal adenocarcinoma.
Given the number of symptoms and the potential for severe complications, GERD has a significant impact on quality of life and, in extreme cases, life expectancy. Treatment may include a combination of lifestyle changes (including weight loss), over the counter medications (OTC), and prescription drug regimens, and, in more severe cases, surgery.
Esophageal Cancer According to the American Cancer Society, about 30 percent of esophageal cancers can be traced to GERD. In 2008, more than 16,000 cases of esophageal cancer were diagnosed. This disease is 3 to 4 times more common among men than among women and about 50% more common among African Americans than among caucasians. Nevertheless, if detected early, the disease is generally curable.
Because esophageal cancer is usually diagnosed at a relatively late stage, it is one of the most deadly forms of gastrointestinal cancer. With a mortality rate exceeding 85%, most patients will eventually die of the disease. However, statistics from the American Cancer Society show that survival rates have been improving. During the early 1960s, only 4% of all white patients and 1% of all African-American patients survived at least 5 years after diagnosis. Today, about 18% of Caucasian, and 11% of African-American patients survive at least 5 years after diagnosis.
Early detection is the best prevention. But screening is invasive and expensive, and therefore not recommended for all patients with GERD. The American College of Gastroenterology therefore recommends periodic endoscopies only for patients with long-standing symptoms of reflux.
Genetics Esophageal carcinogenesis involves multiple genetic alterations. In this study, Cheung and his team of researchers collected DNA samples from 309 patients being treated for esophageal adenocarcinoma (the most common type of esophageal cancer in North America) at Massachusetts General Hospital in Boston, and 275 healthy, matched controls. The investigators analyzed study participants’ genotypes and GERD history.
Baseline characteristics were comparable between cases and controls except that epidermal growth factor (EGF) variants (A/G or G/G) were more common (p=0.02) and GERD was more prevalent (p<0.001)epidermal growth factor (EGF) called G/G who experienced symptoms associated with GERD more than once a month, compared with those who had the A/A (normal, or wild-type) variant epidermal growth factor (EGF) without GERD, were at a 10-fold increased risk of esophageal cancer (OR 1.90; 95% CI, 1.2-3.0; p=0.007).
Stratified analyses revealed that this correlation between G/G genotype and esophageal cancer risk was evident only for the subset of patients with GERD. The researchers noted that the risk of esophageal cancer increased further among patients with the mutation who suffered from GERD more frequently, generally more than 1 time per week (OR 21.8; 95% CI, 5.1-94.0; p<0.001), p="0.007)or for more than 15 years (OR 22.4; 95% CI, 6.5-77.6; p<0.001).
The study showed a highly significant interaction between the G/G genotype and the presence of GERD (p=0.007).
Patients with GERD and the genetic variant called A/G had an intermediate increase in risk.
While researchers concluded that performing EGF genotypingfor patients with severe or longstanding GERD can help to identify individuals at the greatest risk of esophageal adenocarcinoma, the results of this test are just one step that may lead to the development of new tests for finding esophageal cancer at an earlier, more curable stage.
Better understanding of the genetic predisposition may eventually lead to new therapies that repair the abnormal genetic changes in esophageal cancer cells.
The U.S. Food and Drug Administration, in late December 2008, approved imatinib mesylate (Glivec®, Novartis AG, Lichtstrasse 35, 4056 Basel, Switzerland and Gleevec®, Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, NJ) forthe post-surgery treatment of adult patients following complete surgical removal of KIT (CD117)-positive gastrointestinal stromal tumors (GIST).
The tyrosine kinase inhibitorimatinib mesylate is now the only post-surgery treatment indicated to delay the return of this highly aggressive cancer, filling a major need for GIST patients in the United States. The filing received FDA priority review status in August 2008, with regulatory reviews currently underway in other regions, including the European Union (EMEA) and Switzerland.
Soft Tissue Sarcoma While most cancers are carcinomas, gastrointestinal stromal tumors (GIST) belong to a group of cancers known as soft tissue sarcomas. These cancers grow from cells of the body’s connective or supportive tissues such as bone, cartilage, tendons, nerves, fat, muscle, synovial tissue, or blood vessels.
A life-threatening disease GIST is a life-threatening cancer of the GI tract affecting the digestive tract or nearby structures within the abdomen. It is the most common mesenchymal tumor of the gastrointestinal tract originating from cells found in the stomach and small intestine, Interstitial Cells of Cajal (ICCs) or from less differentiated stem cells or precursor cells, known as mesenchymal precurser cells, in the gut wall, which can develop into ICCs.
These Interstitial Cells of Cajal or ICCs are part of the autonomic nervous system , and generally found in the myenteric plexus and nearby areas between the circular and longitudinal layers of the gastrointestinal tract. Their function is to regulate gastrointestinal motility, or peristalsis, which is the autonomic movement of the GI tract to propel food and liquid through the digestive tract through the stomach and intestines.
