Study shows a Survival Benefit with Cancer Vaccine in Glioma.

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.

For more information, read Pubmed abstracts:

• Testori A, Richards J, Whiteman E, et al. Phase III comparison of vitespen, an autologous tumor-derived heat shock protein gp96 peptide complex vaccine, with physician's choice of treatment for stage IV melanoma: the C-100-21 Study Group. J Clin Oncol. 2008 Feb 20;26(6):955-62
  http://www.ncbi.nlm.nih.gov/pubmed/18281670
• Amato RJ. Heat-shock protein-peptide complex-96 for the treatment of cancer. Expert Opin Biol Ther. 2007 Aug;7(8):1267-73.

Also see

• Christopher Wood C, Srivastava P, Bukowski R, et al. An adjuvant autologous therapeutic vaccine (HSPPC-96; vitespen) versus observation alone for patients at high risk of recurrence after nephrectomy for renal cell carcinoma: a multicentre, open-label, randomised phase III trial The Lancet, Volume 372, Issue 9633, Pages 145 - 154, 12 July 2008.
• Yang JC. Vitespen: a vaccine for renal cancer? The Lancet, Volume 372, Issue 9633, Pages 92 - 93, 12 July 2008
• Heat Shock Proteins: How They Work (animation);
• Heat Sock Proteins – How they work (downloadable graphic overview);
• Heat shock proteins ‘mechanism of action’ diagram.

Information for physicians:

• Clinical trials: Brain and Central Nervous System Tumors
  ClinicalTrials.gov Identifier: NCT00293423

Information for your patients:

• National Cancer Institute: Brain Tumor Home Page.
• 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.
• Mayo Clinic medical services: Glioma
• MedlinePlus® Patient Education: Brain Cancer.

New cancer drug may offer broad potential in the treatment of solid tumors

TGen Clinical Research Services (TCRS) is testing a new drug that may offer broad potential to treat solid tumors. Clinical trials of the drug TH-302, an anticancer agent in clinical development by Threshold Pharmaceuticals (1300 Seaport Blvd, Suite 500, Redwood City, CA 94063), are being conducted at the Mayo Clinic in Arizona by TGen Clinical Research Services, a partnership of Translational Genomics Research Institute (TGen) and Scottsdale Healthcare Corp.

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.
• Duan JX, Jiao H, Kaizerman J, et al. Potent and Highly Selective Hypoxia-Activated Achiral Phosphoramidate Mustards as Anticancer Drugs. Journal of Medicinal Chemistry, 51: 2412-2420, 2008.
• Hart C, Meng F, Banica M, et al., In vitro activity profile of the novel hypoxia-activated cytotoxic prodrug, TH-302. 99th American Association for Cancer Research (AACR) Annual Meeting, April 12-16, 2008; San Diego, CA, mTOR/Akt/PI3K Inhibitors and Vascular/Hypoxia Targeting Agents: Poster Presentations - Proffered Abstracts; Abstract 1441
• Jung D, Lin L, Plasma pharmacokinetics, oral bioavailability, and interspecies scaling of the hypoxically activated prodrug, TH-302, in mice, rats, dogs and monkeys. 99th American Association for Cancer Research (AACR) Annual Meeting- April 12-16, 2008; San Diego, CA, mTOR/Akt/PI3K Inhibitors and Vascular/Hypoxia Targeting Agents: Poster Presentations - Proffered Abstracts; Abstract #1447
• Hart C, et al., Discovery of TH-302: an achiral hypoxia-activated cytotoxic prodrug, American Society of Clinical Oncology (ASCO) Annual Meeting, June 2007.
• Wang J. Liu Q, Rosario G, et al., In vivo anti-cancer activity of a hypoxia activated prodrug, TH-302. American Association for Cancer Research (AACR) 98th AACR Annual Meeting, April 2007, 14-18, 2007; Los Angeles, CA. Meeting Abstracts, Apr 2007; 2007: 3988. Abstract # 3988.
• Ammons W, Wang J, Ma H, et al. Anti-tumor activity of a hypoxia activated prodrug, TH-302, in pancreatic and prostate orthotopic models of cancer. American Association for Cancer Research (AACR) 98th AACR Annual Meeting, April 14-18, 2007; Los Angeles, CA. Meeting Abstracts, Apr 2007; 2007: 3985. Abstract #3985

Note:

• 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.

Retuximab receives positive opinion in Europe for first-line treatment of chronic lymphocytic leukemia (CLL)

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.’

