Patients with Stage II and Stage III Colon Cancer Treated with 5-FU-Based Adjuvant Therapy after 1995 Have Improved Overall Survival

(BUSINESS WIRE)--ASCO Abstract Number: 3616 - Patients with stage III colon cancer treated with 5-FU-based chemotherapy after complete surgical removal of their tumor after 1995 had improved overall survival with no change in time to recurrence compared to patients treated before 1995. In contrast, patients with stage II colon cancer treated after 1995 had longer time to recurrence and time from recurrence to death compared to those patients treated prior to 1995, according to Mayo Clinic and Gr Hospitalier Pitie-Salpetriere, Paris, researchers. They will present the study’s findings on June 4-8, 2010, at the 2010 American Society of Clinical Oncology Annual Meeting in Chicago.

“By combining information from 21 cancer treatment trials for patients with stage II and stage III colon cancer, our analysis determined that those patients treated after 1995 had improved overall survival,” says Dan Sargent, Ph.D., Mayo Clinic biostatistician, North Central Cancer Treatment Group (NCCTG) statistician and senior author on the study.

The analysis compared patient data from more than 18,000 patients with stage II and stage III colon cancer treated with 5-FU-based chemotherapy after their primary tumor had been surgically removed for the time period 1978-1995 versus 1996-2007.

“Patients with stage II colon cancer treated after 1995 had had longer time to recurrence, possibly due to improvements in surgery and pathology” says Dr. Sargent. “In addition, after 1995, both stage II and stage III colon cancer patients treated after surgery with the same 5-FU-based chemotherapy after surgery had improved overall survival. This finding provides evidence to support previous findings that access to new medical therapies introduced in the mid-1990s as well as the expanded use of surgery for patients recurrent disease have meaningfully improving overall survival for patients treated in this setting.”

The findings arise from analysis of combined data collected within an expanded database by the Adjuvant Colon Cancer End Points (ACCENT) Group, a consortium of scientists. The ACCENT database includes data from more than 33,500 patients from the United States, Canada, Australia and Europe. ACCENT, chaired by Dr. Sargent, is supported by the North Central Cancer Treatment Group.

Dr. Sargent conducted the analysis on the expanded database in concert with an international team of scientists participating in ACCENT including Qian Shi, Ph.D. and Brian Bot, from Mayo Clinic; Thierry Andre, M.D., Gr Hospitalier Pitie-Salpetriere; Greg Yothers, M.D., NSABP Statistical Center, Pittsburgh; Daniel Haller, M.D., Abramson Cancer Center, University of Pittsburgh; Eric Van Cutsem, M.D., Ph.D., University Hospital Gasthuisberg/Leuven; James Cassidy, M.D., Glasgow University; Jacqueline Benedetti, Ph.D., Fred Hutchinson Cancer Research Center, Seattle; and Michael O’Connell, M.D., National Surgical Adjuvant Breast and Bowel Project (NSABP) Foundation, NSABP Operations Center, Pittsburgh.

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FDA Announces New Safety Plan for Agents Used to Treat Chemotherapy-Related Anemia

The U.S. Food and Drug Administration today approved a risk management program to inform healthcare providers and their patients about the risks of a class of drugs called Erythropoiesis-Stimulating Agents (ESAs). For patients with cancer, the program is also designed to help ensure the appropriate administration of these drugs, which they receive to treat anemia that can occur as a result of chemotherapy.

ESAs, which include epoetin alfa (marketed as Procrit and Epogen) and darbepoetin alfa (marketed as Aranesp), are manufactured by Amgen Inc. ESAs are forms of the human protein erythropoietin, which stimulates bone marrow to make red blood cells.

In April 2008, FDA required Amgen Inc. to establish this risk management program based on studies that found that ESAs caused tumors to grow faster and resulted in earlier deaths in some cancer patients.

Amgen’s risk management program, referred to as a REMS or Risk Evaluation and Mitigation Strategy, requires health care professionals to provide their patients receiving an ESA with a Medication Guide that contains information for patients on how to safely use a drug.