Incidence Data concerning the worldwide prevalence of GIST is lacking. But some population based studies estimate the annual incidence to be 4,500 - 6,000 new cases per year in the United Sates (15-20 cases per million population), of which more than 90% are KIT-positive.
Genetics KIT - also known as CD117 - is a protein that, when mutated, has been identified as one of the major causes of GIST. These mutations result in spontaneous activation of tyrosine kinase domains, providing a constant growth stimulus to the tumor cells.
Many GIST contain mutations in exon 11 and, to a lesser degree, in exons 9, 13 or 16, of the c-kit (KIT) protooncogene coding for C-KIT (CD117). Imatinib mesylate inhibits the activity of several proteins such as KIT.
Some GISTs have a mutation of the platelet-derived growth factor receptor-alpha (PDGFRA) gene. Furthermore, a snall number of GISTs, aproximately 5-15%, have no detectable KIT or gene mutation. This includes most pediatric GISTs and GISTs arising in patients with an inactivation of the neurofibromatosis gene (NF1).
Like most cancers, GIST affects older people. The average age at presentation is 50 to 60 years of age. Children are rarely affected, while familial GIST develops in younger or middle-aged adults.
Difficult to diagnose Most patients, especially those with smaller tumors, are asymptomatic. Asymptomatic GISTs can be discovered incidentally during endoscopy or laparoscopy as well as during computed tomography (CT). Biopsy and endoscopic ultrasound are generally used for staging. However, because tumors are slow growing and symptoms of GIST are generally not different than other GI complaints such as nausea, vomiting, bleeding, dyspepsia and obstruction, earely detection of the cancer is rather dificult.
Approximately 60% of these tumors occur in the muscular wall of the stomach. However tumors may also develop in the small intestine, colon, rectum, esophagus and other intra-abdominal locations. The likelihood of malignant behavior is dependent on the size of the tumor and its rate of growth. Metastases usually occur within the abdominal cavity and/or the liver.
Treatment options Early gastrointestinal stromal tumors, or GIST that has not yet metastasized, is often treated initially with surgery to remove the cancer. Unfortunately, the risk of recurrence is high, and GIST remains relatively resistant to chemotherapy and/or radiation therapy. Targeted drugs that inhibit the KIT, such as imatinib mesylate, offer an important approach to treating these cancers. These drug are intended to be given to patients following surgery to help prevent recurrence.
However, in some cases patients with gastrointestinal stromal tumors (GIST) whose disease has progressed or who are unable to tolerate treatment with imatinib mesylate require alternative treatment. Researchers found that sunitinib malate (Sutent®, Pfizer Oncology, Pfizer Inc, 235 East 42nd Street, New York, NY 10017), an orally-available small-molecule multiple receptor tyrosine kinase inhibitor, delayed the time it takes for tumors or new lesions to grow in patients with this tare type of cancer. Specifically, the median time-to-tumor progression (TTP) for patients treated with sunitinib malate was 27 weeks compared to 6 weeks for patients who were not treated.
Established efficacy The efficacy of imatinib mesylate was established in a clinical trial in which patients received either imatinib mesylate or a placebo for one year after surgical removal of the tumor. The optimal treatment duration is not known.
There were significantly fewer recurrences of GIST in patients receiving imatinib mesylate than in patients who did not. The most frequently reported adverse reactions were diarrhea, fatigue, nausea, swelling of the feet, decreased red blood cell counts, rash, vomiting and abdominal pain.
Recurrence After initial removal, GIST tumors can return in as many as one of two patients. Recurrent GISTs are often more aggressive than primary tumors, with relapses associated with lower survival rates.
'After surgery, my doctor told me there was a high likelihood that my gastrointestinal tumors would come back. I immediately searched for a possible solution and found the Glivec clinical trial, which aimed to help patients like me,' said Roslyn Fuller, a GIST patient. 'This FDA approval is good news for me and other GIST patients who will now have the option to start treatment with Glivec earlier to help prevent recurrence.'
Phase II study The approval for this new indication is based on data from an international Phase III trial sponsored by the National Cancer Institute. The study showed a dramatic reduction in the return of GIST after surgery in patients treated for about one year with imatinib mesylate versus placebo.
The FDA regulatory filing for the adjuvant GIST indication was based on data from a Phase III, double-blind, randomized, multicenter, international study of more than 700 GIST patients who had undergone surgery to remove their tumors. The efficacy endpoint of the study was recurrence-free survival (RFS), defined as the time from the date of randomization to the date of recurrence or death from any cause. Participants were randomized to receive either imatinib mesylate 400 mg/day or a matching placebo for one year.