For more information:

• 50th ASH Annual Meeting and Exposition, Online Abstracts: Chronic Lymphocytic Leukemia - Therapy, Excluding Transplantation (abstract 325 - 330).
• The official MabThera website (Roche).
• International Standard Randomised Controlled Trial Number (ISR CTN) Register: ISRCTN02757147
• National Cancer Institute rituximab
• The Nobel Prize in Physiology or Medicine 1984 laureates
• The Nobel Prize: Presentation Speech (1984)
• Click here for an overview of FDA approved antibodies for the parenteral use in the detection and treatment of cancer.
• Understanding Cancer Series (National Cancer Institute) Slide 36.
• Oldham RK, Dillman RO, Monoclonal Antibodies in Cancer Therapy: 25 Years of Progress. Journal of Clinical Oncology, Vol 26, No 11 (April 10), 2008: pp. 1774-1777 (Full Text Aricle).

Also read PubMed abstracts:

• Foon KA, Boyiadzis M, Land SR, et al. Chemoimmunotherapy With Low-Dose Fludarabine and Cyclophosphamide and High Dose Rituximab in Previously Untreated Patients With Chronic Lymphocytic Leukemia. J Clin Oncol. 2008 Dec 15. [Epub ahead of print].
• Nissim A, Chernajovski Y. Historical development of monoclonal antibody therapeutics. Handb Exp Pharmacol. 2008;(181):3-18.
• Hallek M; German CLL Study Group. Prognostic factors in chronic lymphocytic leukemia. Ann Oncol. 2008 Jun;19 Suppl 4:iv51-3.
• Eichhorst B, Hallek M, Dreyling M; ESMO Guidelines Working Group. Chronic lymphocytic leukemia: ESMO clinical recommendations for diagnosis, treatment and follow-up. Ann Oncol. 2008 May;19 Suppl 2:ii60-2. Click here for Full Text Article.
• Keating MJ, O’Brien S, Albitar M, et al, Early results of a chemoimmunotherapy regimen of fludarabine, cyclophosphamide, and rituximab as initial therapy for chronic lymphocytic leukemia. J Clin Oncol. 2005 Jun 20;23(18):4079-88. Epub 2005 Mar 14.
• Cartron G, Blasco H, Paintaud G, et al. Pharmacokinetics of rituximab and its clinical use: thought for the best use? Crit Rev Oncol Hematol. 2007 Apr;62(1):43-52. Epub 2007 Feb 6.
• Kim H, Csaky KG, Chan CC, et al. The pharmacokinetics of rituximab following an intravitreal injection. Exp Eye Res. 2006 May;82(5):760-6. Epub 2005 Nov 11.
• Sharkey RM, Goldenberg DM. Targeted therapy of cancer: new prospects for antibodies and immunoconjugates. CA Cancer J Clin. 2006 Jul-Aug;56(4):226-43. Click here for Full Text Article. http://caonline.amcancersoc.org/cgi/content/full/56/4/226
• Olszewski AJ, Grossbard ML. Empowering targeted therapy: lessons from rituximab.
  Sci STKE. 2004 Jul 6;2004(241):pe30. Review.
• Grillo-López AJ, White CA, Varns C, et al. Overview of the clinical development of rituximab: first monoclonal antibody approved for the treatment of lymphoma. Semin Oncol 1999; 26: 66-73.
• Piro LD, White CA, Grillo-López AJ, et al. Extended Rituximab (anti-CD20 monoclonal antibody) therapy for relapsed or refractory low-grade or follicular non-Hodgkin's lymphoma. Ann Oncol. 1999 Jun;10(6):655-61.
• Ritz J. Pesando JM, Sallan SE, et al. Serotherapy of acute lymphoblastic leukemia with monoclonal antibody. Blood. 1981 Jul;58(1):141-52.
• De StGroth SF, Scheidegger D. Production of monoclonal antibodies: strategy and tactics. J Immunol Methods. 1980;35(1-2):1-21
• Köhler G, Milstein C. Continuous cultures of fused cells secreting antibody of predefined specificity. Nature. 1975 Aug 7;256(5517):495-7.
• Currie GA, Eighty years of immunotherapy: a review of immunological methods used for the treatment of human cancer. Br J Cancer. 1972 Jun;26(3):141-53.

Download:

• 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.

Mutations in EGF Gene Associated with Increased Esophageal Cancer Risk

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.

The results of this study were presented during the sixth annual Gastrointestinal Cancers Symposium , which is co-sponsored by the American Gastroenterological Association (AGA) Institute , the American Society of Clinical Oncology (ASCO), the American Society for Radiation Oncology (ASTRO) and the Society of Surgical Oncology (SSO), being held in San Francisco, CA (January 15 – 17, 2009).

‘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 genotyping for 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.

