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The Lancet Oncology

Saturday, January 30, 2010

First Targeted Biological Therapy to Show Survival Benefit in Stomach Cancer

The European Commission has approved trastuzumab (herceptin, Roche Pharmaceuticals) in combination with chemotherapy for use in patients with HER2-positive metastatic stomach (gastric) cancer.

Trastuzumab is a humanized antibody, designed to target and block the function of HER2, a protein produced by a specific gene with cancer-causing potential. The mode of action of trastuzumab is unique in that it activates the body’s immune system and suppresses HER2 to target and destroy the tumor. trastuzumab has demonstrated unprecedented efficacy in treating both early and advanced (metastatic) HER2-positive breast cancer.

The approval of trastuzumab in combination with chemotherapy for the treatment of metastatic stomic cancer is based on the impressive results from the international ToGA trial, which showed that treatment with trastuzumab significantly prolongs the lives of patients with this aggressive cancer. Overall survival for patients with high levels of HER2 in the ToGA study was 16 months versus 11.8 months (on average) for patients receiving chemotherapy alone [1]

“Herceptin is the first targeted biological therapy to show a survival benefit in advanced stomach cancer and represents a significant advance in the treatment of this devastating disease”, said Pascal Soriot, Chief Operating Officer of, Roche’s Pharmaceutical Division. “We believe that Herceptin will help patients with HER2-positive stomach cancer, as much as it has helped so many women with HER2-positive breast cancer.”

Based on the strong results from the phase III ToGA study, the submission for the label extension was reviewed in an accelerated process by the European Health Authorities, allowing patients to benefit sooner from this life-extending treatment. This marketing authorization is valid with immediate effect in all European Union (EU) and EEA-EFTA states (Iceland, Liechtenstein and Norway). Following approval in the European Union, approvals for a label extension for trastuzumab in other regions of the world are expected to follow soon.

“I am delighted that today’s approval will make Herceptin available to patients with HER-2 positive metastatic stomach cancer across Europe,” said Professor Eric Van Cutsem, University Hospital Gasthuisberg, Leuven, Belgium, one of the lead investigators of the ToGA trial. “The approval of Herceptin for HER2-positive stomach cancer represents an important advance for the treatment of these patients. Clinicians will need to ensure that patients with metastatic stomach cancer are accurately tested for HER2 expression.”

Diagnosis and treatment
Stomach cancer is the second most common cause of cancer-related death in the world and is the fourth most commonly diagnosed cancer, with over 1,000,000 cases of stomach cancer diagnosed each year [2] Advanced stomach cancer is associated with a poor prognosis; the median survival time after diagnosis is approximately 10-11 months with currently available therapies. [3] Approximately 15 - 18% of stomach tumours show high levels of HER2 [4,5]. Early diagnosis of this disease is challenging because most patients do not show symptoms in the early stage.

ToGA is the first randomized Phase III trial investigating the use of trastuzumab in patients with inoperable locally advanced, recurrent and/or metastatic HER2-positive stomach cancer. Approximately 3,800 patients were tested for HER2-positive tumors and 594 patients with HER2-positive disease were enrolled into the study. The rationale for conducting this trial was based on the knowledge that the targeted therapy trastuzumab has demonstrated unprecedented efficacy in the treatment of HER2-positive breast cancer. In addition, the overexpression of HER2 was also observed in stomach cancer. Targeted cancer therapies are drugs or other substances that block the growth and spread of cancer by interfering with specific molecules involved in tumor growth and progression.

In the ToGA study, patients were randomized to receive one of the following regimens as their first line of treatment:

  • A fluoropyrimidine (capecitabine (xeloda) or intravenous 5-FU (5-fluorouracil)) and cisplatin every 3 weeks for 6 cycles. Most patients were receiving capecitabine and cisplatin as chemotherapy
  • Trastuzumab 6mg/kg every 3 weeks until progression in combination with a fluoropyrimidine and cisplatin for 6 cycles
Study results
The primary objective of the study was to demonstrate superiority in overall survival of the trastuzumab containing treatment arm compared to the chemotherapy alone arm. The pre-planned interim analysis was triggered by the occurrence of 347 events. Secondary endpoints for the study included progression-free survival, overall response rate, duration of response, safety and quality of life. In the ToGA study, no new or unexpected side effects were observed. For overall survival, the Hazard Ratio was 0.74 (CI 0.60, 0.91) with a highly significant p-value of p=0,0046.