In addition, the company’s APPRISE (Assisting Providers and Cancer Patients with Risk Information for the Safe Use of ESAs) program, which is part of the REMS, requires specific training and certification of health care professionals who administer chemotherapy to patients with cancer and counseling of their patients. It does not apply to patients being treated with an ESA for anemia due to other circumstances.

“Evaluation of Erythropoiesis-Stimulating Agents has been an ongoing and intensive process since 2004, involving a series of public meetings, labeling changes, and a required Medication Guide,” said Richard Pazdur, M.D., director of the Office of Oncology Products in the FDA’s Center for Drug Evaluation and Research. “This new risk management program will help ensure that patients and their health care professionals have fully considered the benefits and risks of using ESAs.”

Through the risk management program, Amgen must ensure that health care professionals who treat patients with cancer do the following:

* Register and maintain active enrollment in the ESA APPRISE program,
* Complete a special training module on how to use ESAs in patients with cancer, and
* Discuss the risks, benefits, and FDA-approved uses of ESAs with patients who have cancer before beginning a course of ESA treatment and document this discussion with a written acknowledgement from the patient.

Amgen is also required to oversee and monitor health care professionals and hospitals that use ESAs for patients with cancer to ensure that these caregivers are fully compliant with all aspects of the overall risk management program.

ESAs are approved for the treatment of anemia that may occur as a result of kidney failure, from certain kinds of chemotherapy, from the drug AZT, which can be used for the treatment of HIV infection, and for the treatment of anemia among certain patients undergoing surgery.

Procrit, Epogen and Aranesp are manufactured by Thousand Oaks, Calif-based Amgen.

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Chemotherapy and Radiation After Surgery Prolongs Life for Pancreatic Cancer Patients

Pancreatic cancer patients treated with a combination of chemotherapy and radiation after surgery survive approximately six months longer than those receiving surgery alone, Johns Hopkins Kimmel Cancer Center scientists report.

Previous clinical trials conducted in the 1980s and 90s in the United States established the benefit of postoperative chemotherapy and radiation. However, experts still disagree on whether to administer the treatments because results from European studies suggest the opposite effect — a decrease in survival.

“Some physicians might avoid chemotherapy and radiation if a benefit in survival is uncertain. However, without proof, I believe it is a disservice to these patients if we eliminate chemotherapy and radiation,” says radiation oncologist Joseph Herman, M.D., who led the study.

Herman and his team sought to put the issue to rest by reviewing records of 616 Johns Hopkins patients whose pancreatic cancers were surgically removed between Aug. 30, 1993, and Feb. 28, 2005. The researchers compared the survival of 345 of the patients who had only surgery with 271 who were then treated with 5-fluorouracil (FU)-based chemotherapy agents and modern types of radiation.

Patients receiving the combined chemotherapy and radiation experienced an improved median survival when compared with patients who did not (21.2 vs. 14.4 months). Two-year survival also improved (43.9 percent vs. 31.9 percent), as did five-year survival (20.1 percent vs. 15.4 percent). Results were published in the July 20 issue of the Journal of Clinical Oncology.

“The take-home message of this study is that patients who received combined chemotherapy and radiation appeared to have better survival than patients who have surgery alone, suggesting that it is safe and beneficial if it’s done carefully and properly,” says Herman, assistant professor in the Department of Radiation Oncology and Molecular Radiation Sciences.

He cautions that this is a retrospective study and that selection bias was possible as they may have selected out those patients who are healthy enough to receive the chemotherapy and radiation. “Regardless, it is still encouraging to say that many of these patients had very aggressive cancer and a lot of them are still alive several years after they received this combination therapy,” says Herman.

Because data to assess treatment toxicity were unavailable, Herman and his study team focused on survival instead. He says the majority of patients were able to complete the therapy, suggesting that they tolerated it well.

The study also identified risk factors to determine those patients most likely to benefit from combined chemotherapy and radiation. Patients who clearly benefited included those with lymph-node-positive disease and those with tumors larger than 3 centimeters (about 1.2 inches). Patients with aggressive tumors also benefited, as did those with margin-positive disease, where the surgeon was unable to remove most of the tumor.

Groups were similar with respect to tumor size, nodal status and margin status, but those receiving combined chemotherapy and radiation were younger (median 64 vs. 70 years) and less likely to present with another serious disease.