For more information, read:

• W. Y. Cheung, WY Zhai R, Kulke M, et al. Epidermal growth factor (EGF) gene polymorphism, gastroesophageal reflux disease (GERD) and risk of esophageal adenocarcinoma (EA). 2009 Gastrointestinal Cancers Symposium General Session II: Cancers of the Esophagus and Stomach: Translational Research. Abstract 2. Translational research

Also read PubMed abstracts:

• Xu XC. Risk factors and gene expression in esophageal cancer. Methods Mol Biol. 2009;471:335-60.
• Kuwano H, Kato H, Miyazaki T et al. Genetic alterations in esophageal cancer. Surg Today. 2005;35(1):7-18.
• Feagins LA, Souza RF. Molecular targets for treatment of Barrett's esophagus. Dis Esophagus. 2005;18(2):75-86.
• Souza RF. Molecular and biologic basis of upper gastrointestinal malignancy -esophageal carcinoma. Surg Oncol Clin N Am. 2002 Apr;11(2):257-72, viii.

Also visit:

• American Gastroenterological Association (AGA)
• American Society of Clinical Oncology (ASCO)
• American Society for Radiation Oncology (ASTRO)
• Society of Surgical Oncology (SSO)
• European Society of Surgical Oncology (ESSO)
• Canadian Society for Surgical Oncology (CSSO)

Information for Healthcare Professionals:

• The Merck Manual: Esophageal Cancer.
• NCCN – National Comprehensive Cancer Network (Practice Guidelines).

For your patients:

• Cancer.Net Guide to Esophageal Cancer.
• Mayo Clinic: Esophageal Cancer.

Books to read:

• 100 Questions & Answers About Esophageal Cancer (100 Questions Series)
• Esophageal Cancer Medical Guide
• Esophageal Cancer: Principles and Practice
• Esophageal Cancer
• Esophageal Cancer Toolkit - Comprehensive Medical Encyclopedia with Treatment Options, Clinical Data, and Practical Information
• Esophageal Cancer - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Imatinib mesylate after surgery dramatically reduces risk of cancer returning in patients with gastrointestinal stromal tumors

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) for the post-surgery treatment of adult patients following complete surgical removal of KIT (CD117)-positive gastrointestinal stromal tumors (GIST).

The tyrosine kinase inhibitor imatinib 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.

For more information, visit:

• Gleevec Official site
• GSI (GIST Support International) site
• Novartis corporate site.
• Novartis Oncology Medical Services site

Also read PubMed abstracts:

• Mazzola P, Spitale A, Banfi S, et al. Epidemiology and molecular biology of gastrointestinal stromal tumors (GISTs): a population-based study in the South of Switzerland, 1999-2005. Histol Histopathol. 2008 Nov;23(11):1379-86.
• Yan BM, Kaplan GG, Urbanski S, et al. Epidemiology of gastrointestinal stromal tumors in a defined Canadian Health Region: a population-based study. Int J Surg Pathol. 2008 Jul;16(3):241-50.
• Mucciarini C, Rossi G, Bertolini F, et al. Incidence and clinicopathologic features of gastrointestinal stromal tumors. A population-based study. BMC Cancer. 2007 Dec 20;7:230.
• Tryggvason G, Kristmundsson T, Orvar K, et al. Clinical study on gastrointestinal stromal tumors (GIST) in Iceland, 1990-2003. Dig Dis Sci. 2007 Sep;52(9):2249-53.
• Demetri GD, Benjamin RS, Blanke CD, et al. NCCN Task Force report: management of patients with gastrointestinal stromal tumor (GIST)--update of the NCCN clinical practice guidelines. J Natl Compr Canc Netw. 2007 Jul;5 Suppl 2:S1-29; quiz S30.
• Rubió J, Marcos-Gragera R, Ortiz MR, et al. Population-based incidence and survival of gastrointestinal stromal tumours (GIST) in Girona, Spain. Eur J Cancer. 2007 Jan;43(1):144-8.
• Steigen SE, Eide TJ. Trends in incidence and survival of mesenchymal neoplasm of the digestive tract within a defined population of northern Norway. APMIS. 2006 Mar;114(3):192-200.
• Goettsch WG, Bos SD, Breekveldt-Postma N, et al. Incidence of gastrointestinal stromal tumours is underestimated: results of a nation-wide study. Eur J Cancer. 2005 Dec;41(18):2868-72.
• Tryggvason G, Gislason HG, Magnusson MK, et al. Gastrointestinal stromal tumors in Iceland, 1990-2003: the Icelandic GIST study, a population-based incidence and pathologic risk stratification study. Int J Cancer. 2005 Nov 1;117(2):289-93.
• Irving JA, Lerwill MF, Young RH. Gastrointestinal stromal tumors metastatic to the ovary: a report of five cases. Am J Surg Pathol. 2005 Jul;29(7):920-6.
• Wingen CB, Pauwels PA, Debiec-Rychter M, et al. Uterine gastrointestinal stromal tumour (GIST). Gynecol Oncol. 2005 Jun;97(3):970-2.
  Nilsson B, Bümming P, Meis-Kindblom JM, et al. Gastrointestinal stromal tumors: the incidence, prevalence, clinical course, and prognostication in the preimatinib mesylate era--a population-based study in western Sweden. Cancer. 2005 Feb 15;103(4):821-9.
• Tran T, Davila JA, El-Serag HB. The epidemiology of malignant gastrointestinal stromal tumors: an analysis of 1,458 cases from 1992 to 2000. Am J Gastroenterol. 2005 Jan;100(1):162-8.
• Heinrich MC, Corless CL, Demetri GD et al. Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J Clin Oncol. 2003 Dec 1;21(23):4342-9.
• Belics Z, Csapo Z, Szabo I, et al. Large gastrointestinal stromal tumor presenting as an ovarian tumor. A case report. J Reprod Med. 2003 Aug;48(8):655-8.
• Borden EC, Baker LH, Bell RS, et al. Soft tissue sarcomas of adults: state of the translational science. Clin Cancer Res. 2003 Jun;9(6):1941-56.
• Igwilo OC, Byrne MP, Nguyen KD, et al. Malignant gastric stromal tumor: unusual metastatic patterns. South Med J. 2003 May;96(5):512-5.
• Reith JD, Goldblum JR, Lyles RH, et al. Extragastrointestinal (soft tissue) stromal tumors: an analysis of 48 cases with emphasis on histologic predictors of outcome. Mod Pathol. 2000 May;13(5):577-85.