Trastuzumab increased the median overall survival time by 2.7 months to 13.8 months (intent to treat patient group, defined as IHC3+ or FISH-positive, represented 22% of patients tested for HER2 in the ToGA study). The response rate was increased with trastuzumab from 34.5 % to 47.3%. Patients with tumors exhibiting high levels of HER2 (IHC3+ or IHC2+/FISH-positive, 16% of patients tested for HER2 in the ToGA study) experienced even greater benefit from the addition of trastuzumab. For these patients, overall survival in the study was 16 months on average versus 11.8 months for patients receiving chemotherapy alone. The EU label recommends trastuzumab for patients expressing high levels of HER2.

Personalized Healthcare: Fitting treatments to patients
Different people respond differently to medicines. The aim of aim of a personalized approach to healthcare is to target treatments to the patients most likely to benefit. This means tailoring treatments to specific patient sub-groups who share similar characteristics in their genetic makeup or in the molecular nature of their disease. This approach has enormous potential to make healthcare better, safer and more effective, with benefits for patients, physicians, payers, and society at large.

Trastuzumab treatment in breast cancer is a case in point: Measuring the levels of the protein HER2 in breast cancer cells with specific tests reliably identifies patients who are likely to respond to trastuzumab. The same approach can also be applied in the diagnosis and the treatment of HER2-positive metastatic gastric cancer with trastuzumab.

[1]Van Cutsem et al. Abstract #7BA ECCO/ESMO 2009
[2]American Cancer Society. Global Cancer Facts & Figures 2007
[3] Ohtsu A. J Gastroenterol 2008;43:256-264
[4] Hofmann M, Stoss O, Shi D, Buttner R, van d, V, Kim W et al. Assessment of a HER2 scoring system for gastric cancer: results from a validation study. Histopathology 2008; 52(7):797-805.
[5] Park DI, Yun JW, Park JH, Oh SJ, Kim HJ, Cho YK et al. HER-2/neu amplification is an independent prognostic factor in gastric cancer. Dig Dis Sci 2006; 51(8):1371-1379.


Friday, January 22, 2010

National Discussion on Proper Use and Support of Oral Chemotherapy in Cancer Care

The growing use of oral chemotherapeutics brings clinical benefits but also raises questions in prescribing, adherence, accessibility and long term follow-up care.

Therfore, US Oncology, Inc. partnered with the Association of Community Cancer Centers, Association of Oncology Social Work, American Society for Clinical Oncology, Community Oncology Alliance, Oncology Nursing Society and the National Patient Advocate Foundation in hosting a panel discussion on Capitol Hill to examine the benefits of oral chemotherapy in cancer care, as well as challenges in its prescribing, accessibility and adherence in the current health care system.

"US Oncology recognizes the benefits of oral chemotherapy treatments and supports their use in that many patients have benefited from their convenience; ease of administration; and in some cases, lessened side effects when compared to traditional chemotherapy," said Leonard Kalman, M.D., Chairman of US Oncology's Public Policy Steering Committee. "As more patients request this therapy option, it is critical that patients and their physicians be fully informed and supported when it comes to effective prescribing, access to care and dosing adherence. We applaud our partners in the oncology community for coming together to address this issue."

Oral Agent in Cancer Care
The panel discussion, entitled "Oral Agents in Cancer: Their Impact on the Treatment of Patients and Providers," featured perspectives from practicing medical oncologists, oncology nurses, oncology social workers and a chemotherapy patient who was unable to access her prescribed oral chemotherapy medication following an insurance coverage denial. As the panelists explained, all healthcare stakeholders must work together to ensure that these life-saving treatments are properly prescribed and administered, effectively covered and financially obtainable for patients as the oral chemotherapeutics market grows.

US Oncology's OncologyRx Care Advantage™ national oral oncology specialty pharmacy service provides this type of financial, administrative and clinical support to cancer patients in need. By working directly with various charitable foundations, the program has provided more than $15 million in drug co-pay assistance to cancer patients since its inception in August 2006. OncologyRx Care Advantage also provides home delivery of prescribed oral cancer therapies, utilizes oncology certified nurses to proactively monitor patient compliance and help manage side effects, and gives patients 24-hour access to oncology certified pharmacists to answer their medication and dosing questions.

Patient Adherence
With intravenous chemotherapy, cancer care providers are able to monitor treatment on site and ensure that patients properly follow to their dosing amount and schedule. However, when patients take their own oral chemotherapy treatments at home, other factors may come into play, such as forgotten doses, omitted doses, emotional factors and other priorities. Adequate patient education and follow-up are critical to make certain patients receive the full treatment they need.

Healthcare providers play a unique and important role in assisting patients' healthy behavior changes. Panelists noted that widespread success in oral chemotherapy treatment will call for improved patient access to treatments; a new level of integration in care among physicians, pharmacists and other clinicians involved with the patient's care; and a new infrastructure in care for prescribing, education and support.