“The survival benefit is still seen regardless of high-risk tumor characteristics and after controlling for age, other concurrent diseases and surgical complications,” Herman says.

Patients in this study received about five and a half weeks of combined chemotherapy and radiation, which is referred to as concurrent therapy. The therapy begins about four to eight weeks after surgery.

Most patients also received continuous-infusion 5-FU chemotherapy. This is a form of chemotherapy that enhances the ability of radiation to damage DNA, the building block of the rapidly dividing cancer cells. Patients take four weeks off at the conclusion of their initial therapy, and then may receive maintenance chemotherapy, as prescribed, in the weeks and months ahead.

Pancreatic cancer strikes about five out of 100,000 people each year in the United States. Because pancreatic cancer often has no symptoms in its early stages, cancerous tumors often go unnoticed until the cancer advances and individuals become ill. Prognosis is poor for long-term survival, with only about 5 percent of pancreatic cancer patients surviving five years after their diagnosis.

The most aggressive and effective form of treatment for pancreatic cancer is a complicated surgery commonly known as the Whipple procedure (used in this study), in which the gallbladder, common bile duct, part of the duodenum, and the head of the pancreas are generally removed. Johns Hopkins Hospital has performed more than 3,000 Whipple surgeries over the past 25 years.

The study was funded by the Johns Hopkins Department of Radiation Oncology and Molecular Radiation Sciences.

Michael Swartz, Charles Hsu, Jordan Winter, Timothy Pawlik, Elizabeth Sugar, Ray Robinson, Daniel Laheru, Elizabeth Jaffee, Ralph Hruban, Kurtis Campbell, Christopher Wolfgang, Fariba Asrari, Ross Donehower, Manuel Hidalgo, Luis Diaz, Charles Yeo, John Cameron, Richard Schulick and Ross Abrams, also from Johns Hopkins, assisted with this study.

Solid Tumor Cells Not Killed by Radiation and Chemotherapy Become Stronger

Because of the way solid tumors adapt the body's machinery to bring themselves more oxygen, chemotherapy and radiation may actually make these tumors stronger.

"In a sense, these therapies can make the tumor healthier," said Mark W. Dewhirst, D.V.M., Ph.D., professor of radiation oncology at Duke University Medical Center. "Unless the treatment is very effective in killing many if not most tumor cells, you are shooting yourself in the foot."

Dewhirst and colleagues Yiting Cao, M.D., Ph.D., of Duke Pathology, and Benjamin Moeller, M.D., Ph.D. have introduced this counter-intuitive idea at recent conferences and in a review article featured in the June issue of Nature Reviews Cancer.

Radiation and chemotherapy do kill most solid tumor cells, but in the cells that survive, the therapies drive an increase in a regulatory factor called HIF1 (hypoxia-inducible factor 1), which cells use to get the oxygen they need by increasing blood vessel growth into the tumor. Solid tumors generally have low supplies of oxygen, Dewhirst explained and HIF1 helps them get the oxygen they need.

The review article concludes that blocking (HIF1) would provide a clear mechanism for killing solid-tumor cells, particularly cells that are proving resistant to radiation or chemotherapy treatments.

As a part of this work, Dewhirst's team has been studying the phenomenon of rising and falling oxygen levels in tumors, called cycling hypoxia. Oxygen levels have been found to naturally cycle up and down in individual blood vessels as well as large tumor regions. This instability in the tumor's oxygen levels can increase HIF-1 production and cause radiation therapy to fail, Dewhirst said.

"It is my opinion that the whole tumor grows more aggressively because of this pulsation of oxygen at low levels," Dewhirst said. "Most people thought cycling hypoxia was caused by temporary stoppage of blood flow in single blood vessel in tumors. In fact, however, oxygen levels cycle up and down virtually everywhere in the tumor, which is caused by fluctuations in blood flow rate. It has been a challenge to convince people of this."

Dewhirst and colleagues have made movies of oxygen transport in a tumor of a living animal that show the oxygen levels cycle up and down significantly, pulsing in waves seen as color changes in the movies.