Visit:

• Update in the Management of Gastrointestinal Stromal Tumors (GIST): A Report from ASCO 2007.
• Life Raft Group. Managing Initial Recurrence. Accessed January 2009.
• 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.
• US Department of Health and Human Services. Agency for Healthcare Research and Quality (AHRQ). Technology Assessment: Report on the Relative Efficacy of Oral Cancer Therapy for Medicare Beneficiaries Versus Currently Covered Therapy, Part 2. Imatinib for Gastrointestinal Stromal Tumors (GISTs) Accessed January 2009.

Also see:

• Full prescribing information for imatinib mesylate.
• CenterWatch drug information for imatinib mesylate.
• Full prescribing information for sunitinib mesylate.
• Highlight of prescribing information for sunitinib mesylate.
• CenterWatch drug information for sunitinib malate.

Order the book:

• Magic Cancer Bullet: How a Tiny Orange Pill May Rewrite Medical History.

Tumor Mutation Predicts Effectiveness of Treatment for Colorectal Cancer

Routine screening of patients with metastatic colorectal cancer (mCRC) for mutations of KRAS, a gene that encodes one of the proteins in the epidermal growth factor receptor (EGFR) signaling pathway, before initiating treatment with EGFr-inhibitors, will cut costs by providing treatment only to those patients who will benefit from the treatment and by helping those who will not benefit avoid unnecessary side effects.

This conclusion is based on an analysis of data presented during the sixth annual Gastrointestinal Cancers Symposium being held in San Francisco, California (January 15-17, 2009) by Dr.Veena Shankaran, MD, and his team from Northwestern University Feinberg School of Medicine, in Chicago, Illinois. These results demonstrate that savings can be realized by customizing therapy in any Gastrointestinal (GI) malignancy using a molecular tests.

European and US incidence
Gastrointestinal (GI) cancers include cancers of the esophagus, stomach, small intestine, colon, rectum, anus, pancreas and liver. More than 270,000 people are diagnosed with Gastrointestinal cancers in the United States every year and more than 135,000 people die from them annually.

In Europe, approximately 370,000 people develop colorectal cancer every year, accounting for 13% of the total cancer burden and an estimated 200,000 deaths. Around a quarter of CRC patients present with metastatic disease and for these patients survival rates areas low as 5%. Approximately 60-65% of mCRC patients have KRAS wild-type tumors.

Carcinogenesis
The epidermal growth factor receptor plays an important role in carcinogenesis and tumor progression of colorectal cancer (CRC), a multi-step process involving the accumulation of molecular alterations in a number of genes and pathways of proliferative cells of the colon.
These molecular alterations lead to a loss of coordination between the processes of cellular proliferation and differentiation . Researchers have observed aberrations in the EGFR signaling pathway in a number of cancers including mCRC. Therefore, the EGFR has now evolved as a relevant target in the treatment of mCRC.