Based on a 14-month median follow up, 91.6% of patients receiving imatinib mesylate remained cancer-free compared with 80.2% of those taking placebo. (30 RFS events out of 359 patients in the imatinib mesylate arm (8.4%) compared to 70 RFS events out of 354 patients in the placebo arm (19.8%) (hazard ratio=0.398 [95% CI: 0.259, 0.610], p<0.0001).'Approval of Gleevec offers health care professionals and patients an important new therapeutic option for patients with this uncommon gastrointestinal disease,' said Richard Pazdur, M.D., director, Office of Oncology Drug Products, Center for Drug Evaluation and Research, FDA. 'It illustrates how the continued study of a once novel drug throughout its product lifecycle can yield new and important uses.'
Revolution in the making Imatinib mesylate was first approved by the FDA in 2001. It is one of the first drugs in a class of agents that block cellular communications that result in tumor growth. Soon after the introduction of effective molecularly targeted therapies such as imatinib mesylate and sunitinib malate the standard of practice for GIST rapidly changed.
'When Glivec was first approved for the treatment of inoperable and/or metastasized KIT-positive GIST six years ago, it revolutionized the treatment of this life-threatening cancer,' said David Epstein, President and CEO, Novartis Oncology. 'This atest FDA approval means patients can benefit from Glivec earlier in the course of their disease.'
Multiple indications The drug is now approved for nine indications, including the treatment of Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML), Kit (CD117)-positive gastrointestinal stromal tumors which cannot be surgically removed and/or have already spread to other parts of the body (metastasized) and five other rare diseases.
Mode of Action The effectiveness of imatinib mesylate is based on overall hematological and cytogenetic response rates and progression-free survival in CML, on hematological and cytogenetic response rates in Ph+ ALL, MDS/MPD, on hematological response rates in SM, HES/CEL, on objective response rates and progression-free survival in unresectable and/or metastatic GIST, on recurrence free survival in adjuvant GIST, and on objective response rates in DFSP. Increased survival in controlled trials has been demonstrated only in newly diagnosed chronic phase CML and GIST.
Z9001: A Phase III Randomized Double-blind Study of Adjuvant STI571 (Glivec®) Versus Placebo in Patients Following the Resection of Primary Gastrointestinal Stromal Tumor (GIST). Accessed January 2009.
American Cancer Society. Cancer Reference Information. Detailed Guide for Gastrointestinal Stromal Tumors. Key Statistics. Accessed January 2009.
Onco’Zine – The International Cancer Network, (ISSN 2168-5339) has been created to inform and support physicians, cancer specialists and other medical professionals involved in the management and care of cancer patients.
Onco'Zine reports on current research and development in oncology and hematology and publishes a broad range of topics from all oncology disciplines and subspecialties.
If you have a question or comments about our editorial content, please let us know by contacting our editorial team.
Sunvalley Communication / InPress Media Group, LLC,
605 E. Grant Street, Suite 106, Phoenix, AZ 85004
Editorial Office 4960 South Gilbert Rd, Suite 1-286, Chandler, Arizona 85249
The information in this blog is for North American and European Health professionals and is intended to be an educational resource only. It is not intended or deemed to be a guide regarding appropriate diagnosis or treatment.
This information in this blog is not a substitute for the decisions made by a licensed physician. A treating physician is solely responsible for making evidence-based decisions relating to appropriate patient care, including, but not limited to diagnosis, surgery, medication, dose, scheduling and supporting care. Before prescribing any medication, review the complete prescribing information.
Sunvalley Communication / InPress Media Group, LLC disclaims any liability arising from any errors of the information in this blog.
Sunvalley Communication / InPress Media Group, LLC does not endorse any specific product, service, or treatment.
For more information, please read our Terms of Use.
Hyperlinked terms
Hyperlinked terms are defined in the glossary section. In some cases, hyperlinked terms are linked to appropriate references outside the control of the publisher.
Copyright
Onco'Zine - The International Cancer Network / Onco'Zine Live content is the intellectual property of Sunvalley Communication/InPress Media Group. Any copying, republication or redistribution of Onco'Zine content, including caching, framing or similar means, is expressly prohibited without the prior written consent of Sunvalley Communication/InPress Media Group. Sunvalley Communication/InPress Media Group shall not be liable for any errors or delays in content, or for any actions taken in reliance thereon.
Advisory and Editorial Board
Join the Onco'Zine Advisory and Editorial Board and represent your community of oncologists, hematologist, practitioners and academic specialists with cross-disciplinary expertise. Click here to contact us.
ican Association for Cancer Research (AACR) 98th AACR Annual Meeting, April 2007, 14-18, 2007; Los Angeles, CA. Meeting Abstracts, Apr 2007; 2007: 3988. 
Posts