The Duke team argues that blocking HIF1 is the consistent answer to tumor growth problems. Blocking HIF1 activity interferes with the tumor's ability to undergo glycolysis (energy production) in low-oxygen conditions, which blocks tumor growth, the authors wrote. Exactly how to accomplish chemotherapy or radiation treatment in the safest, most effective ways, in combination with HIF1 blockade, is still open for exploration, Dewhirst said.

For example, targeting HIF1 in the early stages of tumor growth, especially in very early cancer spread, may help, Dewhirst said. "For a woman who has had a primary breast tumor removed, and who is at high risk for cancer spread, this might be a situation in which you'd target HIF1," he explained. "Blocking HIF1 makes sense during the early stages of angiogenesis, which is the accelerated phase of blood vessel formation. In this way, you could keep the early metastasis sites inactive and prevent them from growing."

The Duke team has completed a phase I trial with a HIF1 inhibitor. "We are actively pursuing this clinically and will be moving this study into Phase 2," Dewhirst said. "We are interested in other applications of HIF-1 inhibition in combination with radiation and chemotherapy for different diseases."

Mayo Clinic Researchers find Adding Epratuzumab to Standard Therapy for Aggressive Lymphoma Produces Significant Overall Response

mdash - Adding a second monoclonal antibody drug to chemotherapy looks promising for treatment of diffuse large B-cell lymphoma, according to Mayo Clinic researchers working with the North Central Cancer Treatment Group (NCCTG) (http://ncctg.mayo.edu/). Results of this interim analysis were released May 15 as part of the 44th Annual Meeting of the American Society of Clinical Oncology.

Researchers found that 95 percent of patients responded to treatment that included the drug epratuzumab with the standard "R-CHOP" therapy. R-CHOP combines three chemotherapy drugs (cyclophosphamide, doxorubicin and vincristine) with the steroid drug prednisone and rituximab, a monoclonal antibody. Final results will be reported next year.

Diffuse large B-cell lymphoma is one of the most common and aggressive forms of non-Hodgkin lymphoma (NHL), a cancer of the white blood cells known as B-lymphocytes.

In 78 patients, researchers found:
• 95 percent of participants (75 patients) improved as a result of the treatment.
• 63 percent of participants (47 patients) were disease free.

Researchers also were able to look at the primary endpoint of the study — disease-free survival at 12 months — in 34 patients. Eighty five percent of that group, 29 patients, had no signs of lymphoma.

"These results are good, but whether it will turn out to be better than standard therapy is still unknown," says the study's lead author, Ivana Micallef, M.D. (http://mayoresearch.mayo.edu/mayo/research/staff/micallef_in.cfm), a Mayo Clinic hematologist.

Epratuzumab is much like rituximab because both are monoclonal antibodies, and both attach to proteins commonly found on the surface of B-cells — CD20 for rituximab and CD22 for epratuzumab. Both also are used to treat certain autoimmune disorders, such as rheumatoid arthritis and lupus. "In autoimmune disease, you are trying to stop the B-cells from making the antibodies that cause inflammation, but in cancer, these B-cells are malignant," says Dr. Micallef.

This is the first large study to combine epratuzumab with chemotherapy, in this case R-CHOP.
The rate of toxic side effects among enrolled patients was the same as seen in R-CHOP use, investigators say. "Overall, the combination was well tolerated," says Dr. Micallef. Patients may experience low blood counts, fatigue or infections.

As promising as these results look, researchers will not know if this new treatment provides superior results to R-CHOP unless the two regimens are compared with each other, she says.

Other NCCTG collaborators included Matthew Maurer, Paul Kurtin, M.D., and Thomas Witzig, M.D., all of Mayo Clinic; Daniel Nikcevich, M.D., St. Mary's Duluth Clinic, Duluth, Minn.; Michael Cannon and Dennis Moore, M.D., both of Cancer Center of Kansas PA, Wichita.

NCCTG is a national clinical research group sponsored by the National Cancer Institute. Its research and administration are based at Mayo Clinic. NCCTG consists of a network of cancer specialists at community clinics, hospitals and medical centers in the United States, Canada and Mexico. The group is dedicated to bringing clinical trials with promising new cancer therapies to communities where patients live.