Monoclonal antibodies
Monoclonal antibodies (MoAb), including cetuximab (Erbitux®, ImClone Systems Incorporated, Branchburg, NJ 08876, Bristol-Myers Squibb Company, Princeton, NJ 08543 and Merck KGaA, Darmstadt, Germany), a human antibody against the epidermal growth factor receptor and panitumumab (Vectibix®, Amgen Inc, One Amgen Center Drive, Thousand Oaks, Ca 91320-1799), a fully human IgG2 monoclonal antibody that is highly selective for the epidermal growth factor receptor, inhibit EGFR activity. However, not all colorectal tumors respond, and not all patients benefit from these therapies. Recent discoveries have shown that the KRAS gene, when mutated, confers resistance to cetuximab and panitumumab by circumventing EGFR’s role in the signaling pathway.

In March 2008, the Journal of Clinical Oncology published results from an analysis of the first randomized, controlled clinical trial which showed that mCRC patients with mutated KRAS tumors do not respond to panitumumab monotherapy. Conversely, patients with wild-type KRAS tumors treated with panitumumab had a better response rate and a prolonged progression-free survival (PFS). Compared to best supportive care (BSC) alone, this therapy also had an impact on quality of life (QoL) and disease-related symptoms.

The Role of KRAS
Over twenty year of study has shown that the KRAS gene plays a central role in tumor development, regulating downstream proteins that are involved in proliferation, survival, metastasis and angiogenesis. It serves as a mediator between extracellular ligand binding and intracellular transduction of signals from the EGFR to the nucleus. Researcher identified the presence of activating KRAS mutations as a potent predictor of resistance to EGFR-directed monoclonal antibodies.

Anti-epidermal growth factor receptor (EGFr) therapies work by blocking the activation of EGFr, thereby inhibiting downstream events that lead to cancer cell signaling. However, in patients with tumors harboring a mutated or activated KRAS, the KRAS protein is always turned 'on' regardless of whether EGFr has been activated or therapeutically inhibited. Thus, in patients with mutated KRAS, signaling continues despite anti-EGFr therapy. Mutated KRAS is detected in approximately 40% of CRC tumors.

Long term evidence
Although activating mutations in KRAS correlates with poor response to anti-EGFR antibodies in mCRC, their role as a selection marker had not yet been established in randomized trials. A number of clinical trials have now demonstrated that patients can benefit from the addition of cetuximab to FOLFOX or FOLFIRI regime in the first-line treatment of metastatic CRC (mCRC). However, subsequent correlative analyses of these trials have also shown that this benefit is limited to patients whose tumors have wild type KRAS status by PCR-based testing.

Cetuximab
A study by the Central European Cooperative Oncology Group (CECOG), the CECOG/CORE1.2.001 study, a randomized Phase II trial investigating the influence of KRAS status on the efficacy of cetuximab in combination with FOLFOX or FOLFIRI in the first-line treatment of 117 mCRC patients, provided a response rate (RR) of 53% in patients with KRAS wild-type tumors versus 36% in those with mutant tumors. The study also showed a trend towards improved overall survival (OS) in patients with KRAS wild-type tumors – 24.4 months for patients with KRAS wild-type tumors vs. 16.7 months for patients with KRAS mutant tumors (p=0.057).

‘It is really exciting to see such a consistent efficacy profile for cetuximab in patient populations defined by KRAS mutational status,' commented Prof. Thomas Brodowicz, MD from the University Hospital of Vienna, Austria, lead investigator of the CECOG/CORE1.2.001 study. 'This further highlights the absolute necessity to define mCRC according to the KRAS status of the tumor in order to determine the most effective treatment strategy and to provide patients with the best possible outcomes.’

The results of the CECOG/CORE1.2.001 study support the pivotal cetuximab trials – the randomized Phase III study CRYSTAL, also presented at this meeting, and OPUS recently published in the Journal of Clinical Oncology. Patients receiving cetuximab in the CRYSTAL and OPUS trials who had KRAS wild-type tumors showed similar response rates to those in the CECOG/CORE1.2.001 study, at 59%2 and 61%,3 respectively.

Panitumumab
To further independently evaluate the association of KRAS status seen in a biomarker analysis of a Phase III, randomized, controlled clinical trial (the so-called ‘408’ study) that investigated the treatment effect of panitumumab monotherapy plus Best Supportive Care (BSC) versus BSC alone in patients with mCRC, additional retrospective analyses of all other studies of panitumumab monotherapy in mCRC were performed.