The problem of poor adherence has been a well-recognized problem [1,2,3,4]. Research investigating the effects of nonadherence suggest that in the United States alone, every year more than 125,000 deaths are caused by this phenomenon, accounting for upwards of 10% to 25% of all hospital and nursing home admissions. [5]. These numbers suggest that a patient’s poor or nonadherence is one of the largest and most expensive disease categories in the US. But patient nonadherence is not limited to medications alone. Patients may ‘forget’ to keep their appointments, to follow recommended dietary, adhere to other lifestyle changes, or fail to follow – in some case deliberately sabotage - other aspects of treatment or recommended preventive health practices. As a result, the actual implications of nonadherence go far beyond the financial aspect of patients’ failing to take medication.

"As more cancer patients are likely to look to oral chemotherapy as a more convenient and less invasive treatment option, we need to ensure that systematically, we are ready to meet their needs and providers' needs in terms of ready access to treatment; comprehensive information; and full administrative, clinical and social support throughout the course of treatment," added Dr. Kalman. "We look to the steps we have taken with OncologyRx Care Advantage as a model for this type of support, and we hope the broader healthcare community and policymakers will join us in exploring similar strategies to advance treatment success more broadly in this important area of care."

For more information
[1] Haynes RB. Introduction. In: Haynes RB, Taylor DW, Sackett DL, eds. Compliance in Health Care. Baltimore, Md: Johns Hopkins University Press; 1979:1-18.
[2] Blackwell B. Drug therapy: patient compliance. N Engl J Med. 1973;289:249-252.
[3] Fawcett J. Compliance: definitions and key issues. J Clin Psychiatry. 1995;56(suppl1):4-8.
[4]Davis MS. Variation in patients' compliance with doctors' orders: medical practice and doctor-patient interaction. Psychiatry Med. 1971;2:31-54.
[5] Smith DL. Compliance packaging: a patient education tool. Am Pharm. 1989;NS29(2):42-45, 49-53.


Studies Show Benefit of Advance Detection and Treatment of Gastrointestinal Cancers

A great number of the world's preeminent gastroenterologists will gather during the seventh annual Gastrointestinal Cancers Symposium (ASCO GI) from January 22-24, 2010, at the Orlando World Center Marriott to discuss new research on the treatment of gastrointestinal cancers.

Presentations at the meeting will focus on detection and treatment of gastrointestinal cancers, which includes cancers of the colon/rectum, stomach, pancreas, esophagus, small intestine, anus and other digestive organs. More than 275,000 people in the U.S. are diagnosed with these cancers each year, and nearly 136,000 people die from them. The Gastrointestinal Cancers Symposium is co-sponsored by the American Gastroenterological Association (AGA) Institute, the American Society for Clinical Oncology (ASCO), the American Society for Radiology Oncology (ASTRO) and the Society of Surgical Oncology (SSO).

Highlights from this year Scientific Meeting include the result of four significant studies:

Simple blood test detects colorectal cancer and colorectal adenomas
A new test for blood levels of the CD24 protein is more than 90 percent sensitive and specific for detecting colorectal cancer, and more than 80 percent accurate at detecting potential precancers, called adenomas. These findings may prove useful for identifying patients who would benefit most from colonoscopy.

New test for early detection of pancreatic cancer
Researchers report on a promising immunoassay that detects early-stage pancreatic cancers with a high degree of accuracy. The assay identifies and quantifies blood levels of the PAM4 protein – a unique antigen present in almost 90 percent of pancreatic cancers and precancers. Pancreatic cancer is typically diagnosed at a late stage, when it is more difficult to treat.
Inherited gene variation predicts aggressive gastric cancer
For the first time, researchers report the identification of an inherited genetic variation – located on the CD44 gene – that is linked to increased risk of recurrence in patients with gastric (stomach) cancer.

Adjuvant XELOX chemotherapy regimen slows colon cancer progression in patients of all ages, including those 70+
Adjuvant (post-surgical) treatment with capecitabine and oxaliplatin (XELOX) is more effective than standard 5-fluorouracil and leucovorin (5-FU/LV) for slowing the progression of stage III colon cancer among patients of all ages, including those age 70 and older – findings that may prompt more aggressive treatment for older patients in otherwise good health.
“Growing understanding of molecular biology has helped us make enormous progress in screening, detection and treatment for gastrointestinal cancers,” said Robert P. Sticca, MD, Chairman of the Department of Surgery and Professor at the University of North Dakota School of Medicine and Health Sciences. “These studies describe long-awaited approaches, such as an early detection test for pancreatic cancer and a blood test for colon cancer. Other studies presented during the annual symposium will help us to better personalize treatment for gastric and colon cancers based on patients’ age and genetic factors.”