‘These data are consistent with 30 years of biology which indicate that KRAS is a clinically relevant oncogene,’ said Dr Sean Harper, MD., chief medical officer and head of Global Development at Amgen. ‘We believe the data from our panitumumab monotherapy trial indicates that the benefit-risk profile of panitumumab is improved by restricting use to those patients with mCRC whose tumors have wild-type KRAS genes.’

The data showed the relative effect of panitumumab versus best supportive care (BSC) was significantly greater in patients with non-mutated versus mutated KRAS (HR = 0.45 vs. HR = 0.99). Median PFS in patients without the mutation treated with panitumumab plus BSC was 12.3 weeks versus 7.3 weeks, respectively. When the analysis standardized the time to tumor assessment, the median PFS was 16 weeks versus 8 weeks, respectively (HR= 0.49 vs. 1.07). Some of these data were presented for the first time at the European Cancer Conference (ECCO) in September 2007, but a pooled analysis from data including more than 700 patients was presented at the European Society of Medical Oncology (ESMO) in 2008.

Additional endpoints of this analysis examined overall survival by KRAS status and treatment. When the treatment arms were combined (non-mutated vs. mutated) overall survival was longer in patients with non-mutated compared with mutated KRAS (HR = 0.67). No differences in overall survival were observed between panitumumab and BSC in either KRAS subgroup, potentially due to a high rate of crossover from BSC to panitumumab after progression, and similar efficacy of panitumumab in these patients.

In exploratory analyses, colorectal cancer symptoms and
health-related quality of life (HRQoL) outcomes were compared between panitumumab and BSC treated patients using a validated instrument such as the Functional Assessment of Cancer Therapy-colorectal symptom index and HRQoL using the EQ-5D index, and the EORTC-QLQ-C30 Global Health Status. In patients with tumors carrying non-mutated KRAS genes, the analysis demonstrated that in panitumumab treated patients clinically meaningful inferior symptom control and QoL scores could be excluded compared to BSC, and that in fact, a clinically meaningful difference in favor of

Panitumumab was observed at most time points. In contrast, a clinically significant worsening of symptom control and QoL scores could not be excluded in patients with mutated KRAS tumors treated with panitumumab compared to best supportive care (BSC). The United States (U.S.) prescribing information states that the effectiveness of panitumumab as a single agent is based on progression-free survival. However, there is no currently data available that demonstrates an improvement in disease-related symptoms or increased survival with panitumumab.

In the panitumumab-treated group, patients with non-mutated KRAS had on average double the number of panitumumab infusions as patients with mutated KRAS (10.0 vs. 4.9). Additionally, 20 percent of the KRAS evaluable patients had a treatment-related grade 3 adverse event (12 percent mutated vs. 25 percent non-mutated).

New recommendations and opinions
In November 2008 the National Comprehensive Cancer Network (NCCN) announced, updates to their Guidelines on Colon and Rectal Cancers that included the recommendation that a determination of the KRAS gene status of either the primary tumor or a site of metastasis should be part of the pre-treatment work-up for patients diagnosed with metastatic colorectal cancer. Further, the guidelines recommended that EGFr inhibitors, including panitumumab, should only be used in patients with tumors characterized by the wild-type KRAS gene. These updates were prompted by a systematic review of the relevant literature.

Based on similar evidence, the American Society of Clinical Oncology (ASCO), last week released its first Provisional Clinical Opinion (PCO), reflecting the expert consensus based on clinical evidence on the use of KRAS gene mutation testing in patients with metastatic colorectal cancer. Provisional Clinical Opinions are intended to assist physicians in clinical decision-making and identify questions and settings for further research.

To help guide treatment with the anti-EFGR monoclonal antibodies (MoAb), such as cetuximab and panitumumab, the authors of this Provisional Clinical Opinion recommend that all patients with metastatic colorectal cancer who are candidates for anti-EFGR therapy have their tumors tested for KRAS gene mutations. If a patient has a mutated form of the KRAS gene, it recommends against the use of anti-EFGR antibody therapy, based on recent studies indicating this treatment is only effective in patients with the normal (wild-type) form of the KRAS gene. It is estimated that 40 percent of colon cancer patients have the KRAS mutation.

Recent results from phase II and III clinical trials demonstrate that patients with metastatic colorectal cancer benefit from therapy with MoAbs directed against the EGFR, when used either as monotherapy or combined with chemotherapy. Retrospective subset analyses of the data from these trials strongly suggest that patients who have KRAS mutations detected in codon 12 or 13 do not benefit from this therapy.

Five randomized controlled trials of cetuximab or panitumumab have evaluated outcomes for patients with metastatic colorectal carcinoma in relation to KRAS mutational status as no mutation detected (wild type) or abnormal (mutated). Another five single-arm studies have retrospectively evaluated tumor response according to KRAS status.

Researchers analyzed tumors from 587 patients with metastatic colorectal cancer for a mutated KRAS gene to determine which patients will benefit the most from treatment with a combination of chemotherapy and cetuximab. The KRAS gene is involved in the growth of cancer cells. About 30% to 45% of colorectal cancers have a KRAS mutation, which has been shown in previous studies to predict whether patients will benefit from treatment with drugs that block the epidermal growth factor receptor (EGFR), such as cetuximab.

Testing results in considerable savings
Shankaran and his team calculated the cost savings by creating an economic model derived from publicly available lab and drug-cost information and the 2008 estimated incidence of mCRC from the American Cancer Society. Clinical data were drawn from a recent, 2007, study by Van Cutsem and colleagues published in the
Journal of Clinical Oncology investigated the effectiveness of cetuximab in combination with standard FOLFIRI compared with FOLFIRI alone in the first-line treatment of patients with epidermal growth factor receptor (EGFR)-expressing mCRC. The model used by Shankaran did not include the necessary additional costs associated with clinic appointments, infusion visits, and managing toxicity.

Based on the available data, there are an estimated 29,762 new cases of mCRC annually. The costs for screening is estimated to cost $13 million ($452.00/patient). Using the average wholesale price of cetuximab ($4,032.00/loading dose and $2,880.00/weekly dose for a patient of average height/weight) and assuming an average of 24 doses per patient, as seen in the analysis of the CRYSTAL trial, the first study to compare chemotherapy alone with chemotherapy plus cetuximab as the primary treatment for patients with metastatic colorectal cancer, drug cost per patient were estimated to cost $71,120.00.

According to Shankaran, data from studies indicate that the prevalence of KRAS mutations ranges from 35.6% to 42.3% in all patients with metastatic colorectal cancer. An even higher percentage has been recorded in several trials, suggestion KRAS mutations in up to 46% of all patients. Approximately 59% of patients whose tumors did not have a KRAS mutation and who received cetuximab and chemotherapy had a reduction in tumor size, compared with 43% of patients who received only chemotherapy. Patients with tumors with a mutated KRAS gene did not receive any benefit when cetuximab was added to chemotherapy.

With the assumption that patients with mutated KRAS (35.6% of all patients) would not receive cetuximab, theoretical drug cost savings would be $753 million; considering the cost of KRAS testing, net savings would be $740 million.

Benefit for patients
Commenting on the importance of these studies, Jennifer C. Obel, M.D., a gastrointestinal cancers specialist and attending physician at NorthShore University HealthSystem in Illinois, said ‘These studies address a pressing question in cancer care – how can we identify those patients who will benefit from treatment and differentiate them from those who will not?’

Because patients with colorectal cancer who carry KRAS mutations have been shown not to respond to treatment with EGFr-inhibitors, upfront KRAS testing to limit cetuximab therapy to patients with wild-type KRAS tumors can result in drug cost savings if patients with metastatic colorectal cancer undergoes first-line therapy with a cetuximab-containing regimen.

Dr Obel also said ‘In an era when the cost of cancer care continues to increase, the ability to tailor treatment to each patient’s disease could lead to improved outcomes and fewer side effects for patients, and significant cost savings.’

Personalized medicine
‘This study helps us to identify which patients are most likely to benefit from adding cetuximab to treatment,’ said lead author Eric Van Cutsem, MD, PhD, Professor at the University Hospital Gasthuisberg in Leuven, Belgium. ‘KRAS testing in all people with colorectal cancer immediately after diagnosis could help doctors find the best treatment strategies for the individual patient.’

‘Based on available data, we believe that focusing panitumumab treatment on patients with wild-type KRAS tumors will avoid unnecessary adverse events in patients who are unlikely to benefit, maximize response rates and PFS in patients with wild-type KRAS genes, and redirect patients with a mutated KRAS gene to alternative therapies,' Sean Harper explained. 'We are thrilled to be taking a step forward in advancing the field of personalized medicine by being one of the first to realize the clinical potential of the KRAS gene in guiding treatment of advanced colorectal cancer patients.’

‘Personalized medicine is the next frontier in cancer care. Basing cancer treatment on the unique genetic characteristics of the tumor or the individual with cancer will improve patient outcomes and help avoid unnecessary costs and side effects for patients who are unlikely to benefit,’ said Richard L. Schilsky, MD, ASCO president and Professor of Medicine at the University of Chicago Medical Center. ‘Using KRAS testing to guide colorectal cancer treatment is a prime example of where cancer care is heading.’

Emphasizing the importance and the benefits for individual patients, Dr. Wolfgang Wein, MD Executive Vice President, Oncology, Merck Serono, concluded ‘This can help physicians help in the treatment decision-making process. Tailoring treatment for mCRC is now a reality. Through a simple diagnostic test, patients can be provided with a treatment that is most likely to succeed in their tumor type.’

For more information, read:

• Shankaran V, Bentrem DJ, Mulcahy MF, et al. Economic implications of Kras testing in metastatic colorectal cancer (mCRC).2009 Gastrointestinal Cancers Symposium (GICS). Abstract 298. Presented January 17, 2009. General Poster Session E (Poster Presentation).

Also read:

• F. Di Fiore, E. Van Cutsem, P. Laurent-Puig, et al.
  Role of KRAS mutation in predicting response, progression-free survival, and overall survival in irinotecan-refractory patients treated with cetuximab plus irinotecan for a metastatic colorectal cancer: Analysis of 281 individual data from published series. Journal of Clinical Oncology, 2008 ASCO Annual Meeting Proceedings (Post-Meeting Edition). Vol 26, No 15S (May 20 Supplement), 2008: 4035
• E. Van Cutsem, I. Lang, G. D'haens, et al. KRAS status and efficacy in the first-line treatment of patients with metastatic colorectal cancer (mCRC)treated with FOLFIRI with or without cetuximab: The CRYSTAL experience. Journal of Clinical Oncology, 2008 ASCO Annual Meeting Proceedings (Post-Meeting Edition). Vol 26, No 15S (May 20 Supplement), 2008: 2
• Van Cutsem E, Peeters M, Siena S et al. Panitumumab significantly improves progression-free survival in patients with metastatic colorectal cancer. Ann Oncol 2006; 17 (Suppl 6): vi27 (Abstr O-027).
• Van Cutsem E, Nowacki M, Lang I, et al. Randomized phase III study of irinotecan and 5-FU/FA with or without cetuximab in the first-line treatment of patients with metastatic colorectal cancer (mCRC): The CRYSTAL trial. J Clin Oncol (Meeting Abstracts) 2007 25: 4000.

For more information read PubMed abstracts:

• Heinemann V, Stintzing S, Kirchner T, Boeck S, Jung A. Clinical relevance of EGFR- and KRAS-status in colorectal cancer patients treated with monoclonal antibodies directed against the EGFR. Cancer Treat Rev. 2008 Dec 29. [Epub ahead of print]
• Weber J, McCormack PL. Panitumumab: in metastatic colorectal cancer with wild-type KRAS. BioDrugs. 2008;22(6):403-11.
• Amado RG, Wolf M, Peeters M, et al.
  Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol. 2008 Apr 1;26(10):1626-34. Epub 2008 Mar 3.
• Van Cutsem EJ, Oliveira J; ESMO Guidelines Working Group.
  Colon cancer: ESMO clinical recommendations for diagnosis, adjuvant treatment and follow-up. Ann Oncol. 2008 May;19 Suppl 2:ii29-30.
• Van Cutsem EJ, Oliveira J; ESMO Guidelines Working Group. Advanced colorectal cancer: ESMO clinical recommendations for diagnosis, treatment and follow-up. Ann Oncol. 2008 May;19 Suppl 2:ii33-4
• Van Cutsem E, Dicato M, Haustermans K, et al. The diagnosis and management of rectal cancer: expert discussion and recommendations derived from the 9th World Congress on Gastrointestinal Cancer, Barcelona, 2007. Ann Oncol. 2008 Jun;19 Suppl 6:vi1-8. Contact the author.
• Annemans L, Van Cutsem E, Humblet Y, et al.
  Cost-effectiveness of cetuximab in combination with irinotecan compared with current care in metastatic colorectal cancer after failure on irinotecan--a Belgian analysis. Acta Clin Belg. 2007 Nov-Dec;62(6):419-25
• Van Cutsem E, Peeters M, Siena S. Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol. 2007 May 1;25(13):1658-64
• Tappenden P, Jones R, Paisley S, Carroll C. Systematic review and economic evaluation of bevacizumab and cetuximab for the treatment of metastatic colorectal cancer. Health Technol Assess. 2007 Mar;11(12):1-128, iii-iv
• Starling N, Tilden D, White J, Cunningham D. Cost-effectiveness analysis of cetuximab/irinotecan vs active/best supportive care for the treatment of metastatic colorectal cancer patients who have failed previous chemotherapy treatment.
Br J Cancer. 2007 Jan 29;96(2):206-12.

Also read:

• Full prescribing information (USA) Vectibix®
• Vectibix® website.
• Full prescribing information cetuximab.